Renin Release In Response Research Articles

Abstract P200: Role of Macula Densa Neuronal Nitric Oxide Synthase in Control of Renin Release and Blood Pressure Recovery Following Hemorrhagic Shock

Renin is a rate limiting factor for generation of angiotensin II, which is essential for blood pressure regulation. The role of macula densa nitric oxide (NO) in renin release is not conclusive. The goal of this study was to elucidate the role of macula densa neuronal NO synthase (NOS1) in control of renin release in response to sodium challenges and hemorrhagic shock, as well as in blood pressure recovery after hemorrhagic shock. C57BL/6L mice and macula densa specific NOS1 knockout (MD-NOS1KO) mice were given 10 days of low (0.1% NaCl), normal (0.4% NaCl) and high (1.4% NaCl) sodium diet. Hemorrhagic shock was induced by withdrawing 0.4 ml whole blood from the right retro-orbital sinus. Mean arterial pressure (MAP) in conscious mice was monitored by radio-telemetry system. Plasma renin concentration (PRC) was determined by radioimmunoassay. Low sodium diet stimulated PCR by 29% (from 685 ± 32 to 883 ± 112 ng/ml/hr) in WT mice and by 16% (from 652 ± 24 to 756 ± 124 ng/ml/hr) in the MD-NOS1KO mice (n=5/group, p<0.01 vs WT). PCR was not significantly different between the WT and MD-NOS1KO mice fed a normal or high salt diet. As shown in Fig1A, following removal of 0.4ml of blood, MAP dropped to about 40mmHg in the WT mice and 35mmHg in the MD-NOS1KO mice. MAP recovered faster in WT mice than the MD-NOS1KO mice. In Fig1B, PRC increased over 200% of the basal value in WT mice, but only increased about 26% in the MD-NOS1KO mice (n=4/group, p<0.01 vs WT). We conclude that NOS1 in the macula densa facilitates renin release. Lack of macula densa NO generation impairs blood pressure recovery, which may be mediated by limiting renin release during hemorrhagic shock.

Salt feedback on the renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system (RAAS) is a central element in the control of the salt and water balance of the body and arterial blood pressure. The activity of the RAAS is controlled by the protease renin, which is released from renal juxtaglomerular epithelioid cells (JGE cells) into the circulation. Renin release is regulated by a complex interplay of several locally acting hormones or mechanisms and longer feedback loops one of which involves salt intake. Acute NaCl loads or longer lasting high salt intakes suppress plasma renin activity, whereas reductions in NaCl intake stimulate it. Because the activation of the RAAS conserves the salt content of the body, a classical feedback loop between salt intake/body salt content and renin is established. Despite of its important role for body fluid homeostasis, the precise signaling pathways connecting salt intake with the synthesis and release of renin are only incompletely understood. Four putative controllers of the salt-dependent regulation of the RAAS have been suggested: (1) the macula densa mechanism which adjusts renin release in response to changes in the renal tubular salt concentration; (2) salt-dependent changes in the arterial blood pressure; (3) circulating salt-dependent hormones, particularly the atrial natriuretic peptide (ANP); and (4) renal sympathetic nervous activity, which is regulated by extracellular volume and arterial blood pressure. In this review, the role of these known controllers of the RAAS will be discussed with special emphasis on their relative contributions to the salt-dependent regulation of the RAAS at different time frames.

TRPC channels are involved in calcium‐sensing receptor mediated inhibition of renin release from Juxtaglomerular cells

