Decrease In Plasma Renin Activity Research Articles

Acute Effects of Physiological Increments of Brain Natriuretic Peptide in Humans

To investigate the effects of physiological increases in plasma brain natriuretic peptide concentration in humans, we studied six healthy volunteers who received incremental infusions (0.25 pmol/kg per minute in the first hour and 0.50 pmol/kg per minute in the second) of synthetic human brain natriuretic peptide-32 in a placebo-controlled, crossover study. Peptide plasma levels were 1.69 +/- 0.39 pmol/L at baseline and rose 1.5- and 3-fold with the lower and higher doses, respectively. These values were within the normal range and also comparable to those reported in patients with mild essential hypertension. The urinary excretion rate of cGMP also increased during brain natriuretic peptide infusion, indicating stimulation of natriuretic peptide receptors. Peptide administration induced a significant 1.7-fold increase in urinary sodium excretion without affecting renal plasma flow (para-aminohippurate clearance), glomerular filtration rate (creatinine clearance), and urine flow rate. Fractional proximal sodium reabsorption (lithium clearance method) was unchanged, and fractional distal sodium reabsorption significantly decreased. Brain natriuretic peptide caused no changes in arterial pressure, heart rate, hematocrit, and serum proteins, but it exerted an inhibitory effect on the renin-aldosterone axis, as indicated by the significant 50% or more decrease of plasma renin activity and urinary excretion rate of aldosterone. These results suggest that brain natriuretic peptide may be involved in the overall regulation of body fluid and cardiovascular homeostasis in humans, mainly through its natriuretic and endocrine effects.

Central cardiovascular effects of acetylcholine in the conscious dog.

1. The effects of central cholinomimetic drugs on cardiovascular and vasoactive hormonal responses (blood pressure, heart rate, catecholamines, vasopressin, atrial natriuretic factor, neuropeptide Y plasma levels and plasma renin activity) were investigated in conscious Beagle dogs. For this purpose a catheter was chronically implanted into each dog's cisterna magna to allow repeated central injections in the awake animals. 2. Intracisternal acetylcholine (20 micrograms kg-1) significantly increased systolic and diastolic blood pressure. These changes were accompanied by an initial short term tachycardia followed by a long lasting bradycardia. Intracisternal acetylcholine also increased noradrenaline, adrenaline and vasopressin plasma levels, decreased plasma renin activity but did not modify plasma levels of neuropeptide Y and atrial natriuretic factor. 3. The effects of acetylcholine were completely abolished by pretreatment with intracisternal injection of the muscarinic antagonist, atropine (5 micrograms kg-1) but not by the intracisternal injection of the nicotinic antagonist, mecamylamine (25 micrograms kg-1). 4. The present results demonstrate that there are qualitative and quantitative differences between the central cardiovascular effects of acetylcholine in conscious dogs compared to what we previously reported, using a comparable protocol, in anaesthetized dogs. Under both conditions, we observed a central cholinergically mediated increase in blood pressure secondary to an increase in sympathetic tone and vasopressin release but these responses were shorter (less than 10 min) in the conscious dogs than in anaesthetized dogs (more than 10 min). Moreover, we detected in the response to the central cholinergic stimulation in the conscious dogs a significant increase in plasma adrenaline levels and biphasic changes in heart rate which were not described previously in the anaesthetized dog.

Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites.

