Renal Renin Release Research Articles

Angiotensin II Type 1 Receptor Blockade: a Novel Therapeutic Concept

Angiotensin II type 1 (AT 1 ) receptor blockers, such as candesartan, are attractive alternatives to ACE inhibitors in the treatment of hypertension and cardiovascular disease. Although angiotensin-converting enzyme (ACE) inhibitors are able to suppress the renin-angiotensin system (RAS), their mechanism of action may limit their clinical utility in the treatment of hypertension. For example, they act as competitive inhibitors of ACE. This means that their effects can be overcome by high levels of angiotensin I, which occur after ACE inhibition due to removal of the negative feedback effect of angiotensin II on renal renin release. ACE inhibitors are also unable to block the production of angiotensin II by non-ACE-mediated pathways. Furthermore, ACE is not a specific enzyme. Its inhibition therefore has effects on other substances, such as bradykinin, leading to the class-specific side effects associated with ACE inhibitors. Candesartan, on the other hand, binds insurmountably to the AT 1 -receptor, thereby providing more complete blockade of the negative cardiovascular effects of angiotensin II than is possible with ACE inhibitors. The specificity of AT 1 -receptor blockade also ensures that efficacy is achieved without inducing the side effect of cough that results from the non-specific consequences of ACE inhibition. Preclinical and early clinical studies demonstrate that AT 1 -receptor blockers produce at least the same degree of target-organ protection as has been demonstrated for ACE inhibitors. Additional benefits of AT 1 -receptor blockers may arise from the fact that, unlike ACE inhibitors, they do not prevent the activity of angiotensin II on AT 2 -receptors in the heart, which is thought to reduce cardiac remodelling. From a mechanistic perspective, therefore, AT 1 -receptor blockers appear to have advantages over ACE inhibitors, in terms of a more complete blockade of angiotensin II effects, while also avoiding the specific side effects associated with ACE inhibition.

Regulation of renal renin release.

Renal renin release is affected by several systemic and intrarenal factors. Systemic factors include sympathetic nerves, circulating angiotensin II, blood pressure and salt balance of the organism. Intrarenal factors involved are nitric oxide and the prostaglandins, which stimulate renin secretion.

Roles of prostaglandins and nitric oxide in the effect of endothelin-1 on renal hemodynamics.

It is known that endothelin-1 stimulates the release of nitric oxide and prostaglandins in various vascular beds. We designed the present study to analyze the roles of prostaglandins and nitric oxide in the effect of endothelin-1 on the regulation of renal hemodynamics and renin release. We used N omega-nitro-L-arginine methyl ester (L-NAME) and meclofenamic acid to inhibit the production of nitric oxide and prostaglandins, respectively. With a nonfiltering kidney model, renal blood flow was reduced 21% in dogs treated with L-NAME and 18% in dogs treated with meclofenamic acid. Inhibition of nitric oxide and prostaglandins, however, produced opposite effects on estimated glomerular hydraulic pressure: L-NAME increased glomerular hydraulic pressure from 63.1 +/- 0.9 to 64.6 +/- 1.3 mm Hg (P < .01), and meclofenamic acid reduced glomerular hydraulic pressure from 63.3 +/- 1.4 to 59.8 +/- 1.6 mm Hg (P < .01). Endothelin-1 infusion produced a dose-dependent reduction in renal blood flow after blockade of nitric oxide and prostaglandins. The responses of glomerular hydraulic pressure were different in the two groups during endothelin-1 infusion. Endothelin-1 progressively reduced glomerular hydraulic pressure in a dose-dependent fashion in the meclofenamic acid group. However, endothelin-1 slightly increased glomerular hydraulic pressure until the infusion rate reached 5.0 ng/kg per minute. At that rate, endothelin-1 reduced glomerular hydraulic pressure from 63.3 +/- 1.4 to 47.0 +/- 1.4 mm Hg in the meclofenamic acid group (P < .01), a more than 25% reduction, whereas at the same dose, endothelin-1 reduced glomerular hydraulic pressure only less than 2% in the L-NAME group. In addition, blockade of nitric oxide and prostaglandins did not alter the inhibitory effect of endothelin-1 on renin release in the non-filtering kidney. Therefore, the present study demonstrates that the release of nitric oxide and prostaglandins might modulate the effects of endothelin-1 on the renal circulation. The present findings suggest that the differential vasoconstrictive effects of endothelin-1 on preglomerular and postglomerular vessels are associated with its stimulation of nitric oxide and prostaglandin production.

