RESUMEN
BACKGROUND: A new beta 3-adrenoceptor (beta3-AR) has been shown to mediate peripheral vasodilation. This study was conducted to evaluate effects of the beta3-AR agonist, SR58611 in normal and hypertensive dogs. MATERIALS AND METHODS: In protocol 1, SR58611 was infused in normal dogs after placebo, after beta1/beta2 blockade with nadolol, after beta1/beta2/beta3 blockade with bupranolol and after combined autonomic blockade (CAB). In protocol 2, perinephritic hypertension was produced in dogs, which received SR58611 at 3 and 6 weeks of hypertension. Effects of SR58611 were evaluated at 7 weeks of hypertension after CAB. RESULTS: In normal dogs, SR58611 produced a dose-dependent decrease in mean aortic pressure (AOP) (from 116 +/- 19 to 100 +/- 19 mmHg, - 14%; P < 0.05) that was accompanied by baroreflex activation (heart rate increased by 70%; P < 0.01). This hypotensive effect resulting from peripheral vasodilation persisted after nadolol or CAB while baroreflex activation was blunted or abolished. A biphasic response of cardiac output, characterized by a rise and a decline (P < 0.05) reflected a reduction in after- and pre-load. After CAB, SR58611 did not modify cardiac contractility. SR58611 stimulated lipolysis as reflected by a 4-fold increase in blood free fatty acids (FFA) (P < 0.0005). Under CAB, the rise of FFA was reduced (P < 0.01). In hypertensive dogs, SR58611 produced a dose-dependent decrease in mean AOP (from 168 +/- 32 to 125 +/- 35 mmHg; - 26%, P < 0.0001), that was greater than in normal dogs (P < 0.05). Reflex-mediated tachycardia also occurred but at higher blood pressure values. Blood FFA rose similarly (P < 0.0001). Under CAB, heart rate remained unchanged but SR58611 still induced a decrease (P < 0.0001) in mean AOP concomitantly with a rise of (dP/dt)/DP40 (P < 0.005), an effect not observed in normal dogs. CONCLUSIONS: Beta3-AR stimulation exerts hypotensive effects, increases cardiac contractility and stimulates lipolysis in hypertensive dogs.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Hemodinámica/efectos de los fármacos , Hipertensión Renal/tratamiento farmacológico , Antagonistas Adrenérgicos beta/farmacología , Animales , Aorta/fisiología , Derivados de Atropina/farmacología , Presión Sanguínea/efectos de los fármacos , Bupranolol/farmacología , Perros , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Hexametonio/farmacología , Hipertensión Renal/fisiopatología , Lipólisis/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Nadolol/farmacología , Propanolaminas/farmacología , Receptores Adrenérgicos beta 3/fisiología , Tetrahidronaftalenos/farmacología , Factores de TiempoRESUMEN
BACKGROUND: As endothelin-1 exerts positive inotropic effects, the present study evaluated whether the hypotensive effects of the endothelin-1 receptor antagonist bosentan were partially related to a decrease in myocardial performance. METHODS: In group I, eight anaesthetized open-chest dogs with perinephritic hypertension received four cumulative doses of bosentan (B1-B4). In group II, eight animals received the same doses of bosentan after autonomic blockade. Indices of heart function were derived from the pressure-length loops obtained during vena cava occlusion. RESULTS: In group I, bosentan decreased left ventricular systolic pressure (LVSP) and mean aortic pressure (MAP) dose dependently, reaching 21% and 23% respectively at B4 (LVSP from 190 +/- 8 to 150 +/- 5 mmHg, P < 0.001; MAP from 167 +/- 7 to 128 +/- 5 mmHg, P < 0.001). These effects were only related to peripheral vasodilatation, without depression of myocardial contractility, as systemic vascular resistance dropped (from 670 +/- 83 to 446 +/- 53 mmHg mL-1 min-1 x 10(4); P < 0.05), and the end-systolic pressure-length relationship (ESPLR) remained unchanged (4.0 +/- 0.4 vs. 4.3 +/- 0.7 mmHg mm-1 kg-1). Concomitantly with pressure decline, heart rate tended to increase in this group (from 150 +/- 4 to 156 +/- 6 beats min-1). When autonomic system was blocked (group II), administration of bosentan induced similar hypotensive effects as in group I (26% and 28% reduction in LVSP and MAP respectively, P < 0.001) whereas ESPLR did not change (3.0 +/- 0.9 vs. 3.1 +/- 0.5mmHg-1 mm kg-1 ). Under these sympathetically blocked conditions, heart rate significantly fell after bosentan infusion (from 120 +/- 4 to 110 +/- 6 beats min-1, P < 0.001). CONCLUSIONS: Without influencing heart function, bosentan is an efficient and safe therapy that opens up new therapeutic perspectives in human essential hypertension.
