RESUMEN
A new type soluble guanylyl cyclase, designated as ksGC (kinase-like domain containing soluble guanylyl cyclase), was identified from a kidney cDNA library. By Northern blot analysis, expression of this novel guanylyl cyclase mRNA was found in lung, kidney and skeletal muscle. Although ksGC is a soluble type guanylyl cyclase, it is not a member of soluble alpha or beta guanylyl cyclases. The ksGC contains in its N-terminal region a protein kinase-like domain, which is usually a characteristic feature only of particulate type guanylyl cyclases. This unique feature of ksGC suggests a novel pathway of cGMP synthesis.
Asunto(s)
Guanilato Ciclasa/química , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Cartilla de ADN/química , Expresión Génica , Guanilato Ciclasa/genética , Riñón/enzimología , Datos de Secuencia Molecular , ARN Mensajero/genética , Ratas , Alineación de Secuencia , Homología de Secuencia de Aminoácido , SolubilidadRESUMEN
1. To search for a possible role for endothelin-1 (ET-1) in deoxycorticosterone acetate (DOCA)-salt-induced hypertension, we examined changes in concentration of ET-1 in vascular and renal tissue in DOCA-salt hypertensive rats and evaluated the antihypertensive effect of the ETA receptor antagonist, FR139317. 2. There was an increase in aortic immunoreactive-ET (IR-ET) concentrations in association with hypertension-induced treatment. There were no significant changes in ET-1 levels in the kidney with DOCA-salt treatment. 3. In DOCA-salt hypertensive rats, a significant correlation (r = 0.83, P < 0.01) was found between aortic IR-ET concentrations and systolic blood pressure. 4. High-performance liquid chromatography analysis of the aortic extract from DOCA-salt rats revealed one major component corresponding to the elution position of synthetic ET-1. 5. The intravenous bolus injection of FR139317 (10 mg kg-1) produced a slight decrease in blood pressure in the control rats and in the DOCA-salt hypertensive rat, FR139317 had a more pronounced hypotensive effect. 6. We propose that ET-1 production in vascular tissues is increased in DOCA-salt hypertensive rats. In addition, our study indicates the pathophysiological importance of increased endogenous ET-1 in the maintenance of DOCA-salt-induced hypertension, through interaction of the peptide with ETA receptors.
Asunto(s)
Desoxicorticosterona , Endotelinas/fisiología , Hipertensión/fisiopatología , Receptores de Endotelina/fisiología , Animales , Aorta Torácica/metabolismo , Azepinas/farmacología , Presión Sanguínea/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Antagonistas de los Receptores de Endotelina , Endotelinas/metabolismo , Hipertensión/inducido químicamente , Indoles/farmacología , Riñón/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Vasoconstricción/efectos de los fármacosRESUMEN
We investigated the intrarenal conversion of big endothelin-1 (ET-1) to ET-1 in the isolated perfused rat kidney. Big ET-1 caused a concentration-dependent increase in perfusion pressure, and the pressor molar potency of the peptide was 50-fold less than that of ET-1. The big ET-1 (2 x 10(-8) mol/L)-induced pressor action was accompanied by increases in immunoreactive endothelin levels in both the perfusate and renal tissues. Phosphoramidon (10(-4) mol/L), a metalloproteinase inhibitor, significantly suppressed the big ET-1-induced pressor action and the accumulation of immunoreactive endothelin in renal tissues. On the other hand, phosphoramidon slightly but significantly sustained the ET-1-induced pressor effect. The effect of kelatorphan (10(-4) mol/L), a specific inhibitor of neutral endopeptidase 24.11, on the ET-1-induced pressor effect was the same as that seen with phosphoramidon. When ET-1 was exogenously added to the perfusate, phosphoramidon or kelatorphan significantly increased the immunoreactive endothelin levels in renal tissues after perfusion, without affecting the disappearance rate of immunoreactive endothelin from the perfusate. Therefore, the phosphoramidon-sensitive ET-1-converting enzyme in the kidney seems to contribute to the functional local conversion of big ET-1 to ET-1, and neutral endopeptidase 24.11 may be responsible for the proteolytic degradation of ET-1 in the kidney. In addition, immunoreactive endothelin levels in renal tissues but not in the perfusate can account for the functional conversion of big ET-1 to ET-1 and for the local proteolytic degradation of ET-1 in the kidney.
