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)

To evaluate the contribution of chloride to acute renin inhibition by sodium chloride, plasma renin activity (PRA) was measured before and after peripheral venous infusion of NaCl, NaHCO3, NaBr, NaNO3, lysine monohydrochloride, or lysine glutamate in NaCl-deprived rats. In contrast to controls and animals infused with other sodium salts, PRA decreased (P less than 0.01) after infusion with NaCl [from 28.3 +/- 2.8 to 13.3 +/- 1.8 ng/ml per h (SE)] and NaBr (from 40.6 +/- 6.2 to 21.8 +/- 3.9 ng/ml per h), and renal tubular halide reabsorption increased (P less than 0.05). Arterial pressure, plasma volume, inulin clearance, net sodium balance, serum Na+ and K+, and pH were not different among sodium-loaded groups. PRA was also suppressed (P less than 0.01) by infusion with lysine monohydrochloride (from 51.6 +/- 5.4 to 32.4 +/- 5.1 ng/ml per h) but not with lysine glutamate. These results suggest that inhibition of renin by sodium is dependent on an intrarenal effect of chloride. During infusion with sodium salts which suppressed renin, negative free water clearance (TcH2O) increased, whereas infusion with sodium salts that did not inhibit renin resulted in either no change or decreased TcH2O. The association of renin inhibition and increased TcH2O indirectly supports the hypothesis that renin suppression by chloride is related to the magnitude of absorptive chloride transport in the thick ascending limb of the loop of Henle.
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PMID:Importance of chloride for acute inhibition of renin by sodium chloride. 3 96

1. The effects of different energy substrates, of low temperature, of urea, and of ouabain and ethacrynic acid were studied on the rate of renin release from viable juxtaglomerular cells during superfusion of isolated rat glomeruli. 2. Neither lactate nor glutamate altered renin release rate from that observed using glucose as the sole energy substrate. Succinate 10 mM elevated release transiently but did not influence the release caused by reductions in osmolality through lowering sucrose concentration. 3. Peak renin release was more prolonged and returned more slowly to control following reductions in osmolality in phosphate-Ringer than in bicarbonate-Ringer. 4. At 37 degrees C, the peak of renin released induced by hypo-osmolality was smaller and delayed, and returned earlier to control than at 30 degrees C. Reduction in temperature from 30 to 4 degrees C resulted in a 32-fold increase in basal release rate. At 4 degrees C a 20 m-osmole/kg reduction in tonicity caused an additional 2-5-fold increase in release rate. 6. Increasing superfusate osmolality with urea did not affect basal renin release but 100 mM urea suppressed the releasing effect of a 15 mM reduction in NaCl concentration. 7. Ouabain (10(-4) M) caused a small (33 +/- 9%, P less than 0-025) transient increase in renin release. Ethacrynic acid (10(-3) M) provoked a progressive increase in release reaching 100 +/- 15% above control within 50 min. In the presence of both inhibitors the release provoked by hyposmolality was prolonged. 8. It is concluded that renin release in vitro is a function of actively regulated cell volume and it is proposed that a similar mechanism could underline both barorecptor and macula densa controls of renin secretion in vivo.
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PMID:Studies on renin release from isolated superfused glomeruli: effects of temperature, urea, ouabain and ethacrynic acid. 94 62

