RESUMEN
BACKGROUND AND PURPOSE: Activation of brain α(2) -adrenoceptors in conscious rodents decreases heart rate (HR) and mean arterial blood pressure (MAP) and increases urine output and urinary sodium excretion. In vitro, α(2) -adrenoceptor stimulation activates Gα(i(1-3)) , Gα(o) and Gα(s) -subunit protein-gated signal transduction pathways. Here we have investigated whether these same Gα-subunit protein-gated pathways mediate the cardiovascular and renal excretory responses to central α(2) -adrenoceptor activation in conscious Sprague-Dawley rats. EXPERIMENTAL APPROACH: Rats were pre-treated by intracerebroventricular injection (i.c.v.) with an oligodeoxynucleotide (ODN) targeted to a Gα(i1) , Gα(i2) , Gα(i3) , Gα(o) , Gα(s) or a scrambled (SCR) ODN sequence (25 µg, 24 h). On the day of study, the α(2) -adrenoceptor agonist guanabenz (50 µg) or saline vehicle, was injected i.c.v. into ODN-pre-treated conscious rats. MAP and HR were recorded, and urine was collected for 150 min. KEY RESULTS: In vehicle- and SCR ODN-pre-treated rats, i.c.v. guanabenz decreased MAP and HR, and produced marked diuretic and natriuretic responses. Selective ODN-mediated down-regulation of brain Gα(i2) -subunit proteins abolished the central guanabenz-induced hypotension and natriuresis. In contrast, following selective Gα(s) down-regulation, the characteristic hypotensive response to i.c.v. guanabenz was converted to an immediate increase in MAP. The bradycardic and diuretic responses to i.c.v. guanabenz were not blocked by pre-treatment with any ODN. CONCLUSIONS AND IMPLICATIONS: There was functional selectivity of Gα(i2) and Gα(s) subunit protein-gated signal transduction pathways in mediating the hypotensive and natriuretic, but not bradycardic or diuretic, responses evoked by central α(2) -adrenoceptor activation in vivo.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Oligodesoxirribonucleótidos/administración & dosificación , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Animales , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Guanabenzo/administración & dosificación , Guanabenzo/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The contribution of alpha(2)-receptor mechanisms in the rostral ventrolateral medulla (RVLM) in mediating the enhanced renal excretory responses evoked by the intravenous infusion of the alpha(2)-receptor agonist xylazine was examined in ketamine-anesthetized rats. In ketamine-anesthetized rats, the bilateral microinjection of the alpha(2)-receptor antagonist yohimbine into the RVLM significantly reduced the enhanced levels of urine flow rate (V) and urinary sodium excretion (UNaV) produced by xylazine. In contrast, microinjection of yohimbine into the RVLM of chronically bilaterally renal-denervated rats significantly reduced the xylazine-evoked diuretic, but not natriuretic, response. In separate ketamine-anesthetized rats, intravenous xylazine infusion produced a near complete inhibition of renal sympathetic nerve activity (RSNA). The subsequent microinjection of yohimbine into the RVLM reversed this neural response and concurrently decreased V and UNaV. Together, these results indicate that during intravenous infusion, xylazine activates alpha(2)-receptor mechanisms in the RVLM to selectively promote urinary sodium excretion by a renal nerve-dependent pathway. In contrast, activation of alpha(2)-receptor in the RVLM affects the renal handling of water by a pathway independent of the renal nerves. This latter pathway may involve an interaction with other brain regions involved in antidiuretic hormone release (e.g., paraventricular nucleus of the hypothalamus).
Asunto(s)
Riñón/fisiología , Bulbo Raquídeo/metabolismo , Natriuresis/fisiología , Receptores Adrenérgicos alfa 2/metabolismo , Sistema Nervioso Simpático/fisiología , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Anestésicos Disociativos , Animales , Ketamina , Riñón/inervación , Masculino , Bulbo Raquídeo/efectos de los fármacos , Microinyecciones , Ratas , Ratas Wistar , Sodio/orina , Orina , Xilazina/farmacología , Yohimbina/farmacologíaRESUMEN
Orphanin FQ/Nociceptin (OFQ/N) is a peptide whose structure resembles that of the endogenous opioid peptides (endorphins). OFQ/N and its receptor are distributed in neural tissue and brain regions involved in the regulation of pituitary hormone release. Functional studies have shown that this peptide evokes a unique pattern of cardiovascular and renal excretory responses. This review will focus on the neural and humoral effects of OFQ/N and how this peptide may participate in the regulation of cardiovascular and renal function.