To assess the effects of transjugular intrahepatic portosystemic shunt (TIPS) on systemic and renal hemodynamics, neurohumoral factors, and sodium homeostasis in patients with cirrhosis and refractory ascites. Prospective study with 1-year follow-up. Tertiary referral center and university-affiliated hospital. 7 patients with cirrhosis and refractory ascites had metabolic studies done while receiving a 22 mmol/d sodium, 1 L/d fluid diet. TIPS insertion. Urinary sodium excretion, systemic and renal hemodynamics, hormonal profile, and central blood volume were measured before, at day 1 after, and at 1 month after TIPS insertion. Immediately after TIPS insertion, mean corrected sinusoid pressure decreased from 18.2 +/- 2.2 mm Hg to 7.7 +/- 1.3 mm Hg (P < 0.001); mean cardiac output increased from 6.83 +/- 0.68 L/min to 8.62 L/min (P = 0.005); and mean systemic vascular resistance decreased from 1018 +/- 103 dyne.s.cm-5 to 762 +/- 46 dyne.s.cm-5 (P = 0.011). Mean plasma renin activity, serum aldosterone levels, and 24-hour urinary sodium excretion (5.8 +/- 0.7 mmol/d before TIPS insertion compared with 6.0 +/- 1.8 mmol/d 1 day after insertion) were unchanged; mean elevated plasma norepinephrine levels significantly increased. By 1 month after insertion, mean proximal tubular reabsorption of sodium had decreased, and this had led to a mean natriuresis of 15.1 +/- 3.1 mmol/d (P = 0.02 compared with baseline), which was associated with a decrease in plasma renin activity and aldosterone levels to within the normal range. Our results suggest that natriuresis associated with TIPS is delayed and occurs in the presence of increased systemic vasodilatation at 1 month after insertion and that TIPS insertion should not be done in any patients with refractory ascites without careful attention to cardiac and renal status. However, in carefully selected patients, TIPS is a safe and effective means of managing refractory ascites.

Mechanism of thirst attenuation during head-out water immersion in men.

The purpose was to determine whether extracellular volume or osmolality was the major contributing factor for reduction of thirst in air and head-out water immersion in hypohydrated subjects. Eight males (19-25 yr) were subjected to thermoneutral immersion and thermoneutral air under two hydration conditions without further drinking: euhydration in water (Eu-H2O) and euhydration in air, and hypohydration in water (Hypo-H2O) and hypohydration in air (3.7% wt loss after exercise in heat). The increased thirst sensation with Hypo-H2O decreased (P < 0.05) within 10 min of immersion and continued thereafter. Mean plasma osmolality (288 +/- 1 mosmol/kgH2O) and sodium (140 +/- 1 meq/l) remained elevated, and plasma volume increased by 4.2 +/- 1.0% (P < 0.05) throughout Hypo-H2O. A sustained increase (P < 0.05) in stroke volume accompanied the prompt and sustained decrease in plasma renin activity and sustained increase (P < 0.05) in plasma atrial natriuretic peptide during Eu-H2O and Hypo-H2O. Plasma vasopressin decreased from 5.3 +/- 0.7 to 2.9 +/- 0.5 pg/ml (P < 0.05) during Hypo-H2O but was unchanged in Eu-H2O. These findings suggest a sustained stimulation of the atrial baroreceptors and reduction of a dipsogenic stimulus without major alterations of extracellular osmolality in Hypo-H2O. Thus it appears that vascular volume-induced stimuli of cardiopulmonary baroreceptors play a more important role than extracellular osmolality in reducing thirst sensations during immersion in hypohydrated subjects.

Atrial natriuretic peptide fragments in dogs with experimental heart failure.

1. This study in the canine arteriovenous (AV) fistula model of high-output heart failure (HOHF) evaluated the chronic temporal changes in plasma ANF and pro ANF 31-67 and their relationship to body-fluid balance and the renin-aldosterone axis. In addition, the haemodynamic, hormonal and renal excretory effects of synthetic pro ANF 31-67 infusions were examined in normal and AV fistula dogs with compensated HOHF. 2. Following the construction of the AV fistula, the dogs exhibited chronic parallel elevations in right atrial pressure and the plasma concentrations of ANF and pro ANF 31-67. The gradual increases in the two peptides were associated with a gradual decrease in plasma renin activity and the re-establishment of sodium balance. 3. In normal and compensated AV fistula dogs, synthetic pro ANF 31-67 produced similar significant reductions in arterial blood pressure, right atrial pressure and elevations in urinary sodium excretion. These effects were not associated with increases in plasma or urinary cyclic GMP (cGMP). 4. These results suggest that the elevation in the endogenous circulating levels of pro ANF 31-67 in the AV fistula dogs may represent one chronic adaptive mechanism to achieve body fluid homeostasis. Furthermore, via potentially different mechanisms of action, ANF and pro ANF 31-67 may coordinate and contribute to the regulation of haemodynamic and renal function during physiological and pathophysiological situations.