Renin containing juxtaglomerular (JG) cells express the calcium‐sensing receptor (CaSR), whose activation increases intracellular calcium (Ca). Increases in intracellular Ca decrease renin release. Canonical transient receptor potential channels (TRPC), a seven‐member subfamily of the transient receptor potential (TRP) family of ion channels, can function either as receptor‐operated or as store‐operated Ca channels, whose activation increases intracellular Ca. However, it is not known if these channels are expressed in JG cells and are involved in CaSR‐mediated regulation of renin release. We hypothesized that TRPC channels are expressed in JG cells and participate in the Ca‐mediated inhibition of renin release in response to activation of the CaSR. RT‐ PCR revealed mRNA expression of TRPC isoforms ‐1, ‐2, ‐3, ‐4, ‐5 and ‐6 in freshly isolated mouse JG cells. Incubation of primary cultures of JG cells with the TRPC blocker (SKF 96365, 50μM) did not change control values (0.46±0.09 vs. 0.46±0.08 μg ANGI/ml/hr/mg prot.) CaSR agonist cinacalcet decreased renin release by 46% to 0.25±0.05 μg ANGI/ml/hr/mg prot.(p<0.04). Addition of SKF 96365 completely reversed the CaSR‐mediated inhibition by cinacalcet. Our data suggests that JG cells contain multiple isoforms of TRPC channels, and at least one of these is linked to down‐stream signaling of CaSR‐mediated renin inhibition. (NIH 5PO1HL090550–04)

Predominance of AT1 Blockade Over Mas–Mediated Angiotensin-(1–7) Mechanisms in the Regulation of Blood Pressure and Renin–Angiotensin System in mRen2.Lewis Rats

We investigated whether the antihypertensive actions of the angiotensin II (Ang II) receptor (AT(1)-R) blocker, olmesartan medoxomil, may in part be mediated by increased Ang-(1-7) in the absence of significant changes in plasma Ang II. mRen2.Lewis congenic hypertensive rats were administered either a vehicle (n = 14) or olmesartan (0.5 mg/kg/day; n = 14) by osmotic minipumps. Two weeks later, rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5 mg/kg/day; n = 7 per group) or its vehicle (n = 7 per group) for the next 4 weeks. Blood pressure was monitored by telemetry, and circulating and tissue components of the renin-angiotensin system (RAS) were measured at the completion of the experiments. Antihypertensive effects of olmesartan were associated with an increase in plasma renin concentration, plasma Ang I, Ang II, and Ang-(1-7), whereas serum aldosterone levels and kidney Ang II content were reduced. Preserved Ang-(1-7) content in kidneys was associated with increases of ACE2 protein but not activity and no changes on serum and kidney ACE activity. There was no change in cardiac peptide levels after olmesartan treatment. The antihypertensive effects of olmesartan were not altered by concomitant administration of the Ang-(1-7) receptor antagonist except for a mild further increase in plasma renin concentration. Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT(1)-R blockade. Ang-(1-7) through the mas receptor does not mediate long-term effects of olmesartan besides counterbalancing renin release in response to AT(1)-R blockade.

Abstract 283: Predominance of Angiotensin II Type 1 Receptor Blockade Over Angiotensin-(1-7) Mechanisms in the Regulation of Blood Pressure and Renin Angiotensin System in mRen.Lewis Rats

We investigated the angiotensin-(1-7) [Ang-(1-7)] mediated effects of Ang II receptor (AT 1 -R) blocker -olmesartan medoxomil-on blood pressure, plasma, renal, and cardiac Ang II as well as activities of the enzymes involved in peptide formation or metabolism in mRen2.Lewis congenic hypertensive rats, a model of Ang II tissue-dependent hypertension. mRen2.Lewis rats were treated with either vehicle (n=14) or olmesartan (0.5 mg/kg/day; n=14) by osmotic minipumps. After 2 weeks rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5 mg/kg/day; n=7 per group) or its vehicle (n=7 per group) for the next 4 weeks. Antihypertensive effect of olmesartan monitored by telemetry (Figure) was associated with an increase in plasma renin concentration (PRC), plasma Ang II (513 ± 115 vs. 31 ± 5 fmol/mL; p<0.05) and Ang-(1-7) (60 ± 5 vs. 27 ± 4 fmol/mL; p<0.05) while reduced kidney Ang II content and no changes in kidney Ang-(1-7), angiotensin converting enzyme (ACE), ACE2 and neprilysin activities were noted in olmesartan treated group when compared to the controls (Figure). Olmesartan had no effect on cardiac peptide levels . Concomitant administration of A-779 increased PRC but had no effect on blood pressure or other RAS components. Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT 1 -R blockade. Ang-(1-7) through mas-receptor does not mediate long-term effects of olmesartan besides counterbalancing renal renin release in response to AT 1 -R blockade.