Asunto(s)
Antihipertensivos/farmacología , Antagonistas de los Receptores de Endotelina , Corazón/efectos de los fármacos , Hipertensión/fisiopatología , Sulfonamidas/farmacología , Animales , Bosentán , Perros , Relación Dosis-Respuesta a Droga , Endotelina-1/fisiología , Hemodinámica/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Receptor de Endotelina ARESUMEN
OBJECTIVE: To evaluate whether the cumulative hypotensive effect of the endothelin-1 receptor antagonist bosentan, previously demonstrated in the presence of an angiotensin converting enzyme inhibitor, persists under angiotensin II receptor blockade with losartan. DESIGN: The model of hypertension was canine renovascular hypertension (Page hypertension). METHODS: Ten conscious dogs, studied on two occasions, were administered losartan (a 0.1 mg/kg bolus plus 90 min infusion at 0.1 mg/kg per min) and then bosentan vehicle (experiment I) or losartan and then two cumulative doses of bosentan (a 0.3 mg/kg bolus plus 30 min infusion at 0.7 mg/kg per min; and a 3 mg/kg bolus plus 30 min infusion at 7 mg/kg per min; experiment II). RESULTS: At the end of the study, mean aortic pressure in dogs had decreased by 14% in experiment I (from 139 +/- 4.7 to 119 +/- 4.7 mmHg, P<0.05), whereas a 28% reduction occurred in experiment II (from 145 +/- 8.9 to 104 +/- 5.0 mmHg, P<0.005), corresponding to an additional 14% decrease after administration of bosentan (P<0.005 between groups). This cumulative effect of bosentan was related to a decrease in systemic vascular resistance (from 1220 +/- 119 to 847 +/- 189 mmHg/ml per min per kg x 10(3), P<0.05). Plasma angiotensin II level increased similarly in both experiments (in experiment I from 133 +/- 43 to 622 +/- 145 pg/ml, P=0.01; in experiment II from 198 +/- 63 to 771 +/- 134 pg/ml, P<0.005) whereas plasma endothelin-1 level increased only in experiment II (from 3.8 +/- 0.4 to 32.7 +/- 3.2 pg/ml, P<0.001). CONCLUSION: The cumulative hypotensive effect of bosentan suggests that, besides angiotensin II, endothelin-1 is independently involved in the pathophysiology of hypertension, which presents new therapeutic perspectives.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Presión Sanguínea/efectos de los fármacos , Antagonistas de los Receptores de Endotelina , Hipertensión Renovascular/fisiopatología , Losartán/administración & dosificación , Sulfonamidas/administración & dosificación , Angiotensina II/fisiología , Animales , Bosentán , Modelos Animales de Enfermedad , Perros , Endotelina-1/fisiología , Hipertensión Renovascular/sangre , Infusiones Intravenosas , Radioinmunoensayo , Receptor de Endotelina A , Resistencia Vascular/efectos de los fármacosRESUMEN
We studied effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on left ventricular (LV) diastolic relaxation in 11 normal control dogs and 16 LV hypertrophied (LVH) dogs with perinephritic hypertension. At baseline, LV systolic and end-diastolic pressures and end-systolic elastance were increased in the LVH group (all P < 0.01 vs. the control group). LV relaxation time constant was also prolonged (P < 0.01), suggesting impaired LV diastolic relaxation in this model of LVH. Before and after the administration of enalaprilat (0.25 mg/kg) and L-158,809 (0.30 mg/kg), LV relaxation was assessed over a wide range of LV loading conditions during vena caval occlusion. LV relaxation time constant was insensitive to load reduction in the control group, which was not affected by enalaprilat or L-158,809. In contrast, LV unloading caused a significant prolongation of the relaxation time constant in the LVH group. This load-sensitive LV relaxation abnormality was significantly improved by enalaprilat or L-158,809. These results support the concept that angiotensin II is involved in the pathogenesis of diastolic dysfunction in pressure-overloaded LVH and also suggest that angiotensin-converting enzyme inhibitors and angiotensin II type-1 receptor antagonists are potentially beneficial in the treatment of the hypertrophied heart.
