RESUMEN
The autonomic nervous system plays a central role in both acute and chronic blood pressure regulation in humans. The activity of the sympathetic branch of the autonomic nervous system is positively associated with peripheral resistance, an important determinant of mean arterial pressure in men. In contrast, there is no association between sympathetic nerve activity and peripheral resistance in women before menopause, yet a positive association after menopause. We hypothesized that autonomic support of blood pressure is higher after menopause in women. We examined the effect of ganglionic blockade on arterial blood pressure and how this relates to baseline muscle sympathetic nerve activity in 12 young (25±1 years) and 12 older postmenopausal (61±2 years) women. The women were studied before and during autonomic blockade using trimethaphan camsylate. At baseline, muscle sympathetic nerve activity burst frequency and burst incidence were higher in the older women (33±3 versus 15±1 bursts/min; 57±5 versus 25±2 bursts/100 heartbeats, respectively; P<0.05). Muscle sympathetic nerve activity bursts were abolished by trimethaphan within minutes. Older women had a greater decrease in mean arterial pressure (-29±2 versus -9±2 mm Hg; P<0.01) and total peripheral resistance (-10±1 versus -5±1 mm Hg/L per minute; P<0.01) during trimethaphan. Baseline muscle sympathetic nerve activity was associated with the decrease in mean arterial pressure during trimethaphan (r=-0.74; P<0.05). In summary, our results suggest that autonomic support of blood pressure is greater in older women compared with young women and that elevated sympathetic nerve activity in older women contributes importantly to the increased incidence of hypertension after menopause.
Asunto(s)
Envejecimiento/fisiología , Presión Sanguínea/fisiología , Hipertensión/fisiopatología , Sistema Nervioso Simpático/fisiología , Resistencia Vascular/fisiología , Adulto , Presión Sanguínea/efectos de los fármacos , Arteria Braquial/inervación , Arteria Braquial/fisiología , Femenino , Bloqueadores Ganglionares/administración & dosificación , Humanos , Menopausia/fisiología , Persona de Mediana Edad , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Nervio Peroneo/fisiología , Sistema Nervioso Simpático/efectos de los fármacos , Trimetafan/administración & dosificación , Resistencia Vascular/efectos de los fármacos , Vasodilatadores/administración & dosificación , Adulto JovenRESUMEN
The purpose of this study was to compare ganglionic blockade with trimethaphan (TMP) and an alternative drug strategy using combined muscarinic antagonist (glycopyrrolate, GLY) and alpha-2 agonist (dexmedetomidine, DEX). Protocol 1: incremental phenylephrine was administered during control and combined GLY-DEX, or control and TMP on two control combined GLY and DEX or TMP infusion on two randomized days. Protocol 2: muscle sympathetic nerve activity (MSNA) and the baroreflex MSNA relationship was determined before and after GLY-DEX. Blood pressure was higher with GLY-DEX (99+/-3 mm Hg) and lower with TMP (78+/-3 mm Hg) relative to control (GLY-DEX: 90+/-2 mm Hg; TMP: 91+/-2 mm Hg; P<0.05). Incremental phenylephrine increased pressure during GLY-DEX (P<0.01 vs control) and TMP (P<0.01 vs control) to a similar degree. Both GLY-DEX and TMP infusion inhibited norepinephrine release (P<0.01 vs control). GLY-DEX inhibited baseline MSNA (P<0.05) and baroreflex changes in MSNA (P<0.01). We conclude that the GLY-DEX alternative drug strategy can be used as a reasonable alternative to pharmacologic ganglionic blockade to examine autonomic cardiovascular control.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Dexmedetomidina/administración & dosificación , Bloqueadores Ganglionares/administración & dosificación , Glicopirrolato/administración & dosificación , Trimetafan/administración & dosificación , Agonistas alfa-Adrenérgicos/administración & dosificación , Adulto , Bloqueo Nervioso Autónomo/métodos , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Gasto Cardíaco/efectos de los fármacos , Sistema Cardiovascular/inervación , Catecolaminas/metabolismo , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Antagonistas Muscarínicos/administración & dosificación , Fenilefrina/administración & dosificación , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Cardiac beta-receptor responsiveness is diminished by both aging and hypertension. However, concomitant decreases in the activity of counterregulatory mechanisms, such as the arterial baroreflex and neuronal catecholamine uptake, influence the ultimate cardiac responses to adrenergic agents in vivo. In the present study, we evaluated by echocardiography cardiac responses to intravenous infusion of epinephrine in 14 young and 18 older normotensive men and women and in 10 young and 17 older hypertensive men and women. To assess the relative contribution of intrinsic cardiac and counterregulatory components to the overall response, infusions were repeated combined with a ganglionic blocker in the young groups. Epinephrine-induced increases in heart rate were similar in the four groups. Increases in stroke volume, ejection fraction, and cardiac index were similar in the two hypertensive and two young normotensive groups. In contrast, they were attenuated in the older normotensive group, resulting in higher left ventricular responses in older hypertensive than in normotensive subjects. Heart rate and left ventricular responses to epinephrine in the presence of ganglionic blockade did not differ between the two young groups. Increases in plasma norepinephrine due to epinephrine infusion were larger in hypertensive than in normotensive subjects. One may conclude that compared with young normotensive subjects, in hypertensive subjects mechanisms increasing versus decreasing cardiac responses to epinephrine may remain in balance, and, compared with older normotensive subjects, older hypertensive subjects exhibit enhanced cardiac responses to sympathetic stimulation.