Activation of the Succinate Receptor GPR91 in Macula Densa Cells Causes Renin Release

Macula densa (MD) cells of the juxtaglomerular apparatus (JGA) are salt sensors and generate paracrine signals that control renal blood flow, glomerular filtration, and release of the prohypertensive hormone renin. We hypothesized that the recently identified succinate receptor GPR91 is present in MD cells and regulates renin release. Using immunohistochemistry, we identified GPR91 in the apical plasma membrane of MD cells. Treatment of MD cells with succinate activated mitogen-activated protein kinases (MAPKs; p38 and extracellular signal-regulated kinases 1/2) and cyclooxygenase 2 (COX-2) and induced the synthesis and release of prostaglandin E(2), a potent vasodilator and classic paracrine mediator of renin release. Using microperfused JGA and real-time confocal fluorescence imaging of quinacrine-labeled renin granules, we detected significant renin release in response to tubular succinate (EC(50) 350 microM). Genetic deletion of GPR91 (GPR91(-/-) mice) or pharmacologic inhibition of MAPK or COX-2 blocked succinate-induced renin release. Streptozotocin-induced diabetes caused GPR91-dependent upregulation of renal cortical phospho-p38, extracellular signal-regulated kinases 1/2, COX-2, and renin content. Salt depletion for 1 wk increased plasma renin activity seven-fold in wild-type mice but only 3.4-fold in GPR91(-/-) mice. In summary, MD cells can sense alterations in local tissue metabolism via accumulation of tubular succinate and GPR91 signaling, which involves the activation of MAPKs, COX-2, and the release of prostaglandin E(2). This mechanism may be integral in the regulation of renin release and activation of the renin-angiotensin system in health and disease.

Estrogens, Salt, Blood Pressure, and Cardiovascular Disease in Women

Until recently cardiovascular disease in women has been a largely neglected and poorly understood issue, in part related to the misconception of a lower incidence among females compared with males, underrepresentation of females in clinical trials and observational studies until recently, and nontraditional presentation of symptoms in many females. Women have been typically viewed as largely protected from cardiovascular disease until menopause, and thereafter a rise in prevalence has been recognized, presumably related to hormonal decline. Hormonal replacement therapy (HRT) has been viewed as a useful prophylactic approach to ward off such events after menopause as well as to minimize menopausal symptoms. However, recent studies have yielded conflicting results regarding the protective effects of estrogen administration in preventing myocardial infarction and stroke.1–3 Indeed, the results of the Women’s Health Initiative have been interpreted as showing a neutral effect of estrogen administration in women in the 50 to 59 age decile and an adverse cardiovascular effect in older subjects.1 Whereas different pharmacological regimens may have been used in these replacement trials, the impact of these regimens on known risk factors for cardiovascular disease, such as blood pressure, lipoprotein profiles, insulin sensitivity, endothelin, C- reactive proteins, and other vasoactive substances, has not been carefully investigated. The relationship between estrogen and progesterone administration in the form of oral contraceptives and blood pressure, a major risk factor for stroke and cardiovascular disease, has been recognized for 4 decades.4 Population studies have documented a small but significant rise in systolic blood pressure in women receiving oral contraceptives in the 1970s, but only a small proportion of such women demonstrated a rise into the hypertensive range. Whereas epidemiologists remind us repeatedly that a …

A different vision of the osmolar regulation of renin secretion

in this issue, the proverbial question of osmotic regulation of renin secretion is revisited by Kurtz and Schweda ([9][1]) with rather surprising, yet apparently definitive, results. Since the development of osmotic diuretics, there has been much interest in whether renin secretion by the kidney is