Asunto(s)
Péptidos Opioides/farmacología , Péptidos Opioides/fisiología , Receptores Opioides/fisiología , Animales , Sistema Cardiovascular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Electrofisiología , Humanos , Riñón/efectos de los fármacos , Riñón/inervación , Ratones , Neuronas/efectos de los fármacos , Neurotransmisores/metabolismo , Oxitocina/farmacología , Sistema Nervioso Parasimpático/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Sistema Nervioso Simpático/efectos de los fármacos , Factores de Tiempo , Distribución Tisular , Vejiga Urinaria/efectos de los fármacos , Vasodilatadores/farmacología , Vasopresinas/farmacología , Receptor de Nociceptina , NociceptinaRESUMEN
Orphanin FQ/nociceptin (OFQ/N) is a preferred endogenous ligand for the orphan opioid receptor-like-1 receptor. This peptide has been reported to increase intestinal, but not gastric, motor activity. In the present study, OFQ/N (0.6-60 nmol kg(-1) i.v.) increased intragastric pressure and antral contractility and, as expected, decreased blood pressure in anaesthetized rats. The gastric motor effects of OFQ/N (6 nmol kg(-1)) were not affected by inhibition of nitric oxide synthase or opioid receptor blockade. OFQ/N (6 nmol kg(-1)) evoked gastric motor increases and hypotension were not affected by prior administration of its derivative [Phe(1)Psi(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) unless the pseudopepotide was administered shortly (5 min) prior to OFQ/N. This putative antagonist (6-300 nmol kg(-1)) alone increased antral motility with approximately 100 fold lower potency than OFQ/N. Neither bilateral vagotomy nor spinal cord transection altered OFQ/N-evoked increases in intragastric pressure and antral contractility. In conclusion, OFQ/N induces gastric motor excitation in addition to its known effects to increase intestinal motility. The gastric responses to OFQ/N are not dependent on 'classical' opioid receptor activation or nitric oxide, similar to the case for the intestines. The primary site of action of OFQ/N on the stomach is probably via enteric nerves, since central descending vagal or sympathetic pathways are not necessary for OFQ/N to increase gastric motility. The gastric motor effects of the derivative [Phe(1)Psi(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) are similar to OFQ/N, although with lower potency. The effects of the derivative as a partial agonist or antagonist in different experimental paradigms may reflect tissue OFQ/N receptor reserve.
Asunto(s)
Motilidad Gastrointestinal/efectos de los fármacos , Péptidos Opioides/farmacología , Fragmentos de Péptidos/farmacología , Anestesia , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Ratas Sprague-Dawley/cirugía , Traumatismos de la Médula Espinal , Vagotomía/efectos adversos , NociceptinaRESUMEN
This study examined the contribution of intrarenal alpha(2)-adrenoceptor mechanisms to the enhanced urine flow rate (V) and urinary sodium excretion (U(Na)V) responses in ketamine-xylazine-anesthetized rats. Ten minutes after left renal artery (LRA) injection, the alpha(2)-adrenoceptor antagonist yohimbine (5 microg) significantly decreased V from 58 +/- 8 to 35 +/- 7 microl. min(-1). g kidney wt(-1) and U(Na)V from 2.8 +/- 0.4 to 2.1 +/- 0.4 microeq. min(-1). g kidney wt(-1) without altering right kidney function. The renal effects of the LRA injection of yohimbine were completely abolished in chronic bilaterally renal-denervated (RDNX) rats. In RDNX rats, a higher LRA dose of yohimbine (15 microg) significantly reduced left and right kidney V, with no effects on U(Na)V. In separate bladder-catheterized rats, yohimbine (0.5 mg/kg), 20 min after intravenous injection, significantly decreased V from 63 +/- 9 to 13 +/- 2 microl. min(-1). g kidney wt(-1 )and U(Na)V from 4.5 +/- 0.5 to 1.1 +/- 0.1 microeq. min(-1). g kidney wt(-1). In RDNX rats, this dose of yohimbine reduced V and U(Na)V, but the magnitude was blunted compared with intact rats. In contrast, 0.1 mg/kg iv yohimbine significantly reduced V and U(Na)V to similar magnitudes in intact and RDNX groups. Together, these findings indicate that intravenous xylazine acts by renal nerve-dependent and -independent mechanisms to enhance renal excretory function in ketamine-anesthetized rats. Because the effects of the LRA dose of yohimbine were abolished in renal-denervated animals, it appears that xylazine has a direct renal action to augment the renal excretion of water and sodium via a presynaptic alpha(2)-adrenoceptor pathway that inhibits the release of neurotransmitters from renal sympathetic nerve terminals.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Riñón/química , Riñón/efectos de los fármacos , Receptores Adrenérgicos alfa 2/fisiología , Xilazina/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intraarteriales , Inyecciones Intravenosas , Ketamina/farmacología , Riñón/inervación , Masculino , Ratas , Ratas Wistar , Arteria Renal , Sodio/orina , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Orina , Yohimbina/farmacologíaRESUMEN