Interaction of a neutral endopeptidase inhibitor with an ANP-C receptor ligand in anesthetized dogs.

Inhibition of important degradative pathways of atrial natriuretic peptide (ANP) in vivo could be a valuable therapeutic tool for regulating endogenous levels of ANP. The aim was to investigate the in vivo effects of both blockade of atrial natriuretic peptide clearance receptor and inhibition of neutral endopeptidase 24.11, an enzyme shown to be involved in ANP breakdown. Therefore, we infused a specific neutral endopeptidase inhibitor ((S)-thiorphan) and an ANP-C receptor ligand (AP 811) alone or in combination into anaesthetized beagle dogs. Compared with vehicle controls, coadministration of (S)-thiorphan and AP 811 (100 micrograms/kg/min and 10 micrograms/kg/min, resp.) had greater effects on endocrine and renal parameters than administration of either substance alone. Coadministration of both compounds increased urinary excretion of volume and sodium, cGMP and ANP. We found also increased plasma cGMP, plasma ANP and decreased plasma renin activity. No effects were observed with respect to blood pressure, left ventricular pressure or heart rate during the infusion period of 2 h. We conclude from these investigations, that blocking both degrading pathways of ANP with the ANP-C receptor ligand AP 811 and the neutral endopeptidase inhibitor (S)-thiorphan is more effective than inhibition of either system alone. Such a combination might therefore be a useful therapeutic tool in cardiovascular diseases.

Neuropeptide Y Infusion Decreases Plasma Renin Activity in Postmyocardial Infarction Rats

We wished to determine if chronic neuropeptide Y (NPY) infusion (1 ng/min for 1 week by Alzet minipump) could decrease plasma renin activity (PRA) and norepinephrine (NE) in a rat myocardial infarction (MI) model of moderate compensated congestive heart failure (CHF). CHF was produced by prior (6-8 weeks) ligation of the left coronary artery; control rats were sham-operated. Carotid arterial blood was drawn for PRA and NE in conscious unrestrained rats that had been instrumented 24 h earlier. MI rats had increased PRA as compared with sham-operated rats [8.73 +/- 1.27 vs. 5.10 +/- 0.91 ng angiotensin (AI) I/ml.h, mean +/- SE]. During chronic NPY infusion, PRA was reduced to normal in the MI group (4.78 +/- 0.91) but was not affected in the sham group (5.65 +/- 0.51). Plasma NE was altered similarly, but the changes did not reach statistical significance. These data suggest that NPY has the capacity to restrain renin release in moderate compensated CHF.

Ciprokiren (Ro 44-9375). A renin inhibitor with increasing effects on chronic treatment.

The present study characterizes the new transition-state renin inhibitor ciprokiren (Ro 44-9375) in squirrel monkeys. Arterial blood pressure was monitored by telemetry in freely moving, chronically instrumented conscious animals. In vitro at pH 7.4, ciprokiren inhibited human renin in buffer and human plasma with an IC50 of 0.07 and 0.65 nmol/L, respectively. It was equipotent against primate plasma renin and also inhibited plasma renin from dog and guinea pig in the nanomolar range (IC50, 29 and 65 nmol/L, respectively). After acute oral administration it reduced arterial blood pressure dose dependently in normotensive sodium-depleted and cyclosporin-induced hypertensive squirrel monkeys, starting with the minimal oral dose of 3 micrograms/kg. Daily oral doses of 1 microgram/kg showed a progressive blood pressure decrease, with a maximal response reached after 1 week. The drug could also be applied transdermally with similar hemodynamic effects without any decrease of plasma renin activity or plasma immunoreactive angiotensin II. Thus, ciprokiren is characterized in squirrel monkeys as a renin inhibitor with high in vivo potency that might act mainly in the tissular compartment.

