Decreased Plasma Renin Concentration Research Articles

Normative values of renin and aldosterone in clinically stable preterm neonates

BackgroundThere is a paucity of literature on the normative levels of plasma renin concentration (PRC) and serum aldosterone (SA) in premature neonates. This study aims to provide normative data on PRC and SA levels in preterm neonates in the first 2 weeks after birth and explore associations with maternal, perinatal, or postnatal factors.MethodsNeonates born at 26- to 34-week gestation were recruited from two neonatal intensive care units in Canada and Australia. The direct renin assay PRC and SA were analyzed on day 1 and days 14–21 after birth to compare across categorical variables and to produce normative values.ResultsA total of 262 subjects were enrolled from the Canadian (29%) and Australian (71%) sites. The mean gestational age was 30 weeks, with a mean birth weight of 1457 g. The normative values of PRC and SA for neonates born between 26 + 0 and 29 + 6 weeks and 30 + 0 and 34 + 0 weeks of gestation were produced for day 1 and day 14–21 after birth. Both PRC and SA increased from day 1 to day 14–21. The more premature neonates reached a higher PRC on days 14–21 after birth but exhibited lower SA levels on day 1 after birth. When comparing gender, birth weight, and maternal risk factor categories, no statistical differences in PRC or SA were found. A small but significant decrease in PRC, but not SA, was noted for neonates with placental pathology.ConclusionsThis study produced normative values of PRA and SA in clinically stable preterm neonates that can be referenced for use in clinical practice.Graphical A higher resolution version of the Graphical abstract is available as Supplementary information

SAT-386 Assessment Of Tissue Sodium Content By23Na-MRI In Patients With Adrenal Insufficiency

Patients with chronic primary adrenal insufficiency (PAI) depend on lifelong replacement therapy with gluco- (GC) and mineralocorticoids (MC). Monitoring is based on clinical parameters assessing hemodynamic stability, electrolyte status and plasma renin concentration (PRC). Reduced subjective well-being is however often described by these patients in absence of objectifiable abnormalities, thus suggesting a gap between the concept of adequate hormone substitution and physiological requirements. This study investigated the potential role of 23Na-MRI for noninvasive assessment of sodium status in PAI. Tissue sodium was initially analyzed both in the calf muscle and in the skin of 16 patients with chronic PAI and 16 sex-, age- and BMI-matched controls. Patients were classified into 3 groups (optimal/subtherapeutic/supraphysiological) according to the quality of GC and MC substitution assessed separately by clinical scores based on subjective wellbeing and clinical/laboratory parameters. We additionally performed a longitudinal analysis in 8 patients with newly diagnosed PAI. Muscle and skin sodium content (Muscle-SC, Skin-SC) were determined using a 23NA-MRI protocol on a 3T scanner implementing a 3D sequence. A vial with 100mmol/L of sodium was scanned with every participant. Tissue sodium is presented as the ratio of tissue sodium signal intensity to sodium signal intensity of the reference vial. Muscle-SC was significantly higher in patients with chronic PAI compared to controls (19.1 vs. 16.0, p<0.05), whereas Skin-SC was similar between the two groups (16.1 vs. 17.1). These results were replicated in the subgroups classified as receiving optimal GC and MC replacement, respectively. Skin-SC was significantly correlated with 24h-urine sodium level in the whole cohort. When comparing Muscle-SC and Skin-SC with obtained clinical scores a trend from lower SC for low scores to higher SC for higher scores was observed. The longitudinal analysis of 8 patients with newly diagnosed PAI revealed that Skin-SC was significantly lower at primary diagnosis compared to sex-, age- and BMI-matched controls (12.1 vs. 15.8, p=0.05), whereas the difference in Muscle-SC was less pronounced (14 vs. 16.1, p=0.18). A significant increase in both Muscle- and Skin-SC at follow-up compared to first diagnosis was detected (19.4 vs. 14, p<0.05 and 19.3 vs. 12.1, p<0.05), consistent with a significant decrease in PRC (200 vs. 31.2 ng/l, p<0.05). Interestingly, patients with chronic PAI under replacement therapy exhibited significantly higher Muscle-SC compared to controls. The agreement between tissue SC and clinical scores as well as the significant increase in tissue SC under replacement therapy in newly diagnosed patients indicate that 23Na-MRI might be a quantitative method to assess steroid replacement. Further studies on a larger cohort are, however, needed to prove these initial findings.

