Mediating Renin Release Research Articles

Abstract P201: Macula Densa (Pro)Renin Receptor Contributes to 2-Kidney, 1-Clip-Induced Renovascular Hypertension but not Ischemic Nephropathy in Mice

Our previous presentation at this meeting showed that collecting duct (CD)-specific deletion of (pro)renin receptor (PRR) or renin attenuated hypertension and kidney damage induced by the 2-kidney, 1 clip (2K1C) procedure, highlighting an essential role of the intrarenal renin-angiotensin system (RAS) in the pathogenesis of renovascular hypertension and ischemic nephropathy. Besides the CD, PRR is also expressed in the macula densa (MD), mediating renin release from the juxtaglomerular (JG) cells. Here we examined the phenotype of NKCC2-Cre-mediated MD/TAL-specific deletion of PRR (MD/TAL PRR KO) following the 2K1C procedure. Clipping-induced hypertension was partially attenuated in MD/TAL PRR KO mice compared to floxed controls (MAP on day 24: Floxed/2K1C 148.3±1.8 mm Hg vs. MD/TAL PRR KO/2K1C 138.8±2.9 mm Hg, n=6, p < 0.05), to a similar degree in mice lacking PRR or renin in the CD. However, MD/TAL PRR KO mice did not exhibit protective effects against ischemic nephropathy compared to floxed controls following the 2K1C procedure (urinary albumin/creatinine: Floxed/2K1C 65.9 ± 4.6 mg/g vs. MD/TAL PRR KO/2K1C 59.5 ± 2.7 mg/g, n=6). Furthermore, there were no significant differences in clipping-induced protein abundance of renal fibronectin, α-SMA, or proinflammatory markers such as IL-1β, TNF-α, MCP-1. The protective phenotype against hypertension observed in KO mice was paralleled with suppressed plasma renin activity, active renin content, and total prorenin/renin levels. Additionally, while clipping upregulated renin mRNA expression in both renal cortex and medulla of floxed mice, only cortical renin expression was reduced by 39% in MD/TAL PRR KO mice. The 2K1C-induced increase in circulating sPRR was attenuated by 31% in MD/TAL PRR KO mice. Overall, our results suggest that renovascular hypertension in the 2K1C model is jointly determined by the systemic and intrarenal RAS whereas ischemic nephropathy in this model solely depends on the intrarenal RAS.

Physiological Significance of Macula Densa Neuronal Nitric Oxide Synthase-1 in Renin Release and Renin-dependent Blood Pressure Maintenance

The role of macula densa nitric oxide synthase 1 (NOS1) in regulation of renin release is controversial. This study was conducted to further elucidate the role of macula densa NOS1 in renin release and blood pressure regulation in response to salt challenges and hemorrhagic shock.Tissue specific macula densa-NOS1 knockout (KO) and wild type (WT) mice were given low (0.1% NaCl) and high (1.4% NaCl) sodium diets or induced hemorrhagic shock by retro-orbital bleeding of 0.4 ml blood. Mean arterial pressure (MAP) was measured by radio-telemetry system. Plasma renin concentration (PRC) was determined by radioimmunoassay.PRCs were 496 ± 74 and 552 ± 68 ng/ml/hr in WT and KO mice fed a normal sodium diet, respectively. Low salt intake stimulated the renin release by about 220% in WT mice (PRC = 1364 ± 217 ng/ml/hr) compared to the level of normal salt diet, however, the stimulation was significantly blunted in KO mice (PRC = 688 ± 104 ng/ml/hr). High salt intake suppressed the PRC to the level of about 61% of PRC under normal salt diet. Deletion of macula densa-NOS1 further inhibited renin release to 43% of the levels of normal salt diet.Hemorrhagic shock induced about a 3-fold increase in PRC in WT mice, while only about 54% increase in the KO mice. The MAP values were significantly higher in WT mice than in KO mice during the first 6 hours following hemorrhagic shock. Thus, WT mice showed much quicker recovery in MAP than KO mice.Our study demonstrated that macula densa NOS1 plays an important role in mediating renin release. This mechanism is essential in maintaining blood pressure under hypovolemic situations such as hemorrhagic shock. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Macula Densa Nitric Oxide Synthase 1 Controls Renin Release and Renin-Dependent Blood Pressure Changes.