Asunto(s)
Agonistas Adrenérgicos beta/administración & dosificación , Envejecimiento , Presión Sanguínea/efectos de los fármacos , Epinefrina/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Agonistas Adrenérgicos beta/sangre , Adulto , Factores de Edad , Anciano , Barorreflejo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Epinefrina/sangre , Femenino , Bloqueadores Ganglionares/administración & dosificación , Humanos , Hipertensión/sangre , Hipertensión/diagnóstico por imagen , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Volumen Sistólico/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Trimetafan/administración & dosificación , Ultrasonografía , Resistencia Vascular/efectos de los fármacosRESUMEN
The activity within the autonomic nervous system may be altered following sustained exposure to hypoxia, and it is possible that this increase in activity underlies the early acclimatization of both ventilation and the pulmonary vasculature to hypoxia. To test this hypothesis, seven individuals were infused with the ganglionic blocker trimetaphan before and after an 8 h exposure to hypoxia. The short half-life of trimetaphan should ensure that the initial infusion does not affect acclimatization to the 8 h hypoxia exposure, and the use of a ganglion blocking agent should inhibit activity within all branches of the autonomic nervous system. During the infusions of trimetaphan, measurements of ventilation and echocardiographic assessments of pulmonary vascular tone (DeltaPmax) were made during euoxia and during a short period of isocapnic hypoxia. Subjects were also studied on two control days, when a saline infusion was substituted for trimetaphan. Trimetaphan had no effect on either euoxic ventilation or the sensitivity of ventilation to acute hypoxia. Trimetaphan significantly reduced DeltaPmax in euoxia (P<0.05), but had no significant effect on the sensitivity of DeltaPmax to acute hypoxia once changes in cardiac output had been controlled for. The 8 h period of hypoxia elevated euoxic ventilation (P<0.001) and DeltaPmax (P<0.001) and increased their sensitivities to acute hypoxia (P<0.001 for both), indicating that significant acclimatization had occurred. Trimetaphan had no effect on the acclimatization response of any of these variables. We conclude that altered autonomic activity following 8 h of hypoxia does not underlie the acclimatization observed in ventilation or pulmonary vascular tone.
Asunto(s)
Aclimatación/fisiología , Sistema Nervioso Autónomo/fisiología , Hipoxia/fisiopatología , Circulación Pulmonar/fisiología , Mecánica Respiratoria/fisiología , Aclimatación/efectos de los fármacos , Enfermedad Aguda , Adulto , Sistema Nervioso Autónomo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Femenino , Bloqueadores Ganglionares/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Circulación Pulmonar/efectos de los fármacos , Mecánica Respiratoria/efectos de los fármacos , Trimetafan/administración & dosificaciónRESUMEN
In healthy humans, ganglionic blockade unmasks a clear age-related decrease in cardiac responses to isoproterenol but not to epinephrine. We postulated that an age-related decrease in neuronal uptake (which affects epinephrine but not isoproterenol) may offset a parallel decrease in beta-receptor-mediated responses. To test this concept, nine young (mean 29 +/- 2 yr) and eight older (mean 61 +/- 2 yr) healthy subjects were infused on three different study mornings with epinephrine at increasing rates either alone or combined with desipramine to eliminate differences in neuronal uptake or with desipramine and trimetaphan to induce ganglionic blockade and thereby also eliminate differences in arterial baroreflex activity. Epinephrine caused the expected rate-related increases in systolic blood pressure, heart rate, stroke volume, ejection fraction, and cardiac index. Except for the systolic blood pressure, the extent of the changes was similar in young and older subjects. After desipramine, cardiac responsiveness to epinephrine was markedly enhanced, although more (P < 0.01) in young vs. older subjects for heart rate and cardiac index (+14 vs. 7 beats/min and +1.6 vs. 1.1 l.min(-1).m(-2), respectively, at 20 ng.kg(-1).min(-1)). Combined with desipramine and trimetaphan, cardiac responses to epinephrine were further enhanced, again more (P < 0.01) in young subjects, resulting in large differences in heart rate and ejection fraction increases (+29 vs. 17 beats/min and +14 vs. 7%, respectively, at 20 ng.kg(-1).min(-1)). Here, we show that "healthy aging" in humans is associated with decreased cardiac responsiveness to the beta-agonist epinephrine; however, this decrease can be balanced by concomitant decreases in buffering of these responses by neuronal uptake and the arterial baroreflex.