The present study investigated the role of the renal nerves in mediating the cardiovascular and renal responses produced by the central administration of the opioid-like peptide orphanin FQ/nociceptin (OFQ/N) in conscious Sprague-Dawley rats. In conscious rats, OFQ/N (10 microgram icv) produced a transient bradycardia and hypotension (nadir 20 min). Although renal sympathetic nerve activity (RSNA) initially remained unchanged, a delayed renal sympathoinhibitory response occurred after recovery (30 min) of blood pressure. By 30 and 70 min postinjection, RSNA decreased to 75 and 66% of control, respectively. Coinciding with the decrease in RSNA, central OFQ/N elicited a diuresis and antinatriuresis that occurred independent of changes in renal hemodynamics. In other studies, intracerebroventricular OFQ/N produced similar cardiovascular and renal excretory responses in bilaterally renal-denervated rats. Finally, in conscious sinoaortic deafferentiated rats, intracerebroventricular OFQ/N produced a rapid decrease in RSNA (55% of control, 10 min; 38% of control, 20 min) that paralleled the onset of the hypotension and bradycardia. These studies demonstrate that in conscious rats, intracerebroventricular OFQ/N produces a centrally mediated inhibition of RSNA which, due to activation of baroreflex mechanisms, is temporally dissociated from the hypotensive and bradycardia responses. As revealed in renal-denervated rats, the cardiovascular and renal excretory responses produced by central OFQ/N occur by a pathway that is independent of intact renal nerves or changes in renal hemodynamics.
Asunto(s)
Encéfalo/fisiología , Fenómenos Fisiológicos Cardiovasculares , Sistema Cardiovascular/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/fisiología , Péptidos Opioides/farmacología , Vasodilatadores/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Combinación de Medicamentos , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intraventriculares , Riñón/inervación , Masculino , Inhibición Neural , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , NociceptinaRESUMEN
In vitro studies have shown that [Phe1Psi(CH2-NH)Gly2]OFQ/N(1-13)-NH2 (referred to as [FG]OFQ/N(1-13)-NH2) is the first selective antagonist to prevent the binding of the endogenous ligand orphanin FQ/Nociceptin (OFQ/N) at the orphan opioid-like receptor. In the present study, we examined the potential changes in cardiovascular and renal function produced by the i.c.v. injection of [FG]OFQ/N(1-13)-NH2 in conscious Sprague-Dawley rats. In conscious rats, i.c.v. injection of [FG]OFQ/N(1-13)-NH2 produced a marked and sustained decrease in heart rate, mean arterial pressure, and urinary sodium excretion and a profound increase in urine flow rate (i.e., a water diuresis). The cardiovascular and renal excretory responses produced by i.c.v. [FG]OFQ/N(1-13)-NH2 were dose dependent and were similar in pattern but of longer duration than responses evoked by i.c.v. OFQ/N. In other animals, the i.c.v. injection of OFQ/N(1-13)-NH2, a potential metabolite of [FG]OFQ/N(1-13)-NH2, produced changes in cardiovascular and renal function that were comparable to those evoked by i.c.v. [FG]OFQ/N(1-13)-NH2. In contrast, OFQ/N(2-17), a fragment of OFQ/N [OFQ/N(1-17)], was inactive when administered centrally. Finally, studies were performed to determine whether [FG]OFQ/N(1-13)-NH2 may be an antagonist at the orphan opioid-like receptor receptor when administered centrally at a dose that alone was inactive. In these studies, i.c.v. pretreatment of animals with low-dose [FG]OFQ/N(1-13)-NH2 failed to prevent the cardiovascular and renal excretory response to i.c.v. OFQ/N. Although [FG]OFQ/N(1-13)-NH2 is reported to be an antagonist of the OFQ/N receptor in vitro, these findings indicate that this compound has agonist activity similar to that of the endogenous ligand OFQ/N when administered centrally in vivo.