Hypertension in the Elderly

As a group, elderly hypertensive individuals exhibit volume depletion, a decrease in plasma renin activity, a decrease in total body potassium, and an increase in plasma catecholamines. These factors should be considered when selecting an antihypertensive agent. Large-scale clinical trials in the el

Ammonium urate nephrolithiasis in a variant of Bartter's syndrome with intact renal tubular function

In two patients with Bartter's syndrome proximal tubular function and distal chloride reabsorption were intact on admission; however, chloride reabsorption and distal tubular acidifying capacity decreased in one patient over a period of 10 years. Renal prostaglandin E excretion and urinary and plasma uric acid were in the normal range, but urinary ammonium was significantly elevated during controlled diet. One patient developed ammonium urate nephrolithiasis. In both patients renal biopsy demonstrated lymphocytic infiltration of the interstitial tissue and hypercellularity of the macula densa. Indomethacin treatment improved serum potassium concentration and decreased plasma renin activity, plasma aldosterone concentration, and urinary prostaglandin E but had to be discontinued because of side effects. It is likely that our patients represent a variant form of the syndrome originally described by Bartter.

Effect of inhibition of nitric oxide synthesis on vasopressin secretion in conscious rabbits.

NO synthase is present in magnocellular neurons of supraoptic and paraventricular nuclei as well as in the posterior pituitary gland and may participate in control of vasopressin secretion. To test this possibility, experiments were performed in conscious, chronically prepared rabbits to determine the effect of NO synthesis inhibition with NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) on basal vasopressin secretion and vasopressin responses to increased plasma osmolality (hypertonic saline infusion; P osm) and decreased blood pressure (nitroprusside infusion). L-NAME infusion (0.5 mg.kg-1 x min-1 i.v.) increased mean arterial pressure [MAP; 82.6 +/- 3.4 to 93.0 +/- 3.0 mmHg (P < 0.02)], decreased heart rate [HR; 242 +/- 12 to 209 +/- 9 beats/min (P < 0.02)], decreased plasma renin activity [PRA; 3.1 +/- 0.6 to 2.0 +/- 0.6 ng.ml-.2 h-1 (P < 0.001)], and increased plasma vasopressin concentration [P AVP; 2.2 +/- 0.3 to 4.5 +/- 1.0 pg/ml (P < 0.05)]. P(osm) did not change. Hypertonic saline infusion did not change MAP or HR but decreased PRA [4.3 +/- 0.8 to 0.9 +/- 0.2 ng.ml-1 x 2 h-1 (P < 0.01)], increased P(osm) [284 +/- 1 to 305 +/- 2 mosmol/kg H2O (P < 0.001)], and increased PAVP [2.8 +/- 0.3 to 12.7 +/- 2.7 pg/ml (P < 0.01)].(ABSTRACT TRUNCATED AT 250 WORDS)

Differential regulation of brain angiotensin II in genetically hypertensive and normotensive rats after nephrectomy.

To investigate the role of tissue angiotensin II (Ang II) in the maintenance of hypertension after nephrectomy in spontaneously hypertensive rats (SHR), Ang II levels were measured in various tissues of both 12-week-old SHR and normotensive control, Wistar-Kyoto rats (WKY), 48 h after nephrectomy or sham operation. Ang II was determined by radioimmunoassay coupled with high performance liquid chromatography. Nephrectomy caused a decrease of plasma renin activity and plasma Ang II concentration in both SHR and WKY. Aortic Ang II levels were significantly lowered by nephrectomy only in WKY, and not in SHR. Ang II levels in hypothalamic block, brainstem and cerebellum of SHR increased after nephrectomy, whereas those of WKY were unchanged. Intracerebroventricular administration of ceronapril, an angiotensin converting enzyme inhibitor, significantly decreased sustained high blood pressure in SHR 48 h after nephrectomy compared with vehicle administration, whereas intravenous administration had no effect. These results suggest that in spite of the important role of the renal renin-angiotensin system in maintenance of high blood pressure in SHR, control mechanisms may switch to other systems after nephrectomy, and that the increased brain Ang II levels after nephrectomy may be related to these mechanisms.

