Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.15 (renin)
35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tubular-fluid reabsorption by specialized cells of the nephron at the junction of the ascending limb of the loop of Henle and the distal convoluted tubule, termed the macula densa, releases compounds causing vasoconstriction of the adjacent afferent arteriole. Activation of this tubuloglomerular feedback response reduces glomerular capillary pressure of the nephron and, hence, the glomerular filtration rate. The tubuloglomerular feedback response functions in a negative-feedback mode to relate glomerular capillary pressure to tubular-fluid delivery and reabsorption. This system has been implicated in renal autoregulation, renin release, and longterm body fluid and blood-pressure homeostasis. Here we report that arginine-derived nitric oxide, generated in the macula densa, is an additional intercellular signaling molecule that is released during tubular-fluid reabsorption and counters the vasoconstriction of the afferent arteriole. Antibody to rat cerebellar constitutive nitric oxide synthase stained rat macula densa cells specifically. Microperfusion of the macula densa segment of single nephrons with N omega-methyl-L-arginine (an inhibitor of nitric oxide synthase) or with pyocyanin (a lipid-soluble inhibitor of endothelium-derived relaxation factor) showed that generation of nitric oxide can vasodilate the afferent arteriole and increase glomerular capillary pressure; this effect was blocked by drugs that prevent tubular-fluid reabsorption. We conclude that nitric oxide synthase in macula densa cells is activated by tubular-fluid reabsorption and mediates a vasodilating component to the tubuloglomerular feedback response. These findings imply a role for arginine-derived nitric oxide in body fluid-volume and blood-pressure homeostasis, in addition to its established roles in modulation of vascular tone by the endothelium and in neurotransmission.
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PMID:Nitric oxide synthase in macula densa regulates glomerular capillary pressure. 128 48

Endothelium-derived mediators are released in response to shear stress and a variety of endogenous substances including bradykinin and angiotensins. They may contribute to the regulation of the renin-angiotensin system in the vascular wall and in the kidney. Bradykinin is a powerful agonist at endothelial cells, and the actions of this peptide, which is generated by components of the vascular wall, during angiotensin-converting enzyme (ACE) inhibition may determine some of the vascular effects of ACE inhibitors. In vitro studies demonstrate that the relaxations to bradykinin are mostly endothelium dependent and are mediated by nitric oxide, endothelium-derived hyperpolarizing factor, and/or vasodilator prostaglandins; however, these endothelium-derived relaxing factors do not always contribute simultaneously to the relaxations in every artery. The contribution of ACE in the termination of bradykinin action, relative to the other inactivation processes (including carboxypeptidases and internalization) also may determine the ability of ACE inhibitors to augment the effects of the kinin. Furthermore, it appears that the level of ACE activity and the potency of bradykinin, respectively, are not uniform in all preparations. In arteries in which bradykinin is very efficacious and in which ACE activity may be relatively low, ACE inhibitors may prolong but not amplify the responses to the peptide. The pharmacologic characteristics of the responses of the different vascular beds to bradykinin, together with the modulation of endothelium-dependent responses to other agonists (including purines), may be of importance in the heterogeneity of the vasodilator actions of ACE inhibitors.
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PMID:Heterogeneity of endothelium-dependent vasodilator effects of angiotensin-converting enzyme inhibitors: role of bradykinin generation during ACE inhibition. 128 34

Angiotensin-converting enzyme (ACE) inhibitors exert their beneficial effects not only via endocrine mechanisms, but most probably also via interference with autocrine-paracrine actions involving local renin-angiotensin and kallikrein-kinin systems with subsequent autacoid release. Inhibition of ACE (kininase II) results in the reduction of angiotensin II generation and kinin degradation, leading to beneficial cardiovascular effects. Bradykinin and prostacyclin release from isolated rat hearts was increased by local ACE inhibitions with ramiprilat. In different models the bradykinin-mediated effects of ACE inhibition were abolished with the specific B2 kinin-receptor antagonist Hoe 140: The cardioprotective effects of ramiprilat or ramipril such as reduction of postischemic reperfusion injuries in isolated rat hearts or the reduction in infarct size in dogs and rabbits were abolished by coadministration of Hoe 140. Furthermore, left ventricular hypertrophy in rats with aortic banding could be prevented or regression was induced when the ACE inhibitor was given in a non-blood pressure-lowering dose. These beneficial effects were also abolished by Hoe 140. In conclusion, in different experimental models, ACE inhibitors exert cardioprotective effects. An enhancement of endothelial autacoid formation (nitric oxide and prostacyclin) by inhibiting degradation of bradykinin may contribute to these effects.
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PMID:Role of bradykinin in the cardiac effects of angiotensin-converting enzyme inhibitors. 128 35