Asunto(s)
Diástole/fisiología , Hipertensión Renal/complicaciones , Hipertrofia Ventricular Izquierda/fisiopatología , Angiotensina II/fisiología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Antihipertensivos/farmacología , Presión Sanguínea , Perros , Enalaprilato/farmacología , Hemodinámica , Hipertensión Renal/fisiopatología , Hipertrofia Ventricular Izquierda/etiología , Imidazoles/farmacología , Tetrazoles/farmacologíaRESUMEN
BACKGROUND: Endothelin-1 (ET-1) may play a role in hypertension. ET-1 receptor antagonism by bosentan lowers blood pressure in hypertension. We evaluated whether the effect of bosentan is still observed under ACE inhibitors (ACEI). METHODS AND RESULTS: Thirty anesthetized and 18 conscious hypertensive dogs were studied randomly. Anesthetized dogs were divided into 4 groups: group 1 received cumulative doses of bosentan (bolus+30-minute infusion: 0.1 mg/kg+/-0.23 mg/kg per hour to 3 mg/kg+/-7 mg/kg per hour); group 2, the same dose-responses after 1 mg/kg enalaprilat; group 3, the vehicle after enalaprilat; and group 4, the dose responses to bosentan followed by enalaprilat. The conscious dogs were divided into 3 groups: group 5 received 2 cumulative doses of bosentan; group 6, the vehicle; and group 7, enalaprilat alone. In groups 1 and 2, bosentan produced dose-related decreases (P=.0001) in left ventricular systolic pressure and mean aortic pressure (AOP). In group 1, bosentan decreased mean AOP by 22%. In group 2, enalaprilat decreased mean AOP by 25% (from 173+/-26 to 130+/-25 mm Hg; P<.005); an additional 18% decrease was obtained with bosentan, the mean AOP reaching 98+/-21 mm Hg (P<.01). In group 3, the effect of enalaprilat alone was a 22% decrease in mean AOP (P<.005). The additive effect of the bosentan-ACEI association was also observed in group 4. In group 5, bosentan reduced mean AOP by 20% (P<.005), whereas mean AOP remained unchanged in group 6. The effect of ACEI alone (group 7) was similar to that of bosentan. CONCLUSIONS: Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Enalaprilato/uso terapéutico , Antagonistas de los Receptores de Endotelina , Hipertensión/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Animales , Antihipertensivos/sangre , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Bosentán , Perros , Relación Dosis-Respuesta a Droga , Endotelina-1 , Sulfonamidas/sangre , Sulfonamidas/farmacología , Resistencia Vascular/efectos de los fármacosRESUMEN
OBJECTIVE: Angiotensin II has been suggested to be involved in the pathogenesis of diastolic dysfunction in left ventricular hypertrophy (LVH). The purpose of this study was to asses the effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on LV diastolic function in 16 normal control dogs and 20 LVH dogs with perinephritic hypertension. METHODS: LV hemodynamics was studied before and after intravenous injection of enalaprilat (0.25 mg/kg) or L-158,809 (0.3 mg/kg). The hemodynamic data were analyzed in relation to the changes in myocardial blood flow (measured by radioactive microspheres) and in the circulating angiotensin II and norepinephrine levels. RESULTS AND CONCLUSIONS: At baseline, significant increases were observed for LV/body weight ratio as well as LV systolic and end-diastolic pressure in the LVH dogs (all P < 0.01 vs. the control group). In addition, LV relaxation time constant was prolonged and the chamber and myocardial stiffness constants were increased (P < 0.01) in the LVH dogs, suggesting an impairment of LV diastolic function. Administration of enalaprilat or L-158,809 improved LV stiffness constants in the LVH dogs (P < 0.05). The diastolic LV pressure-diameter relation shifted downwards in the LVH dogs whereas diastolic distensibility was not altered in the control dogs. Although the circulating angiotensin II levels were significantly decreased by enalaprilat in the LVH dogs, they did not correlate with the changes in the stiffness constants. Furthermore, the alterations of LV diastolic properties in the LVH group could not be attributed to myocardial perfusion, which was rather decreased by administration of enalaprilat and L-158,809. These results suggest that angiotensin II, particularly at the local level, is involved in the pathogenesis of diastolic dysfunction in pressure-overload LVH. The data also support the concept that ACE inhibitors and angiotensin II receptor blockers are potentially beneficial in the treatment of the hypertrophied heart.
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Hipertensión Renal/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Imidazoles/farmacología , Receptores de Angiotensina/efectos de los fármacos , Tetrazoles/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Antagonistas de Receptores de Angiotensina , Animales , Diástole , Modelos Animales de Enfermedad , Perros , Enalaprilato/farmacologíaRESUMEN
Octreotide inhibits the secretion of several hormones and exerts vasopressor effects. To clarify the mechanism of atrial natriuretic factor (ANF) secretion and to assess the cardiovascular effects of octreotide in relation to changes in vasoactive peptide secretion, four groups of conscious dogs were studied: group I (n = 11) received saline infusion after placebo, group II (n = 10), the same infusion after octreotide, group III (n = 10), placebo only and group IV (n = 10) octreotide injection only. Saline (10% body wt) was infused over 40 min after subcutaneous injection of placebo or octreotide (1 microgram/kg). Saline produced a rise (p < 0.001) of plasma ANF from 32.4 +/- 4.1 to 59.0 +/- 8.5 pM after placebo and from 35.6 +/- 5.5 to 77.0 +/- 12.6 pM after octreotide. This rise, not significantly different between groups I and II paralleled a 4-5-fold increase (p < 0.005) of right and left atrial pressures. With a higher dose of octreotide (4 micrograms/kg) injected in 4 dogs, plasma ANF increased by 27.5 +/- 5 pM. During hypervolemia, plasma endothelin-1 remained unchanged but plasma angiotensin II and epinephrine decreased (p < 0.05) approximately by 80% without being affected by octreotide. Octreotide did not influence the basal secretion of ANF, endothelin-1, angiotensin II and catecholamines. However, in basal conditions, octreotide injection resulted in a 9% increase (p < 0.005) of left ventricular systolic pressure, unobserved after placebo. Plasma glucose decreased (p < 0.005) in groups receiving octreotide. Thus, octreotide does not impair the stretch-mediated release of ANF which implies a release mechanism independent from somatostatin receptors and consequent changes in intracellular c-AMP. Octreotide has also a pressor effect, unrelated to changes in vasoactive peptide production.