Asunto(s)
Agonistas Adrenérgicos beta/farmacocinética , Envejecimiento/fisiología , Epinefrina/farmacocinética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Inhibidores de Captación Adrenérgica/administración & dosificación , Agonistas Adrenérgicos beta/administración & dosificación , Adulto , Anciano , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Desipramina/administración & dosificación , Sinergismo Farmacológico , Epinefrina/administración & dosificación , Femenino , Bloqueadores Ganglionares/administración & dosificación , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Trimetafan/administración & dosificaciónRESUMEN
STUDY OBJECTIVE: To determine whether nitroglycerin or trimethaphan alters pressor response to intravenous (i.v.) ephedrine. DESIGN: Prospective, randomized study. SETTING: Operating room of a university hospital. PATIENTS: 60 ASA physical status I female patients scheduled for mastectomy. INTERVENTIONS: Patients were assigned to one of six groups (n = 10 in each). Group 1: nitroglycerin + normal saline (NS) i.v., Group 2: nitroglycerin + ephedrine 0.1 mg/kg i.v., Group 3: nitroglycerin + ephedrine 0.15 mg/kg i.v., Group 4: trimethaphan + NS i.v., Group 5: trimethaphan + ephedrine 0.1 mg/kg i.v., and Group 6: trimethaphan + ephedrine 0.15 mg/kg i.v. MEASUREMENTS: Hemodynamic responses to ephedrine following withdrawal of vasodilators were observed for 15 minutes. MAIN RESULTS: Ephedrine increased heart rate and mean blood pressure. After ephedrine 0.1 mg/kg i.v., the maximum pressor response in the trimethaphan group was approximately twofold that of the nitroglycerin group (p = 0.038). CONCLUSIONS: Ephedrine restored BP more easily in those patients who had received trimethaphan compared with those who had received nitroglycerin for deliberate hypotension.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Efedrina , Frecuencia Cardíaca/efectos de los fármacos , Hipotensión Controlada , Vasoconstrictores , Análisis de los Gases de la Sangre , Efedrina/administración & dosificación , Bloqueadores Ganglionares/administración & dosificación , Humanos , Inyecciones Intravenosas , Persona de Mediana Edad , Nitroglicerina/administración & dosificación , Estudios Prospectivos , Factores de Tiempo , Trimetafan/administración & dosificación , Vasoconstrictores/administración & dosificación , Vasodilatadores/administración & dosificaciónRESUMEN
Autonomic nervous system (ANS) control of the circulation is altered with aging in adult humans. Similar changes are observed in obesity, particularly abdominal obesity. To determine whether age-associated differences in ANS-circulatory function can be partially explained by increased body fatness, we examined ANS function and three expressions of adiposity (total body fat, abdominal body fat, and abdominal-to-peripheral body fat distribution; dual-energy X-ray absorptiometry) in 43 healthy men: 27 young (25 +/- 1 yr) and 16 older (65 +/- 1). ANS functions assessed included 1) autonomic support of arterial blood pressure (BP; radial artery catheter), i.e., the reduction in BP during versus before acute ganglionic blockade (GB; intravenous trimethaphan); 2) baroreflex buffering, i.e., the increase in systolic BP with continuous incremental and bolus infusions of phenylephrine during versus before GB; 3) cardiovagal baroreflex sensitivity (Oxford technique); and 4) heart rate variability (time- and frequency-domain analyses). Covarying for abdominal-to-peripheral fat distribution reduced or abolished age-related differences in ANS support of BP, cardiovagal baroreflex sensitivity, and heart rate variability but did not affect age-related differences in baroreflex buffering. Covarying for abdominal and total fat had small selective or no effects on age-associated differences in autonomic-circulatory control. Abdominal-to-peripheral fat distribution explains a significant portion of the variance in a number of autonomic-circulatory functions attributable to aging. Therefore, the development of this fat pattern may contribute to several changes in ANS-cardiovascular function observed with aging. These results may help explain how changes in body fat distribution with advancing age are linked to impairments in circulatory control.
Asunto(s)
Tejido Adiposo/fisiología , Envejecimiento/fisiología , Sistema Nervioso Autónomo/fisiología , Nervio Vago/fisiología , Abdomen , Tejido Adiposo/anatomía & histología , Adulto , Anciano , Sistema Nervioso Autónomo/efectos de los fármacos , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Composición Corporal , Índice de Masa Corporal , Bloqueadores Ganglionares/administración & dosificación , Corazón/inervación , Corazón/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Fenilefrina/administración & dosificación , Trimetafan/administración & dosificación , Vasoconstrictores/administración & dosificaciónRESUMEN
Previous investigations of autoregulatory mechanisms in the control of skin blood flow suffer from the possibility of interfering effects of the autonomic nervous system. To address this question, in 11 subjects cutaneous vascular responses were measured during acute changes in perfusion pressure (using Valsalva maneuver; VM) before and after ganglionic blockade via systemic trimethaphan infusion. Cutaneous vascular conductance at baseline (CVC(base)) and during the last 5 s of the VM (CVC(VM)) were measured from forearm (nonglabrous) and palm (glabrous) skin. During the VM without ganglionic blockade, compared with CVC(base), CVC(VM) decreased significantly at the palm [0.79 +/- 0.17 to 0.55 +/- 0.17 arbitrary units (AU)/mmHg; P = 0.002] but was unchanged at the forearm (0.13 +/- 0.02 to 0.16 +/- 0.02 AU/mmHg; P = 0.50). After ganglionic blockade, VM induced pronounced decreases in perfusion pressure, which resulted in significant increases in CVC(VM) at both forearm (0.19 +/- 0.03 to 0.31 +/- 0.07 AU/mmHg; P = 0.008) and palm (1.84 +/- 0.29 to 2.76 +/- 0.63 AU/mmHg; P = 0.003) sites. These results suggest that, devoid of autonomic control, both glabrous and nonglabrous skin are capable of exhibiting vasomotor autoregulation during pronounced reductions in perfusion pressure.