The natriuretic response was studied in anesthetized rats during the intravenous infusion of L-arginine analogues to inhibit the production of endothelium-derived nitric oxide. In an initial experimental series, rats were administered saline vehicle or vehicle containing 300 mumol/kg body wt N omega-monomethyl-L-arginine, N omega-nitro-L-arginine methyl ester, N omega-monomethyl-D-arginine, or L-arginine. Infusion of the competitive inhibitors N omega-monomethyl-L-arginine and N omega-nitro-L-arginine methyl ester significantly increased mean arterial pressure to 155 +/- 3 and 145 +/- 5 mm Hg, respectively, compared with a mean arterial pressure of 118 +/- 3 mm Hg determined in the vehicle control group. Sodium excretion averaged 3.27 +/- 1.08 and 2.52 +/- 0.78 mu eq/min in the N omega-monomethyl-L-arginine- and N omega-nitro-L-arginine methyl ester-treated rats, respectively, and each was significantly higher than the basal sodium excretion of 0.20 +/- 0.05 mu eq/min in the vehicle-treated control animals. Plasma renin activity was significantly lower in the N omega-monomethyl-L-arginine- and N omega-nitro-L-arginine methyl ester-treated groups than in the vehicle-treated group. Neither L-arginine nor N omega-monomethyl-D-arginine administration significantly altered any of the measured variables compared with vehicle alone. In a second experimental series, an adjustable snare was placed around the suprarenal aorta for the purpose of controlling renal perfusion pressure independently of increases in the systemic mean arterial pressure initiated by infusion of N omega-nitro-L-arginine methyl ester (75 mumol/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pressure natriuresis in rats during blockade of the L-arginine/nitric oxide pathway. 131 94

The in vitro blood-perfused juxtamedullary nephron technique was utilized to determine the contribution of endothelium-derived relaxing factor (EDRF) to resting renal arteriolar caliber and to evaluate the interaction between EDRF and angiotensin II (ANG II) in renal microvascular control. Video microscopy was employed to visualize rat afferent and efferent arterioles and to measure their responses to blockade of nitric oxide (NO), which has been shown to account for much of the biological action of EDRF. The NO synthesis inhibitor, N omega-nitro-L-arginine (L-NNA), elicited vasoconstriction in a concentration-dependent manner, with 1,000 microM L-NNA significantly reducing both afferent (16 +/- 3%) and efferent (13 +/- 1%) diameters. This concentration of L-NNA also blocked the vasodilator response to 10 microM acetylcholine, while responsiveness to sodium nitroprusside was maintained. Vasoconstrictor responses to 1,000 microM L-NNA were attenuated in kidneys from rats pretreated with enalaprilat or losartan, reducing afferent diameter by 7 +/- 1 (n = 8) and 3 +/- 1% (n = 10) of control, respectively. Efferent arteriolar responses to L-NNA were similarly attenuated by losartan. The constrictor response to 10 nM ANG II was not exaggerated by L-NNA, suggesting that ANG II does not stimulate EDRF synthesis. These observations indicate that EDRF is continuously released in a quantity sufficient to affect both afferent and efferent arterioles of juxtamedullary nephrons in vitro. Furthermore, ANG II blockade attenuates the vasoconstriction elicited by L-NNA, suggesting that EDRF interacts with the renin-angiotensin system to control juxtamedullary afferent and efferent arteriolar resistance.
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PMID:EDRF-angiotensin II interactions in rat juxtamedullary afferent and efferent arterioles. 133 6

The role of endothelium-derived nitric oxide (EDRF/NO) for control of systemic and regional vascular resistances and for regulation of neurohumoral systems was investigated by studying the effects of the inhibitor of EDRF/NO-synthesis NG-nitro-L-arginine (L-NNA; 5 mg/kg) in six conscious dogs. L-NNA increased mean arterial pressure by an increase in total peripheral resistance, increased renal vascular, and total pulmonary resistances and reflexly decreased heart rate and cardiac output. Renal plasma flow, urine flow, and urinary sodium excretion were reduced, glomerular filtration rate was not affected. These changes were reversed by additional treatment with L-arginine (150 mg/kg). Plasma concentrations of renin, norepinephrine, vasopressin, and atrial natriuretic peptide were not changed by L-NNA. Our conclusions were that basal release of EDRF/NO plays an important physiologic role for control of systemic and regional vascular resistances, thereby controlling blood pressure, organ blood flow, and function. Neurohumoral systems are not affected by the inhibition of EDRF/NO synthesis and do not contribute to the observed vasoconstriction.
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PMID:Inhibition of synthesis of endothelium-derived nitric oxide in conscious dogs. Hemodynamic, renal, and hormonal effects. 134 12