Furosemide elicits immediate sympathoexcitation via a renal mechanism independent of angiotensin II.

This investigation aimed at examing the hypothesis that furosemide elicits renal sympathoexcitation through stimulation of renal renin release, which in turn produces increased plasma angiotensin II levels, causing centrally mediated sympathoexcitation. In addition, direct central nervous actions of furosemide on central control of mean arterial pressure, heart rate, and efferent renal sympathetic nerve activity were examined. Furosemide (300 mg/kg intravenously) was administered to four groups of rats: (1) control; (2) nephrectomized; (3) with intravenous losartan blockade (10 mumol/kg); and (4) with intracerebroventricular losartan blockade (10 nmol). In a fifth group of rats, furosemide was administered intracerebroventricularly (0, 2.5, 25 or 250 micrograms). To eliminate reflex control of mean arterial pressure, heart rate and efferent renal sympathetic nerve activity, all experiments were performed in rats with sinoaortic denervation and bilateral vagotomy. Experiments were performed during Saffan anaesthesia (0.9% alphaxalone/0.3% alphadolone), and rats were paralyzed with pancuronium and artifically ventilated. Furosemide produced an immediate 40% increase in efferent renal sympathetic nerve activity while the furosemide vehicle, 2 vol.% ethanolamine, did not affect efferent renal sympathetic nerve activity. The furosemide-induced increase in efferent renal sympathetic nerve activity was abolished in rats with bilateral nephrectomy but it was not affected by intravenous or intracerebroventricular losartan blockade. Intracerebroventricular angiotensin II produced an increase in mean arterial pressure and efferent renal sympathetic nerve activity whereas intravenous angiotensin II produced a pressor response in absence of increased efferent renal sympathetic nerve activity. Losartan effectively blocked responses to intravenous or intracerebroventricular angiotensin II. Intracerebroventricular administration of furosemide produced no changes in mean arterial pressure, heart rate or efferent renal sympathetic nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Down-regulation of the intrarenal renin-angiotensin system in the aging rat.

Progressive deterioration of renal function occurs during normal aging. Previous studies on the aging kidney have demonstrated glomerular hemodynamic changes, specifically, glomerular capillary hypertension, as maladaptations that lead to proteinuria and glomerular sclerosis over time. Aging rats treated with angiotensin-converting enzyme inhibition have relatively less proteinuria and sclerosis, suggesting that age-related changes in renal function may be associated with alterations in the intrarenal renin-angiotensin system, which thus may play a major role in the pathogenesis of these maladaptations. To investigate this possibility, renal and systemic renin-angiotensin systems were examined at an early phase of the aging process (3 months) and at a later phase (12 months) in male Sprague-Dawley rats. Although plasma renin and serum angiotensin-converting enzyme concentrations did not differ significantly, the intrarenal system showed down-regulation of renin mRNA and angiotensin-converting enzyme levels with aging, whereas angiotensinogen levels remained stable. The decrease in renin mRNA appeared to precede the fall in plasma renin concentration in the aging process. Additional studies in 15-month-old rats confirmed that, by this time, both basal and stimulated renal renin release rates were impaired in older rats. Thus, both decreased renin synthesis and impaired renin release underlie the fall in plasma renin with normal aging. This decrease may act to lower intrarenal baseline levels of angiotensin II, an adaptation of likely importance in the modulation of intrarenal vascular tone and tubular function in the aging kidney.