Collecting Duct Renin Does Not Mediate DOCA-Salt Hypertension or Renal Injury

Collecting duct (CD)-derived renin is involved in the hypertensive response to chronic angiotensin-II (Ang-II) administration. However, whether CD renin is involved in Ang-II independent hypertension is currently unknown. To begin to examine this, 12 week old male and female CD-specific renin knock out (KO) mice and their littermate controls were subjected to uni-nephrectomy followed by 2 weeks of deoxycorticosterone acetate (DOCA) infusion combined with a high salt diet. Radiotelemetric blood pressure (BP) was similar between KO and control mice at baseline; BP increased in both groups to a similar degree throughout the 2 weeks of DOCA-salt treatment. Urinary albumin excretion and plasma blood urea nitrogen were comparable between the two groups after DOCA-salt treatment. Fibrosis as assessed by Masson’s Trichrome stain/Sirius Red stain and collagen-1 mRNA expression was similar between control and KO mice. Compared to baseline, DOCA-salt treatment decreased plasma renin concentration (PRC), urinary renin excretion and medullary renin mRNA expression in both floxed and CD renin KO mice with no detectable differences between the two groups. Further, in primary culture of rat inner medullary CD, aldosterone treatment did not change renin activity or total renin content. Taken together, these data suggest that CD derived renin does not play a role in DOCA-salt hypertension.

Short-term vitamin D3 supplementation lowers plasma renin activity in patients with stable chronic heart failure: An open-label, blinded end point, randomized prospective trial (VitD-CHF trial)

Many chronic heart failure (CHF) patients have low vitamin D (VitD) and high plasma renin activity (PRA), which are both associated with poor prognosis. Vitamin D may inhibit renin transcription and lower PRA. We investigated whether vitamin D3 (VitD3) supplementation lowers PRA in CHF patients. We conducted a single-center, open-label, blinded end point trial in 101 stable CHF patients with reduced left ventricular ejection fraction. Patients were randomized to 6 weeks of 2,000 IU oral VitD3 daily or control. At baseline, mean age was 64 ± 10 years, 93% male, left ventricular ejection fraction 35% ± 8%, and 56% had VitD deficiency. The geometric mean (95% CI) of 25-hydroxyvitamin D3 increased from 48 nmol/L (43-54) at baseline to 80 nmol/L (75-87) after 6 weeks in the VitD3 treatment group and decreased from 47 nmol/L (42-53) to 44 nmol/L (39-49) in the control group (P < .001). The primary outcome PRA decreased from 6.5 ng/mL per hour (3.8-11.2) to 5.2 ng/mL per hour (2.9-9.5) in the VitD3 treatment group and increased from 4.9 ng/mL per hour (2.9-8.5) to 7.3 ng/mL per hour (4.5-11.8) in the control group (P = .002). This was paralleled by a larger decrease in plasma renin concentration in the VitD3 treatment group compared to control (P = .020). No significant changes were observed in secondary outcome parameters, including N-terminal pro-B-type natriuretic peptide natriuretic peptide and fibrosis markers. Most CHF patients had VitD deficiency and high PRA levels. Six weeks of supplementation with 2,000 IU VitD3 increased 25-hydroxyvitamin D3 levels and decreased PRA and plasma renin concentration.

Normotensive sodium loading in conscious dogs: regulation of renin secretion during β-receptor blockade