Putting the Brakes on Renin Release

Modulation of renin release from juxtaglomerular cells is critical for appropriate adjustments of the cardiovascular and renal systems to internal and external stresses, and dysregulation of renin release participates in the pathophysiology of hypertension, vascular disease, heart failure, and chronic renal disease. This justifies investments in research to elucidate the fundamental mechanisms regulating renin release. These investments have yielded, and continue to yield, high returns, as exemplified by Schweda et al1 in this issue of Hypertension , showing that A1 receptors mediate high perfusion pressure–induced inhibition of renin release, whereas prostaglandins (PGs) participate in low perfusion pressure–mediated stimulation of renin release. The purpose of this commentary is to discuss how Schweda et al’s findings confirm and challenge present-day models of renin release. As comprehensively reviewed by Davis and Freeman2 and Keeton and Campbell,3 investigators recognized early on that three systems, namely the sympathetic nervous system, the macula densa apparatus, and the intrarenal baroreceptor, are the primary physiological mechanisms regulating renin release from juxtaglomerular cells. A key development was the recognition that the two most important biochemical accelerators of renin release are catecholamines (mediating sympathetically induced renin release) and PGI2 (mediating macula densa–induced and intrarenal baroreceptor–stimulated renin release).4 Subsequently, a third autocoid, adenosine (acting via A1 receptors), was proposed to serve as a molecular brake on renin release and thereby to moderate the effects of catecholamines and PGI2 on renin secretion.5 Because cAMP is a critical second messenger mediating the exocytosis of renin from juxtaglomerular cells, adenylyl cyclase unifies these concepts because β-adrenoceptors and PGI2 receptors accelerate, whereas A1 receptors brake the rate of cAMP production. The results reported by Schweda et al corroborate the accelerator/brake model of renin release because they report that PGs mediate stimulation of renin release …

Renin Release in Response to Renin System Blockade: Activation of the Renin System in Type 1 Diabetes Mellitus

Activation of the renin-angiotensin system (RAS) in diabetes is thought to contribute to nephropathy. This is suggested by findings of an enhanced renovascular (RPF) response to RAS blockade with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs). An alternative approach to assess RAS activation is the evaluation of renin release following RAS blockade. Forty-four consecutively enrolled Type 1 diabetic patients (28.2+/-1.5 years) and 37 normal subjects (37+/-2.6 years) in high salt balance were given 25 mg of captopril and 16 mg of candesartan p.o. on consecutive days. All subjects were Caucasian. All, except one diabetic patient, had normal renal function. Plasma renin activity (PRA) and renal plasma flow (RPF) were measured for four hours after both drugs, and at eight, and 24 hours after candesartan. As anticipated, both drugs increased PRA. Peak responses (90' after captopril) were 5.6+/-1 ng/mL Ang I/hour in diabetic patients, and 1.7+/-0.9 ng/mL Ang I/hour in normal subjects (p<0.001). Responses to both drugs were correlated in diabetic patients for PRA (r=0.623; p=0.001) and for RPF (r=0.9; p<0.001). When the PRA response to captopril was below the median, the RPF response was limited (22.1+/-17.6 ml/minute/1.73 m2). When it was above the median, the RPF response was also larger (62.2+/-13.9 ml/minute/1.73 m2; p=0.006). Renin response to ACE-I and ARB confirms activation of the RAS in diabetic patients.

Cyclooxygenase-2 and the renal renin-angiotensin system.