Taurine-induced diuresis and natriuresis in cirrhotic patients with ascites

Taurine is a non-protein sulfur aminoacid widely distributed in mammalian tissues, with poorly understood functions. Taurine administration has a variety of hemodynamic effects, including improvement of cardiac function and suppression of sympathetic activity. Increased urinary volume and sodium excretion have been reported in taurine-fed hamsters. Since patients with ascitic liver cirrhosis have severe hemodynamic and renal abnormalities potentially sensitive to taurine feeding, we evaluated the effects of the i.v. infusion of taurine on urinary flow and sodium excretion and on the hormones involved in the control of hydrosaline homeostatis. Eight cirrhotic patients with tense ascites were given an i.v. bolus of taurine (16 μmoles in 40 ml of saline). The next day patients were given saline only, as a control. Diuresis, urinary sodium and plasma renin activity, aldosterone, atrial natriuretic peptide and arginin vasopressine were measured for the following 6 hrs. Plasma taurine increased ten fold after infusion, then decreased exponentially. No side effects were recorded. After taurine, but not after saline, there was a prompt and significant increase in both urinary volume and sodium excretion. Diuresis increased from 340±43 to 817±116 μl/min (p<0.01); urinary sodium from 13.8±3 to 26.3±4 μmoles/min (p<0.05). Both values returned to normal after 2–3 hrs. Taurine infusion caused a concomitant significant decrease in plasma renin activity (from 7.7±2.2 to 4.3±1.9 ng/ml/hr, p<0.05) and aldosterone (from 588±47 to 348±89 pg/ml, p<0.05), but no changes in atrial natriuretic peptide and arginin vasopressine. We conclude that i.v. taurine infusion in ascitic cirrhosis promotes a transient diuresis and natriuresis, apparently through the inhibition of the renin-aldosterone axis.

Endothelium derived relaxing factor is involved in the pressure control of renin gene expression in the kidney.

To study the influence of endothelium derived relaxing factor/nitric oxide (EDNO) on renin gene expression, the effects of a 2-day treatment with the NO-synthase inhibitor nitro-L-arginine-methylester (L-NAME, 40 mg/kg twice a day) on plasma renin activity (PRA) and renal and adrenal renin m-RNA levels were examined in conscious rats with and without unilateral renal clips (0.2 mm). In sham-clipped animals L-NAME led to a decrease of PRA from 7.5 to 2.5 ng angiotensin (ANGI).h-1.ml-1 and to a 35% decrease of renal renin m-RNA levels. Unilateral renal artery clipping increased PRA to 35 and to 13 ng ANGI.h-1.ml-1 in vehicle and in L-NAME-treated rats, respectively. In the clipped kidneys renin m-RNA levels increased to 450% of control values in vehicle-treated animals and to 220% of control values in L-NAME-treated animals. In the contralaterals as opposed to clipped kidneys, renin m-RNA levels decreased to 16% and 50% of the control values in vehicle- and in L-NAME-treated animals, respectively. In the adrenal glands renin m-RNA levels were not significantly changed either by clipping of one renal artery or by treatment of animals with L-NAME. The NO-donor sodium nitroprusside (100 microM) was found to increase renin secretion and renin m-RNA levels in primary cultures of renal juxtaglomerular cells. These findings suggest that EDNO is involved in the control of the renin gene by the renal perfusion pressure.

Acute and delayed hormonal changes in mitral stenosis treated by balloon valvulotomy

The role of left atrial and aortic pressures on the secretion of the main hormones controlling blood volume is still subject to debate in humans. Because of increased mean left atrial pressure and decreased mean aortic pressure produced by balloon inflation in patients with mitral stenosis treated with balloon valvulotomy, the hormonal changes occurring acutely (group II of patients) were measured. The same studies (group I patients) were also performed 48 hours after this treatment, a period at which left a trial pressure permanently diminished. Inflation of the balloon resulted in a decrease in plasma renin activity and increases in plasma atrial natriuretic factor (ANF) and plasma arginine vasopressin (AVP). Forty-eight hours after balloon valvulotomy, which had produced a decrease in left atrial pressure, plasma ANF was lower (58.9 ± 7.9 vs 95.3 ± 11.9 pg/ ml; p <0.001), and plasma renin activity (2,575 ± 533 vs 960 ± 113 pg/ml/hour; p <0.01), plasma angiotensin 11 (25.0 ± 4.1 vs 9.3 ± 1.3 pg/ml; p <0.001) and plasma aldosterone (181.7 ± 36.7 vs 139.9 ± 19.8 pg/ml; p <0.05) were higher than their respective control levels 24 hours before treatment of the stenosis. In contrast, plasma AVP (3.7 ± 0.25 vs 4.4 ± 0.31 pg/ml; p = 0.001) diminished moderately along with plasma osmolality (282.4 ± 0.1 vs 286.2 ± 0.6 mOsm/kg; p <0.001). Urinary sodium excretion was also examined before and after balloon valvulotomy. Sodium fractional excretion correlated with plasma ANF but not with plasma aldosterone before treatment of the stenosis,. whereas the opposite was observed afterward. These results demonstrate that left atrial pressure is essential in controlling ANF and renin secretion, and that aortic pressure plays a predominant role controlling AVP. Results also suggest that ANF participates in controlling sodium excretion when the renin angiotensin system is not stimulated.