The regulation of coronary hemodynamics is a complex process. One important factor that interferes with the regulation of coronary tone is the pathophysiological state of the vessels: stimuli that in normal vessels provoke no or only a slight vasoconstriction may cause a severe vasoconstriction in diseased vessels. This effect is related to the function of the endothelium and its ability to produce nitric oxide and prostaglandins. The presence of a local renin-angiotensin system implies the possibility of influencing the coronary flow via interference with this local system. Therefore, it is interesting to determine the effects of converting enzyme inhibitors on coronary flow. In animal experiments, a bradykinin-dependent coronary vasodilation by angiotensin-converting enzyme (ACE) inhibitors is suggested. However, reports on the effect of converting enzyme inhibitors in patients with angina pectoris are not consistent. Some authors found an increase in coronary flow and others found no change or a decrease. The importance of the activation of the renin-angiotensin system is discussed. Moreover, it is shown that captopril reduces sympathetic-mediated coronary vasoconstriction during the cold pressor test and that captopril enhances the parasympathetic-mediated bradycardia during the diving response. In conclusion, the effects of converting enzyme inhibitors on coronary flow is an interesting but not fully understood topic. Therefore, the multifactorial mechanism of action of converting enzyme inhibitors deserves further investigation. There are probably subgroups of anginal patients who may benefit from converting enzyme inhibitor therapy. These subgroups have to be defined. Especially, the finding that a converting enzyme inhibitor reduces sympathetically induced coronary vasoconstriction seems promising.
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PMID:Effects of converting enzyme inhibitors on coronary flow and myocardial ischemia. 138 90

1. Male, homozygous Brattleboro (i.e. vasopressin-deficient) rats were chronically instrumented with pulsed Doppler flow probes and intravascular catheters, and were studied 5 h after a subcutaneous injection of an hyperoncotic solution of polyethylene glycol to render them hypovolaemic, and hence dependent on the renin-angiotensin system for maintenance of haemodynamic status. Pilot experiments showed that, in this model, primed infusion of perindoprilat (0.05 mg kg-1 bolus, 0.05 mg kg-1 h-1 infusion) or captopril (0.2 mg kg-1 bolus, 0.2 mg kg-1 h-1 infusion) just abolished the pressor effect of angiotensin I (120 pmol), and had similar initial hypotensive and renal hyperaemic vasodilator effects. 2. Perindoprilat had more sustained hypotensive, and mesenteric and hindquarters vasodilator effects than captopril in the presence of saline. In the presence of NG-nitro-L-arginine methyl ester (L-NAME 3 mg kg-1 h-1), the renal vasodilator effects of perindoprilat were unchanged, whereas the other haemodynamic effects of perindoprilat and captopril were reduced. Hence, in the presence of L-NAME, all haemodynamic effects of perindoprilat were greater than those of captopril. 3. The renal hyperaemic vasodilator effects of acetylcholine were abolished by L-NAME and by perindoprilat, and were markedly reduced by captopril. However, since perindoprilat and captopril caused such marked renal hyperaemic vasodilatation themselves, it is feasible this change in baseline status contributed to their effects. It is unlikely this could be a full explanation of the results, because the haemodynamic effects of lemakalim were unchanged under any experimental conditions. 4. Bradykinin alone, or in the presence of saline, caused mesenteric hyperaemic vasodilatation whereas, in the presence of perindoprilat or captopril, bradykinin caused marked renal and mesenteric vasoconstrictions. However, in the additional presence of L-NAME, the mesenteric vasoconstriction was reduced, yet the hypotensive effect of bradykinin was augmented. One possible explanation of these observations is that, in the presence of L-NAME and either perindoprilat or captopril, bradykinin caused marked coronary vasoconstriction, leading to a reduction in cardiac output. 5. Neither perindoprilat nor captopril impaired the pressor, or renal, mesenteric, or hindquarters vasoconstrictor effects of L-NAME. Indeed, in their presence, the effects of L-NAME were generally enhanced, consistent with perindoprilat and captopril causing activation of nitric oxide-dependent mechanisms that were subsequently inhibited by L-NAME.
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PMID:Involvement of nitric oxide in the regional haemodynamic effects of perindoprilat and captopril in hypovolaemic Brattleboro rats. 146 39

Endogenous nitric oxide has been proposed as one of the mediators of gastric cytoprotection. We studied the effect of the vasodilator hydralazine which acts via nitric oxide and thus is expected to have a gastroprotective action. However, hydralazine aggravates ethanol-induced gastric lesions. This effect is not influenced by pretreatment with the selective alpha 1 adrenergic antagonist prazosin but is abolished by the angiotensin converting enzyme inhibitor, captopril suggesting the involvement of the renin-angiotensin system.
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PMID:Aggravating action of hydralazine on ethanol-induced gastric lesions. 150 78

Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginine orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angiotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164 +/- 6 mm Hg at 4-6 weeks, compared with 108 +/- 3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125 +/- 6 mm Hg, still elevated compared with rats receiving losartan alone (98 +/- 3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfusion, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment. Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomeruli. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. 151 48


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