Plasma Renin Activity Response Research Articles

Targeted disruption of CTCF binding near the Ren gene alters gene expression and plasma renin activity in response to dietary salt

Hypertension is the leading risk factor for cardiovascular disease and impacts one in three adults globally. One genetic mechanism that may affect blood pressure regulation and alter hypertension risk in the general population is the disruption of chromatin conformation by common genetic variation. CCCTCF-binding factor (CTCF) has many important functions including regulating the conformation of chromatin by binding to specific DNA sequences and can thereby alter gene expression. The renin locus has multiple CTCF motifs surrounding the renin gene and cellular expression of CTCF is critical for proper renin expression. Despite these important functions, the role that local chromatin conformation plays to regulate normal renin expression including its response to stimuli such as dietary salt intake and in the downstream regulation of blood pressure is unknown. We hypothesize that disruption of local chromatin conformation can alter gene expression, intermediate physiological mechanisms, and blood pressure. A mutant rat model was created using CRISPR-Cas9 in the genetic background of the Dahl salt-sensitive (SS) rat with a disruption to the CTCF binding motif located within an intron of Golt1a near the Ren gene which we have previously demonstrated an interaction with the renin proximal promoter. Here we report the preliminary characterization of this model for renin expression and plasma renin activity (PRA). Chromatin immunoprecipitation-qPCR showed a reduction in CTCF binding at the Golt1a locus in our mutant model compared to wild-type (WT), confirming our mutation resulted in a disruption in CTCF binding in vivo. An expected reduction (p<0.05) in renin expression was found in male and female WT and mutant rats in response to a high salt diet. WT males showed an expected inverse PRA relationship to dietary salt (WT: 0.1% NaCl=17.52, 0.4% NaCl=12.87, 4.0% NaCl=7.13; p<0.05) however, interestingly, mutant males failed to increase PRA in response to very low salt (0.1% NaCl) challenge (0.1% NaCl mutant=13.87; p<0.05 compared to WT 0.1% NaCl). Female mutants showed a similar but non-significant trend. Taken together, these data suggest that the disruption of CTCF binding in a region which interacts with the renin proximal promoter can alter renin expression and the plasma renin activity in response to very low dietary salt in SS rats. NIH 5P01HL149620-03 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.

PS-BPR03-9: A CASE OF RENAL JUXTAGLOMERULAR CELL TUMOR THAT WAS PREOPERATIVELY DIAGNOSED BY SELECTIVE RENAL VENOUS SAMPLING

A 26-year-old woman without a family history of hypertension was referred to our hospital for a further examination of juvenile hypertension. At 25 years of age, she had headaches, and hypertension (210/120 mmHg) was first noted. A diagnostic examination to assess the hypertension was performed and she was hypokalemic with serum K 2.9 mEq/L. Moreover, the plasma renin activity (PRA) and plasma renin concentration (PRC) was markedly elevated (18.7 ng/mL/h and 196.3 pg/mL), and plasma aldosterone concentration (PAC) was also elevated (291 pg/mL). A captopril challenge test showed a mildly increased PRA response (15.5 ng/mL/h to 20.3 ng/mL/h), but MR angiography and renogram showed no findings suggestive of renal vascular hypertension. On the other hand, dynamic contrast-enhanced CT showed a small neoplastic lesion (10 mm in diameter) without enhancement in the early phase, but with slight enhancement in the late phase, on the left renal upper pole. We performed renal vein sampling, but no obvious lateralization in PRA was found at the main trunk level of the left and right renal veins (14.0 vs. 14.3 ng/mL/h). Therefore, we performed more selective sampling of the branches of the left renal vein and found that PRA in the upper pole branch of the left renal vein was approximately 3.7 times higher than in the inferior pole branch, the main trunk of the left and right renal veins, and the inferior vena cava (51.5 ng/mL/h vs. 14.0–15.1 ng/mL/h). Based on these results, we made a preoperative diagnosis that the tumor in the upper pole of the left kidney was a juxtaglomerular cell tumor producing renin excessively and decided to perform partial left nephrectomy. Juxtaglomerular cell tumors (JCT) are very rare diseases that primarily occur in adolescents and young adults. Excessive renin secretion from the tumor causes secondary hypertension, and hypokalemia. It has been reported that renal vein sampling, in addition to CT and MRI scans, is useful for preoperative localization of JCT. However, the usual method of sampling only the main trunk of the renal vein fails to detect lateralization of the PRAs in many cases. In the present case, we were able to identify the localization of the tumor by performing sampling of the branches of the renal vein. We herein report on the usefulness of selective renal vein sampling for the preoperative diagnosis of JCT.

