Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
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In summary, many lines of evidence indicate that the sympathetic nervous system, via the renal nerves, plays an important role in the pathogenesis of renovascular hypertension in humans and laboratory animals. Patients with established renovascular hypertension have increased sympathetic nervous system activity, as evidenced by increased plasma and urinary norepinephrine levels, elevated excretion of catecholamine metabolites, and an exaggerated depressor response to centrally acting sympatholytic agents. The observation that converting enzyme inhibitors can cause both blood pressure and urinary norepinephrine excretion to return to normal in patients with renovascular hypertension is consistent with the interpretation that activation of the sympathetic nervous system in these subjects is, at least in part, angiotensin-induced. The sympathetic nervous system, via the efferent renal nerves, plays a role in the pathogenesis of hypertension in a number of experimental models. In the spontaneously hypertensive rat of the Okamoto strain (SHR) and in the DOCA/NaCl hypertensive model, increased renal efferent nerve activity contributes to the development of hypertension by causing increased renal sodium retention. In both of these experimental models, renal denervation delays the development and blunts the severity of hypertension. This delay is associated with increased urinary sodium excretion, suggesting a renal efferent mechanism. In contrast to the predominantly efferent renal nerve mechanisms observed in the DOCA-NaCl and SHR models, studies of the effects of renal denervation in one-kidney, one-clip and two-kidney, one-clip Goldblatt hypertensive rats suggest that renal afferent nerves are important in these models of hypertension. Total renal denervation in rats with established 1K, 1C and 2K, 1C hypertension attenuates the severity of the hypertension without altering sodium intake or excretion, renin activity, water intake, or renal function. Thus, efferent renal nerve activity does not appear to be involved in the development of maintenance of 1K, 1C or 2K, 1C hypertension. In contrast with the findings in SHR and DOCA-NaCl rats, these studies provide indirect evidence that the renal afferent nerves play a role in the pathogenesis of this form of experimental hypertension. The major effect of renal denervation in these models appears to be an interruption of renal afferent nerve activity, which by a direct feedback mechanism attenuates systemic sympathetic tone, thereby lowering blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The sympathetic nervous system in clinical and experimental hypertension. 353 49

Six rabbits were sham operated and were given water to drink (sham-water group); six additional rabbits were sham operated and were given saline to drink (sham-salt group); another six rabbits received an implant of deoxycorticosterone (DOCA) and were given water to drink (DOCA-water group); a final group of six rabbits received implants of DOCA and were given saline to drink (DOCA-salt group). Two weeks later, all four groups of rabbits had approximately the same mean arterial pressures, and the sham-salt, DOCA-water, and DOCA-salt groups all had plasma renin activity values less than the sham-water group. The DOCA-salt group had greater pressor responses to norepinephrine (NE) at several doses than did the other three groups of rabbits. In another group of six sham-water and six DOCA-salt rabbits, measurements of cardiac output before and during infusions of NE at 800 ng/min/kg body wt revealed no changes in cardiac output before or during NE infusion, but the DOCA-salt group had significantly greater increases in mean arterial pressure and total peripheral resistance during NE than did the sham-water group. In another group of six DOCA-salt rabbits, the pressor response to several doses of NE were determined during infusion of the angiotensin II (AII) antagonist, [Sar1, Ile8] AII; this AII antagonist failed to alter the enhanced pressor responses to NE. A final experiment examined pressor responses to NE in six normal rabbits before and after cross circulation of blood with six DOCA-salt rabbits. After blood cross circulation the normal rabbits had exaggerated pressor responses to NE at 5, 15, and 30 min, but not at 60 min. Similar cross-circulation experiments between six pairs of normal rabbits did not show any transfer of pressor hyperresponsiveness. These studies indicated that pressor and vascular hyperresponsiveness in DOCA-salt rabbits is conveyed by a fast-acting hormonal factor and that AII probably is not involved in mediating this hyperresponsiveness.
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PMID:A fast-acting humoral factor mediates pressor hyperresponsiveness in deoxycorticosterone-salt rabbits. 388 74

The antihypertensive activities of SGB-1534, 3-[2-[4-(o-methoxyphenyl)-1-piperazinyl]ethyl]-2,4 (1H,3H)-quinazolinedione monohydrochloride, compared with prazosin, were examined in anesthetized or conscious hypertensive rat models. In anesthetized rats, SGB-1534 administered orally (3-10 mg/kg) reduced the blood pressure and significantly inhibited the pressor response to noradrenaline, but did not affect blood pressure responses to angiotensin II, isoproterenol, histamine and acetylcholine. This compound (0.1-3 mg/kg, p.o.) exhibited potent and long-lasting antihypertensive effects in conscious spontaneously hypertensive rats (SHRs), renal hypertensive rats and DOCA-salt rats, but it increased the heart rate only minimally. Repeated p.o. doses of SGB-1534 also reduced the blood pressure in SHRs without noticeable sign of tolerance to antihypertensive effects. In an experimental model for determining blood pressure compensation for postural tilt in anesthetized rats, SGB-1534 was free of postural effects, while prazosin induced orthostatic hypotension. In renal hypertensive rats and SHRs, SGB-1534, unlike prazosin, caused no increase in plasma renin activity. The present results reveal some pharmacological characteristics of SGB-1534 as an orally effective antihypertensive agent.
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PMID:Antihypertensive effects of a novel phenylpiperazine derivative, SGB-1534, on several hypertensive models of rats. 390 51