Renal Effects of Local Infusion of Adenosine in Man

1. The effects of local intra-arterial infusion of adenosine on renal blood flow, glomerular filtration and renin release in eight healthy awake subjects have been examined. 2. Renal blood flow and glomerular filtration rate were measured as the clearances of p-aminohippurate and inulin, respectively. After basal samplings, adenosine was infused intra-arterially at successive rates of 2 and 10 micrograms min-1 kg-1 for 40 min at each rate. 3. Apart from a small increase in heart rate (65 +/- 4 to 71 +/- 4 beats/min), there were no signs of sympathetic activation (unchanged blood pressure and catecholamine levels) during the infusion. Clearance of p-aminohippurate tended to increase, but not significantly, during adenosine infusion (518 +/- 48 ml/min basal, 563 +/- 52 ml/min during the highest dose of adenosine). The arterial plasma concentration of p-aminohippurate decreased by 9 +/- 3% (P < 0.05), consistent with a small increase in renal blood flow in the infused kidney. Inulin clearance was reduced from 115 +/- 3 to 97 +/- 2 ml/min (P < 0.001). The extraction of inulin, reflecting the filtration fraction, was 18% in both kidneys in the basal state. During infusion of adenosine the extraction in the infused kidney decreased to 12 +/- 3% (P < 0.01 compared with the control kidney, 23 +/- 3%). 4. The total excretion of Na+ was unchanged, but there was a minor decrease in K+ clearance. Thus, the K+/Na+ excretion ratio decreased from a basal value of 13 +/- 2 to 10 +/- 2 (P < 0.01) at the highest dose of adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

Pressure control of renal renin release in Lyon hypertensive rats

To assess whether the pressure-independence of renin release by isolated kidneys of Lyon hypertensive (LH) rats could result from long-term exposure to high blood pressure, sodium retention or an altered regulation of intracellular calcium through L-type voltage operated channels. Renin release was studied in kidneys from LH rats, either controls or chronically (aged 3-7 weeks) treated with hydralazine or deprived of sodium. The influence of L-type calcium channels was studied acutely using a specific activator (BAY K8644) or modulator (verapamil). Lyon low blood pressure (LL) rats served as controls. Kidneys were isolated from LH or LL rats aged 7 weeks and single-pass perfused at three pressure levels: 70, 85 and 160 mmHg. LH rat kidneys differed from LL rat kidneys in having elevated vascular resistances, decreased glomerular filtration rate, pressure natriuresis and pressure-dependent renin release. Hydralazine treatment and sodium deprivation did not significantly modify the pressure-independence of renin release by LH rat kidneys. BAY K8644 (1 x 10(-8) and 5 x 10(-8) mol/l) induced significantly greater vasoconstrictor effects in LH than in LL rat kidneys but did not affect the renin release already stimulated by low perfusion pressure. Verapamil (5 x 10(-6) mol/l) dilated LH more than LL rat kidneys. It did not change the renin release observed at low, but enhanced it at high, perfusion pressure. This effect was more marked in LL than in LH rat kidneys. The poor stimulation of renin release by low perfusion pressure in LH rat kidneys does not appear to be a consequence of high blood pressure level, sodium retention and alteration in L-type calcium channels. However, results demonstrate that these channels participate in the increased vascular resistances exhibited by LH rat kidneys.

A potential role for endogenous adenosine in control of human glomerular and tubular function

Adenosine has profound effects on renal function in experimental animals, but little is known about its role in human subjects. The recent advent of specific adenosine agonists and antagonists suitable for human use, however, now makes it possible to evaluate the influence of this potent vasoactive compound in both normal and pathological states. In this study we assessed the effects of FK-453, a nonxanthine, selective adenosine A1-receptor antagonist, on normal renal hemodynamics, tubular function, and plasma renin release. Eight healthy, male subjects each received three single oral doses of FK-453 (50, 100, and 200 mg) in ascending dose order with random allocation of one matched placebo dose, each on a separate study day. Renal hemodynamics, tubular function, and plasma renin concentrations (PRC) were assessed at baseline and postdose on each study day. Glomerular filtration rate (clearance of 51Cr-labeled EDTA) rose by 18.0%, 3 h after the administration of 100 mg of FK-453 and by 18.3% and 23.5%, 2 and 3 h, respectively, after the 200-mg dose, which was significantly different from the changes following placebo. There were no significant changes in mean arterial blood pressure or effective renal plasma flow (clearance of 125I-Hippuran). In contrast there were statistically significant increases in urine flow rate and osmolar clearance, as well as absolute and fractional excretions of sodium, phosphate, bicarbonate, chloride, magnesium, and uric acid in response to FK-453. No glycosuria or aminoaciduria was detected on urinalysis. There was, in addition, a marked increase in PRC in response to FK-453.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the renin-angiotensin system after nephrectomy and adrenalectomy

