Effect of captopril on renal vascular resistance, renin, prostaglandins and kinin in the isolated perfused kidney

Vasodilatory and natriuretic effects of captopril were studied in the isolated hog kidney perfused with modified Krebs-Ringer solution. Renal arterial infusion of captopril caused increases in releases of renin, prostaglandins (PGE2, 6-keto-PGF1 alpha and PGF2 alpha) and kinin, and was accompanied by a decrease in the renal vascular resistance and an increase in urinary sodium excretion. Indomethacin administered with captopril diminished the saluretic effect of captopril and evoked an increase in kinin, but was associated with a marked decrease in prostaglandin and renin releases, while renal vascular resistance remained decreased. Indomethacin alone did not alter vascular resistance and kinin; however, renin and prostaglandin releases were decreased. Aprotinin administered with captopril showed a decrease in releases of prostaglandins, renin and kinin without any change in vascular resistance. These results suggest that increased release of kinin induced by captopril contributes to a reduction in renal vascular resistance. Increased prostaglandin release after captopril administration may be caused by an increase in kinin without direct involvement of captopril in prostaglandin synthesis. Renal prostaglandins may enhance sodium excretion and mediate renin secretion in captopril perfusion.     

Effect of prostacyclin infusion on active and inactive renin release in the isolated perfused kidney

The effect of prostacyclin infusion into the renal artery of the isolated perfused hog kidney on the release of active and inactive renin was investigated. Infusion of prostacyclin at a rate of 0.1 μg/min resulted in a significant increase (p<0.01) in active renin and a significant fall (p<0.01) in inactive renin. Prostacyclin also increased urinary kallikrein excretion (p<0.05). The results indicate that the kidney secretes not only active renin but also inactive renin, and suggest that prostacyclin stimulates the conversion of inactive renin to the active form through the activation of the renal kallikrein system.     

Physiological responses to low dose infusions of atrial peptide in conscious dogs

Mongrel dogs prepared with chronic catheters in their femoral artery and vein and urinary bladder received 60 minute infusions of atrial peptide ranging from 5 to 100 ng/kg/min. Infusion of atrial peptides caused dose dependent increases in plasma atrial peptide concentration with doses of 25 ng/kg/min or less increasing plasma concentrations to levels observed in normal animals during stimulation of endogenous atrial peptide secretion. Atrial peptide infusion at doses of 10 ng/kg/min and above caused significant decreases in mean arterial pressure which were not accompanied by statistically significant changes in heart rate. Atrial peptide infusion at doses of 25 ng/kg/min and above increased urinary sodium excretion and urine flow rate. Atrial peptide infusion was without effect on plasma vasopressin, ACTH and corticosterone concentrations. However, atrial peptide infusion resulted in dose dependent decreases in plasma aldosterone concentration and plasma renin activity, but the decreases were only significant with the high physiologic (25 ng/kg/min) and pharmacologic doses (50 & 100 ng/kg/min). These data show that atrial peptide infusions in conscious dogs have minimal effects when infused in small doses that mimic endogenous atrial peptide release. At higher doses, significant effects on the cardiovascular, renal and endocrine systems can be observed but their physiological significance is unclear.     

Effect of alpha-adrenergic stimulation on prostacyclin and renin release in the rat kidney

The relationship between renin secretion and PGI₂ production, in response to intrarenal infusion of norepinephrine, was examined in the isolated perfused rat kidney. Infusion of norepinephrine in a dose which caused substantial vasoconstriction (100 ng/min), markedly increased urinary excretion of 6-keto PGF_1α, the stable derivative of PGI₂, without significantly altering renin secretion measured in the effluent perfusate. No change in urinary 6-keto PGF_1α occurred when vasoconstriction was prevented by infusing the alpha-adrenoceptor blocking drug phenoxybenzamine (2 × 10³ ng/min) alongside norepinephrine 100 ng/min). However, under these conditions there was marked stimulation of renin secretion which, as has been demonstrated previously, is mediated by a beta-adrenoceptor. There were significant increase in urine flow rates during both vasoconstrictor and non-vasoconstrictor infusions. These findings clearly indicate that in the rat kidney prostacyclin production and renin release in response to norepinephrine are dissociated.     