The function of macula densa nitric oxide synthase 1 (NOS1) in the regulation of renin release is controversial. This study was conducted to further elucidate the role of macula densa NOS1 in renin release and blood pressure regulation in response to salt challenges and hemorrhagic shock. To investigate the specific role of NOS1 in the macula densa within the kidney in response to varying sodium concentrations in the diet, tissue macula densa-specific NOS1 knockout (MD-NOS1KO) and wild type (WT) mice were subjected to sequential low (0.1% NaCl) and high (1.4% NaCl) sodium diets. Separate groups of mice, consisting of both MD-NOS1KO subgroup and WT subgroup, were induced hemorrhagic shock by retro-orbital bleeding of 12 mL blood/kg body weight. Mean arterial pressure (MAP) was measured by a radio-telemetry system. Plasma renin concentration (PRC) was measured with the radioimmunoassay for both sodium diet and hemorrhagic shock experiments. PRCs were 371 ± 95 and 411 ± 68 ng/mL/hr in WT and MD-NOS1KO mice fed a normal sodium diet, respectively. Low salt intake stimulated an increase in the renin release by about 260% in WT mice (PRC = 1364 ± 217 ng/mL/hr, p < 0.0001) compared to the PRC under normal salt diet. However, the stimulation was significantly blunted in MD-NOS1KO mice (PRC = 678 ± 104 ng/mL/hr, p < 0.001). High salt intake suppressed the PRC to about 61% of the PRC level under a normal salt diet (p < 0.0001). Deletion of macula densa NOS1 further inhibited renin release to 33% of the levels of a normal salt diet. Hemorrhagic shock induced about a 3-fold increase in PRC in WT mice, but only about a 54% increase in the MD-NOS1KO mice (p < 0.0001). The MAP values were substantially greater in WT mice than in MD-NOS1KO mice within the first 6 hours following hemorrhagic shock (p < 0.001). Thus, WT mice showed a much quicker recovery in MAP than MD-NOS1KO mice. Our study demonstrated that macula densa NOS1 plays an important role in mediating renin release. This mechanism is essential in maintaining blood pressure under hypovolemic situations such as hemorrhagic shock.

Establishing an in vitro model of olfactory receptor 78‐mediated renin release

Recent studies by our laboratory have identified Olfactory Receptor 78 (Olfr78) as a short chain fatty acid (SCFA) receptor which modulates blood pressure. We previously reported that in ex vivo preparations of glomeruli, Olfr78 responds to SCFA's such as propionate to mediate renin release in the juxtaglomerular apparatus (JGA) in the kidney. Similarly, whole‐animal Olfr78 KO mice have lowered plasma renin levels, and are hypotensive.(Pluznick, Protzko et al. 2013). While it is known that Olfr78 is a G‐protein coupled receptor, the precise signaling pathway linking SCFA binding and renin release is not known. In this study, we aimed to establish a cell model which could recapitulate Olfr78‐mediated renin release. To do this, we utilized As4.1 cells, a juxtaglomerular cell line. We found that this cell line does not natively express Olfr78 by RT‐PCR; therefore we studied As4.1 cells either with or without stable expression of a Lucy‐ FLagRho‐Olfr78 construct. (Lucy and Rho tags have been previously shown by our group and others to promote the stable ectopic expression of olfactory receptors). As4.1 release renin upon treatment with relevant stimuli, including the beta‐agonist isoproterenol. We first established methods by which we can detect and quantify this renin release including immunofluorescence, live‐cell imaging, and media fluorescence. As4.1 cells treated with isoproterenol (100μM, 20min) showed a decrease in intracellular renin staining via immunofluorescence as quantified by ImageJ (−35%, n=3, p&lt;0.05). Live cell imaging with quinacrine, an acidotrophic dye that naturally accumulates in renin‐containing granules, also shows a decrease in the fluorescence of these granules after treatment with 100μM isoproterenol (20 min, 30% decrease, n=3, p&lt;0.05). Additionally, we were able to detect renin release by measuring quinacrine fluorescence in the media after treatment of cells with isoproterenol. Media from As4.1 cells had a fluorescence increase from a relative baseline of 1.00 +/− 0.02 in untreated samples to 1.18 +/− 0.02 after isoproterenol treatment (100uM, 10 min, n=8 p&lt;0.05). After establishing these methods, we tested whether we could also quantify renin release in As4.1 cells that stably express Olfr78 following propionate treatment. Media from cells expressing Olfr78 had a fluorescence increase from a relative baseline of 1.00 +/− 0.02 in untreated samples to 1.21+/−0.023 after treatment with propionate (20mM, 10 min, n=8, p&lt;0.05) as compared to wild‐type AS4.1 cells 1.02+/−0.02 (n=8, p&gt;0.05). We hypothesize that Olfr78‐mediated renin release requires increases in cAMP levels, and that this release is inhibited by the elevation of cytosolic calcium levels. Efforts are underway to test this hypothesis and determine the essential downstream components of Olfr78‐ mediated renin release in this cell model, which will provide insights into renin release and blood pressure regulation in vivo.Support or Funding InformationSupport: NIDDKThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Renal responses to acute reflex activation of renal sympathetic nerve activity and renal denervation in secondary hypertension