The study investigates the change in angiotensinogen (Aogen), angiotensin I (AngI) and renin plasma concentration after nephrectomy and adrenalectomy. The aim of the study was to elucidate the mechanisms that are involved in the up regulation of the Aogen plasma levels after nephrectomy and the contribution of the adrenals. Rats were treated with the β 1-selective adrenoceptor blocker, atenolol, and with the angiotensin antagonist, DuP 753 in order to inhibit renal renin release and to check whether the increase in plasma Aogen after nephrectomy is mediated by angiotensin (AngII), respectively. The plasma Aogen levels increase approx. 5-fold 24 h after nephrectomy. This increase is significantly reduced in the presence of atenolol. After nephrectomy plus adrenalectomy there is a maximal increase of 60% in plasma Aogen levels 8 h after surgery and a subsequent decline. In the presence of atenolol this increase is even smaller. In contrast after adrenalectomy the plasma Aogen levels continuously declined. In the presence of atenolol the plasma Aogen levels were approx. 20% higher at time 0 but declined with the same slope as after adrenalectomy without atenolol treatment. Treatment with DuP 753 caused an almost complete inhibition of the increase in Aogen plasma levels after nephrectomy. Significantly higher Aogen levels were found only after 24 h. At time 0, immediately after nephrectomy the plasma AngI levels were increased compared to the respective control rats. Significantly higher AngI values ( P < 0.05) could also be observed in nephrectomized rats and in nephrectomized plus adrenalectomized rats at time 0 in the presence and absence of atenolol and DuP 753, respectively. In contrast after adrenalectomy alone the AngI levels at time 0, were not different from those of the controls. Subsequently the AngI levels increased at a similar rate as after adrenalectomy in the presence of atenolol. These findings suggest that the increase in plasma Aogen after nephrectomy is essentially mediated by AngII via an adrenal mechanism. It seems likely that this process is triggered by renin released during surgery. The increased renin release after adrenalectomy that is responsible for the increased degradation of Aogen seems not to be mediated by a sympathetic stimulation of the renal β 1-adrenoceptors.

Reciprocal feedback regulation of kidney angiotensinogen and renin mRNA expressions by angiotensin II.

The present study asks whether angiotensin II (ANG II), a potent inhibitor of renal renin synthesis and release, regulates renal angiotensinogen synthesis. ANG II (or vehicle) was intravenously infused into male Sprague-Dawley rats for 3 days (vehicle or 100, 300, and 1,000 ng.kg-1 x min-1, n = 8/group), significantly increasing mean plasma ANG II concentrations and raising mean arterial blood pressure (MAP). ANG II dose dependently suppressed plasma renin concentration, kidney renin concentration, and renal renin mRNA levels. In contrast, ANG II infusion increased renal angiotensinogen mRNA levels stepwise to 122, 136 (P < 0.05), and 150% (P < 0.05) of control and also increased both liver mRNA levels (P < 0.05) and plasma angiotensinogen concentration (P < 0.05). Three days of angiotensin-converting enzyme inhibition (10 mg.kg-1 x day-1 quinapril in drinking water, n = 8) significantly decreased MAP (P < 0.05) and increased both mean plasma renin concentration (P < 0.05) and renal renin mRNA levels (P < 0.005). Plasma ANG II concentration tended to decrease (not significant), and neither renal nor hepatic angiotensinogen mRNA levels displayed significant difference. However, when data from ANG II-infused and quinapril-treated rats were analyzed together, correlation between plasma ANG II concentrations and renal angiotensinogen mRNA levels was highly significant (P < 0.005, r = 0.585). Thus plasma ANG II upregulates renal angiotensinogen gene expression and downregulates renal renin gene expression, a reciprocal feedback regulation that may have important physiological consequences.