Asunto(s)
Antebrazo/irrigación sanguínea , Ganglios Simpáticos/fisiología , Flujo Sanguíneo Regional/fisiología , Piel/irrigación sanguínea , Adulto , Presión Sanguínea/fisiología , Femenino , Antebrazo/inervación , Ganglios Simpáticos/efectos de los fármacos , Bloqueadores Ganglionares/administración & dosificación , Frecuencia Cardíaca/fisiología , Homeostasis/fisiología , Humanos , Masculino , Piel/inervación , Trimetafan/administración & dosificación , Maniobra de Valsalva/fisiologíaRESUMEN
Some parasympathetic ganglionic cells are located in the epicardial fat pad between the medial superior vena cava and the aortic root (SVC-Ao fat pad) of the dog. We investigated whether the ganglionic cells in the SVC-Ao fat pad control the right atrial contractile force, sinus cycle length (SCL), and atrioventricular (AV) conduction in the autonomically decentralized heart of the anesthetized dog. Stimulation of both sides of the cervical vagal complexes (CVS) decreased right atrial contractile force, increased SCL, and prolonged AV interval. Stimulation of the rate-related parasympathetic nerves to the sinoatrial (SA) node (SAPS) increased SCL and decreased atrial contractile force. Stimulation of the AV conduction-related parasympathetic nerves to the AV node prolonged AV interval. Trimethaphan, a ganglionic nicotinic receptor blocker, injected into the SVC-Ao fat pad attenuated the negative inotropic, chronotropic, and dromotropic responses to CVS by 33 approximately 37%. On the other hand, lidocaine, a sodium channel blocker, injected into the SVC-Ao fat pad almost totally inhibited the inotropic and chronotropic responses to CVS and partly inhibited the dromotropic one. Lidocaine or trimethaphan injected into the SAPS locus abolished the inotropic responses to SAPS, but it partly attenuated those to CVS, although these treatments abolished the chronotropic responses to SAPS or CVS. These results suggest that parasympathetic ganglionic cells in the SVC-Ao fat pad, differing from those in SA and AV fat pads, nonselectively control the atrial contractile force, SCL, and AV conduction partially in the dog heart.
Asunto(s)
Función del Atrio Derecho/fisiología , Ganglios Parasimpáticos/fisiología , Frecuencia Cardíaca/fisiología , Corazón/fisiología , Contracción Miocárdica/fisiología , Animales , Función del Atrio Derecho/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Depresión Química , Perros , Estimulación Eléctrica , Ganglios Parasimpáticos/efectos de los fármacos , Bloqueadores Ganglionares/administración & dosificación , Corazón/efectos de los fármacos , Corazón/inervación , Sistema de Conducción Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones , Lidocaína/administración & dosificación , Contracción Miocárdica/efectos de los fármacos , Pericardio/inervación , Tiempo de Reacción/efectos de los fármacos , Nodo Sinoatrial/efectos de los fármacos , Nodo Sinoatrial/inervación , Bloqueadores de los Canales de Sodio , Estimulación Química , Trimetafan/administración & dosificación , Nervio Vago/fisiología , Vena Cava Superior/inervaciónRESUMEN
Patients with reflex sympathetic dystrophy have posttraumatic pain disproportionate to the injury and spreading beyond the distribution of any single peripheral nerve. We examined sympathetic neurocirculatory function and the role of sympathetic postganglionic nerve traffic in maintaining the pain in 30 patients with reflex sympathetic dystrophy. Most had had the condition for more than 1 year, and 14 had undergone sympathectomy for the pain. Positron emission tomographic scanning after administration of 13N-ammonia was used to assess local perfusion, and 6-[18F]fluorodopamine was used to assess sympathetic innervation. Rates of entry of norepinephrine in the regional venous drainage (spillovers) and regional plasma levels of L-dihydroxyphenylalanine (the immediate product of the rate-limiting enzymatic step in norepinephrine biosynthesis) and dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) were measured with and without intravenous trimethaphan for ganglion blockade. 13N-Ammonia-derived radioactivity was less on the affected side than on the unaffected side, whereas 6-[18F]fluorodopamine-derived radioactivity was symmetrical. Thus, perfusion-adjusted 6-[18F]fluorodopamine-derived radioactivity was higher on the affected side. Norepinephrine spillover and arteriovenous increments in plasma levels of L-dihydroxyphenylalanine and dihydroxyphenylglycol did not differ significantly between affected and unaffected limbs, although 4 patients had noticeably less norepinephrine spillover and smaller arteriovenous increments in plasma dihydroxyphenylglycol on the affected side. Trimethaphan decreased the pain in only 2 of 12 nonsympathectomized patients. The results indicate that patients with chronic unilateral reflex sympathetic dystrophy have decreased perfusion of the affected limb, symmetrical sympathetic innervation and norepinephrine synthesis, variably decreased release and turnover of norepinephrine in the affected limb, and failure of ganglion blockade to improve the pain in most cases. These findings suggest augmented vasoconstriction, intact sympathetic terminal innervation, possibly impaired sympathetic neurotransmission, and pain usually independent of sympathetic neurocirculatory outflows.