Renin secretion is regulated in part by renal nerves operating through beta1-receptors of the renal juxtaglomerular cells. Slow sodium loading may decrease plasma renin concentration (PRC) and cause natriuresis at constant mean arterial blood pressure (MAP) and glomerular filtration rate (GFR). We hypothesized that in this setting, renin secretion and renin-dependent sodium excretion are controlled by via the renal nerves and therefore are eliminated or reduced by blocking the action of norepinephrine on the juxtaglomerular cells with the beta1-receptor antagonist metoprolol. This was tested in conscious dogs by infusion of NaCl (20 micromol.kg(-1).min(-1) for 180 min, NaLoad) during regular or low-sodium diet (0.03 mmol.kg(-1).day(-1), LowNa) with and without metoprolol (2 mg/kg plus 0.9 mg.kg(-1).h(-1)). Vasopressin V2 receptors were blocked by Otsuka compound OPC31260 to facilitate clearance measurements. Body fluid volume was maintained by servocontrolled fluid infusion. Metoprolol per se did not affect MAP, heart rate, or sodium excretion significantly, but reduced PRC and ANG II by 30-40%, increased plasma atrial natriuretic peptide (ANP), and tripled potassium excretion. LowNa per se increased PRC (+53%), ANG II (+93%), and aldosterone (+660%), and shifted the vasopressin function curve to the left. NaLoad elevated plasma [Na+] by 4.5% and vasopressin by threefold, but MAP and plasma ANP remained unchanged. NaLoad decreased PRC by approximately 30%, ANG II by approximately 40%, and aldosterone by approximately 60%, regardless of diet and metoprolol. The natriuretic response to NaLoad was augmented during metoprolol regardless of diet. In conclusion, PRC depended on dietary sodium and beta1-adrenergic control as expected; however, the acute sodium-driven decrease in PRC at constant MAP and GFR was unaffected by beta1-receptor blockade demonstrating that renin may be regulated without changes in MAP, GFR, or beta1-mediated effects of norepinephrine. Low-sodium diet augments vasopressin secretion, whereas ANP secretion is reduced.

Normotensive sodium loading in normal man: regulation of renin secretion during β-receptor blockade

Saline administration may change renin-angiotensin-aldosterone system (RAAS) activity and sodium excretion at constant mean arterial pressure (MAP). We hypothesized that such responses are elicited mainly by renal sympathetic nerve activity by beta1-receptors (beta1-RSNA), and tested the hypothesis by studying RAAS and renal excretion during slow saline loading at constant plasma sodium concentration (Na+ loading; 12 micromol Na+.kg(-1).min(-1) for 4 h). Normal subjects were studied on low-sodium intake with and without beta1-adrenergic blockade by metoprolol. Metoprolol per se reduced RAAS activity as expected. Na+ loading decreased plasma renin concentration (PRC) by one-third, plasma ANG II by one-half, and plasma aldosterone by two-thirds (all P < 0.05); surprisingly, these changes were found without, as well as during, acute metoprolol administration. Concomitantly, sodium excretion increased indistinguishably with and without metoprolol (16 +/- 2 to 71 +/- 14 micromol/min; 13 +/- 2 to 55 +/- 13 micromol/min, respectively). Na+ loading did not increase plasma atrial natriuretic peptide, glomerular filtration rate (GFR by 51Cr-EDTA), MAP, or cardiac output (CO by impedance cardiography), but increased central venous pressure (CVP) by approximately 2.0 mmHg (P < 0.05). During Na+ loading, sodium excretion increased with CVP at an average slope of 7 micromol.min(-1).mmHg(-1). Concomitantly, plasma vasopressin decreased by 30-40% (P < 0.05). In conclusion, beta1-adrenoceptor blockade affects neither the acute saline-mediated deactivation of RAAS nor the associated natriuretic response, and the RAAS response to modest saline loading seems independent of changes in MAP, CO, GFR, beta1-mediated effects of norepinephrine, and ANP. Unexpectedly, the results do not allow assessment of the relative importance of RAAS-dependent and -independent regulation of renal sodium excretion. The results are compatible with the notion that at constant arterial pressure, a volume receptor elicited reduction in RSNA via receptors other than beta1-adrenoceptors, decreases renal tubular sodium reabsorption proximal to the macula densa leading to increased NaCl concentration at the macula densa, and subsequent inhibition of renin secretion.

Role of the renin-angiotensin system during alterations of sodium intake in conscious mice.