A Patient with Bilateral Primary Aldosteronism Refractory to Oral Eplerenone Who Responded to Esaxerenone with Increased Renin Activity

Patient: Male, 45-year-oldFinal Diagnosis: Bilateral primary aldosteronismSymptoms: HypertensionMedication: Mineralocorticoid receptor blockerClinical Procedure: Segmental adrenal venous sampling and medicationSpecialty: CardiologyObjective:Adverse events of drug therapyBackground:When mineralocorticoid receptor antagonist therapy is initiated for primary aldosteronism, the response of plasma renin activity indicates the level of cardiovascular risk. The purpose of this article was to compare the effect of mineralocorticoid receptor blockers on plasma renin activity levels in a patient with primary aldosteronism.Case Report:The patient was a 45-year-old male with severe hypertension. Because his aldosterone/renin ratio was high and a saline infusion test was positive, primary aldosteronism was diagnosed. Computed tomography revealed a low-density mass measuring 10 mm in the left adrenal gland. Segmental adrenal vein sampling demonstrated bilateral primary aldosteronism, so pharmacotherapy was started. Before treatment, his plasma renin activity was 0.5 ng/mL/hour. Eplerenone was commenced and the dose was increased to 100 mg/day. However, his plasma renin activity was still 0.8 ng/mL/hour and the maximum dose of eplerenone did not elevate plasma renin activity above 1 ng/mL/hour. Since plasma renin activity remained below 1 ng/mL/hour with mineralocorticoid receptor antagonist therapy, this patient was considered to have a higher cardiovascular risk than patients with essential hypertension. Accordingly, eplerenone was switched to esaxerenone, a new generation mineralocorticoid receptor blocker that became available in May 2019. After switching to esaxerenone (5 mg/day), the patient’s plasma renin activity increased to 1.8 ng/mL/hour and subsequently remained at 1 ng/mL/hour or higher.Conclusions:This is the first case report to present interesting changes of plasma renin activity in a primary aldosteronism patient after switching from eplerenone to esaxerenone. Elevation of plasma renin activity by esaxerenone in our primary aldosteronism patient reflected a mineralocorticoid receptor antagonistic effect that may have alleviated excessive mineralocorticoid receptor activation and volume expansion.

OP.LB.02.01] STRATEGY TO OPTIMIZE SODIUM INTAKE FOR INDIVIDUAL PATIENTS

Objective: Most Americans (90%) have dietary sodium intakes between 2.5 and 5.0 g/d. These limits are coterminous with optimal Cardiovascular (CVD) outcomes and, outcomes do not vary within this range. Beyond those limits, CVD risk increases. The health consequences of raising low, or lowering high intakes, is unknown. Thus, for persons at the extremes of sodium intake, we propose a strategy for their identification, dietary remediation, and ongoing health assessment may benefit as much as10% of the nation's population. Design and method: Epidemiological studies linking sodium intake with subsequent CVD were reviewed. History, physical exam, urine and blood tests can identify patients with sodium intakes < 2.5, and > 5.0 g/d. Dietary modification and/or supplementation can alter sodium intake. Although the strategy proposed is experimental, because its components are safe, and its effects readily assessed, it can be safely applied in clinical settings pending feasible rigorous scientific testing. Results: Persons with sodium intake < 2.5 or > 5. g/d can be identified and treated. Restricted diets and elevated Plasma Renin Activity (PRA), or signs of volume depletion, are associated with low sodium intakes < 2.5. Increased CVD risk is also present at sodium intakes >5.0 g/, but only when associated with hypertension. These patients have suppressed PRA. Sequential spot and, finally, 24-hour urine-analyses, can identify those most likely to benefit from optimtimizing sodium intake through a 1.0 g/d dietary change. Urinary sodium, PRA and blood pressure response should be monitored. Randomized trials – ultimately with hard clinical endpoints - must validate these interventions. Conclusions: The sodium intake of most Americans is optimal, yet 10% with intakes <2.5 or >5.0 g/d are at increased CVD risk. Since health consequences of altering dietary sodium are unknown, any intervention to modify intake is experimental and can and should be evaluated through clinical trials. Nevertheless, concerned and informed patients and physicians may seek to improve health outcomes by increasing or decreasing their sodium intakes. We have described a feasible strategy to identify individual patients for whom proven intervention to optimize sodium intake may be beneficial.