Asunto(s)
Endotelinas/metabolismo , Glicopéptidos/farmacología , Riñón/metabolismo , Neprilisina/antagonistas & inhibidores , Animales , Ácido Aspártico Endopeptidasas/fisiología , Presión Sanguínea/efectos de los fármacos , Enzimas Convertidoras de Endotelina , Endotelinas/farmacología , Masculino , Metaloendopeptidasas , Perfusión , Ratas , Ratas Sprague-DawleyRESUMEN
We examined the involvement of endogenous nitric oxide (NO) in noradrenergic neurotransmission and renal function in anesthetized dogs, by using NG-nitro-L-arginine (NOARG), a NO synthase inhibitor. Renal nerve stimulation (RNS) produced the frequency-dependent increase in the rate of norepinephrine secretion. The low frequency RNS (0.5-2.0 Hz) decreased urine flow and urinary excretion of sodium, without affecting renal hemodynamics. High frequency RNS (2.5-5.0 Hz) caused a more potent antidiuresis and renal vasoconstriction that resulted in reductions in renal blood flow and glomerular filtration rate. Intrarenal arterial infusion of NOARG, at a dose (10 micrograms/kg/min) which had no effect on renal hemodynamics, significantly enhanced the RNS-induced reductions of urine formation and renal vasoconstriction and increments in norepinephrine secretion rate. Qualitatively similar results were observed with a higher dose of NOARG (40 micrograms/kg/min), although this dose did decrease basal levels of renal blood flow and urine flow. Enhancement of NOARG on RNS-induced actions was abolished by the simultaneous administration of L-arginine. Endogenous NO probably has a role as inhibitory modulator of renal noradrenergic neurotransmission.
Asunto(s)
Aminoácido Oxidorreductasas/antagonistas & inhibidores , Arginina/análogos & derivados , Diuresis/efectos de los fármacos , Riñón/fisiología , Óxido Nítrico/fisiología , Norepinefrina/metabolismo , Animales , Arginina/farmacología , Perros , Estimulación Eléctrica , Femenino , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Riñón/inervación , Masculino , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Vasoconstricción/efectos de los fármacos , omega-N-MetilargininaRESUMEN
We examined conversion of Big endothelin-1 (ET-1) to mature ET-1 and pressor action during perfusion of the isolated perfused rat lung with Big ET-1. Big ET-1 caused a concentration-related increase in perfusion pressure and the pressor molar potency of the peptide was fivefold less than that of ET-1. Pressor responses to Big ET-1 were accompanied by an increase in immunoreactive-ET (IR-ET) levels in the perfusate and in the lung tissues. Pretreatment with phosphoramidon (10(-4) M), a metalloproteinase inhibitor, markedly suppressed the pressor action and increment in IR-ET in the tissues. Unexpectedly, the amount of IR-ET in the perfusate during perfusion of Big ET-1 was not influenced by phosphoramidon treatment. On the other hand, chymostatin, an inhibitor of chymotrypsin-like enzymes, effectively suppressed IR-ET levels in the perfusate; however, this enzyme inhibitor was without effect on the pressor action of Big ET-1 or on the increase in IR-ET levels in lung tissues. We tentatively conclude that the phosphoramidon-sensitive conversion of Big ET-T to ET-1 is linked to the pressor action of Big ET-1 in the isolated perfused rat lung. In addition, it seems likely that chymostatin-sensitive conversion of Big ET-1 to ET-1 does not play a major role in the conversion of the precursor to the mature form. We propose that IR-ET present in the tissues rather than that in the perfusate is a better indicator of the functional conversion of Big ET-1 in the rat lung.