In the kidney, cyclooxygenase-2 (COX-2) is expressed in the macula densa/cTALH and medullary interstitial cells. The macula densa is involved in regulating afferent arteriolar tone and renin release by sensing alterations in luminal chloride via changes in the rate of Na(+)/K(+)/2Cl(-) cotransport, and administration of non-specific cyclooxygenase inhibitors will blunt increases in renin release mediated by macula densa sensing of decreases in luminal NaCl. High renin states [salt deficiency, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers, diuretic administration or experimental renovascular hypertension] are associated with increased macula densa/cTALH COX-2 expression. Furthermore, there is evidence that angiotensin II and/or aldosterone may inhibit COX-2 expression. In AT1 receptor knockout mice, COX-2 expression is increased similar to increases with ACE inhibitors or AT1 receptor blockers. Direct administration of angiotensin II inhibits macula densa COX-2 expression. Previous studies demonstrated that alterations in intraluminal chloride concentration are the signal for macula densa regulation of tubuloglomerular feedback and renin secretion, with high chloride stimulating tubuloglomerular feedback and low chloride stimulating renin release. When cultured cTALH or macula densa cells were incubated in media with selective substitution of chloride ions, COX-2 expression and prostaglandin production were significantly increased. A variety of studies have indicated a role for COX-2 in the macula densa mediation of renin release. In isolated perfused glomerular preparations, renin release induced by macula densa perfusion with a low chloride solution was inhibited by a COX-2 inhibitor but not a COX-1 inhibitor. In vivo studies in rats indicated that increased renin release in response to low-salt diet, ACE inhibitor, loop diuretics or aortic coarctation could be inhibited by administration of COX-2-selective inhibitors. In mice with genetic deletion of COX-2, ACE inhibitors or low-salt diet failed to increase renal renin expression, although renin significantly increased in wild type mice. In contrast, in COX-1 null mice there were no significant differences in either the basal or ACE inhibitor-stimulated level of renal renin activity from plasma or renal tissue compared with wild type mice. In summary, there is increasing evidence that COX-2 expression in the macula densa and surrounding cortical thick ascending limb cells is regulated by angiotensin II and is a modulator of renal renin production. These interactions of COX-2 derived prostaglandins and the renin-angiotensin system may underlie physiological and pathophysiological regulation of renal function.

Lesions of the dorsal noradrenergic bundle augment the renin response to blood loss but do not alter hypothalamic Fos expression

The goal of this study was to determine if the dorsal noradrenergic bundle (DNAB) plays an essential role in mediating increased plasma renin activity (PRA) and hypothalamic activation, as indicated by increased Fos expression, in response to a small volume blood loss in unanesthetized animals. Male Sprague–Dawley rats were prepared with bilateral 6-hydroxydopamine or sham lesions of the dorsal noradrenergic bundle. In both groups of animals, blood pressure decreased by only 10–15 mmHg following hemorrhage (10 ml/kg over 15 min). Plasma renin activity increased similarly in both groups after 5 ml/kg blood loss, but showed a significantly greater increase after 10 ml/kg blood loss in animals with 6-hydroxydopamine lesions than in those with sham lesions (increase of 13.8±2.0 ng/ml/h versus 8.4±1.2 ng/ml/h; P < 0.025). There were numerous Fos-immunoreactive cell nuclei in the supraoptic nucleus (SON) and parvicellular paraventricular hypothalamic nucleus (PVN) of hemorrhaged animals. The number of Fos-positive neurons did not differ between groups, indicating that the dorsal noradrenergic bundle does not convey the primary drive for supraoptic and paraventricular nucleus activation during blood loss. However, one or more of the forebrain regions innervated by the dorsal noradrenergic bundle may attenuate the sympathetic outflow that initiates renin release in response to hemorrhage.

Lesions of the dorsal noradrenergic bundle augment the renin response to blood loss but do not alter hypothalamic Fos expression

The goal of this study was to determine if the dorsal noradrenergic bundle (DNAB) plays an essential role in mediating increased plasma renin activity (PRA) and hypothalamic activation, as indicated by increased Fos expression, in response to a small volume blood loss in unanesthetized animals. Male Sprague–Dawley rats were prepared with bilateral 6-hydroxydopamine or sham lesions of the dorsal noradrenergic bundle. In both groups of animals, blood pressure decreased by only 10–15 mmHg following hemorrhage (10 ml/kg over 15 min). Plasma renin activity increased similarly in both groups after 5 ml/kg blood loss, but showed a significantly greater increase after 10 ml/kg blood loss in animals with 6-hydroxydopamine lesions than in those with sham lesions (increase of 13.8±2.0 ng/ml/h versus 8.4±1.2 ng/ml/h; P < 0.025). There were numerous Fos-immunoreactive cell nuclei in the supraoptic nucleus (SON) and parvicellular paraventricular hypothalamic nucleus (PVN) of hemorrhaged animals. The number of Fos-positive neurons did not differ between groups, indicating that the dorsal noradrenergic bundle does not convey the primary drive for supraoptic and paraventricular nucleus activation during blood loss. However, one or more of the forebrain regions innervated by the dorsal noradrenergic bundle may attenuate the sympathetic outflow that initiates renin release in response to hemorrhage.