A previous history of repeated amphetamine exposure modifies brain angiotensin II AT1 receptor functionality

Previous results from our laboratory showed that angiotensin II AT1 receptors (AT1-R) are involved in the neuroadaptative changes induced by amphetamine. The aim of the present work was to study functional and neurochemical responses to angiotensin II (ANG II) mediated by AT1-R activation in animals previously exposed to amphetamine. For this purpose male Wistar rats (250–320g) were treated with amphetamine (2.5mg/kg/day intraperitoneal) or saline for 5days and implanted with intracerebroventricular (i.c.v.) cannulae. Seven days after the last amphetamine administration the animals received ANG II (400pmol) i.c.v. One group was tested in a free choice paradigm for sodium (2% NaCl) and water intake and sacrificed for Fos immunoreactivity (Fos-IR) determinations. In a second group of rats, urine and plasma samples were collected for electrolytes and plasma renin activity determination and then they were sacrificed for Fos-IR determination in Oxytocinergic neurons (Fos-OT-IR). Results: Repeated amphetamine exposure (a) prevented the increase in sodium intake and Fos-IR cells in caudate-putamen and accumbens nucleus induced by ANG II i.c.v. (b) potentiated urinary sodium excretion and Fos-OT-IR in hypothalamus and (c) increased the inhibitory response in plasma renin activity, in response to ANG II i.c.v. Our results indicate a possible functional desensitisation of AT1-R in response to ANG II, induced by repeated amphetamine exposure. This functional AT1-R desensitisation allows to unmask the effects of ANG II i.c.v. mediated by oxytocin. We conclude that the long lasting changes in brain AT1-R functionality should be considered among the psychostimulant-induced neuroadaptations.

Unique Dominant Negative Mutation in the N-Terminal Mitochondrial Targeting Sequence of StAR, Causing a Variant Form of Congenital Lipoid Adrenal Hyperplasia

Steroid acute regulatory (StAR) protein is a mitochondria-targeted protein that is part of the transduceosome complex crucial for transport of cholesterol to mitochondria. Recessive mutations cause classic and nonclassic congenital lipoid adrenal hyperplasia. The aim of this study was to report the clinical, hormonal, genetic, and functional data of a novel heterozygous mutation in the StAR gene found in a 46,XY patient with ambiguous genitalia and neonatal severe steroidogenic deficiency. Undetectable serum steroids with high ACTH and plasma renin activity but normal acute GnRH response were found in infancy. After gonadectomy (at 3 yr of age), serum LH and testosterone were undetectable, whereas FSH was normal but increased slowly afterward. Estrogen replacement therapy, started at 10.2 yr of age, suppressed gonadotropins (for 2 yr). However, after 1 month off estrogens, the patient showed castrated levels. At 11.9 yr old, after fludrocortisone withdrawal because of hypertension, plasma renin activity and aldosterone remained normal, suggesting mineralocorticoid recovery by a StAR-independent mechanism. We found a de novo heterozygous IVS-2A>G StAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1, and TSPO genes. The mutant StAR transcript lacked exon 2, resulting in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. In vitro, the mutant protein exhibited reduced StAR activity in a dominant-negative manner and almost no mitochondria localization. A misfolded p.G22_L59del StAR might interfere with wild-type StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype. We speculated that estrogen might have modulated mineralocorticoid function and pubertal maturation in a human natural model lacking endogenous steroid production.