Effects of endothelin on renal hemodynamics and excretory functions in anesthetized dogs

The effects of endothelin on renal hemodynamics and excretory functions were investigated in anesthetized dogs. Infusion of endothelin at a rate of 1 ng/kg.min resulted in a slight but significant decrease in renal blood flow and an increase in renal vascular resistance and filtration fraction. Endothelin at doses higher than 10 ng/kg.min significantly decreased cardiac output, glomerular filtration rate, urine volume, and urinary sodium and potassium excretion, whereas it increased systemic vascular resistance. Mean arterial pressure and heart rate showed a transient decrease and increase, respectively, at doses higher than 50 ng/kg.min. Plasma renin activity and plasma aldosterone concentrations were increased only at the dose of 100 ng/kg.min. These effects lasted for more than 60 min. These results suggest that endothelin may have an important role in the modulation of renal functions as well as in the modulation of systemic hemodynamics.     

Induction of renin release by exogenous prostaglandins in hyporeninemic hypoaldosteronism

A deficiency in renal prostaglandin synthesis has been proposed as the cause of the syndrome of hyporeninemic hypoaldosteronism. To determine if renin release could be stimulated by pharmacologic infusions of PGA₁, we infused PGA₁ 0.075 to 0.60 μg/kg/min to nine patients with the syndrome. Total renal PGE production as measured by urinary PGE excretion was normal (650 ± 169 vs 400 ± 55 ng/24hr in normal subjects). Renin (PRA) was markedly depressed in all patients despite stimulation with upright posture and furosemide (1.0 ± 0.4 vs 9.3 ± 0.7 ng/ml/hr, p<0.001). But in two patients PGA₁ induced an increase in renin similar to that of normal subjects. PRA increased to a lesser degree in two other patients and plasma aldosterone slightly increased. Five showed no response. Infusions of nitroprusside in doses and duration that mimicked the hypotensive effects of PGA₁ failed to increase PRA or aldosterone. The data suggest that total renal PGE production is normal in patients with the syndrome of hyporeninemic hypoaldosteronism. Although orthostasis, furosemide and nitroprusside do not increase renin, prostaglandin A₁ infusion appears to be a potent stimulus to renin release in some of the patients.     

The treatment of the hepatorenal syndrome with intra-renal administration of prostaglandin E1

Three patients with the hepatorenal syndrome were treated with prostaglandin E₁ administered through a selective renal arterial catheter. Prostaglandin E₁ was given in progressively increasing doses (2 to 100 ng/kg/min) over a 60-minute period. Control plasma prostaglandin E levels were elevated in all three patients, 0.98, 0.91, and 0.83 ng/ml, respectively. At the end of the infusion, plasma prostaglandin E levels had risen to 10.4, 2.63, and 10.3 ng/ml in the three patients respectively. Plasma renin activity increased during the course of the infusion in two of the patients. The plasma aldosterone concentration did not change during the prostaglandin E₁ infusion. Intrarenal prostaglandin E₁ failed to increase urine volume or urinary sodium concentration in three patients with the hepatorenal syndrome.     

Effect of alpha-adrenergic stimulation on prostacyclin and renin release in the rat kidney

The relationship between renin secretion and PGI2 production, in response to intrarenal infusion of norepinephrine, was examined in the isolated perfused rat kidney. Infusion of norepinephrine in a dose which caused substantial vasoconstriction (100 ng/min), markedly increased urinary excretion of 6-keto PGF1 alpha, the stable derivative of PGI2, without significantly altering renin secretion measured in the effluent perfusate. No change in urinary 6-keto PGF1 alpha occurred when vasoconstriction was prevented by infusing the alpha-adrenoceptor blocking drug phenoxybenzamine (2 x 10(3) ng/min) alongside norepinephrine (100 ng/min). However, under these conditions there was marked stimulation of renin secretion which, as has been demonstrated previously, is mediated by a beta-adrenoceptor. There were significant increases in urine flow rates during both vasoconstrictor and non-vasoconstrictor infusions. These findings clearly indicate that in the rat kidney prostacyclin production and renin release in response to norepinephrine are dissociated.     