Asunto(s)
Factor Natriurético Atrial/sangre , Hemodinámica/efectos de los fármacos , Hormonas/farmacología , Octreótido/farmacología , Angiotensina II/metabolismo , Animales , Factor Natriurético Atrial/metabolismo , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Volumen Sanguíneo , Catecolaminas/sangre , Circulación Coronaria/efectos de los fármacos , Perros , Endotelinas/sangre , Frecuencia Cardíaca/efectos de los fármacosRESUMEN
BACKGROUND: Endothelin-1, a vasoconstrictive peptide released by endothelium, may be involved in the pathophysiology of hypertension. The goal of the present study was to evaluate the role of endogenous endothelin-1 in renal hypertension in dogs. The model of hypertension consisted of silk tissue wrapping of the left kidney, which produced hypertension associated with perinephritis after 6 to 8 weeks. METHODS AND RESULTS: Thirty-two anesthetized open chest dogs were studied randomly: 8 dogs with perinephritic hypertension received the nonpeptidic ETA-ETB receptor antagonist bosentan (group 1); 8 other hypertensive dogs received the vehicle solution (group 2); 8 healthy dogs received bosentan (group 3); and 8 healthy dogs received the vehicle solution (group 4). Bosentan was injected as an intravenous bolus (3 mg/kg) followed by a 1-hour infusion at a rate of 7 mg.kg-1.h-1. In hypertensive dogs, bosentan produced a similar decrease (P = .0001) of both left ventricular systolic and mean aortic pressures, which averaged 38 mm Hg (-22% and -24%, respectively). These parameters remained unchanged with the vehicle solution. Left ventricular end-diastolic and left atrial pressures also declined significantly with bosentan (P = .0005 and P < .05, respectively). Left ventricular lengths tended to decrease. The other cardiovascular parameters (heart rate, peak [+]dP/dt, time constant of relaxation, and coronary vascular resistance) did not change significantly. In healthy dogs, bosentan decreased mean aortic pressure by 19 mm Hg (P = .004). Vehicle solution had no effect. Plasma endothelin-1 levels, similar under basal conditions in healthy and hypertensive dogs, increased 30-fold with bosentan (P = .0001). CONCLUSIONS: Specific endothelin-1 receptor antagonism markedly lowers blood pressure in experimental hypertension but is less effective on blood pressure of healthy animals. This suggests that endothelin-1 plays a role in the pathophysiology of hypertension but contributes to a lesser extent to the maintenance of normal blood pressure. This role of endothelin-1 is unrelated to its plasma levels. The increase of plasma endothelin-1 with bosentan, due either to a displacement of endothelin-1 from its receptor or to a feedback mechanism, does not prevent this blood pressure reduction.
Asunto(s)
Endotelinas/fisiología , Hipertensión Renal/etiología , Sulfonamidas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Bosentán , Perros , Endotelinas/sangre , Epinefrina/sangre , Frecuencia Cardíaca/efectos de los fármacos , Norepinefrina/sangreRESUMEN
We assess hemodynamic, vascular, and hormonal effects of endothelin-1 (ET-1) at pathophysiologic levels on normal and ischemic myocardium. Thirty conscious chronically instrumented dogs were studied before, during, and after a 10-min coronary artery occlusion (CAO) performed either during ET-1 infusion (2.5 ng/kg.min, n = 15) or during placebo infusion (n = 15). ET-1 infusion produced an increase in plasma ET-1 (from 1.3 +/- 0.1 to 11.5 +/- 1.1 pM, p < 0.0001) during CAO (pathophysiologic value). Left anterior descending artery (LAD) blood flow (measured by Doppler flow probe) decreased similarly during CAO with ET-1 or placebo (p = 0.0001, NS, ET-1 vs. placebo). Both endocardial and epicardial blood flows in ischemic regions also decreased (p = 0.0001) during CAO but were threefold greater with ET-1 than with placebo (endocardium 42 +/- 7 vs. 14 +/- 2 ml/min/100 g, p = 0.003). No significant difference in myocardial blood flows between groups was observed in control regions. CAO produced increases (p < 0.005) in heart rate (HR), mean aortic pressure (AOP), and ventricular pressures but no change in atrial pressures. The changes in these parameters were comparable in the ET-1 and placebo groups. Despite the greater residual flow during CAO, however, ET-1 decreased the function of the ischemic zone during reperfusion as assessed by systolic shortening (p < 0.05). Atrial natriuretic factor (ANF), unchanged during CAO with placebo, increased from 38.3 +/- 6.1 to 53.3 +/- 10 pM with ET-1 (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Circulación Coronaria/efectos de los fármacos , Endotelinas/farmacología , Contracción Miocárdica/efectos de los fármacos , Isquemia Miocárdica/fisiopatología , Animales , Factor Natriurético Atrial/sangre , Nitrógeno de la Urea Sanguínea , Catecolaminas/sangre , Creatinina/sangre , Perros , Endotelinas/sangre , Hemodinámica/efectos de los fármacos , Microesferas , Potasio/sangre , Flujo Sanguíneo Regional/efectos de los fármacos , Circulación Renal/efectos de los fármacosRESUMEN
The purpose of this study was to examine the effects of endothelin-1 (ET-1) on "diastolic stunning" in the postischemic myocardium. In 14 conscious dogs receiving either placebo (n = 7) or ET-1 (2.5 ng.kg-1.min-1, n = 7), left ventricular (LV) hemodynamics and regional wall motion (systolic segmental shortening by sonomicrometry and the ischemic-nonischemic regional asynchrony during isovolumic relaxation) were assessed at baseline, during 10 min of left anterior descending coronary artery occlusion (CAO) and at 60 min after reflow (R-60). During CAO, the ischemic segment shortening was severely depressed and both regional asynchrony and LV relaxation time constant were significantly increased in the placebo and ET-1 groups. At R-60, this LV diastolic dysfunction recovered to baseline conditions in the placebo group but was still present in the ET-1 group. Because coronary and myocardial blood flow returned to the baseline level at R-60 in both groups, the deleterious effects of ET-1 on diastolic stunning are probably mediated by its direct action on the myocardium.