We tested whether the responsiveness of the kidney to basal renal sympathetic nerve activity (RSNA) or hypoxia-induced reflex increases in RSNA, is enhanced in angiotensin-dependent hypertension in rabbits. Mean arterial pressure, measured in conscious rabbits, was similarly increased (+16 +/- 3 mmHg) 4 wk after clipping the left (n = 6) or right (n = 5) renal artery or commencing a subcutaneous ANG II infusion (n = 9) but was not increased after sham surgery (n = 10). Under pentobarbital sodium anesthesia, reflex increases in RSNA (51 +/- 7%) and whole body norepinephrine spillover (90 +/- 17%), and the reductions in glomerular filtration rate (-27 +/- 5%), urine flow (-43 +/- 7%), sodium excretion (-40 +/- 7%), and renal cortical perfusion (-7 +/- 3%) produced by hypoxia were similar in normotensive and hypertensive groups. Hypoxia-induced increases in renal norepinephrine spillover tended to be less in hypertensive (1.1 +/- 0.5 ng/min) than normotensive (3.7 +/- 1.2 ng/min) rabbits, but basal overflow of endogenous and exogenous dihydroxyphenolglycol was greater. Renal plasma renin activity (PRA) overflow increased less in hypertensive (22 +/- 29 ng/min) than normotensive rabbits (253 +/- 88 ng/min) during hypoxia. Acute renal denervation did not alter renal hemodynamics or excretory function but reduced renal PRA overflow. Renal vascular and excretory responses to reflex increases in RSNA induced by hypoxia are relatively normal in angiotensin-dependent hypertension, possibly due to the combined effects of reduced neural norepinephrine release and increased postjunctional reactivity. In contrast, neurally mediated renin release is attenuated. These findings do not support the hypothesis that enhanced neural control of renal function contributes to maintenance of hypertension associated with activation of the renin-angiotensin system.

Prostaglandins in macula densa function

Cyclooxygenase (COX)-2 mRNA and immunoreactive protein localize to the macula densa and adjacent cortical thick ascending limb in renal cortex, and chronic NaCl restriction increases expression of this enzyme. These findings suggest an integral role for eicosanoids generated by macula densa-associated COX-2 in mediating renin release. As selective inhibitors of COX-2 become available, it will be important to assess their effects on the renin-angiotensin system and glomerular hemodynamics.

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.

Molecular and cellular aspects of renin during kidney ontogeny

The activity of the renin-angiotensin system is subjected to remarkable developmental changes. Circulating as well as renal concentrations of renin are high in early life, decreasing progressively as maturation evolves. This review summarizes the current molecular framework underlying those changes during kidney development. Evidence is presented demonstrating that expression of the renin gene is developmentally regulated. Renin messenger ribonucleic acid (mRNA) levels are higher in fetuses and newborns than in adult mammals. As maturation progresses, the distribution of renin and its mRNA shifts from large intrarenal arteries in the fetus to the classic juxtaglomerular localization in the adult. Potential explanations for these changes as well as the cytosolic events mediating renin release and gene expression are discussed. Evidence is also presented demonstrating that under diverse physiologic and pathologic conditions the adult kidney vasculature has the capability to recruit renin gene expressing and/or containing cells. Throughout, an effort has been made to identify gaps in our knowledge. Not without bias, we hope that future research in this area will lead to a better understanding of the biology of renin in the developing as well as the adult individual.