Neurohumoral and hemodynamic effects of sim 2055 in conscious beagle dogs

In the sympathetic nervous system the physiologic effects of the endogenous catecholamines noradrenaline (NA) and adrenaline (A) are mediated by α- and β-adrenoreceptors (ARs). Both AR-types can be subdivided into two major subtypes: α-ARs into α-1 (predominant effect: vasoconstriction) and α-2 (presynaptic: inhibition of NA-release; postsynaptic: vasoconstriction), β-ARs into β-1 (cardiac effects, renal renin release, and lipolysis) and β-2 (presynaptic: facilitation of NA-release; postsynaptic: vascular, bronchial, and uterine smooth muscle relaxation, glycogenolysis and possibly part of the A-mediated cardiac effects). During the last 30 years growing evidence has accumulated that dopamine (DA), the third endogenous catecholamine and the immediate precursor of NA, may also cause peripheral effects through stimulation of specific DA-receptors, in addition to its known action at α- and β-ARs. It is now well accepted that at least two different DA-receptors are present in many peripheral tissues (DA1 and DA2), including those of the cardiovascular and autonomic nervous system. They seem to be involved in dilation of certain vascular beds, inhibition of NA-release during nerve stimulation, natriuresis, and aldosterone release. In chronic heart failure cardiac β-AR function decreases (presumably due to endogenous “down-regulation” by the elevated catecholamines), and this decrease is related to the severity of heart failure (judged clinically by New York Heart Association functional class). The human heart contains both functional β-1 and β-2 ARs; cardiac β-1 and β-2 ARs seem to be differentially affected by different kinds of heart failure; in end-stage dilated cardiomyopathy β-1 ARs are selectively reduced, whereas β-2 ARs are nearly normal. Under these (pathologic) conditions β-2 ARs may substitute for the loss in β-1 AR function, thereby maintaining contractility, at least partially. In mitral valve disease and end-stage ischemic cardiomyopathy, on the other hand, the decrease in cardiac β-AR function is due to a concomitant decrease in β-1 and β-2 ARs. However, very little is known about changes in α-ARs and DA-receptors in chronic heart failure. Epinine (N-metyl-DA), the active metabolite of ibopamine, is a full agonist at DA1 and DA2 receptors with an affinity equal to or even slightly higher than DA. Similarly, its affinity to α-1 and α-2 as well as to β-1 ARs is comparable with DA, whereas at β-2 ARs the affinity of epinine is about 10 times higher than that of DA. In addition, epinine induces in isolated electrically driven human right atria its positive inotropic effect via stimulation of β-1 and β-2 ARs (being a full agonist), whereas DA is a partial agonist acting solely at β-1 ARs. Thus long-term application of ibopamine (i.e. epinine) should lead to the following cardiovascular and endocrine effects: it should cause positive inotropic effects through stimulation of cardiac β-1 and β-2 ARs, direct vasodilation through stimulation of β-2 ARs and DA1 receptors, indirect vasodilation through stimulation of presynaptic DA2 receptors and α-2 ARs (which leads to inhibition of NA-release), diuresis and natriuresis through stimulation of (renal) DA1 receptors. Blood pressure may increase slightly (but only at higher doses) via stimulation of postsynaptic α-1 and α-2 ARs. Thus the properties of epinine may be a suitable combination of effects to treat patients with chronic heart failure, provided that downregulation of receptor function can be prevented.

Renal Prostacyclin, Renin and Glomerular Filtration in Pregnancy-Induced Hypertension