Administration of adenosine results in profound hypotension without the expected activation of reflex sympathetic and renin mechanisms in most animal models. This action can be explained by the vasodilatory and neuroinhibitory effects of adenosine. It is generally considered an inhibitory neuromodulator because it inhibits the release of virtually all neurotransmitters studied and produces hyperpolarization of neurons. In contrast, adenosine produces vasoconstriction of some vascular beds, including the renal and pulmonary circulations. Renal vasoconstriction is caused by activation of A1 receptors and involves an interaction with angiotensin II. In other vascular beds adenosine releases eicosanoids, including thromboxane, also resulting in vasoconstriction. Adenosine-induced vasoconstriction is transient and species dependent. Neither the receptor type, the molecular mechanisms of these actions, nor their significance to pathophysiological processes have been defined. Adenosine also has an apparent excitatory effect in the nucleus tractus solitarii. Microinjections of adenosine into this brain stem nucleus lead to decreased sympathetic tone and hypotension similar to those produced by the excitatory amino acid glutamate. The mechanism that explains this action has recently been explored and involves the release of glutamate by adenosine. Adenosine also stimulates afferent fibers mediating sympathetic activity, including renal and myocardial afferent nerves, and carotid and aortic chemoreceptors. Afferent nerve activation seems to be more pronounced in humans and may explain most of the cardiovascular and respiratory actions of adenosine in this species. Finally, animal studies suggest that endogenous adenosine plays a role in the regulation of the baroreceptor reflex and restrains the full expression of renin-dependent hypertension.
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PMID:Contrasting excitatory and inhibitory effects of adenosine in blood pressure regulation. 139 81

Replacing one amide bond in macrocyclic renin inhibitors of the general structure 1 and 2 with an ester linkage gave glutamate-derived inhibitors 3 and serine-derived inhibitors 4. While this oxygen-for-nitrogen exchange had little effect on potency in the glutamate series, potency was dramatically increased in the serine series. In this series, the 14-membered ring compounds proved to be more potent than the corresponding 13-membered ring derivatives. Substitution of the ring at the position corresponding to P2' generally increased potency. The absolute configuration at this center was shown to be R for the 4-morpholinomethyl derivative (4o), both by asymmetric synthesis and X-ray crystallography. Replacing the "Boc-Phe" moiety of inhibitor 4o with a variety of substituents led to subnanomolar inhibitors, one of which (the "3(S)-quinuclidinyl-Phe" derivative 33) lowered blood pressure 20 mmHg and completely inhibited plasma renin activity for 6 h in sodium-depleted rhesus monkeys. This compound proved to have limited bioavailability (1% in rats) due to cleavage of the serine ester bond and rapid hepatic extraction.
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PMID:Highly potent, orally active diester macrocyclic human renin inhibitors. 143 90

The spontaneously hypertensive rat (SHR) exhibits an enhanced activity of the peripheral sympathetic and brain renin-angiotensin systems. In the present experiments, we evaluated the cardiovascular response of angiotensin II (ANG II) microinjected in the rostral (RVLM) and the caudal (CVLM) ventrolateral medulla of age-matched (14-16 wk old) SHR and Wistar-Kyoto (WKY) rats. Responses of mean arterial pressure (MAP) and heart rate (HR) to microinjection of ANG II (5, 20 and 100 pmol) into histologically verified sites of the RVLM and CVLM were compared with those obtained by injections of the excitatory agent L-glutamate (2 nmol) at the same site. In both strains, ANG II elicited dose-dependent pressor responses in the RVLM and depressor responses in the CVLM, both of which peaked at a dose of 20 pmol. The magnitude of the fall in MAP produced by injections of ANG II into the CVLM were significantly (P less than 0.01) greater in SHR than in WKY group. In contrast, peak pressor responses elicited by injection of ANG II into the RVLM were of similar magnitude in the two groups. When compared with the MAP response produced by L-glutamate injections, responses to ANG II microinjection were slower in onset, and the latency to the peak response was longer. Ganglionic blockade with hexamethonium bromide prevented the effect of ANG II injection in the RVLM. This study provides evidence that ANG II acts as an excitatory agent at sites within the ventrolateral medulla that determine the vasomotor control of blood pressure in both normotensive and hypertensive rats.
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PMID:Effect of angiotensin II in ventrolateral medulla of spontaneously hypertensive rats. 167 44