Rat Juxtaglomerular Cells are Endowed with DA-1 Dopamine Receptors Mediating Renin Release

Under control conditions a primary culture containing about 80-90% of granular juxtaglomerular (JG) cells prepared from rat kidneys continuously released renin into the culture medium at a rate of 17.9 +/- 1.4 ng angiotensin I/h per mg of cell proteins per 30 min (n = 14). Dopamine (1.0 microM), the DA-1 dopamine receptor agonist fenoldopam (0.5 microM), and isoproterenol (1.0 microM) increased renin secretion markedly (130-200%). Propranolol (0.1 microM) reduced the effects of isoproterenol significantly (80%), but not those of dopamine or fenoldopam. In contrast, SCH 23390 (0.01 microM), a DA-1 dopamine receptor antagonist, inhibited markedly only the renin release evoked by the latter two agonists, whereas S-sulpiride (10 microM), a DA-2 dopamine receptor antagonist, and phentolamine (10 microM), a nonselective alpha-adrenoceptor antagonist, did not modify the effects of either dopamine or fenoldopam. In rats, pithed to eliminate reflexogenic mechanisms regulating renin release, at the end of a 15 min i.v. infusion of fenoldopam (20 micrograms/kg per min) there was a significant increase in plasma renin activity. This effect was completely prevented by SCH 23390 (0.1 mg/kg i.v.) but not significantly changed by S-sulpiride (0.3 mg/kg i.v.) or phentolamine (3.0 mg/kg i.v.) plus propranolol (0.75 mg/kg i.v.). In conclusion, these results indicate that DA-1 dopamine receptors are present in rat kidney JG cells and that pharmacological stimulation of these receptors with dopamine or fenoldopam leads to renin secretion.

Changes in plasma catecholamines and plasma renin activity during hypotension in conscious rats with lesions of the nucleus tractus solitarii

The purpose of the present study was to examine the effects of lesions of the nucleus tractus solitarii on the reflex control of sympathetic activity and renin release in the conscious rat. Two doses of the arteriolar vasodilator hydralazine (0.3 and 1 mg/kg, i.v.) were used to activate reflexively the sympathetic nervous system in nucleus tractus solitarii lesion and control rats. Administration of 1 mg/kg of hydralazine to the control rats caused mean arterial pressure to fall from 120 ± 2 mm Hg to 84 ± 2 mm Hg and elicited an 11.2-fold increase in plasma renin activity and a 2.7-fold increase in plasma norepinephrine concentration. Administration of 0.3 mg/kg of hydralazine caused the arterial pressure of the lesion group to fall from 118 ± 3 mm Hg to a comparable value of 85 ± 4 mmg Hg, but plasma renin activity and plasma norepinephrine concentration did not rise significantly. However, administration of 1 mg/kg of hydralazine to the lesion group caused arterial pressure to fall from 128 ± 6 mm Hg to 64 ± 2 mm Hg, in association with a 12.4-fold increase in plasma renin activity and a 1.6-fold elevation in plasma norepinephrine concentration. Atenolol, a β 1-adrenoceptor antagonist, blocked 70% of the rise in plasma renin activity caused by 1 mg/kg of hydralazine in both groups of rats. In addition, prior renal denervation also markedly attenuated the rise in plasma renin activity caused by hydralazine in the lesion group. Finally, electrical stimulation of the vagus nerves, which caused a large vasodepressor response in the control group, failed to lower the arterial pressure of the lesion group. Based on these observations, we conclude that in the conscious rat (1) nucleus tractus solitarii lesions eliminate the arterial baroreflexes as well as the the cardiopulmonary baroreflex, and (2) severe hypotension induces sympathetically mediated renin release in the apparent absence of arterial and cardiopulmonary baroreflex function.

Parabrachial lesions increase plasma norepinephrine concentration, plasma renin activity and enhance baroreflex sensitivity in the conscious rat

Electrolytic lesions of the parabrachial nucleus (PBN) caused significant increases in basal plasma renin activity (+433%) and basal plasma norepinephrine concentration (+98%) in conscious rats. Plasma epinephrine concentration, mean arterial pressure, heart rate, hematocrit, plasma osmolality and plasma sodium and potassium concentrations were not significantly affected by the lesions. Atenolol reduced the elevated plasma renin activity in the lesion group to a value similar to that of a control group (sham lesions or lesions in areas adjacent to the PBN). Captopril significantly lowered mean arterial pressure in the lesion group, but it had no effect on arterial pressure in the control group. Lesions of the PBN also increased the baroreflex-mediated bradycardia evoked by an abrupt elevation of arterial pressure. We propose that the PBN tonically inhibits sympathetic activity, sympathetically mediated renin release and baroreflex sensitivity.