Decreased renal production of prostacyclin (PgI2) might impair both renal release of renin and glomerular filtration rate (GFR) in women with pregnancy-induced hypertension (PIH). We measured renal excretion of the PgI2 metabolite 6-keto PgFla and thromboxane B2 (TB2) as well as plasma active renin concentration (PRC) and creatinine in 20 non-pregnant, 37 normal pregnant and 41 women with PIH (21 mild, 20 severe).Urinary 6-keto PgFla and TB2 excretion, the ratio 6-keto PgFla:TB2 and PRC were increased and plasma creatinine decreased in normal pregnancy compared with non-pregnant women. All prostanoid measurements and PRC were reduced significantly in those with severe PIH compared with normal pregnant women. Urinary 6-keto PgFla and TB2 were correlated negatively with both PRC and plasma creatinine in those with severe, but not mild, PIH.In a separate study, PRC was increased by head-up tilt in seven normal pregnant women and five women with PIH but urinary 6-keto PgFla was not altered significantly by this manoeuver.These studies do not support a significant role for renal PgI2 in the control of renin release in women with PIH. However, they do provide preliminary evidence that failure of renal PgI2 production may contribute to a fall in GFR in severe PIH.

Effects of bradykinin and papaverine on renal autoregulation and renin release in the anaesthetized dog

The present study on six anaesthetized dogs investigates the influences of two different vasodilators, bradykinin and papaverine, on the relationship between autoregulation of renal blood flow and glomerular filtration rate, sodium excretion and renin release. At control conditions renal blood flow and glomerular filtration rate was autoregulated to the same levels of renal arterial pressure, 55 +/- 3 and 58 +/- 3 mmHg, respectively. Renin release increased from 0.3 +/- 0.1 to 22 +/- 4 micrograms AI min-1, and sodium excretion decreased from 99 +/- 29 to 4.6 +/- 3.3 mumol min-1 when renal arterial pressure was reduced from 122 +/- 6 to 44 +/- 2 mmHg. Infusion of bradykinin (50 ng kg-1 min-1) increased renal blood flow by 50% at control blood pressure without changing glomerular filtration rate, and both renal blood flow and glomerular filtration rate autoregulated to the same pressure levels as during control. Sodium excretion increased threefold at control renal arterial pressure, but was unchanged at low renal arterial pressure. Bradykinin did not change renin release neither at control nor low renal arterial pressure. Papaverine infusion at a rate of 4 mg min-1 increased renal blood flow 50% without changing glomerular filtration rate. The lower pressure limits of renal blood flow and glomerular filtration rate autoregulation were increased to 94 +/- 6 and 93 +/- 6 mmHg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of centrally administered angiotensin on sympathetic nerve activity and blood flow to the kidney in conscious rats

The effects of intracerebroventricular (i.c.v.) administration of different doses (10 pg-100 ng) of angiotensin II (AII) on renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MAP), heart rate (HR), renal blood flow and femoral blood flow have been examined in conscious rats. Administration of AII (10 ng) through a chronically implanted cannula induced an increase in MAP (20-22 mmHg), a decrease in HR (24 bpm), a decrease in RSNA by 57%, a decrease of femoral blood flow by 21% but no change in renal blood flow. The effects on MAP, HR and RSNA are greatly attenuated by the prior i.c.v. injection of an AII-antagonist saralasin. In anesthetized rats, renal denervation significantly attenuated an increase in urinary sodium excretion induced by i.c.v. injection of AII. Since activation of the renal nerve is known to induce sodium reabsorption from the renal tubule and renin release, the relevance of the present finding is discussed in relation to the effect of AII on sodium excretion.

Influence of the plasma protein concentration on renal function

1. The effect of the plasma protein concentration on renal function remains controversial. Most, but not all, experimental studies suggest that a reduced plasma protein concentration perfusing the kidney may reduce tubular sodium reabsorption. Hypoproteinaemic disease states are usually associated with sodium retention, which is not always volume-dependent. 2. We induced a 21% and 24% reduction in plasma total protein and plasma albumin, respectively, in unanaesthetized sheep by acute extracorporeal plasmapheresis. Arterial pressure did not change, and changes in circulatory volume were minimised by infusion of crystalloid to maintain pulmonary artery occlusion pressure, measured using a Swann-Ganz pulmonary artery catheter. 3. After plasmapheresis, there was no significant change in creatinine clearance, sodium excretion, plasma renin activity or urinary kallikrein excretion. 4. After plasmapheresis, there was no significant reduction in plasma osmolality, increase in urine osmolality and fall in free water clearance. 5. The results suggest that in the absence of detectable changes in circulating volume or arterial pressure, acute hypoproteinaemia is associated with significant changes in renal water handling, but has no direct effect on sodium excretion or on renal release of renin and kallikrein.