Effects of captopril and enalapril on sodium excretion and blood pressure in sodium-deficient dogs

Inhibition of angiotensin I-converting enzyme (ACE) (kininase II) provides a powerful new method for evaluating the role of the renin-angiotensin-aldosterone and kallikrein-kinin systems in the control of aldosterone secretion, renal function, and arterial blood pressure. This study compares the effects of long-term administration of a sulfhydryl inhibitor, captopril, with a nonsulfhydryl inhibitor, enalapril (1-[N-[1-(ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-L-proline), in conscious sodium-deficient dogs. Plasma aldosterone concentration (PAC), plasma renin activity (PRA), urinary sodium excretion (UNaV), arterial pressure (AP), blood kinins (BK), urinary kinins (UK), and urinary kallikrein activity (UKA) were determined during long-term inhibition of ACE in sodium-deficient dogs. In response to captopril administration (20 mg/(kg . day], PAC decreased from 38.9 +/- 6.7 to 14.3 +/- 2.3 ng/dl, PRA increased from 3.58 +/- 0.53 to 13.7 +/- 1.6 ng/(ml . h), UNaV increased from 0.65 +/- 0.27 to 6.4 +/- 1.2 meq/day, AP decreased from 102 +/- 3 to 65 +/- 2 mm Hg, BK increased from 0.17 +/- 0.02 to 0.41 +/- 0.04 ng/ml, UK increased from 7.2 +/- 1.5 to 31.4 +/- 3.2 micrograms/day, and UKA decreased from 23.6 +/- 3.1 to 5.3 +/- 1.2 EU/day. Quantitatively similar changes in AP, UNaV, and PAC were observed in sodium-deficient dogs in response to long-term enalapril administration (4 mg/(kg X day]. In sodium-deficient dogs maintained on captopril or enalapril for several days, angiotensin II (AngII) infusion (3 ng/(kg X min] restored PAC, UNaV, and AP to levels observed in untreated sodium-deficient dogs. These data indicate that the long-term hypotensive and natriuretic actions of inhibitors of ACE are mediated by inhibition of AngII formation and that the renin-angiotensin system plays an essential role in regulating aldosterone secretion, renal function, and AP during sodium deficiency.     

Effect of vasodilator prostaglandins on the vascular renin-angiotensin system

The interaction of prostaglandin (PG) with the vascular renin-angiotensin (R-A) system was examined by studies on the effects of PGI2, PGE2 and the inhibitor of PG synthesis, indomethacin, on the release of angiotensin II (Ang II) from isolated rat mesenteric arteries. The Ang II released from the vasculature was measured after its concentration in a Sep-Pak C18 cartridge connected to the perfusion system. After perfusion with drugs, the specific vascular renin activity inhibited by anti-renin antibody was determined. The basal perfusion pressure was constant (19.6 +/- 1.1 mmHg) at a flow rate of 4.5 ml/min, and was not changed by any of these drugs. The basal levels of Ang II release and vascular renin activity were 44 +/- 5 pg/30 min and 113 +/- 8 pg Ang I/mg protein/hr, respectively. Infusion of PGI2 (10(-6) M) significantly decreased both Ang II release (p less than 0.01) and vascular renin activity (p less than 0.05) as compared with the control levels. Infusion of PGE2 (10(-6) M) decreased Ang II release significantly (p less than 0.05) and vascular renin activity slightly. Infusion of indomethacin (10(-6)M) increased vascular renin activity significantly (p less than 0.01). Pretreatment with indomethacin (10 mg/kg, ip) for 2 days also increased vascular renin activity (p less than 0.01). These results indicate that in contrast to their effects on the renal R-A system, PGs suppress the vascular R-A system and that these two local vasoactive factors interact to regulate vascular tone.     