The present studies were performed to quantify circulating components of the renin-angiotensin-aldosterone axis and to determine the functional importance of this system during alterations in sodium intake in conscious mice. Increasing sodium intake from approximately 200 to 1,000 microeq/day significantly decreased plasma renin concentration from 472 +/- 96 to 304 +/- 83 ng ANG I. ml(-1). h(-1) (n = 5) but did not alter plasma renin activity from the low-sodium level of 7.7 +/- 1.1 ng ANG I. ml(-1). h(-1). Despite the elevated plasma renin concentration, plasma ANG II in mice on low-sodium level averaged 14 +/- 3 pg/ml and was significantly suppressed to 6 +/- 1 pg/ml by high-sodium intake (n = 7). Consistent with the modulation of ANG II, plasma aldosterone significantly decreased from 41 +/- 8 to 8 +/- 3 ng/dl when sodium intake was elevated (n = 6). In a final set of experiments, the continuous infusion of ANG II (20 ng. kg(-1). min(-1)) led to a mild salt-sensitive increase in mean arterial pressure from 108 +/- 2 to 131 +/- 2 mmHg as sodium intake was varied from low to high (n = 7). In vehicle-infused mice, mean arterial pressure was unaltered from 109 +/- 2 mmHg when sodium intake was increased (n = 6). These studies indicate that the physiological suppression of circulating ANG II may be required to maintain a constancy of arterial pressure during alterations in sodium intake in normal mice.

Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats.

Both the density and level of mRNA encoding insulin receptors in the kidney are inversely related to the dietary sodium content, suggesting a feedback mechanism that limits the insulin-induced sodium retention when extracellular fluid volume is expanded. Because angiotensin II affects tissue sensitivity to insulin in humans, we investigated whether angiotensin II affects insulin receptor binding and mRNA levels in the kidney, liver, and renal arteries of normal rats and rats with streptozotocin-induced diabetes mellitus. Non-diabetic and diabetic rats were infused for 7 days with either vehicle or angiotensin II at a rate of 200 ng. kg-1. min-1. In a separate experiment, normal rats were treated with an angiotensin converting enzyme inhibitor (captopril, 100 mg/dl in the drinking water) or vehicle for 7 days. Regional analysis of insulin receptor binding in the kidney and renal arteries was performed by an in situ technique using computerized microdensitometry and emulsion autoradiography. Insulin receptor mRNA levels were determined in renal and hepatic tissue by Northern blot hybridization and normalized with 28S rRNA. No differences in blood pressure were observed among diabetic and non-diabetic rats infused with either vehicle or angiotensin II, whereas captopril-treated rats had significantly lower blood pressure levels than their respective controls. Angiotensin II significantly decreased plasma renin concentration in both non-diabetic and diabetic rats. Insulin receptor number was significantly greater in the renal cortex of diabetic rats than in non-diabetics, whereas no significant differences were found in the outer medulla, inner medulla, or renal arteries. Angiotensin II infusion did not affect either the number or affinity of insulin receptors in any of the renal regions studied. Insulin receptor mRNA levels were significantly greater in the kidney and liver of diabetic rats than in non-diabetics and were not affected by angiotensin II infusion. Similar to angiotensin II infusion, captopril treatment did not affect either renal insulin receptor binding or mRNA levels. Thus, diabetic rats have increased insulin receptor binding and mRNA levels in comparison to non-diabetic rats. Angiotensin II infusion and captopril treatment do not affect insulin receptor binding and mRNA levels in the kidney, arguing against a role for this peptide in the modulation of renal sensitivity to insulin.

Effects of renin gene transfer on blood pressure and renin gene expression in a congenic strain of Dahl salt-resistant rats.

To investigate whether a BP-regulatory locus exists in the vicinity of the renin locus on rat chromosome 13, we transferred this chromosome segment from the Dahl salt-sensitive (S) rat onto the genetic background of the Dahl salt-resistant (R) rat. In congenic Dahl R rats carrying the S renin gene and fed an 8% salt diet, systolic BP was significantly lower than in progenitor Dahl R rats: 127 +/- 1 mmHg versus 138 +/- 4 mmHg, respectively (P < 0.05). Moreover, the decreased BP in the congenic Dahl R strain was associated with decreased kidney renin mRNA and decreased plasma renin concentration. These findings demonstrate that the Dahl S strain carries alleles in or near the renin locus that confer lower plasma renin concentration and lower BP than the corresponding alleles in the Dahl R strain, at least when studied on the genetic background of the Dahl R rat and in the environment of a high salt diet. The occurrence of coincident reductions in kidney renin mRNA, plasma renin concentration, and BP after interstrain transfer of naturally occurring renin gene variants strongly suggests that genetically determined variation in renin gene expression can affect BP.

Effect of contraceptive steroid and enalapril treatment of systolic blood pressure and plasma renin-angiotensin in the rat.