Dietary calcium modulates renal BBM angiotensin II binding and Na(+)-H+ antiporter activity in SHR

Dietary Ca is an important modulator of blood pressure in the spontaneously hypertensive rat (SHR). Since the kidney plays a key role in the pathogenesis of hypertension, the purpose of this study was to determine the potential renal mechanisms of the blood pressure-lowering effect of increasing dietary Ca content. In 21-day-old SHR fed 0.1 vs. 3.6% Ca diet for 14 days, increasing dietary Ca had no significant effects on basal [704 +/- 50 in 0.1% Ca vs. 784 +/- 61 ng angiotensin I (ANG I).mg-1.h-1 in 3.6% Ca, P = not significant (NS)], isoproterenol-stimulated (1,057 +/- 52 in 0.1% Ca vs. 1,104 +/- 59 ng ANG I.mg-1.h-1 in 3.6% Ca, P = NS), or angiotensin II (ANG II)-inhibited (370 +/- 50 in 0.1% Ca vs. 411 +/- 39 ng ANG I.mg-1.h-1 in 3.6% Ca, P = NS) renal superficial cortical slice renin release. In contrast, in apical brush-border membrane (BBM) vesicles isolated from the superficial cortex, increasing dietary Ca caused a significant decrease in ANG II binding, which was mediated by a decrease in the number of binding sites (Bmax, 376 +/- 14 in 0.1% Ca vs. 234 +/- 6 fmol ANG II/mg BBM protein in 3.6% Ca, P less than 0.01), and no change in the affinity [dissociation constant (Kd), 17.8 +/- 1.4 in 0.1% Ca vs. 13.4 +/- 2.8 nM ANG II in 3.6% Ca, P = NS].(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogeny of renal renin release in spontaneously hypertensive rat and Wistar-Kyoto rat

The role of renin-angiotensin system in generation of genetic hypertension is unclear. Renal renin secretion was examined in renal superficial cortical slices from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at 4 wk (prehypertensive), 6 wk (early hypertensive), and 12 wk (established hypertension) of age. Basal renin release in SHR was greater at 4 wk (749 +/- 55 vs. 480 +/- 50 ng/mg, P less than 0.005) and at 6 wk (428 +/- 70 vs. 266 +/- 60 ng/mg, P less than 0.02). Basal renin release declined by 43% between 4 and 6 wk and by 34% between 6- and 12-wk time periods in SHR. In SHR and WKY at all ages, renin responses to stimulation with isoproterenol (ISO, 10(-5) and 10(-6) M, respectively) were similar. Angiotensin II (ANG II) resulted in a significant reduction in renin release in both SHR and WKY at 10(-7) M in all age groups. The ANG II-induced percent change in renin release from control of SHR was less compared with WKY rats at 10(-8) and 10(-9)M at 4 wk of age. When ANG II was tested in presence of beta-adrenergic stimulation, a comparable renin inhibitory response was observed in both SHR and WKY. The number of ANG II-binding sites in proximal tubular brush-border membrane (BBM) was increased in SHR vs. WKY rats (458 +/- 18 vs. 235 +/- 12 fmol ANG II/mg BBM protein, P less than 0.001) at 4 wk of age. These data document increased basal renin release and ANG II-binding sites in proximal tubular BBM in 4 wk SHR compared with age-matched WKY rat.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Physiology and pharmacology of cardiovascular catecholamine receptors: Implications for treatment of chronic heart failure