The most important central autonomic pathways in the control of arterial blood pressure are the baroreceptor reflex pathway and descending pathways from the hypothalamus. Central neurotransmitters in these pathways are L-glutamate, substance P, norepinephrine (NE), gamma-aminobutyric acid, epinephrine, neuropeptide Y, and acetylcholine. At peripheral autonomic neurovascular junctions, there are prejunctional alpha 2- and dopamine-2 receptors, which inhibit NE release, and beta- and serotonin receptors, which stimulate NE release. Postjunctional alpha 1-receptors open sodium channels, open calcium channels via phosphoinositol release, and release intracytoplasmic calcium. Postjunctional alpha 2-receptors, which are extrasynaptic, inhibit adenylate cyclase and also open calcium channels. In animal models of hypertension, changes in alpha-receptor density have been reported. In spontaneously hypertensive rats, increased renal beta- and alpha 2-receptors, respectively, may enhance renin release and cause sodium and water retention. In experimental (renovascular) hypertension, vascular postsynaptic (vasoconstrictor) alpha 1- and alpha 2-receptors are increased. In both models of hypertension, beta-receptors are down-regulated. Selective alpha 1-antagonists, such as indoramin and prazosin, decrease arterial blood pressure by postsynaptic alpha 1-blockade; alpha 2-receptor inhibition of NE release is unaffected so that there is no beta-receptor-mediated tachycardia.
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PMID:Alpha-adrenoreceptors in hypertension. 242 93

The purpose of this study was to determine the interactions of the renin-angiotensin system with adenosine and glutamate in the area postrema (AP) of rats. Male Sprague-Dawley rats were anesthetized with urethane. Adenosine, angiotensins (Ang) II, III and their antagonist 1,3-Dipropyl-8-p-sulfophenylxanthine (DPSPX), [Sar1Ile7]Ang III and glutamate antagonist, L-glutamic acid diethyl ester (GDEE) were microinjected into the AP of rats. Our results demonstrated that microinjection of DPSPX significantly attenuated the depressor and bradycardic effects of Ang II and III at low (9.6 pmol) and high dose (480 pmol) of Ang II in normotensive rats. To test the interaction of glutamate and renin-angiotensin system, we found that glutamate antagonist, GDEE, markedly lowered depressor and bradycardic responses of Ang II but did not influence Ang III in rats. On the other hand, microinjection of the Ang antagonist [Sar1Ile7]Ang III 10 min prior to the injection of adenosine significantly altered the cardiovascular effects of adenosine in the AP. In conclusion, the endogenous adenosine and glutamate may influence the renin-angiotensin system on cardiovascular responses in the AP of rats.
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PMID:Adenosine and glutamate modulate the cardiovascular responses of angiotensins II and III in the area postrema of rats. 772 12

Angiotensin (Ang) II increases substance P (SP) efflux from perfused slices of medulla oblongata, and a peptide antagonist of SP, [Leu11,psiCH2NH10-11]SP, blocks the acute hypotension and bradycardia caused by Ang II injected into the nucleus tractus solitarii (nTS) of Harlan Sprague-Dawley (SD) rats. We investigated whether the same relationships exist in (mRen2)27 renin transgenic (TG) rats, which have chronic elevations of medullary tissue Ang II levels. Ang II increased SP efflux (48% above control; P<0.01) from slices of medulla prepared from 8- to 12-week old male TG rats. Injections of Ang II (250 fmol in 30 nL) into the nTS of chloralose-urethane anesthetized TG rats produced a significant increase in pressure of 7+/-2 mm Hg before a 13+/-3 mm Hg fall in pressure. Ang II induced similar depressor responses in Hannover SD rats but no increase in pressure. After nTS injection of the NK1-selective SP antagonist CP-96,345 (30 pmol in 60 nL), Ang II-induced hypotension was blocked in both groups, as was the pressor component in hypertensive rats. Hypotensive and bradycardic effects of glutamate (0.6 nmol in 30 nL) injected into the nTS were not altered by CP-96,345. In vitro receptor autoradiography showed that the SP antagonist (10 or 100 microM) did not compete for 125I-Ang II binding in the dorsal medulla, a result suggesting that it did not interact directly with Ang II receptors. Thus, the nTS cardiovascular effects of Ang II are mediated by SP in both normotensive rats and a model of hypertension with altered endogenous levels of Ang II. These findings link Ang II-induced effects on SP release from brain slices of the medulla oblongata to acute cardiovascular actions of the peptide through an NK1 receptor.
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PMID:NK1 receptor antagonist blocks angiotensin II responses in renin transgenic rat medulla oblongata. 945 48