Propranolol compared with propranolol plus isosorbide dinitrate in portal-hypertensive patients: Long-term hemodynamic and renal effects

The long-term hemodynamic and renal effects of propranolol were compared with those of propranolol plus isosorbide dinitrate in 44 portal-hypertensive alcoholic cirrhotic patients. Eight control patients, 8 patients receiving propranolol and 14 patients receiving propranolol plus isosorbide dinitrate were hemodynamically evaluated. Renal function was studied in a fourth group of 14 patients receiving propranolol plus isosorbide dinitrate. Portal pressure decreased more (p < 0.05) with combined therapy (-21.6%, from 19.5 +/- 4.8 to 15.4 +/- 4.3 mm Hg) than with propranolol alone (-12.5%, from 19.9 +/- 1.2 to 17.4 +/- 1.8 mm Hg). Serum urea and creatinine levels, plasma sodium concentration, urine volume and urinary sodium excretion showed nonsignificant changes in all groups studied. Combined therapy induced a significant (p < 0.05) decrease in plasma renin activity (from 4.42 +/- 4.7 to 1.59 +/- 1.9 ng/ml/hr) and nonsignificant reductions in plasma aldosterone concentration and creatinine clearance. None of the eight patients with ascites or history of ascites not receiving isosorbide dinitrate showed evidence of impairment in renal sodium metabolism during the study period. In contrast, 8 of the 14 patients (57%) with ascites or history of ascites receiving isosorbide dinitrate showed impairment in renal sodium metabolism (p < 0.01), as reflected by the development or worsening of ascites and the need of higher diuretic requirements. Long-term combined administration of propranolol plus isosorbide dinitrate is superior to propranolol alone in the pharmacological treatment of portal hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Propranolol compared with propranolol plus isosorbide dinitrate in portal-hypertensive patients: Long-term hemodynamic and renal effects

The long-term hemodynamic and renal effects of propranolol were compared with those of propranolol plus isosorbide dinitrate in 44 portal-hypertensive alcoholic cirrhotic patients. Eight control patients, 8 patients receiving propranolol and 14 patients receiving propranolol plus isosorbide dinitrate were hemodynamically evaluated. Renal function was studied in a fourth group of 14 patients receiving propranolol plus isosorbide dinitrate. Portal pressure decreased more (p < 0.05) with combined therapy (-21.6%, from 19.5 ± 4.8 to 15.4 ± 4.3 mm Hg) than with propranolol alone (− 12.5%, from 19.9 ± 1.2 to 17.4 ± 1.8 mm Hg). Serum urea and creatinine levels, plasma sodium concentration, urine volume and urinary sodium excretion showed nonsignificant changes in all groups studied. Combined therapy induced a significant (p < 0.05) decrease in plasma renin activity (from 4.42 ± 4.7 to 1.59 ± 1.9 ng/ml/hr) and nonsignificant reductions in plasma aldosterone concentration and creatinine clearance. None of the eight patients with ascites or history of ascites not receiving isosorbide dinitrate showed evidence of impairment in renal sodium metabolism during the study period. In contrast, 8 of the 14 patients (57%) with ascites or history of ascites receiving isosorbide dinitrate showed impairment in renal sodium metabolism (p < 0.01), as reflected by the development or worsening of ascites and the need of higher diuretic requirements. Long-term combined administration of propranolol plus isosorbide dinitrate is superior to propranolol alone in the pharmacological treatment of portal hypertension. However, the deleterious effects observed in patients with ascites or even with a prior history of ascites preclude recommendation of this therapy for all patients, making it more suitable for patients without advanced liver disease. (HEPATOLOGY 1993;18:477–484.)