Asunto(s)
Circulación Coronaria/efectos de los fármacos , Diástole/fisiología , Hemodinámica/efectos de los fármacos , Isquemia Miocárdica/fisiopatología , Aturdimiento Miocárdico , Animales , Estado de Conciencia , Diástole/efectos de los fármacos , Perros , Electrocardiografía/efectos de los fármacos , Endotelinas/administración & dosificación , Endotelinas/sangre , Endotelinas/farmacología , Epinefrina/sangre , Frecuencia Cardíaca/efectos de los fármacos , Infusiones Intravenosas , Contracción Miocárdica/efectos de los fármacos , Isquemia Miocárdica/sangre , Norepinefrina/sangre , Flujo Sanguíneo Regional/efectos de los fármacos , Sístole/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
To evaluate the role of calcium in volume-induced secretion of atrial natriuretic factor (ANF), effects of verapamil and endothelin-1 (ET-1), both known to influence free intracellular calcium, were studied during saline infusion in seven conscious instrumented dogs. Fifteen minutes after intravenous injection of placebo or verapamil (0.25 mg/kg) or during continuous ET-1 infusion (at 5 ng.kg-1.min-1), saline (10% body wt) was infused during 40 min. Saline produced a rise (P less than 0.001) of plasma ANF from 28.1 +/- 6.3 to 50.4 +/- 12.9 pM after placebo, from 30.2 +/- 6.1 to 51.1 +/- 8.5 pM after verapamil, and from 31.2 +/- 6.1 to 81.0 +/- 12.9 pM with ET-1. This increase was comparable after placebo and verapamil, but was 80% greater with ET-1 (P less than 0.02). Plasma ET-1, unchanged after placebo, rose (P less than 0.001) from 1.7 +/- 0.5 to 38.3 +/- 9.2 pM with ET-1. In the three experiments, heart rate and left atrial pressure (LAP) increased (P less than 0.001) similarly. The linear relation between ANF and LAP was steeper with ET-1 than with saline or verapamil (both P less than 0.05), indicating that the enhanced ANF secretion with ET-1 was occurring at all levels of LAP. Thus volume-induced secretion of ANF is not suppressed by verapamil, but is directly enhanced by low-dose ET-1, known to activate the phosphoinositide pathway.
Asunto(s)
Factor Natriurético Atrial/metabolismo , Volumen Sanguíneo/fisiología , Endotelinas/administración & dosificación , Angiotensina II/sangre , Animales , Factor Natriurético Atrial/sangre , Sistema Cardiovascular/efectos de los fármacos , Catecolaminas/sangre , Perros , Relación Dosis-Respuesta a Droga , Endotelinas/sangre , Endotelinas/farmacología , Corazón/fisiología , Atrios Cardíacos , Presión , Verapamilo/administración & dosificación , Verapamilo/farmacologíaRESUMEN
Twenty-six patients with mild to moderate heart failure were studied to determine the effects of epinine infusion (at a rate producing plasma levels similar to those measured after oral administration of 100 mg of the prodrug ibopamine) on left ventricular (LV) function (14 patients), and coronary flow and circulating catecholamines (12 patients). The only significant hemodynamic change at an infusion rate of 0.5 microgram/kg/min was a 9% (p less than 0.05) decrease in systemic vascular resistance (SVR). At an infusion rate of 1 microgram/kg/min (mean free epinine plasma levels 14.3 +/- 3.7 ng/ml), heart rate (HR), dP/dtmax (1,405 +/- 255 to 1,490 +/- 320 mm Hg, NS), (dP/dt)/DP40, and the relaxation rate remained unchanged, but the ejection fraction (EF) increased from 32 to 38% (p less than 0.001), cardiac output (CO) increased, and SVR decreased by 22% (p less than 0.05). In a separate group of 12 patients, epinine infusion at rates of 0.5-1 microgram/kg/min produced no significant changes in coronary blood flow or myocardial oxygen uptake. At these infusion rates, arterial norepinephrine (NE) and dopamine (DA) levels decreased slightly and arterial and coronary sinus epinephrine increased. In conclusion, epinine, at concentrations similar to those achieved during therapeutic use of ibopamine, had negligible effect on myocardial contractility and relaxation rate in heart failure patients. Cardiac pump function was improved by a decrease in SVR rather than by inotropic stimulation. The data also suggest that these low concentrations of epinine may modulate the sympathetic nervous system, but further studies are needed to determine whether this effect could have clinical significance.