Blood pressure and plasma renin activity responses to different strategies to inhibit the renin-angiotensin-aldosterone system during exercise

The effect of two different strategies for renin-angiotensin-aldosterone system (RAAS) blockade; direct renin inhibition (DRI) versus angiotensin receptor blockade (ARB) on blood pressure (BP) and plasma renin activity (PRA) was compared during exercise. Hypertensive adults were randomised to aliskiren (300 mg once daily, n=33) or valsartan (320 mg once daily, n=35). BP and PRA were measured during treadmill exercise (Bruce protocol), at baseline, end of treatment (eight weeks), and after treatment withdrawal (48 hours after last dose). After eight weeks treatment, Aliskiren inhibited PRA (>80%) at rest and during exercise, with inhibition remaining undiminished 48 hours after treatment withdrawal. In contrast, valsartan increased PRA at rest, and more-so during exercise (>400%). Angiotensin receptor blockade, as indicated by PRA increase, was reduced, 48 hours after valsartan treatment withdrawal, suggesting more sustained RAAS blockade with aliskiren. Despite divergent effects on PRA, similar exercise-induced changes in BP were seen. The primary outcome, the rise in systolic BP from rest to peak exercise (baseline to after treatment withdrawal) did not differ between treatments (p=0.25). Measurement of PRA is a more sensitive index of RAAS blockade than the BP response during exercise. Furthermore, after treatment withdrawal, aliskiren provides more sustained RAAS inhibition than valsartan at rest and during exercise.

β2-Adrenergic receptor genotype affects the renin-angiotensin-aldosterone system response to the Dietary Approaches to Stop Hypertension (DASH) dietary pattern

Beta(2)-adrenergic receptor (beta2-AR) is a susceptibility locus for hypertension, and polymorphisms at this site relate to salt sensitivity and low plasma renin activity (PRA). The Dietary Approaches to Stop Hypertension (DASH) dietary pattern lowers blood pressure and appears to interact with the renin-angiotensin-aldosterone system (RAAS). We hypothesized that the DASH diet associates with increased RAAS activity, and genotype status at beta2-AR G46A modifies this response. We genotyped participants in the DASH-Sodium study (n = 372) at beta2-AR G46A to determine the association with blood pressure, RAAS components, and consumption of the DASH diet. We used 2-way mixed linear regression and an additive model for all primary analyses. Mean (+/-SEM) PRA was significantly higher in participants in the DASH group than in participants in the control group (0.68 +/- 0.03 compared with 0.54 +/- 0.03 ng x mL(-1) x h(-1), P = 0.002). Serum aldosterone, urinary aldosterone, and urinary potassium concentrations were also significantly higher in the DASH group (P < 0.01 for all). We observed significant gene-diet interactions for changes in systolic blood pressure (SBP) and concentrations of aldosterone and urinary potassium (P for interaction = 0.048, 0.017, and 0.001 for SBP and aldosterone and urinary potassium concentrations, respectively). There was an association between the A allele of beta2-AR G46A and greater blood pressure reduction and blunted aldosterone and PRA responses to the DASH diet. Our results indicate that the DASH diet lowers blood pressure and increases PRA and aldosterone concentrations. There is an association between the G46A polymorphism of beta2-AR and blood pressure and RAAS responses to the DASH diet, which suggests that beta2-AR may be a genetic modifier of DASH-diet responsiveness. This trial was registered at clinicaltrials.gov as NCT00000608.

Difficult-to-control hypertension due to bilateral aldosterone-producing adrenocortical microadenomas associated with a cortisol-producing adrenal macroadenoma

The patient was a 54-year-old woman who developed a right adrenal tumour, Cushingoid features, elevated levels of cortisol that were not suppressed by 1 nor 8 mg of dexamethasone, and suppression of adrenocorticotropin (ACTH) during treatment for severe hypertension. Computed tomography (CT) revealed a right adrenal tumour and an atrophic left adrenal gland. In addition, elevated plasma aldosterone concentration (PAC) and suppressed plasma renin activity (PRA) with an aldosterone-to-renin ratio of 128 (ng per 100 ml per ng ml–1 h−1) suggested aldosterone excess. Urinary excretion of aldosterone was relatively high, and the captopril and rapid ACTH tests resulted in no response of PRA and exaggerated increase in PAC, respectively. ACTH-loaded adrenal venous sampling showed bilateral excess of aldosterone with right predominance of cortisol. Right laparoscopic partial adrenalectomy (ADX) and immunohistochemical analysis showed both a cortisol-producing adenoma and an aldosterone-producing microadenoma (microAPA) within the attached adrenal, which had not been detected by CT preoperatively. After the right partial ADX, her blood pressure, aldosterone level and suppressed PRA remained unchanged. Subsequently, laparoscopic total left ADX was performed. Two microAPAs with paradoxical hyperplasia were revealed within the apparently atrophic left adrenal gland. Soon after the second surgery, her blood pressure normalized without requiring any anti-hypertensive medication.