Characterization of beta-adrenoceptor subtypes in rat kidney with new highly selective β1 blockers and their role in renin release

Highly selective beta-adrenoceptor blocking agents with a β 1 : β 2-selectivity ratio of 0.015 to 3400 were used to characterize the β-adrenoceptors present in rat kidney and to identify those mediating renin release. The results obtained with ICYP binding to kidney membranes revealed the presence of both β 1- and β 2-adrenoceptors in a ratio of 1:1. The p K D β 1 and p K D β 2- values of selective β-antagonists obtained in rat kidney membranes correlated well with those found in guinea pig left ventricle ( β 1) and lung ( β 2), indicating that kidney receptor subtypes are pharmacologically identical with those in the ventricle and lung, respectively. In the isolated perfused rat kidney, the apparent p A 2 values of β 1-selective blockers for inhibition of isoprenaline-stimulated renin release correlated well with p K D β 1, but not with p K D β 2 values. These results clearly show that the β 1-adrenoceptor subtype mediates renin release in the rat kidney.

Prostacyclin-independence in beta-adrenoceptor mediated renin release from dog renal cortical slices

There is some controversy regarding whether stimulation of renin release by the β-adrenergic system is dependent on prostaglandin (PG) production. We have examined this problem in renal cortical slices of the dog and have obtained the following results: (1) Isoproterenol (4×10 −6 M) stimulated renin release, but had no effect on the formation of 6-keto PGF 1α, a stable metabolite of PGI 2; (2) Indomethacin (2×10 −5 M) had no effect on isoproterenol stimulated renin release, but inhibited 6-keto PGF 1α formation; (3) Dibutyryl cyclic AMP (10 −3 M) stimulated both renin release, and 6-keto PGF 1α release. Indomethacin (2×10 −5 M) did not inhibit dibutyryl cyclic AMP-stimulated renin release, but did inhibit the production of 6 keto PGF 1α. These results indicate that the β-adrenoceptor mediated renin release does not depend on the formation of PGI 2, but renin release is dependent on cyclic AMP formation.

Contribution of Beta-Adrenergic Receptor Mediated Renin Release to the Maintenance of Blood Pressure During Nitroprusside Infusion in Conscious Rats

The extent to which beta-adrenergic receptor mediated renin release contributes to the maintenance of blood pressure during hypotension induced by sodium nitroprusside (SNP, 40 micrograms/kg/min for 30 min) was assessed in conscious Wistar rats fitted with chronic aortic and vena caval catheters. Propranolol, (1.5 mg/kg, i.v.), reduced the basal level of plasma renin activity (PRA) in control rats from 4.4 +/- 0.4 to 2.4 +/- 0.4 ng angiotensin I/ml/min (p less than .05) and decreased PRA obtained during SNP infusion from 35.3 +/- 6.6 to 16.7 +/- 2.2 ng angiotensin I/ml/min (p less than .01). Despite the reduced PRA, the hypotensive response to SNP was not enhanced after propranolol. Treatment of these animals with captopril in order to block the actions of the remaining non-beta-receptor released renin, resulted in augmentation of the SNP hypotension. Captopril also potentiated SNP hypotension in rats that had not received propranolol. The addition of propranolol to the captopril treated rats produced no further change in SNP hypotension. The results of this study indicate that beta-receptor-mediated and beta-receptor-independent mechanisms contribute to the renin released during SNP hypotension. However, if the beta-receptor-mediated component alone is blocked, the remaining renin secretion is adequate to maintain blood pressure during SNP infusion.