Previous work has demonstrated contraceptive steroid-induced hypertension in rats. Here, we examined the relationship between steroid-induced hypertension and components of the renin-angiotensin system. Female Sprague-Dawley rats were injected s.c. with 0.2 micrograms ethynyloestradiol, 2.0 micrograms levonorgestrel, a combination of both or vehicle, six days per week. A second group of rats received 2.0 micrograms enalapril maleate, enalapril plus ethynyloestradiol or levonorgestrel, or vehicle. Systolic blood pressure increased with both ethynyloestradiol. (6 weeks, +17 mmHg; 12 weeks, +32 mmHg) and levonorgestrel (6 weeks, +24 mmHg) treatment. This effect of levonorgestrel was attenuated by co-administration of enalapril, which also reversed the hypertension seen with ethynyloestradiol. Ethynyloestradiol, but not levonorgestrel treatment caused a significant increase in plasma renin concentration, plasma renin activity, and plasma angiotensin II at both 6 and 12 weeks. Plasma renin substrate was increased by ethynyloestradiol at 3, 6 and 12 weeks, prior to the observed increase in systolic blood pressure. Combined steroid treatment had less pronounced effects. Enalapril alone or in combination with ethynyloestradiol decreased plasma renin concentration, activity and angiotensin II, and in combination with levonorgestrel decreased plasma renin concentration, substrate and activity (6 weeks only) but not angiotensin II. The data indicate a positive relationship between hypertension and the renin-angiotensin system with ethynyloestradiol, but not levonorgestrel treatment in rats.

Role of endogenous endothelin on renal functions in rats

This study was conducted to determine the involvement of endogenous endothelin (ET), a novel potent vasoconstricting peptide, in systemic and renal hemodynamics and in the renin-angiotensin system by inhibiting ET action via infusion of a specific ET antiserum at a time of altered sodium balance. Infusion of 1:50 diluted ET antiserum, which completely inhibited renal vasoconstriction by the exogenously administered ET (0.25 to 1.0 nmol/kg), caused an increase in urinary sodium excretion and fractional excretion of sodium and a decrease in plasma renin concentration without significant changes in blood pressure, heart rate, glomerular filtration rate, renal plasma flow, and urine volume compared with the values with nonimmune serum in conscious rats fed a low-salt diet. A time control study showed no significant changes in all parameters. These results suggest that the state of low- compared to high-salt intake causes a relatively stronger activity of endogenous ET, and that the endogenous ET contributes to the adaptative modulations of sodium excretion via renal tubular action and renin release in association with the changed state of sodium balance.

Effects of Physical Training during the Growth on the Granulation of Myo-Epithelioid Cells of the Rat Kidney

The behaviour of the granulation of the myo-epithelioid cells of the juxtaglomerular apparatus of the kidney and its relationship with the plasma concentrations of renin, sodium and potassium, and plasma osmolality have been studied in male and female Wistar rats that have been subjected to a programme of moderate physical exercise throughout their period of growth. In the trained rats a significant increase in the juxtaglomerular granulation index and a significant decrease in plasma renin concentration has been observed, the changes being more prominent in the female animals. Moreover in the trained rats significant increases in plasma sodium, potassium and osmolality have been observed.

Renal effects of selective adenosine receptor agonists in anesthetized rats.

Exogenous adenosine affects renal hemodynamics, renal tubular transport processes, and the secretion of renin. However, adenosine is not a selective agonist; it activates both A1 and A2 cell-surface receptors and it binds to an intracellular P-site that inhibits adenylate cyclase activity. Recent in vitro studies have suggested that activation of A1- and A2- adenosine receptors results in opposite effects on renin secretion. The purpose of these experiments was to examine the renal effects of A1- and A2-adenosine receptor agonists in vivo. 5'-N-ethylcarboxamide adenosine (NECA), 2-chloroadenosine (2-CLA), and N6-cyclohexyladenosine (CHA) were infused intravenously at rates that produced comparable decreases in systemic arterial blood pressure. All three of these adenosine analogues produced comparable decreases in para-aminohippurate (PAH) and inulin clearances and in Na and K excretion rates. CHA, an A1-selective agonist, markedly decreased plasma renin concentration (PRC), whereas NECA, an A2-selective agonist, markedly increased PRC; 2-CLA, a nonselective agonist, produced a smaller increase in PRC. Taken together, these results suggest that occupation of A1- and A2-receptors inhibits and stimulates renin secretion in vivo, independently of the effects of these adenosine receptor agonists on arterial blood pressure, renal hemodynamics, and tubular Na and K transport.