Effects of chronic sympatho‐inhibition on reflex control of renal blood flow and plasma renin activity in renovascular hypertension

We determined if chronic sympatho-inhibition with rilmenidine has functional significance for the kidney by altering responses of renal blood flow (RBF) and plasma renin activity (PRA) to stress and acute hypotension in rabbits with renovascular hypertension. RBF to each kidney and renal sympathetic nerve activity (RSNA) to the left kidney were measured in rabbits in which a renal artery clip induced hypertension (2K1C) and in sham-operated rabbits. After 2 weeks, a subcutaneous minipump was implanted to deliver rilmenidine (2.5 mg.kg(-1).day(-1)) to 2K1C rabbits for 3 weeks. After 5 weeks of renal artery stenosis, mean arterial pressure (MAP) was 23% higher and PRA 3-fold greater than in sham-operated rabbits. Blood flow and renal vascular conductance in the stenosed kidney were lower (-75% and -80%) compared with sham, and higher in the non-clipped kidney (68% and 39%). Responses of RBF and PRA to hypotension were similar in 2K1C and sham rabbits. Airjet stress evoked a greater increase in MAP in 2K1C rabbits than sham controls. Chronic rilmenidine normalized MAP, reduced RSNA and PRA, and did not reduce RBF in the stenosed kidney. Responses of RBF (clipped and non-clipped kidney), RSNA and PRA to hypotension and airjet were little affected by rilmenidine. Our observations suggest that chronic sympatho-inhibition is an effective antihypertensive therapy in renovascular hypertension. It normalizes MAP and reduces basal PRA without compromising blood flow in the stenosed kidney or altering responses of MAP, haemodynamics and PRA to acute hypotension and stress.

Effect of Sodium Depletion on the Renin-Angiotensin-Aldosterone System and Renal Prostaglandins in Acromegalic Patients

The effects of 5 days low sodium diet and diuretic were studied in 7 normotensive acromegalics, 8 hypertensive acromegalics and 12 normal subjects. Plasma renin activity was significantly lower in both groups acromegalics, compared with that of normal subjects. Plasma aldosterone was similar in normotensive acromegalics and healthy controls. The hypertensive acromegalics showed increased plasma aldosterone levels and blunted responses of plasma renin activity and plasma aldosterone to sodium depletion. Urinary prostaglandin E2 was significantly lower in hypertensive acromegalics before and after sodium depletion in comparison with normal subjects. Urinary 6-keto prostaglandin F1 alpha and thromboxane B2 were similar in all groups studied. The decreased production of PGE2 could contribute to the development of arterial hypertension in actomegaly.

Effect of metoclopramide on orthostatic hypotension in diabetes mellitus: failure to demonstrate the role of vasoconstrictive hormones.

Effect of metoclopramide (MCP), a dopaminergic antagonist, on orthostatic hypotension associated with diabetes mellitus, was investigated to prove its plausible role of renin-angiotensin-aldosterone and catecholamine activation by comparative study in 6 diabetics with orthostatic hypotension (OH) and 9 diabetics without OH. With MCP treatment, drop of systolic blood pressure (SBP) on standing was significantly improved. However, the postural responses of plasma renin activity (PRA), plasma aldosterone and norepinephrine were not enhanced by MCP treatment. Moreover, MCP treatment did not modify the vascular reactivity to the exogenously infused angiotensin II and norepinephrine. Thus, it would be interesting to speculate that MCP can improve SBP through its suppressive effect on some depressor substance(s) such as bradykinin which liberates exaggeratively in diabetic OH.

Function of dynamically stimulated endothelium and renin–angiotensin–aldosterone system in normotensive subjects with a family history of hypertension