Asunto(s)
Dolor/fisiopatología , Distrofia Simpática Refleja/fisiopatología , Fibras Simpáticas Posganglionares/fisiopatología , Adulto , Catecoles/sangre , Femenino , Radioisótopos de Flúor , Ganglios Simpáticos/efectos de los fármacos , Ganglios Simpáticos/fisiopatología , Bloqueadores Ganglionares/administración & dosificación , Humanos , Cinética , Masculino , Persona de Mediana Edad , Radioisótopos de Nitrógeno , Norepinefrina/sangre , Dolor/diagnóstico por imagen , Distrofia Simpática Refleja/diagnóstico por imagen , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Fibras Simpáticas Posganglionares/efectos de los fármacos , Tomografía Computarizada de Emisión , Trimetafan/administración & dosificación , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
BACKGROUND: Approximately 50% of patients with primary autonomic failure have supine hypertension. We investigated whether this supine hypertension could be driven by residual sympathetic activity. METHODS AND RESULTS: In patients with multiple system atrophy (MSA) or pure autonomic failure (PAF), we studied the effect of oral yohimbine on seated systolic blood pressure (SBP), the effect of ganglionic blockade (with trimethaphan) on supine SBP and plasma catecholamine levels, and the effect of alpha(1)-adrenoreceptor blockade (phentolamine) on supine SBP. The SBP response to yohimbine was greater in patients with MSA than in those with PAF (area under the curve, 2248+/-543 versus 467+/-209 mm Hg. min; P=0.022). MSA patients with a higher supine SBP had a greater response than those with a lower supine SBP (3874+/-809 versus 785+/-189 mm Hg. min; P=0. 0017); this relationship was not seen in PAF patients. MSA patients had a marked depressor response to low infusion rates of trimethaphan; the response in PAF patients was more variable. Plasma norepinephrine decreased in both groups, but heart rate did not change in either group. At 1 mg/min, trimethaphan decreased supine SBP by 67+/-8 and 12+/-6 mm Hg in MSA and PAF patients, respectively (P<0.0001). Cardiac index and total peripheral resistance decreased in MSA patients by 33.4+/-5.8% and 40.7+/-9.5%, respectively (P=0. 0015). Patients having a depressor response to trimethaphan also had a depressor response to phentolamine. In MSA patients, the pressor response to yohimbine and the decrease in SBP with 1 mg/min trimethaphan were correlated (r=0.98; P=0.001). CONCLUSIONS: Residual sympathetic activity drives supine hypertension in MSA. It contributes to, but does not completely explain, supine hypertension in PAF.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/complicaciones , Insuficiencia Cardíaca/fisiopatología , Corazón/inervación , Hipertensión/complicaciones , Sistema Nervioso Simpático/fisiopatología , Antagonistas Adrenérgicos alfa/administración & dosificación , Anciano , Antihipertensivos/administración & dosificación , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Femenino , Bloqueadores Ganglionares/administración & dosificación , Corazón/fisiopatología , Insuficiencia Cardíaca/complicaciones , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Masculino , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/fisiopatología , Norepinefrina/sangre , Fentolamina/administración & dosificación , Reflejo/fisiología , Trimetafan/administración & dosificación , Resistencia Vascular/efectos de los fármacos , Yohimbina/administración & dosificaciónRESUMEN
Dopamine in the circulation occurs mainly as dopamine sulfate, the sources and physiological significance of which have been obscure. In this study, plasma concentrations of dopamine sulfate were measured after a meal, after fasting for 4 days, and during i.v. L-DOPA, nitroprusside, or trimethaphan infusion in volunteers; after dopamine infusion in patients with L-aromatic-amino-acid decarboxylase deficiency; in arterial and portal venous plasma of gastrointestinal surgery patients; and in patients with sympathetic neurocirculatory failure. Meal ingestion increased plasma dopamine sulfate by more than 50-fold; however, prolonged fasting decreased plasma dopamine sulfate only slightly. L-DOPA infusion produced much larger increments in dopamine sulfate than in dopamine; the other drugs were without effect. Patients with L-aromatic amino acid decarboxylase deficiency had decreased dopamine sulfate levels, and patients with sympathetic neurocirculatory failure had normal levels. Decarboxylase-deficient patients undergoing dopamine infusion had a dopamine sulfate/dopamine ratio about 25 times less than that at baseline in volunteers. Surgery patients had large arterial-portal venous increments in plasma concentrations of dopamine sulfate, so that mesenteric dopamine sulfate production accounted for most of urinary dopamine sulfate excretion, a finding consistent with the localization of the dopamine sulfoconjugating enzyme to gastrointestinal tissues. The results indicate that plasma dopamine sulfate derives mainly from sulfoconjugation of dopamine synthesized from L-DOPA in the gastrointestinal tract. Both dietary and endogenous determinants affect plasma dopamine sulfate. The findings suggest an enzymatic gut-blood barrier for detoxifying exogenous dopamine and delimiting autocrine/paracrine effects of endogenous dopamine generated in a "third catecholamine system."
Asunto(s)
Dopamina/análogos & derivados , Ayuno , Alimentos , Adulto , Descarboxilasas de Aminoácido-L-Aromático/deficiencia , Arterias , Enfermedades del Sistema Nervioso Autónomo/sangre , Western Blotting , Dopamina/sangre , Dopaminérgicos , Femenino , Neoplasias Gastrointestinales/sangre , Neoplasias Gastrointestinales/cirugía , Humanos , Levodopa/administración & dosificación , Levodopa/sangre , Masculino , Nitroprusiato/administración & dosificación , Vena Porta , Trimetafan/administración & dosificaciónRESUMEN
Our aim was to study the relationship between cerebral blood flow (CBF) responses to induced hypotension and to CO2 inhalation in patients with occlusive disease of the carotid or middle cerebral arteries. In 13 patients (8 men, 5 women) aged 31-73 years (mean +/- 1 SD = 63.2 +/- 10.6), regional CBF values during the resting state (CBFrest), 7% CO2 inhalation (CBFhypercapnia), and hypotension induced by 10-20 microg/kg/min intravenous trimethaphan (CBFhypotension) were measured using positron-emission tomography (PET) with H2(15)O. The % CBF change during induced hypotension (% CBFhypotension) was defined as (CBFhypotension - CBFrest)/CBFrest multiplied by 100. The % CBF change during CO2 inhalation (% CBFhypercapnia) was defined as (CBFhypercapnia - CBFrest)/CBFrest/mm Hg arterial partial pressure of CO2 x 100. We defined symptomatic hemispheres as those with a stenotic or occlusive lesion with neurological symptoms or signs and asymptomatic hemispheres as those which had a similar lesion and/or were influenced by the collateral flow pattern without neurological symptoms. In the territory of the occlusive lesion, % CBFhypotension correlated significantly with % CBFhypercapnia (r = 0.793, P < 0.002) in the symptomatic hemispheres. In the brain regions in which trimethaphan did not induce a reduction in CBF. % CBFhypercapnia was 6.13 +/- 1.79. In those in which % CBFhypotension ranged from 0 to -5, from -5 to -10, and more than -10%, % CBFhypercapnia was 4.05 +/- 1.99, 3.21 +/- 1.17, and 1.73 +/- 1.61, respectively, with significant differences between each pair of groups. In the asymptomatic hemispheres, % CBFhypotension also correlated with % CBFhypercapnia (r = 0.979, P < 0.0001). Failure to maintain CBF during induced hypotension was associated with diminished cerebrovascular vasoreactivity to hypercapnia in patients with arterial disease. This may indicate that failure of autoregulation can be assessed by the CBF response to both induced hypotension and CO2 inhalation. From the technical point of view, estimation of the CO2 response may be useful for assessing failure of autoregulation.