Role of prostaglandis in the control of renin secretion in the dog (II)

Infusion of prostaglandin E₁ (PGE₁) into the renal artery of anesthetized dogs (1.03 μg/min) caused increases in urine flow rate (V), renal plasma flow (RPF) and renin secretion rate without any change in mean arterial blood pressure (MABP), whereas infusion of prostaglandin F₂α (PGF_2α), (1.03 μg/min) caused no consistent change in V, RPF, or renin secretion rate. Infusion of prostaglandin E₂ (PGE₂) (1.03 μg/min) into the renal artery of “non-filtering” kidneys caused renin secretion rate to rise from 567.7 ± 152.0 U/min(M ± SEM) during control periods to 1373.6 ± 358.5 U/min after 60 minutes of infusion of PGE₂ (P < 0.01), without significant change in MABP (P > 0.1). The data suggest that PGE₁ and PGE₂ play a role in the control of renin secretion. The data further suggest that PGE may control renin secretion through a direct effect on renin-secreting granular cells.     

The tissue kallikrein-kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction

Tissue kallikrein (hK1) cleaves low-molecular-weight kininogen to produce kinin peptide, which binds to kinin receptors and triggers a wide spectrum of biological effects. Tissue kallikrein levels are reduced in humans and in animal models with hypertension, cardiovascular and renal diseases. Transgenic mice or rats over-expressing human tissue kallikrein or kinin B2 receptor are permanently hypotensive, and somatic kallikrein gene delivery reduces blood pressure in several hypertensive rat models. Moreover, kallikrein gene delivery or kallikrein protein infusion can directly improve cardiac, renal and neurological function without blood pressure reduction. Kallikrein has pleiotropic effects in inhibiting apoptosis, inflammation, proliferation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in different experimental animal models. Kallikrein's effects can be blocked by kinin B2 receptor antagonists. Mechanistically, tissue kallikrein/kinin leads to increased nitric oxide levels and Akt activation, and reduced reactive oxygen species formation, TGF-beta1 expression, MAPK and nuclear factor-kappaB activation. Our studies indicate that tissue kallikrein, through the kinin B2 receptor and nitric oxide formation, can protect against oxidative damage in cardiovascular and renal diseases and ischemic stroke. These novel findings suggest that kallikrein/kinin may serve as new drug targets for the prevention and treatment of heart failure, renal disease and stroke in humans.     

A simple and sensitive method for determination of human urinary kallikrein activity (kininogenase activity), using human low molecular weight kininogen

Human low molecular weight kininogen was partially purified and applied to the measurement of human glandular kallikrein as a substrate. The prepared human low molecular weight kininogen did not contain any significant amounts of kinin generating or destroying enzymes. When ethanol was added to the assay tube to stop the enzyme reaction, the substrate was almost completely removed from the incubation solution. Moreover, less than 1.25% ethanol had no effect on the kinin radioimmunoassay. These data suggest that the measurement of generated kinin can be done directly after the addition of ethanol. In this assay system, control tubes were unnecessary since the small volume of the urine samples (0.5 to 2.0 nl) contained negligible amounts of endogenous kinin. In a comparison of the availability as a substrate for human urinary kallikrein among human, dog and bovine low molecular weight kininogens, the enzyme activity was 5 or 100 times as high in the human substrate as in the dog and bovine substrates, suggesting that a human substrate is best for the human enzyme. A significant correlation was found between our previous method using bovine substrate and this method for human urinary kallikrein activity. In both methods, urinary kallikrein excretions were significantly lower in patients with essential hypertension and higher in those with primary aldosteronism, respectively. This simple, specific and sensitive kininogenase assay system seems to be very useful for investigating the physiological or pathophysiological role of the renal kallikrein-kinin system in hypertensive and renal diseases.     