Activation of the sympathetic nervous system and renin-angiotensin system has been suggested to contribute to the hypertension caused by chronic nitric oxide synthase inhibition. The aim of the present study was to determine whether angiotensin within the nucleus tractus solitarii (NTS) plays a role in activation of the sympathetic nervous system in this model. Rats were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg. kg(-1). d(-1) in drinking water) for 2 weeks. Experiments were performed on anesthetized rats with denervated arterial and cardiopulmonary baroreceptors. Arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) were measured. Microinjection of an angiotensin II type 1 (AT(1)) receptor antagonist (CV11974) or an angiotensin II type 2 (AT(2)) receptor antagonist (PD123319) into the depressor region within the NTS (identified by prior injection of L-glutamate) was performed. Microinjection of CV11974, but not of PD123319, produced greater decreases in arterial pressure, heart rate, and RSNA in L-NAME-treated rats than in control rats. The administration of hexamethonium resulted in a larger fall in arterial pressure in L-NAME-treated rats than in control rats. The ACE mRNA level in the brain stem was greater in L-NAME-treated rats than in control rats. These results suggest that increased sympathetic nerve activity plays a role in hypertension caused by chronic nitric oxide synthase inhibition and that activation of the renin-angiotensin system in the NTS is involved at least in part in this increased sympathetic nerve activity via AT(1) receptors.
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PMID:Angiotensin in the nucleus tractus solitarii contributes to neurogenic hypertension caused by chronic nitric oxide synthase inhibition. 1094 87

1. The brain renin-angiotensin system can influence arterial baroreceptor reflex control of blood pressure (BP) through both direct and indirect effects on sympathetic premotor neurons of the rostral ventrolateral medulla (RVLM). The present study examined the direct effect of angiotensin (Ang) II applied by microiontophoresis on the ongoing activity of single RVLM neurons. 2. In 26 urethane-anaesthetized Wistar rats, recordings of single unit activities of barosensitive RVLM neurons were made from one barrel of a six-barrel micropipette assembly. The other five barrels were filled with either L-glutamate, AngII, valsartan (an AT1 receptor antagonist), PD 123177 (an AT2 receptor antagonist) and saline. All drugs were applied by microiontophoresis. 3. Mean BP was 83 +/- 3 mmHg. Application of AngII inhibited the ongoing activity of RVLM neurons, identified as barosensitive because their activity was inhibited by a phenylephrine- induced increase in BP, from 12.6 +/- 1.5 to 5.4 +/- 1.1 Hz (n=24; P < 0.001). Angiotensin II also inhibited the glutamate-evoked excitation of barosensitive RVLM neurons from 15 +/- 3 to 5.8 +/- 2.0 Hz (n=6; P < 0.001). Valsartan significantly increased neuronal activity from 9.5 +/- 2.3 to 13.5 +/- 3.2 Hz (n=7, P < 0.01), whereas PD 123177 significantly decreased neuronal activity from 13.5 +/- 3.5 to 9.9 +/- 2.8 Hz (n=13; P < 0.01). 4. The results suggest that AngII exerts a tonic inhibitory effect on barosensitive RVLM neurons, which is presumably mediated through AT1 receptor stimulation.
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PMID:Inhibitory effects of angiotensin II on barosensitive rostral ventrolateral medulla neurons of the rat. 1190 28


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