Asunto(s)
Hemodinámica/efectos de los fármacos , Riñón/efectos de los fármacos , Péptidos Opioides/farmacología , Fragmentos de Péptidos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intraventriculares , Riñón/fisiología , Masculino , Péptidos Opioides/administración & dosificación , Péptidos Opioides/metabolismo , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Opioides/metabolismo , Urodinámica/efectos de los fármacos , Receptor de Nociceptina , NociceptinaRESUMEN
We have recently developed an experimental approach to study central opioid control of renal function in anesthetized rats. This model system uses the intravenous infusion of the alpha2-agonist xylazine to enhance basal levels of urine flow rate and urinary sodium excretion in ketamine-anesthetized rats. This study examined the contribution of central and peripheral alpha2-adrenergic receptor mechanisms in mediating the enhanced renal excretory responses produced by xylazine. In ketamine-anesthetized rats, the enhanced levels of urine flow rate and urinary sodium excretion produced by the intravenous infusion of xylazine were reversed by the intravenous bolus injection of the alpha2-adrenoceptor antagonist yohimbine but not by the alpha1-adrenoceptor antagonist terazosin. In separate animals the intracerebroventricular administration of yohimbine only reduced urine flow rate by approximately 50% but did not alter urinary sodium excretion. The decrease in urine flow rate produced by intracerebroventricular yohimbine was reversed by the intravenous injection of a selective V2-vasopressin receptor antagonist. In a separate group of ketamine- and xylazine-anesthetized rats, the bilateral microinjection of yohimbine into the hypothalamic paraventricular nucleus (PVN) also significantly decreased urine flow rate by 54% without altering urinary sodium excretion. The microinjection of the beta-adrenoceptor antagonist propranolol into the PVN did not alter either renal excretory parameter. These results suggest that during intravenous infusion, xylazine increases urine flow rate by activating alpha2-adrenergic receptors in the PVN, which in turn decrease vasopressin release. The ability of alpha-adrenergic mechanisms in the PVN to selectively influence the renal handling of water, but not sodium, may contribute to the reported dissociation of the natriuretic and diuretic responses of alpha2-adrenoceptor agonists.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Anestesia , Anestésicos Disociativos , Sistema Nervioso Central/metabolismo , Ketamina , Riñón/fisiología , Receptores Adrenérgicos alfa/fisiología , Xilazina/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Diuresis/efectos de los fármacos , Infusiones Intravenosas , Inyecciones Intraventriculares , Riñón/efectos de los fármacos , Masculino , Microinyecciones , Natriuresis/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Studies were performed in conscious Sprague-Dawley rats to characterize the changes in renal excretory function produced by activation of delta opioid systems. The intravenous infusion of 50 microgram/kg/min, BW373U86 (BW), a nonpeptide delta opioid receptor agonist, produced a significant increase in urine flow rate and urinary sodium excretion. The infusion of BW at a dose of 30 microgram/kg/min produced diuresis without affecting urinary sodium excretion. In contrast, BW did not alter either renal excretory parameter at a dose of 10 microgram/kg/min. The renal responses produced by BW occurred without changes in heart rate or mean arterial blood pressure. The diuretic and natriuretic responses produced by the i.v. infusion of BW (50 microgram/kg/min) were prevented by pretreatment of animals with the selective delta opioid receptor antagonist, naltrindole (1 mg/kg, i.v.). When administered alone, naltrindole (1 mg/kg, i.v.) failed to change any systemic cardiovascular or renal excretory parameter. In other groups of animals, the peripheral administration of the delta opioid receptor agonist, SNC80, also evoked a profound diuretic and natriuretic response (naltrindole sensitive) similar to that produced by BW. In contrast to these findings, the diuretic and natriuretic response produced by BW infusion (30 or 50 microgram/kg/min, i.v.) was abolished in rats having undergone chronic bilateral renal denervation. Together, these results demonstrate that the peripheral administration of BW373U86 or SNC80 produce marked diuretic and natriuretic responses in conscious Sprague-Dawley rats via a delta opioid receptor pathway and that intact renal nerves are required for mediating these responses. Although endogenous delta opioid systems do not appear to exert a tonic influence under basal conditions, these findings suggest that delta opioid pathways may evoke significant changes in renal excretory function under conditions in which these systems are activated.