Yohimbine induces sympathetically mediated renin release in the conscious rat

The preferential α 2-adrenergic antagonist yohimbine (4 mg/kg s.c) caused a time-related increase in serum renin activity and heart rate in conscious Sprague-Dawley rats. Although mean arterial pressure was not decreased significantly over the 2-h period, heart rate was elevated significantly at 15 and 30 min post-injection. In contrast, serum renin activity remained elevated for up to 2 h with a 9-fold and 9.7-fold increase occuring at 30 and 60 min post-injection, respectively. Yohimbine (0.3, 1, 3 and 10 mg/kg s.c.) elicited a dose-related increase in serum renin activity and heart rate (30 min post-injection). The 1 mg/kg dose of yohimbine did not alter blood pressure whereas the 3 mg/kg dose caused a variable decrease in mean arterial pressure. The highest dose of yohimbine (10 mg/kg) significantly lowered blood pressure. The β-adrenergic receptor antagonist propranolol (1.5 mg/kg s.c.), blocked the renin release and tachycardia caused by yohimbine (1 and 3 mg/kg s.c.), and the ganglionic blocking agent chlorisondamine partially inhibited the renin release elicited by 3 mg/kg (s.c.) of yohimbine. The prostaglandin synthetase inhibitors indomethacin (5 mg/kg s.c.) and meclofenamate (5 mg/kg s.c.) impaired the ability of yohimbine (3 mg/kg) to elevate SRA but did not alter the hemodynamic effects of yohimbine. Thus, the increase in renin release caused by yohimbine appears to be mediated by the sympathetic nervous system. Because the smaller doses of yohimbine increase renin release in the absence of a decrease in mean arterial pressure, it is unlikely that yohimbine stimulates renin release by baroreflex-mediated activation of the renal sympathetic nerves. We feel that yohimbine increases the rate of release of norepinephrine onto the granular juxtaglomerular cells of the kidney by blocking prejunctional α 2-adrenergic receptors on the renal sympathetic nerve and/or a centrally mediated activation of the peripheral sympathetic nervous system.

Subclassification of human beta-adrenergic receptors mediating renin release.

To determine the beta-adrenoceptor subtype controlling renin release from the kidneys, several beta-adrenoceptor subtype selective agonists and antagonists were administered to 15 healthy volunteers. While isoprenaline infusion (1, 2 and 4 micrograms/min for 5 min each) markedly increased plasma renin activity (PRA), the beta 2-selective agonist fenoterol failed to change PRA. The isoprenaline induced rise in PRA could be completely prevented by the beta 1-selective antagonists metoprolol (10 mg i.v. 45 min prior to isoprenaline infusion) and betaxolol (5 mg i.v. 45 min prior to infusion) indicating that renin release is mediated by beta 1-adrenoceptors. Binding studies with the highly specific beta-adrenoceptor radioligand (+/-)-125iodocyanopindolol demonstrated that membranes from human kidney cortical slices contain predominantly, if not exclusively, beta 1-adrenoceptors. These in vivo and in vitro results support the view that the beta-adrenoceptor mediating renin release from the human kidney is of the beta 1-subtype.

Inhibition of captopril-induced increase in plasma renin activity by propranolol.

The inhibition of renin release by angiotensin II (AII) is well documented. However, the interaction of this short loop feedback mechanism of AII with the sympathetic nervous system is still unclear. This study was designed to investigate the possible functional relationship between AII and the beta-adrenergic receptors with respect to renin release in vivo. First, the effect of propranolol on captopril-induced renin release was examined in conscious rats. Secondly, the effect of AII on isoproterenol-induced renin release was determined. Captopril (1 mg/Kg) increased plasma renin activity (PRA) from 1.6 +/- 0.3 ng/ml/hr to 4.5 +/- 0.6 ng/ml/hr (p less than 0.01). In contrast, there was no significant change in PRA in rats which received both captopril and propranolol (before 0.9 +/- 0.2 ng/ml/hr, after 1.3 +/- 0.3 ng/ml/hr). Thus, propranolol attenuated the increase in PRA caused by captopril. Isoproterenol infusion (0.1 micrograms/Kg/min) provoked a significant increase in PRA (before 1.3 +/- 0.4 ng/ml/hr, after 6.6 +/- 1.7 ng/ml/hr, p less than 0.01). AII infusion in combination with isoproterenol also increased PRA from 1.6 +/- 0.4 ng/ml/hr to 5.2 +/- 0.3 ng/ml/hr (p less than 0.01). AII in this dose did not suppress isoproterenol-induced renin release. These results suggest that the beta-adrenergic receptor mediating renin release is functionally located distal to the AII receptor in the short loop mechanism controlling renin release.

An investigation into the type of beta-adrenoceptor mediating sympathetically activated renin release in the cat.