In the sympathetic nervous system the physiologic effects of the endogenous catecholamines noradrenaline (NA) and adrenaline (A) are mediated by α- and β-adrenoreceptors (ARs). Both AR-types can be subdivided into two major subtypes: α-ARs into α-1 (predominant effect: vasoconstriction) and α-2 (presynaptic: inhibition of NA-release; postsynaptic: vasoconstriction), β-ARs into β-1 (cardiac effects, renal renin release, and lipolysis) and β-2 (presynaptic: facilitation of NA-release; postsynaptic: vascular, bronchial, and uterine smooth muscle relaxation, glycogenolysis and possibly part of the A-mediated cardiac effects). During the last 30 years growing evidence has accumulated that dopamine (DA), the third endogenous catecholamine and the immediate precursor of NA, may also cause peripheral effects through stimulation of specific DA-receptors, in addition to its known action at α- and β-ARs. It is now well accepted that at least two different DA-receptors are present in many peripheral tissues (DA 1 and DA 2), including those of the cardiovascular and autonomic nervous system. They seem to be involved in dilation of certain vascular beds, inhibition of NA-release during nerve stimulation, natriuresis, and aldosterone release. In chronic heart failure cardiac β-AR function decreases (presumably due to endogenous “down-regulation” by the elevated catecholamines), and this decrease is related to the severity of heart failure (judged clinically by New York Heart Association functional class). The human heart contains both functional β-1 and β-2 ARs; cardiac β-1 and β-2 ARs seem to be differentially affected by different kinds of heart failure; in end-stage dilated cardiomyopathy β-1 ARs are selectively reduced, whereas β-2 ARs are nearly normal. Under these (pathologic) conditions β-2 ARs may substitute for the loss in β-1 AR function, thereby maintaining contractility, at least partially. In mitral valve disease and end-stage ischemic cardiomyopathy, on the other hand, the decrease in cardiac β-AR function is due to a concomitant decrease in β-1 and β-2 ARs. However, very little is known about changes in α-ARs and DA-receptors in chronic heart failure. Epinine (N-metyl-DA), the active metabolite of ibopamine, is a full agonist at DA 1 and DA 2 receptors with an affinity equal to or even slightly higher than DA. Similarly, its affinity to α-1 and α-2 as well as to β-1 ARs is comparable with DA, whereas at β-2 ARs the affinity of epinine is about 10 times higher than that of DA. In addition, epinine induces in isolated electrically driven human right atria its positive inotropic effect via stimulation of β-1 and β-2 ARs (being a full agonist), whereas DA is a partial agonist acting solely at β-1 ARs. Thus long-term application of ibopamine (i.e. epinine) should lead to the following cardiovascular and endocrine effects: it should cause positive inotropic effects through stimulation of cardiac β-1 and β-2 ARs, direct vasodilation through stimulation of β-2 ARs and DA 1 receptors, indirect vasodilation through stimulation of presynaptic DA 2 receptors and α-2 ARs (which leads to inhibition of NA-release), diuresis and natriuresis through stimulation of (renal) DA 1 receptors. Blood pressure may increase slightly (but only at higher doses) via stimulation of postsynaptic α-1 and α-2 ARs. Thus the properties of epinine may be a suitable combination of effects to treat patients with chronic heart failure, provided that downregulation of receptor function can be prevented.

Renal responses to lower body negative pressure in humans

Renal blood flow, renal sympathetic nerve activity, assessed by the renal overflows of norepinephrine (NE), dopamine (DA), and neuropeptide Y-like immunoreactivity (NPY-LI), as well as plasma renin activity and angiotensin II (ANG II) were evaluated during stepwise increases in lower body negative pressure (LBNP) in 10 healthy volunteers. The fractional extraction of epinephrine (Epi) was used to assess renal catecholamine removal (approximately 50%) from arterial plasma. Renal NE, DA, and NPY-LI overflows at rest were 235 +/- 31, 30 +/- 5, and 0.6 +/- 0.2 pmol/min, respectively. LBNP increased renal vascular resistance (RVR) by 52% and renal NE overflow by 31%. Renin release increased by 330% (from 64 +/- 12 units/min) and arterial ANG II levels by 119%, without altering the renal ANG II extraction (which was approximately 50%). Renal DA and NPY-LI overflows were unaffected. A "vaso-vagal" reaction in one subject was associated with cessation of renal NE overflow and marked elevations of arterial Epi, renal renin release, and arterial ANG II. Selective unloading of cardiopulmonary baroreceptors by low-level LBNP did not affect RVR, whereas higher levels of LBNP caused renal vasoconstriction probably mediated in part by increased renal sympathetic nerve activity and in part by ANG II.