Asunto(s)
Benzamidas/farmacología , Riñón/efectos de los fármacos , Piperazinas/farmacología , Receptores Opioides delta/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Animales , Benzamidas/administración & dosificación , Desnervación , Infusiones Intravenosas , Riñón/inervación , Riñón/metabolismo , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacología , Oligopéptidos/farmacología , Péptidos Opioides , Piperazinas/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
This study tests the hypothesis that nitric oxide synthase (NOS) inhibition is linked to NG-nitro-L-arginine methyl ester (L-NAME)-mediated intrauterine growth retardation (IUGR) and fetal limb reduction deficits (LRD) in pregnant dams. Administration of L-NAME (1 mg/ml) or aminoguanidine (AG, 500 micrograms/ml) in the drinking water or intraperitoneal administration of L-N5-(1-iminoethyl)-ornithine (L-NIO, 10 mg.kg-1.day-1) on gestational days 13-20 decreased nitrite and nitrate plus nitrate (RNI) levels in the urine and plasma and decreased RNI in incubates of aorta and fetal limbs compared with pregnant rats given amiloride (50 micrograms/ml) or water (control). Although all drugs caused fetal IUGR, only L-NAME and amiloride caused fetal deaths and LRD. Urine and tissue levels of RNI were unchanged in rats fed and arginine-free diet (AFD) on gestational days 13-20, and yet fetal IUGR, deaths, and LRD were prevalent. L-NAME potentiated the fetal abnormalities and resorptions. Plasma arginine concentrations decreased with AFD > > L-NAME > L-NIO. Plasma ornithine, a precursor for polyamine synthesis, decreased with AFD and increased with L-NAME. Thus inhibition of NOS is not linked to LRD. The ability of L-NAME and amiloride to produce fetal IUGR and LRD may result from L-NAME-mediated modulation of amino acid delivery to the fetus and amiloride-mediated inhibition of protein synthesis. Finally, IUGR appears unrelated to LRD.
Asunto(s)
Amilorida/farmacología , Arginina/deficiencia , Muerte Fetal , Retardo del Crecimiento Fetal/inducido químicamente , Guanidinas/toxicidad , Deformidades Congénitas de las Extremidades , NG-Nitroarginina Metil Éster/toxicidad , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ornitina/análogos & derivados , Preñez/fisiología , Anomalías Inducidas por Medicamentos , Análisis de Varianza , Animales , Femenino , Edad Gestacional , Nitratos/metabolismo , Nitritos/metabolismo , Ornitina/toxicidad , Embarazo , Preñez/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/análisisRESUMEN
This study examined the renal excretory responses produced by the intravenous (i.v.) infusion of the alpha-2 agonist, xylazine, in ketamine-anesthetized rats. In addition, the renal responses produced by the intracerebroventricular (i.c.v.) injection of opioid agonists were also examined with use of this anesthetic paradigm. In male Sprague-Dawley rats, the i.v. infusion of isotonic saline (55 microl/min) containing ketamine alone (1.0 mg/kg/min) produced low levels of urine flow rate (6.3 +/- 1.3 microl/min/gkw) and urinary sodium excretion (0.28 +/- 0.08 microeq/min/gkw). However, after adding xylazine (50 microg/kg/min) to the ketamine infusate, these renal excretory responses were significantly augmented. Steady-state levels of urine flow rate and urinary sodium excretion were attained approximately 120 min after starting the xylazine infusion and were similar in magnitude to the levels of water and sodium excretion previously observed in untreated, conscious rats. In ketamine/xylazine-anesthetized rats, the i.c.v. injection of the mu opioid agonist, dermorphin (0.1 nmol/kg), or the kappa opioid agonist, U-50488H (1 microg total), produced profound and concurrent diuretic and antinatriuretic responses. The pattern (direction and magnitude) of these opioid-induced renal excretory responses was similar to those previously reported in conscious rats. Together, these results indicate that the i.v. infusion of xylazine enhances the renal excretion of water and sodium in ketamine-anesthetized rats. Moreover, the renal responses produced by i.c.v. administration of opioids are similar in ketamine/xylazine-anesthetized and conscious rats. Thus, it appears that the ketamine/xylazine infusion protocol may provide a valid and useful approach to investigate various aspects of the central opioid control of renal function in rats during experimental procedures that require anesthesia.