Genetic influences on the acute stimulation of the renin-angiotensin-aldosterone system (RAAS) and on endothelial activation were studied by examining healthy blood donors with and without hypertensive parents. Healthy blood donors were assigned to two groups, according to the presence or absence of a parental history of hypertension. Plasma levels of renin, nitric oxide (NO) and plasminogen activator inhibitor 1 (PAI-1) were studied before and after acute alterations in renal perfusion induced by phlebotomy, and the two groups compared. During phlebotomy, 400-500 mL of blood was extracted from each subject, with that volume varying relative to each subject's body surface area (m(2)). No statistically significant inter-group differences were observed between the baseline mean levels of plasma renin, NO or PAI-1. After phlebotomy, significant increases were detected in mean plasma renin activity (PRA) and NO levels and in PAI-1 activity (P < 0.001). However, the increases in mean PRA (P < 0.05) level and PAI-1 activity (P < 0.05) were more pronounced in those with hypertensive parents than those without; conversely, the increase in NO levels was more pronounced in the latter group. No statistically or clinically significant difference was found between the mean body mass indices of these two groups. Only two subjects were overweight, and none were obese; the remainder had weights that were normal. We found no significant correlation between body mass index and either NO or PAI-1 level. Post-phlebotomy, PRA and PAI-1 responses were more dramatic, but the NO response less in normotensive subjects having a parental history of hypertension, suggesting that these changes may represent familial, possibly genetic influences before overt hypertension occurs.

CENTRAL CHOLINE SUPPRESSES PLASMA RENIN RESPONSE TO GRADED HAEMORRHAGE IN RATS

Central administration of choline increases blood pressure in normotensive and hypotensive states by increasing plasma concentrations of vasopressin and catecholamines. We hypothesized that choline could also modulate the renin-angiotensin pathway, the third main pressor system in the body. Plasma renin activity (PRA), which serves as an index of the function of the peripheral renin-angiotensin system, was determined in rats subjected to graded haemorrhage following central choline administration. Intracerebroventricular (i.c.v.) injection of choline (12.5-150 microg), a precursor of the neurotransmitter acetylcholine (ACh), inhibited the increase in PRA in rats subjected to graded haemorrhage by sequential removal of 0.55 mL blood/100 g bodyweight. Choline, in the range 50-150 microg, increased blood pressure. Intraperitoneal (i.p.) administration of 150 microg choline failed to alter blood pressure and plasma renin responses to graded haemorrhage. Administration of a higher dose (90 mg/kg, i.p.) of choline decreased blood pressure and enhanced PRA in the first two blood samples obtained during the graded haemorrhage. Physostigmine (10 microg, i.c.v.), ACh (10 microg, i.c.v.), carbamylcholine (10 microg, i.c.v.) and cytidine 5'-diphosphocholine (CDP-choline; 250 microg, i.c.v.) increased blood pressure and attenuated plasma renin responses to graded haemorrhage. Inhibition of PRA by i.c.v. choline was abolished by i.c.v. pretreatment with mecamylamine (50 microg), but not atropine (10 microg). Blood pressure responses to choline (150 microg) were attenuated by pretreatment with both mecamylamine and atropine. Inhibition of PRA in response to central choline administration was associated with enhanced plasma vasopressin and catecholamine responses to graded haemorrhage. Pretreatment of rats with a vasopressin antagonist reversed central choline-induced inhibition of plasma renin responses to graded haemorrhage without altering the blood pressure response. In conclusion, central administration of choline inhibits the plasma renin response to graded haemorrhage. Nicotinic receptor activation and an increase in plasma vasopressin appear to be involved in this effect.

Effects of Dietary Salt on Intrarenal Angiotensin System, NAD(P)H Oxidase, COX-2, MCP-1 and PAI-1 Expressions and NF-κB Activity in Salt-Sensitive and -Resistant Rat Kidneys