Increased plasma vasopressin in low renin essential hypertension.

Baseline plasma vasopressin concentrations were measured in 48 men (all 50 years old) with decreased plasma renin concentration and untreated, sustained essential hypertension and in 29 healthy normotensive men. Mean hypertensive plasma vasopressin concentration was more than twice as high as the corresponding normotensive level (15.7 +/- 2.2 [SE] vs 7.5 +/- 1.0 pg/ml; p less than 0.001). Plasma renin concentration in the hypertensive group was reduced compared with that in the normotensive group (0.28 +/- 0.04 vs 0.46 +/- 0.06 Goldblatt units X 10(-4)/ml). These differences appeared despite virtually identical serum osmolality, creatinine clearance, and urinary sodium excretion in the two groups. In the first 38 hypertensive subjects, arterial plasma epinephrine concentrations were significantly increased over those of the first 28 control subjects (99 +/- 12 vs 68 +/- 6 pg/ml; p less than 0.025). In contrast to those with low renin essential hypertension, 35 men with normal renin essential hypertension (all 40 years old) had normal plasma vasopressin levels that were not significantly different from those in a comparable normotensive control group (3.7 +/- 0.8 vs 3.5 +/- 0.4 pg/ml). Arterial epinephrine concentrations were not significantly different between normal renin subjects and the control group. After 6 weeks of treatment with the nonselective beta-adrenergic receptor blocker oxprenolol in 11 subjects with low renin hypertension, blood pressure was reduced and the plasma vasopressin concentration fell from 27.6 +/- 6.4 to 13.5 +/- 4.2 pg/ml (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

An Analysis of Blood Pressure Effects of Nipradilol and Prizidilol in Normotensive and Spontaneously Hypertensive Rats

Nipradilol and prizidilol are β-adrenoceptor blocking drugs with vasodilator action. These drugs lowered blood pressure (BP) in spontaneously hypertensive (SHR) rats acutely (24 hr) and subacutely (3 weeks) at doses of 10 and 20 mg/kg per day, p.o., respectively. Nipradilol decreased plasma renin concentration in acute and subacute studies, whereas it was unchanged with prizidilol treatment. Paradoxical effects of these drugs on BP were analyzed further: BP determined indirectly at the tail was slightly higher in SHR rats than the control, whereas BP determined directly through an aortic cannula without anesthesia, restraint, or prewarming was lower. We found that the discrepancy between BP values determined directly and indirectly was due to the increase in BP by prewarming stress during the determination by the tail cuff method.

Effect of Clonidine on Blood Pressure in Chronic One-Kidney, One-Clip and Two-Kidney, One-Clip Hypertensive Rats

Oral administration of clonidine lowered the high blood pressure in two-kidney, one-clip hypertensive rats in chronic stage (three to four months), but not in one-kidney, one-clip hypertensive rats. This reduction of blood pressure was well correlated with decrease in plasma renin concentration, but not with decrease in urinary noradrenaline excretion. These results suggest that the reduction of blood pressure in twokidney, one-clip hypertensive rats may be due to reduced renin release through the action of clonidine, while in one-kidney, one-clip hypertensive rats the sympathetic nervous activity may play little or no role in the maintenance of high blood pressure. Oral administration of clonidine lowered the high blood pressure in two-kidney, one-clip hypertensive rats in chronic stage (three to four months), but not in one-kidney, one-clip hypertensive rats. This reduction of blood pressure was well correlated with decrease in plasma renin concentration, but not with decrease in urinary noradrenaline excretion. These results suggest that the reduction of blood pressure in twokidney, one-clip hypertensive rats may be due to reduced renin release through the action of clonidine, while in one-kidney, one-clip hypertensive rats the sympathetic nervous activity may play little or no role in the maintenance of high blood pressure.

Effect of Clonidine on Blood Pressure in Chronic One-Kidney, One-Clip and Two-Kidney, One-Clip Hypertensive Rats

Oral administration of clonidine lowered the high blood pressure in two-kidney, one-clip hypertensive rats in chronic stage (three to four months), but not in one-kidney, one-clip hypertensive rats. This reduction of blood pressure was well correlated with decrease in plasma renin concentration, but not with decrease in urinary noradrenaline excretion. These results suggest that the reduction of blood pressure in two-kidney, one-clip hypertensive rats may be due to reduced renin release through the action of clonidine, while in one-kidney, one-clip hypertensive rats the sympathetic nervous activity may play little or no role in the maintenance of high blood pressure.