Asunto(s)
Catecolaminas/sangre , Circulación Coronaria/efectos de los fármacos , Desoxiepinefrina/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacos , Adulto , Anciano , Desoxiepinefrina/análogos & derivados , Desoxiepinefrina/farmacología , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Increased plasma concentrations of endothelin-1, a potent vasoconstrictor produced by the endothelium, have been reported in various pathological conditions. This study was conducted to evaluate effects of endothelin-1 at pathophysiological and pharmacological plasma concentrations. METHODS AND RESULTS: Endothelin-1 was infused at increasing doses (2.5, 5, 10, and 20 ng/kg.min for 1 hour each) in nine conscious dogs. During endothelin-1 infusion, plasma endothelin-1 rose from a basal value of 1.8 +/- 0.4 pmol/l to 5.8 +/- 1.1 (pathophysiological), 20.8 +/- 3.9 (pathophysiological), 85.4 +/- 18.9 (pharmacological), and 311.4 +/- 55.7 (pharmacological) pmol/l at each dose, respectively. Heart rate increased at 2.5 ng/kg.min (from 129 +/- 7 to 146 +/- 12 beats/min) but decreased at 20 ng/kg.min (97 +/- 7 beats/min) (p less than 0.001). Such a biphasic response was also observed for peak (+)dP/dt and (dP/dt)/DP40 (p less than 0.005). Left ventricular systolic pressures, mean aortic pressure, and left atrial pressure increased over time (p less than 0.05, p less than 0.005, and p less than 0.001, respectively). The time constant of early isovolumic relaxation rose progressively (p less than 0.001). The percent systolic shortening decreased at 10 and 20 ng/kg.min (p less than 0.005). Pressure-segment length loops showed a reduction in systolic shortening associated with an increase in left ventricular systolic pressure at 20 ng/kg.min. Atrial natriuretic factor rose after 5 ng/kg.min from 28.5 +/- 6.5 to 92.0 +/- 18.2 pmol/l (p less than 0.005). Angiotensin II and catecholamines did not change significantly. Serum urea and creatinine rose progressively (p less than 0.05), whereas glucose decreased (p less than 0.05). The above results differed significantly from measurements obtained in a time-control group of six dogs. CONCLUSIONS: A fourfold increase of plasma endothelin-1 obtained after doubling the infusion rate suggests a reduction in endothelin-1 clearance or endothelin-1 endogenous production. The biphasic response of heart rate is consistent with baroreflex-mediated effects resulting from vasodilation at the pathophysiological level and vasoconstriction at the pharmacological level. Hemodynamic data suggest an increase followed by a decrease in contractility at both levels, respectively. Finally, endothelin-1 is a stimulator of atrial natriuretic factor.
Asunto(s)
Endotelinas/farmacología , Hemodinámica/efectos de los fármacos , Animales , Factor Natriurético Atrial/sangre , Presión Sanguínea/efectos de los fármacos , Catecolaminas/sangre , Perros , Relación Dosis-Respuesta a Droga , Electrólitos/sangre , Endotelinas/sangre , Endotelinas/toxicidad , Frecuencia Cardíaca/efectos de los fármacosRESUMEN
To determine if alterations in regional coronary vascular resistance could occur in the type of myocardial ischemia present in severe angina pectoris, regional perfusion and function were studied in 35 conscious sedated dogs. A stenosis producing severe hypokinesia of the perfused segment was created for 2 h on the left anterior descending coronary artery and 10 episodes of 1 min of high demand ischemia (atrial pacing at a rate sufficient to induce dyskinesia in the hypoperfused segment) were superimposed before reperfusion. The dogs were randomized into three treatment groups: control (n = 13), dipyridamole (n = 10) or WEB-2086 (n = 12), an antagonist of the effects of the endogenous platelet-activating factor. During stenosis, residual endocardial blood flow in the ischemic but nonnecrotic area averaged 0.72 +/- 0.14, 0.38 +/- 0.13 and 0.68 +/- 0.17 ml/min per g in the control, WEB-2086 and dipyridamole groups, respectively. Twenty-four hours after reperfusion, endocardial blood flow in the ischemic area was significantly lower in control dogs (1.04 +/- 0.15 ml/min per g) than in dogs treated with WEB-2086 (1.44 +/- 0.28 ml/min per g; p less than 0.03) or dipyridamole (3.00 +/- 0.83 ml/min per g; p less than 0.01). Accordingly, in control dogs, endocardial coronary vascular resistance in the ischemic area was increased after reperfusion from 85 +/- 11 to 124 +/- 27 mm Hg/(ml/min per g) (p less than 0.05) after 24 h. In contrast, coronary vascular resistance in the ischemic area remained unchanged in dogs receiving WEB-2086 (77 +/- 8 to 79 +/- 9 mm Hg/(ml/min per g); p = NS) and it decreased significantly in dogs receiving dipyridamole (72 +/- 8 to 44 +/- 8 mm Hg/(ml/min per g); p less than 0.01). Regional function after 24 h remained depressed in all three groups. These data indicate that low flow, high demand ischemia induces alterations in the subendocardial microvasculature. Such alterations in regional coronary vascular resistance might play a role in several forms of ischemic heart disease such as in severe angina, but they appear susceptible to improvement by therapeutic interventions that influence granulocyte and platelet activation.