Background: Chronic consumption of a high-salt diet causes hypertension (HTN) and renal injury in Dahl salt-sensitive (SSR) but not salt-resistant rats (SRR). These events are, in part, mediated by oxidative stress and inflammation in the kidney and vascular tissues. Activation of the angiotensin II type 1 (AT₁) receptor plays an important role in the pathogenesis of oxidative stress and inflammation in many hypertensive disorders. However, the systemic renin-angiotensin system (RAS) is typically suppressed in salt-sensitive HTN. This study was designed to test the hypothesis that differential response to a high-salt diet in SSR versus SRR may be related to upregulation of tissue RAS and pathways involved in inflammation and reactive oxygen species (ROS) production. Methods and Results: SSR and SRR were studied 3 weeks after consumption of high- (8%) or low-salt (0.07%) diets. The SSR consuming a low-salt diet exhibited significant increases in AT₁ receptor, cyclooxygenase (COX) 2, plasminogen activator inhibitor (PAI) and phospho-IĸB in the kidney as compared to those found in SRR. The high-salt diet resulted in severe HTN and proteinuria (in SSR but not SRR) and marked elevations of renal tissue monocyte chemoattractant protein 1, p22^phox, NADPH oxidase subunit 4, angiotensin-II-positive cell count, infiltrating T cells and macrophages and further increases in AT₁ receptor, COX-2, PAI-1 and phospho-IĸB in the SSR group. The high-salt diet significantly lowered plasma renin activity (PRA) in SRR but not in the SSR. COX-1 abundance was similar on the low-salt diet and rose equally with the high-salt diet in both groups. Among subgroups of animals fed the low-salt diet, kidney glutathione peroxidase (GPX) abundance was significantly lower in the SSR than SRR. The high-salt diet raised GPX and mitochondrial superoxide dismutase (SOD) abundance in the SRR kidneys but failed to do so in SSR. Cu/Zn-SOD abundance was similar in the subgroups of SSR and SRR fed the low-salt diet. The high-salt diet resulted in downregulation of Cu/Zn-SOD in SSR but not SRR. Conclusions: Salt sensitivity in the SSR is associated with upregulations of the intrarenal angiotensin system, ROS-generating and proinflammatory/profibrotic proteins and an inability to raise antioxidant enzymes and maximally suppress PRA in response to high salt intake. These events can contribute to renal injury with high salt intake in SSR.

H 034 SPIRONOLACTONE LOWERS BLOOD PRESSURE IN RESISTANT HYPERTENSIVE PATIENTS WITH LOW PLASMA RENIN ACTIVITY

The purpose of this study was to examine the systolic blood pressure and plasma renin activity (PRA) responses to chronic stress in normotensive rats and in rats with one hypertensive parent. Twenty-four male Wistar-Kyoto (WKR) and 24 male F1 offspring of spontaneously hypertensive and WKY rats (BHR) were randomly assigned to 3 groups of 8 each. Experimental (E) animals were subjected to 2 hr daily of shock-shock conflict. Each response produced a 0.2 sec, 0.2–0.4 mA cutaneous electric shock. Failure to respond in 10 sec resulted in a train of 5 shocks (0.2 sec each sec). Yoked animals (Y) received the same shocks as E but had no control over their presentation. Finally, a control group (C) for maturation received no shocks. The E and Y animals were subjected to 14 weeks of conflict and were then monitored an additional 14 weeks in the absence of shock. All animals had their tail cuff blood pressures taken weekly except for 3 times when bloods were obtained for PRA assays. Analysis of blood pressure data revealed that: (1) BHR animals showed more of a blood pressure response to shock than WKY animals; (2) Y animals showed more of a response to conflict than E, especially for the BHR group; and (3) BHR shocked animals remained permanently elevated compared to BHR control animals even in the 14 week post-conflict period during which no shocks were given. Although PRAs for BHR animals were significantly higher than for WKY at the beginning of study, the stress-induced hypertension was associated with either normal or suppressed PRA values, suggesting that the hypertension in these animals is not a high renin hypertension.

Bradykinin B2 Receptor Does Not Contribute to Blood Pressure Lowering during AT1 Receptor Blockade

This study tested the hypothesis that endogenous bradykinin contributes to the effects of angiotensin AT(1) receptor blockade in humans. The effect of the bradykinin B(2) receptor antagonist d-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-d-Tic-Oic-Arg (HOE-140) (18 microg/kg/h i.v. for 6 h) on hemodynamic and endocrine responses to acute and chronic (1-month) treatment with valsartan (160 mg/day) was determined in 13 normotensive and 12 hypertensive salt-deplete subjects. Acute valsartan increased plasma renin activity (PRA) from 5.3 +/- 9.9 to 15.6 +/- 19.8 ng of angiotensin (Ang) I/ml/h (P < 0.001) and decreased aldosterone from 18.3 +/- 10.5 to 12.0 +/- 9.6 ng/dl (P < 0.001). Chronic valsartan significantly increased baseline PRA (10.5 +/- 15.5 ng of Ang I/ml/h; P = 0.004) but did not affect baseline angiotensin-converting enzyme activity or aldosterone. HOE-140 tended to increase the PRA response to valsartan, and it attenuated the decrease in aldosterone following chronic valsartan (P = 0.03). Acute valsartan decreased mean arterial pressure 12.7 +/- 6.9% (from 100.2 +/- 8.4 to 87.5 +/- 9.8 mm Hg in hypertensives and from 82.4 +/- 8.6 to 70.3 +/- 8.4 mm Hg in normotensives). HOE-140 did not affect the blood pressure response to either acute (effect of valsartan, P < 0.001; effect of HOE-140, P = 0.98) or chronic (valsartan, P = 0.01; HOE-140, P = 0.84) valsartan. Plasma cGMP was increased significantly during chronic valsartan (P = 0.048) through a bradykinin receptor-independent mechanism (effect of HOE-140, P = 0.13). Both acute (P < 0.001) and chronic (P < 0.001) valsartan increased heart rate. HOE-140 augmented the heart rate response to chronic valsartan (P = 0.04). These data suggest that endogenous bradykinin does not contribute significantly to the blood pressure-lowering effect of valsartan through its B(2) receptor.