Asunto(s)
Arteriopatías Oclusivas/fisiopatología , Enfermedades Arteriales Cerebrales/fisiopatología , Circulación Cerebrovascular , Hipercapnia/fisiopatología , Hipotensión/fisiopatología , Tomografía Computarizada de Emisión , Administración por Inhalación , Adulto , Anciano , Arteriopatías Oclusivas/diagnóstico por imagen , Dióxido de Carbono/administración & dosificación , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/fisiopatología , Enfermedades Arteriales Cerebrales/diagnóstico por imagen , Femenino , Homeostasis , Humanos , Hipotensión/inducido químicamente , Masculino , Persona de Mediana Edad , Trimetafan/administración & dosificaciónRESUMEN
BACKGROUND: Isoflurane-anesthetized rats have better outcome from global cerebral ischemia than rats anesthetized with fentanyl and nitrous oxide. The authors wanted to determine whether circulating catecholamine concentrations depend on the anesthetic agent and whether sympathetic ganglionic blockade affects anesthetic-mediated differences in outcome from near-complete forebrain ischemia. METHODS: For two different experiments, normothermic Sprague-Dawley rats that had fasted were assigned to one of four groups and subjected to 10 min of 30 mm Hg mean arterial pressure and bilateral carotid occlusion. Rats were anesthetized with 1.4% isoflurane or fentanyl (25 microg x kg(-1) x h(-1)) and 70% nitrous oxide, with or without preischemic trimethaphan (2.5 mg given intravenously). In experiment 1, arterial plasma catecholamine concentrations were measured before, at 2 and 8 min during, and after ischemia (n = 5-8). In experiment 2, animals (n = 15) underwent histologic analysis 5 days after ischemia. RESULTS: In experiment 1, intraischemic increases in plasma norepinephrine and epinephrine levels were 28 and 12 times greater in the fentanyl-nitrous oxide group than in the isoflurane group (P<0.01). Trimethaphan blocked all changes in plasma catecholamine concentrations (P<0.02). In experiment 2, isoflurane reduced the mean +/- SD percentage of dead hippocampal CA1 neurons compared with fentanyl-nitrous oxide (43+/-22% vs. 87+/-10%; P<0.001). Trimethaphan abolished the beneficial effects of isoflurane (91+/-6%; P<0.001). Similar observations were made in the cortex. CONCLUSIONS: Isoflurane attenuated the peripheral sympathetic response to ischemia and improved histologic outcome compared with fentanyl and nitrous oxide. This outcome benefit was reversed by sympathetic ganglionic blockade. The beneficial effects of isoflurane may result from a neuroprotective influence of an intermediate sympathetic response that is abolished by trimethaphan.
Asunto(s)
Anestésicos por Inhalación/administración & dosificación , Isquemia Encefálica/fisiopatología , Ganglios Simpáticos/fisiopatología , Isoflurano/administración & dosificación , Animales , Isquemia Encefálica/patología , Ganglios Simpáticos/efectos de los fármacos , Bloqueadores Ganglionares/administración & dosificación , Inyecciones Intravenosas , Masculino , Prosencéfalo/irrigación sanguínea , Prosencéfalo/patología , Prosencéfalo/fisiopatología , Ratas , Ratas Sprague-Dawley , Trimetafan/administración & dosificaciónRESUMEN
We hypothesized that selective control of ventricular contractility might be mediated by postganglionic parasympathetic neurons in the cranial medial ventricular (CMV) ganglion plexus located in a fat pad at the base of the aorta. Sinus rate, atrioventricular (AV) conduction (ventricular rate during atrial pacing), and left ventricular contractile force (LV dP/dt during right ventricular pacing) were measured in eight chloralose-anesthetized dogs both before and during bilateral cervical vagus stimulation (20-30 V, 0.5 ms pulses, 15-20 Hz). Seven of these dogs were tested under beta-adrenergic blockade (propranolol, 0.8 mg kg(-1) i.v.). Control responses included sinus node bradycardia or arrest during spontaneous rhythm, high grade AV block or complete heart block, and a 30% decrease in contractility from 2118 +/- 186 to 1526 +/- 187 mm Hg s(-1) (P < 0.05). Next, the ganglionic blocker trimethaphan (0.3-1.0 ml of a 50 microg ml(-1) solution) was injected into the CMV fat pad. Then vagal stimulation was repeated, which now produced a relatively small 5% (N.S., P > 0.05) decrease in contractility but still elicited the same degree of sinus bradycardia and AV block (N = 8, P < 0.05). Five dogs were re-tested 3 h after trimethaphan fat pad injection, at which time blockade of vagally-induced negative inotropy was partially reversed, as vagal stimulation decreased LV dP/dt by 19%. The same dose of trimethaphan given either locally into other fat pads (PVFP or IVC-ILA) or systemically (i.v.) had no effect on vagally-induced negative inotropy. Thus, parasympathetic ganglia located in the CMV fat pad mediated a decrease in ventricular contractility during vagal stimulation. Blockade of the CMV fat pad had no effect on vagally-mediated slowing of sinus rate or AV conduction.