Effect of prostaglandin E1 on renin and aldosterone in hypertensive patients.

The effect of prostaglandin E1 (PGE1) on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was studied in the hypertensive subjects treated with or without 75 mg indomethacin or 60 mg propranolol for a week. Subsequent to the treatment with indomethacin for a week, PRA and PAC levels were decreased as compared to the control, without changes in the blood pressure and heart rate. During the infusion of PGE1, the blood pressure was decreased and the pulse rate was increased. PRA and PAC levels were also elevated. These changes of parameters were not different between the control and the indomethacin-treated subjects. PRA and PAC were suppressed after the treatment with propranolol. With the infusion of PGE1, the level of PRA was not significantly elevated, while, PAC was significantly increased by the infusion of 100 ng/Kg/min of PGE1. During the infusion of PGE1, the blood pressure was decreased while the pulse rate was increased in the subjects treated with propranolol. However, the elevation of the pulse rate was less remarkable than the control. These data indicate that PGE1 have important roles in the regulation of the release of renin and aldosterone. These findings also suggest that PGE1 may act to stimulate the secretion of aldosterone in man.     

Impaired prostaglandin release from the kidneys of salt-loaded and hypertensive rats

Prostaglandin (PG) release by the isolated perfused kidney of the rat has been stimulated by nor-adrenaline infusion and measured by bioassay. There was no basal output of PGE₂-like activity, but stimulated release reached mean concentrations of 9.1 ng/g kidney/ml perfusate in kidneys from female albino rats drinking water and 2.9 ng/g/ml in those from animals given 1.5% NaCl to drink. Kidneys from uninephrectomised animals with mock-clipped renal arteries released 7.3 ng PG/g/ml and those from rats with uninephrectomy and constricted renal arteries 3.3 ng/g/ml.     

Decreased renin release and constant kallikrein secretion after injection of L-NAME in isolated perfused rat kidney.

A possible role of the endothelial L-arginine/NO pathway in the control of renal hemodynamics, renin release and kallikrein secretion was studied in an isolated rat kidney model perfused in a closed-circuit. NG-nitro-L-arginine methyl ester (L-NAME, 1-50 microM), an inhibitor of nitric oxide biosynthesis, caused a dose-dependent increase in perfusion pressure (PP) and a dose-dependent decrease in renal perfusate flow. Renin release was inhibited independently of a rise in PP. L-NAME did not change the urinary kallikrein secretion. These results confirm the intervention of the L-arginine/NO pathway in the vasodilation of this isolated perfused kidney model and demonstrate the inhibitory effect of L-NAME on renin release. They suggest that nitric oxide synthesis plays a role in stimulating renin release and is not involved in the regulation of urinary kallikrein secretion.     

Adenovirus-mediated human prostasin gene delivery is linked to increased aldosterone production and hypertension in rats

Prostasin has been demonstrated to be an activator of epithelial sodium channels in cultured renal and bronchial epithelial cells. In this study, we evaluated the effects of adenovirus-mediated gene transfer of human prostasin on blood pressure regulation and sodium reabsorption in Wistar rats. Expression of human prostasin mRNA was identified in rat adrenal gland, liver, kidney, heart, lung, and aorta, and immunoreactive human prostasin was detected in the circulation and urine of rats receiving prostasin gene transfer. A single injection of adenovirus carrying the prostasin gene caused prolonged increases in blood pressure for 3-4 wk. Blood pressure increase was accompanied by elevated plasma aldosterone levels and reduced plasma renin activity. The increase in blood pressure and plasma aldosterone levels as well as the reduction of plasma renin activity correlated with the expression of human prostasin transgene. Elevated plasma aldosterone levels were detected at 3 days after gene transfer before the development of hypertension, indicating that stimulation of mineralocorticoid production is the primary target of prostasin. Prostasin gene transfer significantly reduced urinary K(+) excretion but increased urinary Na(+) and kallikrein excretion. Elevated renal kallikrein levels promote natriuresis, which may lead to sodium escape and prevent further increases of blood pressure after prostasin gene transfer. In summary, these results suggest that prostasin participates in blood pressure and electrolyte homeostasis by regulating the renin-angiotensin-aldosterone and kallikrein-kinin systems.     