Increasing evidence suggests that the renal nerves may contribute to the pathogenesis of several types of experimental hypertension. It has been demonstrated that renal denervation can either attenuate the severity or delay the development of hypertension in spontaneously hypertensive rats (SHR), in DOCA-salt treated rats and in renovascular hypertensive rats. On the other hand, intrarenal administration of catecholamines has been shown to elicit an increase in systemic arterial pressure as long as the infusion is continued. The underlying mechanisms by which renal nerves might participate in the regulation of cardiovascular homeostasis have not been entirely clarified. It is known that efferent renal nerve activity, by exerting a direct influence on renal arteriolar tone, renin release and sodium and water excretion, can interfere with the control of arterial pressure by modifying peripheral resistances, circulating angiotensin II and volume balance. In addition, a role of afferent renal nerve activity in cardiovascular control and, possibly, in the pathogenesis of renovascular hypertension, has recently been proposed after the demonstration of mechano- and chemoreceptors inside the kidney. Indeed, blood pressure is reflexly influenced either by several manoeuvres applied to the kidney or by the electrical stimulation of afferent renal nerve fibres. Afferent and efferent renal nerve activity appear to be closely related since recent experiments by our group have provided further evidence of the existence of neural renorenal reflexes by which one kidney exerts a tonic inhibitory effect on the release of renin from juxtaglomerular cells and on tubular sodium and water reabsorption of the contralateral kidney.
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PMID:Interactions between the sympathetic nervous system and the kidney: experimental observations. 391 55

Ethanol-induced motor impairment in rats was measured following a number of different dietary or drug treatments. A low sodium diet combined with injections of the diuretic furosemide, but not a low sodium diet alone, increased motor impairment while a high sodium diet decreased impairment. Blood ethanol measurements indicated that both effects were probably mediated by changes in blood ethanol levels. However, the synthetic mineralocorticoid, DOCA, and the nonsteroidal anti-inflammatory, indomethacin, both altered ethanol-induced motor impairment without concomitant changes in blood ethanol levels. The aldosterone antagonist, spironolactone, failed to produce any effect. Since all treatments can modulate activity in the renin-angiotension system, this system appears to play a role in altering some of the behavioral properties of ethanol.
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PMID:Modification of ethanol-induced motor impairment by diet, diuretic, mineralocorticoid, or prostaglandin synthetase inhibitor. 393 34

1. Rats in normal fluid balance drank water 1-2 hr after complete ligation of the inferior vena cava either above or below the renal veins. At the same time there was a fall in urine flow and excretion of electrolyte, especially after caval ligation above the renal veins, so that the animals ended the initial 6 hr period in positive fluid balance.2. Caval ligation was relatively ineffective as a stimulus to drinking after bilateral nephrectomy, but was effective in rats made anuric by ureteric ligation.3. Rats subjected to caval ligation and offered a choice between water and 1.8% saline (w/v) drank water, despite the increasing hypotonicity of the body fluids thereby resulting.4. During the secondary polydipsia, which generally occurred on about the third day after caval ligation as renal function was recovering, there was an increased preference for 1.8% saline.5. Constriction of the aorta above the renal arteries, or constriction of both renal arteries, also caused drinking, oliguria and the development of positive fluid balance.6. Constriction of the aorta below the renal arteries, or after nephrectomy, was ineffective as a stimulus to drinking.7. Saline extracts of renal cortex caused rats in normal water balance to drink. Activity was destroyed by boiling the extract for 10 min. Renal medullary and hepatic extracts were without effect on drinking.8. It proved impossible to separate dipsogenic and pressor activities of renal extracts during the different stages of fractionation which lead to the production of renin; disappearance of one activity was invariably accompanied by disappearance of the other.9. Dipsogenic and pressor actions were greater in nephrectomized rats than in normal rats.10. Both extractable dipsogenic factor and extractable pressor activity were reduced by treating the rat with DOCA and saline for several weeks beforehand.11. The renal dipsogen therefore has similar properties to renin. It may prove to be identical with renin, particularly in view of the fact that angiotensin also stimulates drinking.12. Adrenalectomy did not affect drinking induced by renin or by caval ligation.13. It is concluded that the renin angiotensin system may play a role in the genesis of the thirst which follows certain extracellular stimuli.
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PMID:The role of a renal thirst factor in drinking induced by extracellular stimuli. 430 8