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.

PGE 2 alleviates kidney and liver damage, decreases plasma renin activity and acute phase response in cirrhotic rats with acute liver damage

In this study, we evaluated the effect of prostaglandin E 2 (PGE 2) on renal and hepatic function using an experimental cirrhosis model plus acute liver damage (ALD). Male Wistar rats treated with carbon tetrachloride (CCl 4) for 8 weeks were used for the cirrhosis model. Cirrhotic rats were further exposed to an additional acute dose of CCl 4 to induce ALD and then treated with PGE 2 intramuscularly twice a day for 7 days (200 μg/Kg/day). PGE 2 administration started 3 h after the additional dosing of CCl 4 and PGE 2 effect on hepatorenal function was examined on days 1, 2, 3, and 7. PGE 2-treatment ameliorated the decrease in urinary sodium excretion, and normalized serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and plasma renin observed in cirrhotic rats with ALD. In addition, PGE 2-treatment decreased mean arterial pressure, glomerular hypercellularity and thickening of the kidney capillary wall, and liver steatosis and cellular necrosis. Also, PGE 2 increased the number of regenerative nodules. Finally, PGE 2-treatment inhibited the increase in Alpha 1-acid glycoprotein (pAGP), fibrinogen, and Apo A-1 mRNA expression by 83%, 59%, and 77%, respectively. These results suggest that PGE 2 administration may decrease the expression of acute phase proteins. In conclusion, PGE 2-treatment improved hepatic and renal function and may be useful to down-regulate the acute phase response in cirrhotic rats presenting ALD induced by CCl 4.

Plasma volume restoration with salt tablets and water after bed rest prevents orthostatic hypotension and changes in supine hemodynamic and endocrine variables.

Head-down bed rest changes the values of many cardiovascular and endocrine variables and also elicits significant hypovolemia. Because previous studies had not controlled for hypovolemia, it is unknown whether the reported changes were primary effects of bed rest or secondary effects of bed rest-induced hypovolemia. We hypothesized that restoring plasma volume with salt tablets and water after 12 days of head-down bed rest would result in an absence of hemodynamic and endocrine changes and a reduced incidence of orthostatic hypotension. In 10 men, we measured changes from pre-bed-rest to post-bed-rest in venous and arterial pressures; heart rate; stroke volume; cardiac output; vascular resistance; plasma norepinephrine, epinephrine, vasopressin, renin activity (PRA), and aldosterone responses to different tilt levels (0 degrees, -10 degrees, 20 degrees, 30 degrees, and 70 degrees); and plasma volume and platelet alpha2- and lymphocyte beta2-adrenoreceptor densities and affinities (0 degrees tilt only). Fluid loading at the end of bed rest restored plasma volume and resulted in the absence of post-bed-rest orthostatic hypotension and changes in supine hemodynamic and endocrine variables. Fluid loading did not prevent post-bed-rest increases in beta2-adrenoreceptor density or decreases in the aldosterone-to-PRA ratio (P = 0.05 for each). Heart rate, epinephrine, and PRA responses to upright tilt after bed rest were increased (P < 0.05), despite the fluid load. These results suggest that incidents of orthostatic hypotension and many of the changes in supine hemodynamic and endocrine variables in volume-depleted bed-rested subjects occur secondarily to the hypovolemia. Despite normovolemia after bed rest, beta2-adrenoreceptors were upregulated, and heart rate, epinephrine, and PRA responses to tilt were augmented, indicating that these changes are independent of volume depletion.