Asunto(s)
Azepinas/uso terapéutico , Vasos Coronarios/efectos de los fármacos , Dipiridamol/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Factor de Activación Plaquetaria/antagonistas & inhibidores , Triazoles/uso terapéutico , Resistencia Vascular/efectos de los fármacos , Adenosina/fisiología , Animales , Perros , Hemodinámica/fisiología , Daño por Reperfusión Miocárdica/fisiopatologíaRESUMEN
Detailed left ventricular haemodynamic investigations were performed in eight patients with New York Heart Association (NYHA) Class II heart failure, eight with NYHA Class III heart failure with an ejection fraction less than 35%, and six with severe heart failure. Xamoterol (200 mg b.d. for 3 months) caused a fall in left ventricular end-diastolic pressure, an increase in dP/dTmax and a shorter systole in all groups of patients.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Corazón/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Propanolaminas/farmacología , Agonistas Adrenérgicos beta/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco Bajo/tratamiento farmacológico , Humanos , Propanolaminas/uso terapéutico , XamoterolRESUMEN
Acute intravenous administration of the new beta 1-adrenergic receptor partial agonist xamoterol lowers left ventricular end-diastolic pressure and improves the isovolumic indexes of inotropic state and relaxation. To determine if these hemodynamic changes were maintained after prolonged administration, the dose-response relation to cumulative doses of xamoterol was determined in a group of 14 patients with mild (n = 6)-to-serve (n = 8) ischemic left ventricular dysfunction. These patients had been treated with xamoterol (200 mg, b.i.d.) for a mean of 51 +/- 17 months, and the drug had been stopped for 72 hours before testing the responsiveness to xamoterol. In these patients, xamoterol administration still induced dose-dependent decreases in left ventricular end-diastolic pressure from 21.4 +/- 8.2 to 15.8 +/- 7.7 mm Hg (p less than 0.01, vs. baseline and vs. the control data 51 +/- 17 months before). Peak positive dP/dt and dP/dt normalized to a developed pressure of 40 mm Hg [( dP/dt]/DP40) increased by 14% and 23%, respectively (p less than 0.01), whereas the rate of isovolumic pressure decrease improved by 12% (p less than 0.01). It is concluded that the myocardial response to xamoterol is maintained after years of continuous therapy, and that in patients with heart failure, this response was expressed mainly as a reduction in left ventricular end-diastolic pressure.
Asunto(s)
Agonistas Adrenérgicos beta/uso terapéutico , Enfermedad Coronaria/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Contracción Miocárdica/efectos de los fármacos , Propanolaminas/uso terapéutico , Administración Oral , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , XamoterolRESUMEN
Myocardial oxygen uptake and an index of mechanical left ventricular efficiency were determined in basal conditions or during prolonged therapy with the new beta 1-adrenoceptor partial agonist xamoterol in 16 patients with mild to moderate ischemic heart failure. During xamoterol therapy, left ventricular end-diastolic pressure decreased from 24.4 +/- 6.5 to 17.8 +/- 8.6 mm Hg (P less than 0.01) and the isovolumic index of inotropic state (dP/dt)/DP40 increased by 14% (P less than 0.01). The heart rate increased slightly and the mean systolic and peak systolic wall stress also tended to increase (+ 7%; NS) but myocardial oxygen uptake (14.1 vs 14.7 ml/min; NS) and the index of efficiency (8.77 +/- 3.44 to 8.82 +/- 4.27; NS) were not significantly modified. In conclusion, prolonged therapy with xamoterol was not accompanied by a deterioration in the mechanical efficiency of the ventricle, even in patients with ischemic heart disease.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Enfermedad Coronaria/fisiopatología , Corazón/efectos de los fármacos , Propanolaminas/farmacología , Corazón/fisiopatología , Humanos , XamoterolRESUMEN
The purpose of this study was to examine the time course of the changes in left ventricular inotropic state after intravenous pimobendan administration. In conscious dogs, cumulative doses of 1 and 2.5 mg of pimobendan significantly increased heart rate and the isovolumic indices of inotropic state and relaxation. The maximal effect, however, required 2 h to be present. The changes in cardiac index and capillary wedge pressure after the intravenous administration of 5 mg to patients with heart failure confirmed this slightly delayed action of pimobendan. Accordingly, the effects of pimobendan on left ventricular inotropic state in patients with moderate to severe heart failure were determined during cardiac catheterization 130-150 min after injection of 5 (n = 3) or 2.5 (n = 4) mg. After drug administration, heart rate increased slightly (+7 beats/min; NS) while left ventricular end-diastolic and systolic pressure both decreased significantly (from 22.7 to 9.2 mm Hg, p less than 0.007 and from 123 to 90 mm Hg, p less than 0.025, respectively). The isovolumic index of contractility (dP/dt)/DP40 increased by 19.6 +/- 14.7% (p less than 0.02) and the slope of the late systolic stress-volume relationship improved by 48% (p less than 0.05). It is concluded that pimobendan is a positive inotropic agent in the failing human heart as well as a powerful veno- and arteriodilator.