Circulatory and metabolic responses in awake dogs to infusion of iso-rANP/(rBNP)

We reported that a second rat atrial peptide, iso-atrial natriuretic peptide (iso-rANP(1–45)) and a potential putative homologue, iso-rANP(17–45) (identical with rat brain natriuretic peptide except for one amino acid) elicited circulatory and renal responses in anesthetized rats. In the present studies, low-dose intravenous infusions of iso-rANP(1–45) (6.3–25 pmolkg −1min −1) and iso-rANP(17–45) (12.5–50 pmolkg −1min −1) into conscious dogs produced subtle circulatory effects compared to control studies. Relative to oxygen consumption, cardiac output was lower and total peripheral resistance higher with both iso-rANP(1–45) and iso-rANP(17–45). Heart rate tended to be slightly lower relative to control studies during peptide infusions, and the highest infusion doses caused a decrease in mean arterial pressure. Plasma protein increased and plasma osmolality decreased with iso-rANP(1–45); infusion of iso-rANP(17–45) caused a decrease in the respiratory exchange ratio. The mechanism of action of iso-rANP may have been direct, via an active receptor. However, we previously reported for these same experiments that infusion of iso-rANP(1–45) and iso-rANP(17–45) increased plasma ANP and decreased plasma renin activity. Thus, circulatory changes during infusion of iso-rANP were consistent with an indirect mechanism related to increased endogenous ANP.

Effects of bucindolol in heart failure

Bucindolol hydrochloride is a phenoxypropanolamine with potent nonselective β antagonist and mild vasodilatory properties. In humans with congestive heart failure, it is extremely well tolerated and produces improvements in left ventricular systolic (ejection fraction, systolic elastance, cardiac index, and stroke work) and diastolic (isovolumic relaxation) performance while reducin pulmonary artery pressures and heart rate. These improvements occur without an increase in myocardial oxygen extraction or oxygen consumption. In addition, functional class improves with this agent although exercise tolerance and maximal oxygen consumption (VO 2max) does not change, an effect that is not unexpected with a β-adrenergic antagonist. Bucindolol produces a decrease in plasma renin activity and plasma norepinephrine, effects that may be beneficial for the long-term treatment of congestive heart failure. However, these effects are most marked in patients with idiopathic dilated cardiomyopathy compared with patients with ischemic heart disease. This agent holds great promise for the treatment of heart failure patients.

Circulating levels of active, total and inactive renin (prorenin), angiotensin I and angiotensinogen in carbon tetrachloride-treated rats.

1. Plasma renin activity (PRA), plasma angiotensin I concentration (ANG I), plasma angiotensinogen concentration (PAC) and the plasma levels of active, total and inactive renin (prorenin) were measured in rats with carbon tetrachloride (CCl4)-induced acute renal failure. Rats were treated with a single oral dose of CCl4 (2.5 mL/kg) and killed 1, 2, 3 and 7 days later. 2. On days 1-3 PRA, ANG I and PAC decreased and increased on day 7. Active renin fell on days 2 and 3, total renin (trypsin treatment) augmented on day 1 and diminished on day 3, prorenin and per cent prorenin increased on days 1 and 2. Angiotensin I concentration paralleled PRA and PAC. The CCl4-induced decrease in PRA was secondary to the fall in active renin and in PAC. Total renin augmented as a consequence of the elevation of prorenin. Renal function, evaluated by serum urea, serum creatinine and creatinine clearance, decreased on days 1 and 2 when PRA was low and plasma prorenin was high. 3. These data do not support the involvement of the circulating active renin-angiotensin system (RAS) in the pathophysiology of acute renal failure induced by CCl4, however, increased prorenin levels were associated with the decrease in renal function.