Asunto(s)
Anestésicos/farmacología , Ketamina/farmacología , Oligopéptidos/farmacología , Pirrolidinas/farmacología , Xilazina/farmacología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero , Anestésicos/administración & dosificación , Animales , Fenómenos Fisiológicos Cardiovasculares , Sistema Cardiovascular/efectos de los fármacos , Infusiones Intravenosas , Inyecciones Intraventriculares , Ketamina/administración & dosificación , Riñón/efectos de los fármacos , Riñón/fisiología , Masculino , Oligopéptidos/administración & dosificación , Péptidos Opioides , Pirrolidinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Xilazina/administración & dosificaciónRESUMEN
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
The purpose of the present study was to investigate the effects of nociceptin on peripheral arterial rings from the cat. When feline renal, mesenteric, carotid and femoral rings with intact endothelium were precontracted with phenylephrine (100 nanomolar), nociceptin (3 x 10(-11)-3 x 10(-6) M) decreased tension in a concentration-dependent manner. The present data suggest nociceptin possesses biologic activity outside the CNS and may contribute to the regulation of systemic blood pressure and regional blood flow.
Asunto(s)
Arterias/fisiología , Péptidos Opioides/fisiología , Receptores Opioides/agonistas , Vasodilatación/fisiología , Animales , Gatos , Femenino , Técnicas In Vitro , Masculino , NociceptinaRESUMEN
Nociceptin (orphanin FQ) is a novel peptide isolated from brain tissue that has an amino acid sequence most similar to that of the endogenous opioid peptide dynorphin A. Aside from this similarity, the association of nociceptin to the endogenous opioid peptide systems and the functional importance of this new peptide in vivo are not completely known. Here we report that nociceptin is physiologically active in vivo and produces marked changes in the renal excretion of water and sodium. In conscious Sprague-Dawley rats, intravenous infusion of nociceptin produced a profound increase in urine flow rate and decrease in urinary sodium excretion. In further studies, intracerebroventricular (i.c.v.) injection of nociceptin into conscious rats produced a concurrent diuresis (dose-dependent) and antinatriuresis. The magnitude and pattern of the central nociceptin-induced water diuresis was similar to that produced by i.c.v. dynorphin A. Whereas i.c.v. pretreatment with the selective kappa-opioid receptor antagonist, nor-binaltorphimine, completely prevented the renal responses produced by dynorphin A, this antagonist did not alter the diuresis or antinatriuresis produced by central nociceptin. Thus, these results indicate that in conscious rats, nociceptin produces a selective water diuresis via a central nervous system mechanism independent of kappa-opioid receptors. Together, these observations suggest that endogenous nociceptin may be a novel peptide involved in the central control of water balance and ultimately in the regulation of arterial blood pressure. In the future, analogues of nociceptin may prove to be the first clinically useful water diuretics for patients with water-retaining diseases.
Asunto(s)
Diuréticos/farmacología , Natriuresis/efectos de los fármacos , Péptidos Opioides/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Diuresis/efectos de los fármacos , Diuréticos/administración & dosificación , Dinorfinas/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Infusiones Intravenosas , Inyecciones Intraventriculares , Masculino , Péptidos Opioides/administración & dosificación , Ratas , Ratas Sprague-Dawley , Micción/efectos de los fármacos , NociceptinaRESUMEN
1. Over the past 50 years considerable evidence has been reported suggesting that endogenous opioids participate in the control of renal function. 2. Exogenous administration of opioids produces profound changes in the renal excretion of water and sodium. 3. Opioids produce changes in urine output and urine sodium excretion by multiple integrated neural and hormonal mechanisms within the periphery, central nervous system and kidneys. 4. Although opioid antagonist administration does not consistently reveal an action of endogenous opioid systems on renal function, this may result from the quiescent nature of the endogenous opioid system under basal conditions. 5. Manipulations that activate endogenous opioid systems have begun to reveal important, previously unrecognized mechanisms that control kidney function and can enhance renal tubular sodium reabsorption in normal and potentially pathological states.