Asunto(s)
Ácido Aspártico Endopeptidasas/metabolismo , Endotelinas/metabolismo , Endotelinas/farmacología , Glicopéptidos/farmacología , Pulmón/fisiología , Metaloendopeptidasas/antagonistas & inhibidores , Circulación Pulmonar/fisiología , Animales , Quimotripsina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Endotelina-1 , Enzimas Convertidoras de Endotelina , Técnicas In Vitro , Cinética , Pulmón/efectos de los fármacos , Pulmón/enzimología , Masculino , Oligopéptidos/farmacología , Perfusión , Precursores de Proteínas/metabolismo , Circulación Pulmonar/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
We compared the pressor response to endothelin-1 (ET-1) with that of big endothelin-1 (big ET-1) in mesenteric arteries, hindquarters and lungs of rats. In these three preparations, both peptides caused a concentration-dependent increase in the perfusion pressure. The ratio of big ET-1 concentration to ET-1 concentration needed for causing the same pressor action is different between organs; i.e., a mesentery >> a hindquarter > or = a lung. Exposure to phosphoramidon, a metalloproteinase inhibitor, significantly suppressed the pressor response to big ET-1, in a similar fashion. This suppression is likely to be due to the inhibition of phosphoramidon-sensitive endothelin converting enzyme, since the inhibitor does not suppress an action of ET-1. Apparently there is a difference in potency for phosphoramidon-sensitive vasoconstriction of big ET-1 between organs and presumably regional differences in the functional phosphoramidon-sensitive conversion of big ET-1 in vasculatures.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Endotelinas/farmacología , Miembro Posterior/irrigación sanguínea , Pulmón/irrigación sanguínea , Arteria Mesentérica Superior/efectos de los fármacos , Precursores de Proteínas/farmacología , Animales , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Endotelina-1 , Enzimas Convertidoras de Endotelina , Glicopéptidos/farmacología , Masculino , Metaloendopeptidasas , Perfusión , Ratas , Ratas Sprague-Dawley , Vasoconstricción/efectos de los fármacosRESUMEN
Intravenous (i.v.) or intrarenal arterial (i.r.a.) injection of big endothelin-1 (big ET-1) (1.6 nmol/kg) in anesthetized rats produced a significant increase in mean arterial pressure (MAP), a decrease in renal blood flow (RBF) and an increase in renal vascular resistance (RVR). Although the pressor responses to big ET-1 of i.v. and i.r.a. injection were not significantly different, i.r.a. injection of big ET-1 caused a significantly greater reduction in RBF than that seen with i.v. injection of big ET-1. The effects of i.r.a. injection of the peptide on MAP and RBF were markedly suppressed by phosphoramidon. Big ET-1 caused dose-dependent pressor effects in isolated perfused rat kidney and these pressor effects were significantly suppressed by phosphoramidon. Thus, renal vasculature possesses a phosphoramidon-sensitive endothelin converting enzyme, which may play an important role for the renal hemodynamic regulation.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Endotelinas/metabolismo , Riñón/irrigación sanguínea , Precursores de Proteínas/metabolismo , Circulación Renal/efectos de los fármacos , Animales , Endotelina-1 , Endotelinas/administración & dosificación , Endotelinas/farmacología , Glicopéptidos/farmacología , Técnicas In Vitro , Inyecciones Intravenosas , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Precursores de Proteínas/administración & dosificación , Precursores de Proteínas/farmacología , Ratas , Ratas Sprague-Dawley , Resistencia Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
We asked whether or not the endothelium plays a functional role in the conversion of big endothelin-1 to endothelin-1 in the perfused rat mesenteric artery. In endothelium-denuded preparations, big endothelin-1 produced a much more potent pressor effect than in intact preparations. Phosphoramidon suppressed the big endothelin-1-induced pressor action without affecting the action of endothelin-1, irrespective of the presence or absence of the endothelium. The amounts of immunoreactive-endothelin in the perfusate during perfusion of endothelium-denuded preparations with big endothelin-1 were extremely low compared with those observed in intact preparations and were not significantly suppressed by the metalloproteinase inhibitor, phosphoramidon, in contrast to the case with intact preparations. When synthetic endothelin-1 was perfused in the endothelium-denuded mesentery, the peptide disappeared from the perfusate more rapidly than with intact preparations, suggesting that endothelin-1 generated from big endothelin-1 is effectively trapped by vascular smooth muscle cells in the endothelium-denuded preparation. Our results suggest that the endothelium is not essential for the conversion of big endothelin-1 to endothelin-1, in rat mesenteric artery.