Asunto(s)
Ganglios Parasimpáticos/citología , Ganglios Parasimpáticos/fisiología , Corazón/inervación , Contracción Miocárdica/fisiología , Neuronas/fisiología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/inervación , Tejido Adiposo/fisiología , Animales , Nodo Atrioventricular/efectos de los fármacos , Nodo Atrioventricular/inervación , Nodo Atrioventricular/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Antagonistas Colinérgicos/administración & dosificación , Antagonistas Colinérgicos/farmacología , Perros , Estimulación Eléctrica , Electrocardiografía , Ganglios Parasimpáticos/efectos de los fármacos , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/inervación , Contracción Miocárdica/efectos de los fármacos , Neuronas/efectos de los fármacos , Nodo Sinoatrial/efectos de los fármacos , Nodo Sinoatrial/inervación , Nodo Sinoatrial/fisiología , Trimetafan/administración & dosificación , Trimetafan/farmacología , Nervio Vago/efectos de los fármacos , Nervio Vago/fisiología , Función VentricularRESUMEN
Pure autonomic failure has been conceptualized as deficient sympathetic and parasympathetic innervation. Several recent observations in chronic autonomic failure, however, cannot be explained simply by loss of autonomic innervation, at least according to our current understanding. To simulate acute autonomic failure, we blocked N(N)-nicotinic receptors with intravenous trimethaphan (6+/-0.4 mg/min) in 7 healthy subjects (4 men, 3 women, aged 32+/-3 years, 68+/-4 kg, 171+/-5 cm). N(N)-Nicotinic receptor blockade resulted in near-complete interruption of sympathetic and parasympathetic efferents as indicated by a battery of autonomic function tests. With trimethaphan, small postural changes from the horizontal were associated with significant blood pressure changes without compensatory changes in heart rate. Gastrointestinal motility, pupillary function, saliva production, and tearing were profoundly suppressed with trimethaphan. Plasma norepinephrine level decreased from 1.1+/-0.12 nmol/L (180+/-20 pg/mL) at baseline to 0.23+/-0.05 nmol/L (39+/-8 pg/mL) with trimethaphan (P<.001). There was a more than 16-fold increase in plasma vasopressin (P<.01) and no change in plasma renin activity. We conclude that blockade of N(N)-cholinergic receptors is useful to simulate the hemodynamic alterations of acute autonomic failure in humans. The loss of function with acute N(N)-cholinergic blockade is more complete than in most cases of chronic autonomic failure. This difference may be exploited to elucidate the contributions of acute denervation and chronic adaptation to the pathophysiology of autonomic failure. N(N)-Cholinergic blockade may also be applied to study human cardiovascular physiology and pharmacology in the absence of confounding baroreflexes.
Asunto(s)
Sistema Nervioso Autónomo/fisiopatología , Antagonistas Nicotínicos/administración & dosificación , Receptores Nicotínicos/fisiología , Trimetafan/administración & dosificación , Adulto , Presión Sanguínea/fisiología , Catecolaminas/fisiología , Femenino , Humanos , Inyecciones Intravenosas , MasculinoRESUMEN
In order to observe the reaction of cochlear blood flow (CBF) to trimetaphan (TMP)-induced hypotension, CBF was measured with laser-Doppler flowmetry in 7 human subjects during general anaesthesia for middle ear surgery. All subjects showed a decrease in mean arterial pressure (MAP) during intravenous infusion of TMP, followed by a gradual return to the baseline level after termination of the infusion. The CBF generally followed the MAP changes with the same pattern. Three of the seven subjects demonstrated a CBF change larger than the maximum MAP change, indicating the lack of a local autoregulatory mechanism in CBF. On the other hand, CBF changes were smaller in magnitude than the maximum change in MAP for the rest of the subjects, suggesting an autoregulatory mechanism in CBF. However, since the audiograms from these subjects indicated profound damage along the cochlear basal turn probably due to middle ear inflammation, concomitant vascular damage in this region offers another possible explanation for the inappropriate CBF changes. The present observations may also suggest that deliberately TMP-induced hypotension has a potentially harmful effect on CBF during otological surgery that attempts to preserve or improve hearing.