Renin release in response to renin system blockade: further evidence for activation of the intrarenal renin system in type-1 diabetes mellitus

Renin release in response to renin system blockade: further evidence for activation of the intrarenal renin system in type-1 diabetes mellitus

Atrial distension, haemodilution, and acute control of renin release during water immersion in humans.

We tested the hypothesis that atrial distension (stimulation of cardiopulmonary baroreceptors) is not the single pivotal stimulus for the acute suppression of renin release during water immersion in humans and that immersion-induced haemodilution constitutes an important additional stimulus. In nine healthy male subjects, identical increases in atrial distension were induced by two immersion procedures (of 30 min each); one without (WI) and one with attenuation (WI + cuff) of the concomitant haemodilution (estimated from changes in plasma protein concentration) by inflating thigh cuffs during immersion. During WI, central venous pressure (CVP) and left atrial diameter (LAD) increased (P < 0.05) by 5.5 +/- 0.4 mmHg and 4.6 +/- 0.5 mm, respectively, and plasma protein concentration and plasma renin activity (PRA) progressively decreased (P < 0.05) by 4.8 +/- 0.5 g L(-1) and 1.6 +/- 0.2 ng mL(-1) h(-1) (to 49 +/- 4% of baseline values), respectively. The WI + cuff caused similar atrial distension as WI (CVP and LAD increased by 6.9 +/- 0.5 mmHg and 5.5 +/- 0.5 mm, respectively), attenuated haemodilution (plasma protein concentration decreased by 1.9 +/- 0.4 g L(-1), P < 0.05 vs. WI), and markedly inhibited suppression of PRA, which decreased by 0.4 +/- 0.1 ng mL(-1) h(-1) (to 87 +/- 4% of baseline values, P < 0.05 vs. WI). Differences in renin release could not be accounted for by differences in mean arterial pressure. In conclusion, baroreceptor stimulation induced by atrial distension is not the single pivotal stimulus for the acute suppression of renin release in response to intravascular volume expansion by water immersion in humans. Haemodilution constitutes a significant and conceivably the principal stimulus for the acute immersion-induced suppression of renin-angiotensin system activity.

Urinary prostaglandin excretion in pregnancy: the effect of dietary sodium restriction

Introduction: Dietary sodium restriction results in activation of the renin-angiotensin-aldosterone-system. In the non-pregnant situation renin release in response to a low sodium diet is mediated by prostaglandins. We studied the effect of dietary sodium restriction on urinary prostaglandin metabolism in pregnancy.Patients and methods: In a randomized, longitudinal study the excretion of urinary metabolites of prostacyclin (6-keto-PGF1 αand 2,3-dinor-6-keto-PGF1 α) and thromboxane A2(TxB2and 2,3-dinor-TxB2) was determined throughout pregnancy and post partum in 12 women on a low sodium diet and in 12 controls.Results: In pregnancy the excretion of all urinary prostaglandins is increased. The 6-keto-PGF1 α/ TxB2-ratio as well as the 2,3-dinor-6-keto-PGF1α/ 2,3-dinor-TxB2-ratio did not significantly change in pregnancy.Conclusion:Prostacyclin and thromboxane do not seem to play an important role in sodium balance during pregnancy.

Renin Angiotensin System Antagonists and Anesthesia

R enin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II

Interferon-y Inhibits the Synthesis and Release of Renin from Human Decidual Cells1