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Riñón/efectos de los fármacos , Narcóticos/farmacología , Animales , Diuréticos/farmacología , Humanos , Receptores Opioides kappa/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacos , Micción/efectos de los fármacosRESUMEN
To determine the effects of kappa-opioid receptor agonists on phosphoinositide metabolism in rat renal cortex, tissue slices labelled with [3H]inositol were stimulated with norepinephrine or carbachol alone or in combination with the kappa-opioid receptor agonists, ethylketocyclazocine, trans-3,4-dichloro-N-methyl-N-[2-(pyrrolindinyl)-cyclohexyl)- benzeneacetamide (U50,488) and nalorphine. Both norepinephrine and carbachol stimulated phosphoinositide hydrolysis (measured in a LiCl buffer) concentration- and time-dependently. The EC50 and maximal stimulation of phosphoinositide hydrolysis for norepinephrine and carbachol were approximately 3 microM and 0.15 dpm released/dpm incorporated, respectively. Concentrations up to 1 mM of ethylketocyclazocine, U50,488 or nalorphine alone did not affect phosphoinositide hydrolysis. However, ethylketocyclazocine and U50,488 decreased 10 microM norepinephrine-stimulated phosphonositide hydrolysis concentration-dependently, each with an approximate IC50 of 30 microM. In contrast, nalorphine had no effect on norepinephrine-stimulated phosphoinositide hydrolysis. In addition, concentrations of up to 1 mM ethylketocyclazocine or U50,488 did not alter carbachol-stimulated phosphoinositide hydrolysis. The inhibitory effect of U50,488 and ethylketocyclazocine on norepinephrine-stimulated phosphoinositide hydrolysis was blocked by the selective kappa-opioid receptor antagonist, nor-binaltorphimine. These results indicate that kappa 1-opioid receptor stimulation may affect phosphoinositide metabolism in rat renal cortex by modulating the subcellular effects of renal alpha 1-adrenoceptor activation.
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Corteza Renal/metabolismo , Fosfatidilinositoles/metabolismo , Receptores Opioides kappa/agonistas , Animales , Carbacol/farmacología , Etilcetociclazocina/farmacología , Hidrólisis , Técnicas In Vitro , Corteza Renal/efectos de los fármacos , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacología , Norepinefrina/farmacología , Ratas , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Estimulación QuímicaRESUMEN
Central administration of kappa opioids produce significant alteration in the renal excretion of sodium and water under basal conditions. To determine whether enhanced central kappa opioid activity alters the renal handling of sodium and water to an integrated physiological stimuli, we compared the renal excretory responses produced by acute i.v. isotonic saline volume expansion in conscious Sprague-Dawley rats pretreated with i.c.v. isotonic saline vehicle or the selective kappa opioid agonist, U-50488H. In vehicle-treated animals, isotonic saline volume expansion produce an increase in urine flow rate and urinary sodium excretion and a decrease in efferent renal sympathetic nerve activity. In comparison with these control responses, isotonic saline volume expansion produced a similar magnitude change in urine flow rate in rats pretreated i.c.v. with U-50488H. In contrast, the natriuretic response produced by the isotonic saline load was markedly blunted in these central kappa opioid-treated animals. Moreover, the sympathoinhibitory response characteristically produced by the isotonic saline volume expansion was completely prevented in animals receiving i.c.v. U-50488H. To elucidate further the role of the renal nerves in mediating this central kappa opioid-induced renal excretory response, these studies were repeated in chronic bilaterally renal denervated rats. The results of these studies demonstrated that bilateral renal denervation restored the capacity of i.c.v. U-50488H-pretreated rats to maximally excrete the sodium load. Together, these studies demonstrate that, in conscious Sprague-Dawley rats, increased central kappa opioid activity significantly blunts the natriuretic response to isotonic saline volume expansion by a renal nerve-dependent mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Encéfalo/fisiología , Riñón/metabolismo , Pirrolidinas/farmacología , Receptores Opioides kappa/fisiología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero , Animales , Agua Corporal/metabolismo , Desnervación , Riñón/inervación , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/agonistas , Sodio/metabolismoRESUMEN