Asunto(s)
Velocidad del Flujo Sanguíneo/efectos de los fármacos , Cóclea/irrigación sanguínea , Cóclea/cirugía , Bloqueadores Ganglionares/administración & dosificación , Hipotensión/inducido químicamente , Trimetafan/administración & dosificación , Adulto , Anestesia General , Presión Sanguínea/fisiología , Femenino , Bloqueadores Ganglionares/efectos adversos , Humanos , Flujometría por Láser-Doppler , Masculino , Persona de Mediana Edad , Trimetafan/efectos adversosRESUMEN
Intravenous administration of the antihyperglycemic agent metformin decreases arterial pressure and sympathetic nerve activity (SNA). To test the hypothesis that metformin inhibits SNA by interrupting ganglionic neurotransmission, we compared the actions of intravenous administration of metformin and the ganglionic blocker trimethaphan on postganglionic renal and preganglionic adrenal sympathetic nerves in pentobarbital-anesthetized male Sprague-Dawley rats. Intravenous metformin elicited dose-dependent decreases in postganglionic renal SNA (1 mg/kg: 0 +/- 0%; 10 mg/kg: -20 +/- 4%; 100 mg/kg: -92 +/- 3%; n = 7). Conversely, only the maximal dose of metformin affected preganglionic adrenal SNA (100 mg/kg: delta adrenal SNA = -14 +/- 6%; n = 8). Ganglionic blockade with intravenous trimethaphan (5 mg/kg) produced a differential sympathoinhibitory response similar to the response observed after high-dose metformin (delta renal SNA = -100 +/- 3%; delta adrenal SNA = -17 +/- 7%; P < .001). Preganglionic renal neurons were electrically stimulated in the spinal cord, before and during the peak of the sympathoinhibitory response to intravenous metformin, and the magnitude of the stimulus-evoked increases in postganglionic renal SNA were compared. Metformin dose-dependently attenuated the magnitude of the increase in postganglionic renal SNA elicited by stimulation of the spinal cord (30 mg/kg: -23 +/- 8%; 90 mg/kg: -65 +/- 11%; 270 mg/kg: -91 +/- 8%; n = 6 per dose). We conclude that high-dose intravenous metformin interrupts ganglionic neurotransmission in renal nerves.
Asunto(s)
Bloqueadores Ganglionares/administración & dosificación , Hipoglucemiantes/administración & dosificación , Riñón/inervación , Metformina/administración & dosificación , Sistema Nervioso Simpático/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Trimetafan/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Inyecciones Intravenosas , Riñón/fisiopatología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: Whereas the effects of ageing on beta-receptor mediated responses have been extensively studied in vitro and in vivo using the beta-adrenoceptor agonist isoprenaline, little is known regarding ageing induced changes in responses to endogenous catecholamines. In the present study, we assessed age-related changes in cardiac responses to the endogenous beta-adrenoceptor agonist adrenaline and the influence of age-related changes in arterial baroreflex function on these responses. METHODS: Adrenaline alone was infused in 14 young subjects, age 30 +/- 2 years (eight males, six females), and 18 older subjects (six males, 12 females), age 60 +/- 2 years, and together with ganglionic blockade (trimetaphan) in seven young and 11 older subjects. Adrenaline was infused at 3-4 incremental rates, each rate for 8 min. Cardiac function was assessed by echocardiography. RESULTS: Adrenaline alone, at infusion rates 20-160 ng kg-1 min-1 caused similar increases in heart rate in the two groups. In contrast, adrenaline caused larger increases in stroke volume, ejection fraction, cardiac index and systolic blood pressure and larger decreases in end-systolic wall stress and diastolic blood pressure in the young compared with older subjects. Older females exhibited the smallest increases in stroke volume index and ejection fraction. With concomitant ganglionic blockade, all above cardiovascular responses to adrenaline were similar in the young and older group. Plasma adrenaline increased similarly in the two groups. CONCLUSIONS: We conclude that ganglionic blockade does not unmask an age-related decrease in cardiovascular responses to adrenaline (in contrast to isoprenaline). A concomitant ageing induced decrease in neuronal uptake (which applies to adrenaline, but not isoprenaline) may explain such a differential effect.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Envejecimiento/fisiología , Barorreflejo/fisiología , Epinefrina/farmacología , Bloqueadores Ganglionares/farmacología , Hemodinámica/efectos de los fármacos , Trimetafan/farmacología , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/sangre , Adulto , Anciano , Análisis de Varianza , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Catéteres de Permanencia , Interacciones Farmacológicas , Ecocardiografía/efectos de los fármacos , Epinefrina/administración & dosificación , Epinefrina/sangre , Femenino , Bloqueadores Ganglionares/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Factores Sexuales , Volumen Sistólico/efectos de los fármacos , Trimetafan/administración & dosificaciónRESUMEN
STUDY OBJECTIVE: To ascertain the optimal dose of trimethaphan camsylate administered by intravenous (i.v.) bolus injection for the control of hypertension and tachycardia during electroconvulsive therapy (ECT). DESIGN: Prospective, double blind, within-subject study. SETTING: Treating room of the psychiatric unit of the University Hospital at Stony Brook, NY. SUBJECTS: Patients undergoing ECT for major psychiatric illnesses. MEASUREMENTS AND MAIN RESULTS: Fifteen ASA status I or II patients received in a random sequence placebo, or 5, 10, or 15 mg boluses of trimethaphan during their second to fifth treatments. Blood pressure (BP) and heart rate (HR) were recorded every 30 seconds by automated oscillometric recorder. Recordings taken before administration, during seizure, 5, and 20 minutes after seizure were examined. All doses ameliorated BP (systolic, diastolic, and mean), HR, and rate pressure product (RPP) increases during the seizure, compared with placebo. The group that received 15 mg exhibited smaller increases in RPP, i.e., 67.7% increase compared with 155.4%, 110.9%, and 98.7% increases for the placebo, 5, and 10 mg, respectively. The 10 mg and 15 mg doses caused a faster return to baseline than did the 5 mg dose or placebo. No rebound hypertension, prolonged hypotension, arrhythmias, or other side effects were noted. Trimethaphan did not alter seizure duration. CONCLUSIONS: Trimethaphan is safe, practical, and effective in the management of the hyperdynamic response to ECT. An i.v. bolus injection of 15 mg is more effective than 10 mg or 5 mg.