The effects of 4-week administration and subsequent 2-week withdrawal of indenolol, 50 mg/kg/day p.o., were investigated in spontaneously hypertensive rats (SHR), renal hypertensive rats (RHR) and DOCA-salt hypertensive rats (DHR) at established stage, and compared with those of propranolol, 100 mg/kg/day p.o. Indenolol and propranolol caused a marked decrease in heart rate in SHR, RHR and DHR without showing a pronounced antihypertensive activity. Both drugs did not affect the body weight gain in RHR and DHR. On the other hand, the drugs suppressed the body weight gain in SHR, which recovered during 2-week withdrawal period. Weights of the heart, kidney, liver, spleen and adrenals were not affected by the drugs. Indenolol and propranolol markedly lowered the plasma renin activity (PRA) in SHR, RHR and DHR. PRA in RHR and DHR recovered to the control level during 2-week withdrawal period, while that in SHR did not. The results indicate that indenolol produces essentially the same effect as propranolol in SHR, RHR and DHR. Prolonged administration of indenolol to SHR, RHR and DHR with established hypertension produces a marked suppression of cardiac performance and PRA with showing antihypertensive activity.
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PMID:Effects of prolonged administration of indenolol in hypertensive rats. 613 7

The mechanism of the hypotensive effect of 1-O-octadecyl-2-O-acetyl-glycero-3-phosphorylcholine (C18- AGPC ) was examined. Synthetic C18- AGPC caused dose-dependent hypotension in conscious rats. The activity was almost the same in DOCA and renal hypertensive rats. This suggests that it is not a renin inhibitor. Hypotension also appeared in pithed rats. This suggests that the effect is not due to a central mechanism. Hypotension did not result from platelet aggregation or bronchial constriction. Since C18- AGPC suppressed not only the pressor response to noradrenaline but also to angiotensin II and vasopressin, and furthermore, did not disturb the dose-response curve of noradrenaline in the isolated aorta, the possibility of the agent being an alpha-adrenergic antagonist is ruled out. In the PGF2 alpha-contracted rat aorta. C18- AGPC caused marked vasodilation, which disappeared after removal of the endothelium. Perfusion pressure decreased in the blood-perfused rat hindquarters but not in the Tyrode solution-perfused ones. C18- AGPC induced a positive inotropic effect in isolated rat atrium. The hypotensive effect of synthetic C18- AGPC seems to be mainly due to endothelium-dependent vasodilation.
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PMID:Mechanism(s) of the hypotensive effect of synthetic 1-O-octadecyl-2-O-acetyl-glycero-3-phosphorylcholine. 614 57

The effect of SQ-20881, an inhibitor of the peptidyl dipeptidase that degrades kinins and converts angiotensin I to angiotensin II, on the urinary excretion of immunoreactive prostaglandin E2 (iPGE2) was studied in rats receiving either deoxycorticosterone (DOCA, 5 mg/day s.c.) or sesame oil vehicle for 10 days before and then during the study, DOCA-treated animals had higher urinary excretion of iPHE2 and kallikrein, and lower plasma renin, than did animals injected with oil only. In rats pretreated with DOCA, infusion of SQ-20881 (1.2 mg/day s.c.) for 6 days increased iPGE2 excretion from 87.3 +/- 1.9 to 150.9 +/- 14.5 ng/day (P < .05). In contrast, in rats pretreated with vehicle, SQ-20881 had no significant effect on urine iPGE2. The enzyme inhibitor did not affect the intake of fluid, the volume of urine or the urinary excretion of kallikrein and electrolytes in either DOCA- or vehicle-treated animals. The blood pressure reduction elicited by a bolus injection of bradykinin (1.0 microgram i.v.) was greater in rats receiving SQ-20881 than in vehicle-infused controls, both in the DOCA- and in the sesame oil-treated groups, suggesting inhibition of kinin degradation by the converting enzyme inhibitor. These results indicate that DOCA or the consequences of its administration are required for SQ-20881 to increase iPHE2 excretion in the rat. Such an effect of the inhibitor probably relates to stimulation of renal prostaglandin synthesis consequent to elevation of kinin levels.
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PMID:Effect of the converting enzyme inhibitor SQ-20881 on urinary excretion of prostaglandin E2 in the rat: influence of pretreatment with deoxycorticosterone. 616 Dec 43

The hypotensive effect of YS-980, (4R)-3-[(2S)-3-mercapto-2-methyl propanoyl]-4-thiazolidinecarboxylic acid, was investigated in normotensive and different models of hypertensive rats. Experiments were carried out in both anesthetized rats (1 mg/kg i.v.), and conscious unrestrained rats (10 mg/kg p.o.) YS-980 markedly lowered blood pressure in acute renal hypertensive and two-kidney, one-clip hypertensive rats and moderately lowered the pressure in SHR. Contrary to these hypotensive effects, this agent did not reduce the blood pressure in DOCA hypertensive rats. In normotensive rats, YS-980 had a slight hypotensive action in anesthetized rats but not in the conscious animals. The hypotensive effect of YS-980 is attributed mainly to suppression of the renin angiotensin system.
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PMID:Effects of YS-980, an orally active converting enzyme inhibitor, on blood pressure in normotensive and hypertensive rats. 627 29


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