Experiments were performed to examine the effect of interferon-gamma (IFN gamma) on the expression of renin by human uterine decidual cells and decidual macrophages. Exposure of a mixed population of decidual cells consisting of 80% decidualized stromal cells and 20% macrophages to IFN gamma for 4 days caused a dose-dependent inhibition of renin release beginning 2 days after exposure. Renin release on Day 4 was inhibited by a maximum of 83.9%, and the half-maximal effective dose of IFN gamma was 5 ng/ml (290 pM). The inhibition of renin release in response to IFN gamma was accompanied by a comparable inhibition of renin mRNA levels. In addition to inhibiting basal renin expression, IFN gamma potentiated the inhibitory effect of tumor necrosis factor alpha (TNF alpha) on renin expression. IFN gamma also inhibited basal renin release and potentiated the inhibitory effect of TNF alpha by highly purified populations of decidual stromal cells and decidual macrophages prepared by immunomagnetic separation with beads coupled to an anti-human leukocyte antigen (HLA-DR) antibody that binds macrophages but not stromal cells. Reverse transcription-polymerase chain reaction analysis showed that HLA-DR(+) cells express IFN gamma mRNA, and that both HLA-DR(+) and HLA-DR(-) cells express IFN gamma receptors. Since IFN gamma is expressed only by decidual macrophages, the results of this study strongly suggest that IFN gamma inhibits the expression of decidual renin by a paracrine action.

Cyclic GMP-linked pathway for renin secretion

The role of cGMP as a second messenger for renin secretion is contentious. This was investigated using a superfused collagenase-dispersed rat kidney cortex cell preparation devoid of indirect influences on renin secretion. Nitroprusside, atriopeptin II and 8-Br-cGMP all increased renin release but the dose-response relationships were biphasic. At low dose ranges there was a positive correlation between increasing drug concentration and renin secretion, but at high drug concentrations, a negative correlation was apparent. Methylene blue, a guanylate cyclase inhibitor, also suppressed baseline renin release at 10(-5) and 10(-6) M, but stimulated release at 10(-3) M. Using mid-range drug concentrations, the cGMP specific phosphodiesterase inhibitor MB22948 potentiated renin release in response to nitroprusside and 8-Br-cGMP. Inhibition of guanylate cyclase with either methylene blue or LY83583 attenuated renin release in response to nitroprusside, but, as expected, had no effect on 8-Br-cGMP induced release. We conclude that, under physiological conditions, cGMP is a stimulatory second messenger for renin release. This activity is mimicked at low dose ranges by 8-Br-cGMP, nitroprusside and atriopeptin II. In response to high doses of these drugs an unknown inhibitory pathway is activated and this opposes, in a dose-related manner, the stimulatory actions of cGMP for renin release.

Sympathetic Neural Blockade by Thoracic Epidural Anesthesia Suppresses Renin Release in Response to Arterial Hypotension

The renin-angiotensin and vasopressin systems, in addition to the sympathetic system, are important backup mechanisms for maintaining arterial blood pressure during circulatory challenges. We tested the hypothesis that preganglionic sympathetic blockade by thoracic epidural anesthesia interferes with the functional integrity of the renin-angiotensin system. Renin concentrations were assessed in awake non-sedated patients in response to induced arterial hypotension both before and during sympathetic blockade by thoracic epidural anesthesia (n = 10). Heart rate (electrocardiogram) and mean arterial blood pressure (electromanometry) were recorded continuously. Active renin (radioimmunoassay), vasopressin (radioimmunoassay), and osmolality (osmometry) in arterial blood were measured intermittently: (1) at baseline, (2) during a hypotensive challenge (15 min) induced by sodium nitroprusside (titrated to decrease mean arterial blood pressure by at least 25%) with the sympathetic system intact, (3) during recovery, (4) with epidural anesthesia alone (sensory blockade T1-T11), and (5) during a second hypotensive challenge and sympathetic blockade with sodium nitroprusside titrated to the same mean arterial blood pressure as with the sympathetic system intact. With the sympathetic system intact hypotension almost doubled renin concentration (34 +/- 32 SD to 60 +/- 58 pg.ml-1, P = 0.019), while vasopressin concentration remained unchanged. In contrast, during sympathetic blockade and despite identical hypotension (mean arterial blood pressure 68 +/- 8 vs. 67 +/- 5 mmHg), renin concentration did not change (35 +/- 27 vs. 35 +/- 29 pg.ml-1, P = 0.5), whereas vasopressin concentration increased (4.6 +/- 2.5 to 13.4 +/- 9.4 pg.ml-1, P = 0.01). Osmolality remained unchanged. Our results indicate a key role of renal sympathetic fibers in mediating renin release during hypotension in humans, and that epidural anesthesia interferes with the functional integrity of the renin-angiotensin system.