Asunto(s)
Cardiotónicos/farmacología , Contracción Miocárdica/efectos de los fármacos , Piridazinas/farmacología , Animales , Gasto Cardíaco Bajo/fisiopatología , Cardiotónicos/administración & dosificación , Perros , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Hemodinámica/efectos de los fármacos , Inyecciones Intravenosas , Piridazinas/administración & dosificación , Factores de TiempoRESUMEN
Pimobendan (UD-CG 115) is a long-acting positive inotropic drug with arterio- and venodilator properties. To determine to what extent this new agent is able to affect contractile function in previously ischemic areas of the left ventricle (LV), the effects of pimobendan on global and regional LV function were studied in eight conscious dogs, 2 days after a 2-h coronary occlusion followed by reperfusion. Before pimobendan, percentage of systolic shortening and mean velocity of shortening were lower in reperfused segments than in control areas (0.41 +/- 0.17 vs. 0.93 +/- 0.07 s-1 and 7 +/- 3 vs. 15 +/- 1%, respectively; both p less than 0.05). Infusion of 1 mg of pimobendan significantly improved peak + dP/dt (3202 +/- 372 to 3848 +/- 498 mm Hg/s; p less than 0.05) and ejection time (166 +/- 13 to 156 +/- 15 ms; p less than 0.05). Cumulative infusion up to 2.5 mg further improved these indexes to 5199 +/- 934 mm Hg/s and to 125 +/- 11 ms, (respectively; both p less than 0.05) without affecting mean arterial pressure (91 +/- 14 to 93 +/- 22 mm Hg; NS). Mean velocity of shortening rose to 1.18 +/- 0.09 s-1 (p less than 0.05) in control segments and to 0.62 +/- 0.18 s-1 (p less than 0.05) in reperfused segments. The ratio between end-systolic pressure and length increased by 26 +/- 9% (p less than 0.05) in the reperfused segments and by 20 +/- 8% (p less than 0.05) in control areas.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Cardiotónicos/farmacología , Enfermedad Coronaria/tratamiento farmacológico , Contracción Miocárdica/efectos de los fármacos , Piridazinas/farmacología , Animales , Circulación Coronaria/efectos de los fármacos , Enfermedad Coronaria/fisiopatología , Perros , Músculos/irrigación sanguínea , Flujo Sanguíneo Regional/efectos de los fármacos , Circulación Renal/efectos de los fármacosRESUMEN
The effects of atriopeptin III (AP III) on the left ventricular and renal functions were studied in thirteen chronically instrumented conscious dogs and compared to those of the solvent (saline). In the normovolaemic state, an AP III infusion (1 microgram kg-1 min-1 i.v.) had no effects on heart rate, on mean arterial or left ventricular pressure, on (dP/dt) Max (2989 +/- 119 vs. 3007 +/- 155 mmHg s-1; NS) or on the relaxation rate. The left ventricular endocardial and epicardial coronary blood flows (radioactive microspheres) and the renal flow in the outer cortex (707-683 ml (min-1 100 g-1); NS) or in the inner cortex (563-570; NS) were also insignificantly affected by AP III infusion. However, AP III increased urinary flow from 24 +/- 6 to 36 +/- 7 ml h-1 (P less than 0.025) and the Na+ and Cl- excretions by 92 and 98%, respectively, (P less than 0.025 and P less than 0.01 vs. saline group) without altering significantly K+, urea and creatinine eliminations. In the moderately hypovolaemic state (mean reduction in renal flow: outer cortex - 15%; P less than 0.05, inner cortex - 5%; NS), AP III infusion at two doses (1 and 3 micrograms kg-1 min-1) still had no effects on arterial pressure and on the indexes of left ventricular inotropic state and relaxation but in this setting, the diuretic effect of AP III became variable. Five dogs markedly increased their excretion of water, Na+ and Cl- whereas no change was noted in the seven remaining dogs.(ABSTRACT TRUNCATED AT 250 WORDS)