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Endotelinas/farmacología , Endotelio Vascular/fisiología , Glicopéptidos/farmacología , Arteria Mesentérica Superior/fisiología , Neprilisina/antagonistas & inhibidores , Precursores de Proteínas/farmacología , Animales , Carbacol/farmacología , Ácidos Cólicos/farmacología , Cromatografía Líquida de Alta Presión , Endotelina-1 , Endotelinas/antagonistas & inhibidores , Técnicas In Vitro , Masculino , Arteria Mesentérica Superior/efectos de los fármacos , Norepinefrina/farmacología , Perfusión , Precursores de Proteínas/antagonistas & inhibidores , Radioinmunoensayo , Ratas , Ratas Sprague-DawleyRESUMEN
A neutral proteinase with endothelin (ET)-1 converting activity was identified in cytosol and membrane fractions prepared from rat lung, in a ratio of 1:4, respectively. The membrane-bound proteinase was solubilized by 0.5% 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate (CHAPS) with an increase in specific activity, and then was characterized. The solubilized proteinase was capable of converting big ET-1 to ET-1 with an optimum pH of 6.5, and the conversion was dose-dependently suppressed by phosphoramidon (IC50 = 0.5 microM). The molecular mass of the proteinase was estimated to be about 500 kDa by gel filtration in the presence of 0.5% CHAPS. These results indicate that rat lung contains a phosphoramidon-sensitive neutral proteinase catalyzing conversion of big ET-1 to ET-1. The proteinase may be involved in the biosynthetic pathway of ET-1 in the lung and/or the conversion of circulating big ET-1.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Pulmón/enzimología , Animales , Ácido Aspártico Endopeptidasas/aislamiento & purificación , Ácidos Cólicos , Enzimas Convertidoras de Endotelina , Endotelinas , Glicopéptidos/farmacología , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Masculino , Membranas/enzimología , Metaloendopeptidasas , Peso Molecular , Ratas , SolubilidadRESUMEN
The effect of phosphoramidon, a metalloproteinase inhibitor, on the pressor response to big endothelin-1 (big ET-1) in the isolated perfused rat mesenteric artery was examined. Big ET-1 (10(-9)-10(-7) M) caused a concentration-dependent increase in the perfusion pressure. The pressor response was markedly suppressed by phosphoramidon (10(-5) M). The inhibitor did not influence the ET-1 (5 X 10(-11)-10(-8) M)-induced pressor action. Big ET-1 (5 X 10(-8) M)-induced pressor action was accompanied by an increase in immunoreactive (IR)-ET in the perfusate, and this increase was suppressed by the addition of phosphoramidon. IR-ET in the perfusate was confirmed to be ET-1, as determined by reverse-phase HPLC. These findings strongly suggest that phosphoramidon-sensitive metalloproteinase contributes to the conversion of big ET-1 to ET-1, in vivo.
Asunto(s)
Endotelinas/farmacología , Glicopéptidos/farmacología , Arterias Mesentéricas/fisiología , Músculo Liso Vascular/fisiología , Precursores de Proteínas/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Animales , Antibacterianos/farmacología , Cromatografía Líquida de Alta Presión , Endotelina-1 , Endotelinas/genética , Endotelinas/aislamiento & purificación , Endotelinas/metabolismo , Técnicas In Vitro , Cinética , Masculino , Arterias Mesentéricas/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Perfusión , Precursores de Proteínas/metabolismo , Ratas , Ratas EndogámicasRESUMEN
When big endothelin-1 (big ET-1, 1-39) was incubated with the membrane fraction obtained from cultured endothelial cells (ECs) at pH 7.0 for 6 h, the immunoreactive (ir) ET in the reaction mixture was markedly increased. Phosphoramidon, a metalloproteinase inhibitor, as well as metal chelators specifically suppressed the above increase. Using reverse-phase high-performance liquid chromatography, ir-ET was confirmed to be ET-1[1-21]. In addition, we noted that the alterations in ET-1 correlated with those in the C-terminal fragment (CTF, 22-39) of big ET-1. When cultured ECs were incubated with phosphoramidon, time-dependent secretion of ET-1 and CTF from the cells was markedly suppressed. In contrast, the secretion of big ET-1 was increased by phosphoramidon. Thiorphan, a specific inhibitor of neutral endopeptidase 24.11, was without effect on the secretion of ET-related peptides. Moreover, phosphoramidon potently inhibited the hypertensive effect of big ET-1 without affecting the ET-1-induced hypertension in anesthetized rats. From these findings, it seems reasonable to consider that phosphoramidon-sensitive and membrane-bound metalloproteinase, which is not a neutral endopeptidase 24.11, is the most plausible candidate for big ET-1-converting enzyme in vivo.