1 Stimulation of the renal nerves in the cat was previously shown to cause renin release which could be blocked by propranolol. An attempt was made in this study to determine the type of beta-adrenoceptor mediating this response.2 In anaesthetized, unilaterally nephrectomized cats, a comparison was made of the ability of two selective beta-adrenoceptor antagonists to block the tachycardia and hypotension caused by isoprenaline (mediated respectively by beta(1)- and beta(2)-adrenoceptors) and the release of renin caused by renal nerve stimulation.3 Isoprenaline (mean dose of 0.224 +/- 0.022 nmol/kg), increased heart rate by approximately 43 beats/min and decreased mean blood pressure by 47 mmHg. Stimulation of the distal cut ends of the renal nerves, at a rate sufficient to reduce renal blood flow by 30%, resulted in an approximately 150% increase in plasma renin activity.4 Administration of the selective beta(1)-adrenoceptor antagonist, atenolol (0.38 to 11.28 mumol/kg), caused a dose-related inhibition of nerve stimulated renin release and of isoprenaline-induced tachycardia, with no diminution of the vasodepressor response to isoprenaline; in contrast, the selective beta(2)-adrenoceptor antagonist, erythro-DL-(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol (ICI 118, 551, 0.03 to 2.86 mumol/kg), caused a dose-related inhibition of the isoprenaline-induced vasodepression without altering the increase in plasma renin activity caused by renal nerve stimulation. Only at the highest dose of ICI 118, 551 was there a reduction of isoprenaline-induced tachycardia, by about 40%.5 The selective inhibition of neurally activated renin release by atenolol but not by ICI, 118, 551 is consistent with the suggestion that the beta-adrenoceptors mediating renin release resemble those in the heart more closely than those in peripheral blood vessels.

Maintenance of blood pressure by beta adrenoceptor mediated renin release during different forms of anesthesia in rats.

In rats we assessed the role of the sympathetic nervous system in the increase of plasma renin activity (PRA) following induction of anesthesia by urethane, ether, or pentobarbital and the role of these increased levels of PRA in the maintenance of blood pressure.Urethane and ether induced marked, sustained increases in PRA. Pentobarbital was less effective in this regard. Propranolol inhibited the response of PRA to urethane and ether in a dose-dependent manner but not the renin response to pentobarbital. Similarly, neonatal sympathectomy with 6-hydroxydopamine together with removal of the adrenal medulla prevented the renin response to urethane but not to pentobarbital.Blood pressure changed only slightly during urethane anesthesia, showed a sustained decrease during ether anesthesia, and a gradual return to normal following a marked initial drop during pentobarbital anesthesia. Saralasin pretreatment induced a marked decrease (40–45 mmHg; 1 mmHg = 133.322 Pa) in blood pressure during urethane anesthesia and smaller (10–20 mmHg) additional decreases during ether and pentobarbital anesthesia. In contrast, propranolol pretreatment did not significantly affect blood pressure during ether anesthesia and affected it to a minor degree (by 10–15 mmHg) during urethane and pentobarbital anesthesia.The results indicate that the increases in PRA following induction of anesthesia by urethane or ether, but not by pentobarbital, are mediated through the peripheral sympathetic nervous system via β adrenoceptors. The rennin–angiotensin system appears to be essential for the maintenance of a normal blood pressure during urethane anesthesia but plays a less prominent role in this regard during ether and pentobarbital anesthesia. The propranolol studies suggest that the hypotensive effect of propranolol through blockade of the renin response during urethane- and ether-induced anesthesia is masked by a pressor effect of propranolol.

Renin secretion and renal vascular resistance following prolonged administration of desoxycorticosterone (DOC) in rats drinking normal saline.

1. The effect of long-term administration of desoxycorticosterone (DOC)-saline on arterial blood pressure, renal vascular resistance and renin secretion rate was studied in the rat. 2. Renin secretion rate and peripheral plasma renin activity was markedly reduced in the DOC-saline treated rats. Renal vascular resistance was comparable to that found in a corresponding control group. Responsiveness to isoprenaline suggested that the beta-adrenoceptor mediating renin release was grossly intact. 3. A significant rise in blood pressure occurred in only 50% of the treated animals: However, no differences in weight gain, renal vascular resistance or renin levels were apparent when compared with animals which remained normotensive. 4. These findings indicate that suppression of renin secretion during prolonged DOC-saline administration cannot be directly attributed to changes in arterial pressure, renal vascular resistance or beta-adrenoceptor sensitivity.