β-Adrenoceptor Blockade and Genetic Hypertension Development in Rats

The effects of propranolol (100 mg/kg), atenolol (200 mg/kg) and acebutolol (1000 mg/kg) administered daily by gavage to spontaneously hypertensive rats (SHRs) from their 6th to 20th weeks of age were investigated on genetic hypertension development (GHD) and at regular intervals on heart rate (HR), cardiac output (CO), stroke volume (SV), peripheral resistence (PR), plasma renin concentration (PRC) and heart weight/body weight ratio (HW/BW). Treatment with propranolol and especially atenolol markedly inhibited GHD while acebutolol was ineffective. No correlation was found between GHD prevention and (1) the degree of beta-adrenergic blockade (2) the reductions in HR and CO and (3) the decrease in PRC induced by the three treatments. Although none of the three drugs prevented the progressive increase in PR which develops in SHRs during their growth, propranolol and atenolol opposed GHD mainly by reducing CO, this effect being however partly counterbalanced for atenolol by a secondary potentiation of PR increase. With acebutolol, a similar reinforcement of PR increase occurred which completely neutralized the reduction in CO, resulting in the drug's ineffectiveness against GHD. These differential effects of the three drugs probably reflect different early induced structural modifications at cardiac and/or vascular levels.

The renin and isorenin-angiotensin system in rats with hereditary hypothalamic diabetes insipidus

It is known that the active end product of the renin-angiotensin system, angiotensin II, will stimulate ADH release in the brain and corticosteroid release from the adrenal gland and it is possible that isorenin-angiotensin systems present in those tissues are important control mechanisms for that release. In these experiments plasma renin and adrenal gland and brain isorenin concentration (ISO-RC) measurements were made in rats of the Brattleboro strain with hereditary hypothalamic diabetes insipidus (DI) both with and without ADH substitution. Heterozygous DI rats have low storage levels of ADH but can maintain normal water balance. These animals had normal plasma renin concentrations and increased ISO-RC in the hypothalamus and neurohypophysis compared to Long-Evans control rats. Substitution with 100 mU ADH/day, given subcutaneously, decreased ISO-RC in both hypothalamic and neurohypophyseal tissues of heterozygous DI to control levels. In comparison with Long-Evans control rats, higher plasma renin concentrations and increased ISO-RC were found in adrenal gland and brain hypothalamus tissue of homozygous DI rats while no differences were observed in frontal cortex, medulla oblongata or choroid plexus. Substitution of homozygous DI rats with 100 mU ADH/day decreased plasma renin concentration but resulted in no correction of adrenal gland or brain ISO-RC. These results suggest the plasma renin-angiotensin system is altered by changes in fluid balance in the DI rat which can be corrected by ADH substitution. Changes in tissue ISO-RC in DI compared to controls are not related to fluid balance but may be correlated with brain ADH content.

Sympathetic responsiveness and antihypertensive effect of beta-receptor blockade in essential hypertension

The relationship between sympathetic responsiveness and the blood pressure reduction induced by long-term beta-blockade was assessed in patients with essential hypertension. The increase in plasma noradrenaline concentration during physical exercise was used as an index of sympathetic responsiveness. The cardioselective beta-blocker, atenolol, was given to 16 patients with sustained benign essential hypertension for five weeks at a dose of 200 mg/day. Atenolol induced a marked decrease in blood pressure and pulse rate during recumbency, orthostasis and exercise concomitant with a marked increase in plasma noradrenaline concentration (p < 0.0125) and a pronounced decrease in plasma renin concentration (p < 0.01). The ratio of plasma noradrenaline during exercise to the base line concentration correlated significantly with the subsequent decrease in mean arterial blood pressure induced by beta-blockade (r = 0.840; p < 0.001). A less significant correlation was observed between the plasma renin concentration and the subsequent decrease in mean arterial pressure (r = 0.542; p < 0.05). The results obtained indicate that sympathetic responsiveness is an important determinant of blood pressure response to beta-blockade induced by atenolol.