Asunto(s)
Endotelinas/metabolismo , Endotelio/enzimología , Glicopéptidos/farmacología , Metaloendopeptidasas/metabolismo , Precursores de Proteínas/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/enzimología , Células Cultivadas , Cromatografía Líquida de Alta Presión , Endotelina-1 , Endotelio/citología , Masculino , Membranas/efectos de los fármacos , Membranas/enzimología , Metaloendopeptidasas/antagonistas & inhibidores , Ratas , Ratas EndogámicasRESUMEN
Intravenous (i.v.) injection of big endothelin-1 (1-39, 0.05-1.0 nmol/kg) to anaesthetized rats produced a dose-dependent and long-lasting hypertensive effect, the magnitude of which was similar to that evoked by ET-1 (1-21). In animals given phosphoramidon (0.25 mg/kg per min i.v.), a metalloproteinase inhibitor, the hypertensive effect of big endothelin-1 was markedly attenuated. The same dose of phosphoramidon did not influence the endothelin-1-induced hypertensive effect. The possibility that big endothelin-1 is converted to endothelin-1 by a phosphoramidon-sensitive metalloproteinase in vivo warrants further attention.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Endotelinas/antagonistas & inhibidores , Glicopéptidos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Precursores de Proteínas/antagonistas & inhibidores , Anestesia , Animales , Relación Dosis-Respuesta a Droga , Endotelina-1 , Endotelinas/farmacología , Inyecciones Intravenosas , Masculino , Precursores de Proteínas/farmacología , Ratas , Ratas EndogámicasRESUMEN
The effects of BRL 34915, a newly developed potassium channel opener, on renal hemodynamics and function were investigated in anesthetized dogs. An i.v. injection of BRL 34915 (4, 20 and 100 micrograms/kg) caused a dose-related reduction of mean arterial pressure but there were no significant changes in renal blood flow. The agent at lower doses (4 and 20 micrograms/kg) produced a slight increasing action on urine formation. When BRL 34915 was infused intrarenally at nonhypotensive doses (0.04 and 0.2 micrograms/kg/min), there were no significant increases in renal blood flow and glomerular filtration rate. At 1.0 micrograms/kg/min, a dose which produced a slight reduction in mean arterial pressure, significant decreases in calculated renal vascular resistance were observed, thereby indicating that BRL 34915 has vasodilator action on the renal vasculature. In cases of infusion at higher doses (0.2 and 1.0 micrograms/kg/min), the levels of urine flow, urinary excretion of sodium and fractional excretion of sodium were elevated significantly and these events were accompanied by decreases in urine osmolality. Although the intrarenal administration of BRL 34915 at higher doses produced no alterations in the fractional excretion of lithium (index of sodium excretion at the proximal tubules), the agent did increase the calculated value of the fractional distal excretion of sodium. These effects seen when BRL 34915 was infused intrarenally were suppressed markedly by glibenclamide (6 mg/kg i.v.), a putative inhibitor of the ATP-sensitive potassium channel. Our results suggest that BRL 34915 has renal vasodilating and diuretic effects as a result of opening the potassium channels within the kidney. The agent-induced diuresis may be due partly to an inhibitory effect on sodium reabsorption at the distal portion of the tubules beyond the proximal tubules.