Renin release in anesthetized rats is enhanced by the calmodulin antagonist W-7

In foregoing work, we found that the release of renin from rat kidney cortical slices was stimulated by the calmodulin antagonist W-7. The present work was done to determine whether W-7 would stimulate renin release in vivo. W-7 and its control agent, W-5 were directly infused into the renal artery of anesthetized rats. W-7 and W-5, at 50 micrograms/kg/min, produced no significant effects on renin release. Infusion of W-7 at 100 micrograms/kg/min resulted in a marked stimulation of renin release, but there was no significant alteration in the release when the same dose of W-5 was infused. Both compounds elicited a slight decrease in renal blood flow. The alterations in renin release and renal blood flow seen with W-7 were not affected by pretreatment with phentolamine or propranolol. As W-7 stimulates renin release in vivo, the hypothesis that Ca2+-calmodulin plays an inhibitory role in renin release from the kidney is given added support.     

Acute changes in plasma renin activity, plasma aldosterone concentration and plasma electrolyte concentrations following furosemide administration in patients with congestive heart failure--interrelationships and diuretic response

We studied the effects of furosemide on plasma renin and plasma aldosterone in 8 patients with mild to moderate congestive heart failure. In particular, we tried to correlate these effects with changes in plasma electrolyte concentrations and with the diuretic response on furosemide. We concluded that the diuretic response in patients with congestive heart failure is not dependent on the initial serum renin nor on the initial serum aldosterone concentration. The diuretic response did not correlate either with the changes in serum renin and/or serum aldosterone concentration. Serum renin and serum aldosterone correlated mutually before and after intravenous furosemide. We confirmed the inverse correlation between serum sodium and serum renin. SeNa and SeK correlated at all times with serum aldosterone; SeCl correlated with serum aldosterone only before intravenous furosemide administration. Indirect evidence could be provided that in patients with congestive heart failure a decreased renal blood flow is present, using the urinary beta 2-microglobulin concentration. Aldosterone has again, indirectly, proved to be integrated in the renal magnesium handling.     

Rapid non-genomic effects of aldosterone on the renal vasculature

There is increasing evidence for the importance of rapid non-genomic effects of aldosterone on the human vasculature including renal vessels. Arima and colleagues by examining isolated perfused afferent and efferent arterioles from rabbit kidneys found a vasoconstriction in both. In another study the same group showed that endothelium-derived nitric oxide (NO) modulates the vasoconstrictor response to aldosterone in rabbit preglomerular afferent arterioles. Disrupting the endothelium as well as blockade of endothelial NO synthase (eNOS) augmented aldosterone-induced vasoconstriction in this study. Uhrenholt et al. found no effect of aldosterone alone to afferent arterioles but a suppression of depolarisation-induced vasoconstriction. After the blockade of eNOS the aldosterone effect was completely suppressed. In a clinical study in healthy male volunteers injection of aldosterone had no statistically significant effects. Co-infusion of the eNOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) changed the effect of aldosterone on renal hemodynamics. Aldosterone in co-infusion with L-NMMA decreased renal plasma flow (RPF) much stronger than L-NMMA alone. Infusion of L-NMMA alone increased GFR whereas aldosterone/L-NMMA lowered GFR slightly. Aldosterone co-infused with L-NMMA strongly increased renal vascular resistance (RVR). The increase was on top of the smaller increase that was induced by L-NMMA infusion. These data indicate that aldosterone acts via rapid non-genomic effects in vivo in humans at the renal vasculature. Antagonizing the endothelial nitric oxide synthase unmasks these effects. Therefore, rapid non-genomic aldosterone effects increase renal vascular resistance and thereby may mediate arterial hypertension if endothelial dysfunction is present.