The cobalt atom of hydroxocobalamin (OHC) binds cyanide and nitric oxide (NO) and OHC attenuates vascular responses to NO in vitro. NO mediates the hypotension of endotoxemia. Thus, we tested the postulate that OHC may attenuate the acute phase hypotension and toxicity associated with administration of Escherichia coli endotoxin (LPS). Rats were given OHC (20 mg/kg i.v.) or phosphate-buffered saline (PBS, 1 ml/kg i.v.) 30 min before or 15 min after giving LPS (0.8 mg/kg i.v.). Administration of OHC to PBS-treated control rats did not affect mean arterial pressure (MAP), heart rate or the plasma or urine content of the reactive nitrogen intermediates nitrate and nitrite (RNI). LPS decreased MAP by 50 mm Hg in PBS-treated rats and increased the plasma and urinary content of RNI. Administration of OHC to PBS-treated rats did not affect MAP or RNI. However, treatment with OHC before or after giving LPS attenuated LPS-induced hypotension and increases in plasma RNI and enhanced LPS-induced urinary excretion of RNI. OHC (20 mg/kg i.p.) or cyanocobalamin (10 mg/kg i.p.) given to Swiss-Webster mice 30 min before giving LPS (16 mg/kg i.p.) decreased the 24-hr mortality of LPS from 80 to 50% and the 36- and 96-hr mortality from 100 to 60% (OHC) or 70% (cyanocobalamin). Urine obtained from conscious rats given LPS (5 mg/kg i.p.) and OHC (20 mg/kg i.p.) exhibited a UV-visible absorbance spectrum with absorbance peaks characteristic of that formed after coincubation of NO and OHC.(ABSTRACT TRUNCATED AT 250 WORDS)
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Hidroxocobalamina/farmacología , Hipotensión/prevención & control , Lipopolisacáridos/toxicidad , Óxido Nítrico/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Masculino , Ratones , Mortalidad , Óxido Nítrico/análisis , Ratas , Ratas Sprague-Dawley , Espectrofotometría , Vitamina B 12/análisisRESUMEN
The role of endogenous central opioids in the regulation of renal function was studied in Sprague-Dawley rats. In metabolism studies, changes in sodium balance were examined during normal dietary sodium intake (days 1-7; Na+ of 174 meq/kg) and sodium restriction (days 8-14; Na+ of 4.0 meq/kg). The influence of endogenous central opioids was investigated by repeating the protocol in the same rats during intracerebroventricular infusion of the opioid antagonist naltrexone methylbromide (NMBR). Intracerebroventricular NMBR did not alter sodium balance in rats fed normal sodium chow. In contrast, on low-sodium days 8 and 9, rats exhibited a more negative sodium balance during intracerebroventricular NMBR (day 8; -1,191 +/- 37 mu eq) compared with respective predrug control levels (day 8; -641 +/- 39 mu eq). Subcutaneous NMBR did not alter renal adaptation to sodium restriction. Thus central opioids are not involved in the maintenance of sodium balance during normal sodium intake. However, when dietary sodium is restricted, central opioid pathways are activated as a mechanism to maximally retain sodium.
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Natriuresis/fisiología , Péptidos Opioides/fisiología , Sodio/metabolismo , Adaptación Fisiológica/efectos de los fármacos , Animales , Inyecciones Intraventriculares , Riñón/efectos de los fármacos , Riñón/fisiología , Masculino , Naltrexona/administración & dosificación , Naltrexona/análogos & derivados , Antagonistas de Narcóticos/administración & dosificación , Natriuresis/efectos de los fármacos , Péptidos Opioides/antagonistas & inhibidores , Compuestos de Amonio Cuaternario , Ratas , Ratas Sprague-Dawley , Sodio en la Dieta/administración & dosificación , Equilibrio Hidroelectrolítico/efectos de los fármacos , Equilibrio Hidroelectrolítico/fisiologíaRESUMEN
Central administration of the selective mu opioid agonist, dermorphin, produces a concurrent diuretic and antinatriuretic response in conscious rats. To determine whether central mu opioids differentially affect the renal excretion of water and sodium, we examined changes in renal function produced by intracerebroventricular (i.c.v.) administration of dermorphin during continuous intravenous (i.v.) infusion of a synthetic ADH analogue in conscious Sprague-Dawley rats. During ADH infusion the typical diuresis produced by i.c.v. dermorphin was abolished although the antinatriuresis remained intact. Alone, i.v. ADH produced a decrease in urine flow rate without significantly altering urinary sodium excretion. In other studies, the effects of i.c.v. dermorphin were examined on the renal responses produced by i.v. infusion of a V2-ADH receptor antagonist. In these studies the magnitude of the V2 antagonist-induced diuresis was not altered by i.c.v. dermorphin but the increase in urinary sodium excretion produced by this antagonist was converted to an antinatriuresis. Central dermorphin did not alter heart rate or mean arterial pressure in either study. These findings suggest that the effects of central dermorphin on renal sodium and water handling are mediated by separate mechanisms; the effects on water involving changes in circulating ADH levels and the effects on sodium independent of the action of this hormone.