Asunto(s)
Benzopiranos/farmacología , Riñón/efectos de los fármacos , Parasimpatolíticos/farmacología , Pirroles/farmacología , Animales , Cromakalim , Perros , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Gliburida/farmacología , Hemodinámica/efectos de los fármacos , Inyecciones Intravenosas , Riñón/metabolismo , Masculino , Pentobarbital , Circulación Renal/efectos de los fármacosRESUMEN
A synthetic amino acid, L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), can be converted to (-)-norepinephrine (NE) by aromatic L-amino acid decarboxylase (AADC) in various mammalian tissues. Recent studies have indicated the pressor and diuretic effects of L-threo-DOPS. In this study, we examined the effects of L-threo-DOPS on renal hemodynamics and function in anesthetized rats, and evaluated possible mechanisms of the diuresis. Intravenous infusion of L-threo-DOPS at 120 micrograms/kg/min exerted a significant increase in mean arterial pressure (MAP). There was a slight but nonsignificant decrease in renal blood flow (RBF). Although the glomerular filtration rate (GFR) remained at a constant level, urine flow (UF) and urinary sodium excretion (UNaV) increased significantly during the drug infusion. Pretreatment with AADC inhibitor, benserazide, completely blocked both the pressor and diuretic effects of L-threo-DOPS. When the renal perfusion pressure was protected from the pressor effect of the drug by using a Blalock clamp, the drug-induced diuresis was abolished. The diuretic effect of L-threo-DOPS was markedly attenuated by the administration of phentolamine. There was a positive correlation between plasma NE concentration and UF during the infusion of L-threo-DOPS. Intrarenal arterial infusion of L-threo-DOPS at 20 micrograms/kg/min was without effect on renal function. These results indicate that diuresis and natriuresis induced by L-threo-DOPS are dependent on the pressor effect of NE via peripheral alpha-adrenoceptor activation.
Asunto(s)
Diuréticos/farmacología , Droxidopa/farmacología , Serina/análogos & derivados , Anestesia , Animales , Inhibidores de Descarboxilasas de Aminoácidos Aromáticos , Benserazida/farmacología , Presión Sanguínea/efectos de los fármacos , Droxidopa/administración & dosificación , Tasa de Filtración Glomerular/efectos de los fármacos , Infusiones Intraarteriales , Infusiones Intravenosas , Masculino , Norepinefrina/sangre , Fentolamina/farmacología , Ratas , Ratas Endogámicas , Circulación Renal/efectos de los fármacosRESUMEN
Renal effects of CV-4093, a newly developed dihydropyridine calcium channel blocker, were examined using anesthetized stroke-prone spontaneously hypertensive rats, and the findings were compared with those of nicardipine. An intravenous injection of CV-4093 (2 micrograms/kg) produced long-lasting hypotension with a slow-onset accompanied by moderate renal vasodilation. There were no appreciable alterations in glomerular filtration rate (GFR) and urine formation, except that urine flow (UF) increased significantly during the first 10 min after injection. When CV-4093 was administered at 10 micrograms/kg, the hypotensive action was markedly augmented. Eighty minutes after the injection, a decrease in mean arterial pressure of about 45 mmHg was observed. Simultaneously, renal blood flow increased significantly from the control value of 5.76 +/- 0.46 ml/g.min to 6.94 +/- 0.28 ml/g.min. Renal vascular resistance decreased immediately after the injection, and the response lasted for over 3 hr, thereby indicating the marked and sustained renal vasodilating effect of CV-4093. GFR was constant throughout the experiment, but UF and urinary excretion of sodium were increased significantly. Fractional excretion of sodium was also elevated, thereby suggesting an inhibitory action of CV-4093 on renal tubular reabsorption of sodium. Nicardipine at a dose of 10 micrograms/kg, a dose producing an effective hypotensive action, caused no significant increases in RBF and urine formation. The renal vasodilating and diuretic actions of CV-4093 may provide a beneficial effect in the treatment of hypertension.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Trastornos Cerebrovasculares/fisiopatología , Dihidropiridinas/farmacología , Hipertensión/fisiopatología , Circulación Renal/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Dihidropiridinas/administración & dosificación , Hemodinámica/efectos de los fármacos , Inyecciones Intravenosas , Pruebas de Función Renal , Masculino , Nicardipino/administración & dosificación , Nicardipino/farmacología , Nitrobencenos , Tamaño de los Órganos/efectos de los fármacos , Piperazinas , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Urodinámica/efectos de los fármacosRESUMEN
The infusion of endothelin into the renal artery of anesthetized rats at 1 ng/kg per min, a dose with no influence on renal function, had no effect on the basal levels of plasma renin activity (PRA) and renin secretory rate (RSR), but significantly inhibited the isoproterenol-induced increases in PRA and RSR. Endothelin, 2 ng/kg per min, elicited significant decreases in renal hemodynamics and in urine formation but the mean arterial pressure was not affected. The possibility that endothelin may participate in controlling renal function and renin secretion in vivo warrants further attention.