Compartmental prostaglandin release by angiotensin II and arginine-vasopressin in rabbit isolated perfused kidneys

The compartmental effects of angiotensin II (AII) and arginine-vasopressin (AVP) on renal prostaglandin (PG) formation were studied in the isolated perfused kidney of the rabbit by superfusion bioassay of venous and ureteral effluents (VE and UE) and radioimmunoassay (RIA). Comparable results were obtained with either bioassay or RIA when used to quantitate renal PG release. The effects on PG release into the VE were similar for AII and AVP, as were their pressor responses. However, their effects on PG release into the UE differed markedly. AII resulted in a 6-fold greater urinary efflux than venous of bioassayable PGs, whereas AVP-induced PG release into UE was slightly less than PG efflux into the VE at all doses of the peptide. The profile of released PGs varied according to the sampling source (VE or UE). Moreover, each peptide released a similar profile of PGs at all doses, i.e. UE PGE2 greater than PGF2 alpha greater than 6-keto PGF1 alpha; VE PGE2 greater than 6-keto PGF1 alpha greater than PGF2 alpha (TxB2 was not detected in either effluent). Thus, renal vascular PG release is similar for the vasoactive peptides, AII and AVP, whereas the urinary efflux of PGs is considerably greater in response to AII.     

Modulation of neural noradrenaline and ATP release by angiotensin II and prostaglandin E2 in guinea-pig vas deferens

Effects of angiotensin II and prostaglandin E₂ on contractions, release of noradrenaline and release of ATP elicited by electrical stimulation (210 pulses, 7 Hz) were studied in the isolated vas deferens of the guinea pig. Release of noradrenaline was assessed as overflow of tritium after preincubation with [³H]-noradrenaline. ATP was measured by means of the luciferin-luciferase technique. In some experiments postsynaptic a ₁-adrenoceptors and P_2X-purinoceptors were blocked by prazosin and suramin, respectively, to isolate the neural fraction of the overflow of ATP.Electrical stimulation elicited an overflow of tritium and ATP and, in the absence of prazosin and suramin, contraction. In the absence of prazosin and suramin, angiotensin II (1–100 nM) enhanced contractions as well as the evoked overflow of tritium and ATP. All parameters were increased by about the same percentage for a given concentration of angiotensin 11. The effect of prostaglandin E₂ (1–100 nM) was complex. Contractions were mainly enhanced, the evoked overflow of tritium was reduced, whereas the evoked overflow of ATP was predominantly increased. No or almost no contraction remained in the presence of prazosin and suramin, and the evoked overflow of ATP was decreased to about 16%. Angiotensin II (1–100 nM) again enhanced the evoked overflow of tritium and ATP. Both were increased by about the same percentage for a given concentration of angiotensin II and also were increased by about the same percentage as obtained in the absence of prazosin and suramin. Prostaglandin E₂ (1–100 nM) decreased the evoked overflow of tritium and ATP in the presence of prazosin and suramin, both by about the same percentage at a given prostaglandin E₂ concentration.It is concluded that neural release of ATP, like the release of noradrenaline, is presynaptically facilitated by angiotensin II and depressed by prostaglandin E₂. In the case of angiotensin II, increases in neural and postsynaptic ATP release contribute to the increase in ATP over flow observed in the absence of prazosin and suramin. In the case of prostaglandin E₂, an increase in postsynaptic ATP release can override the reduction in neural ATP release and give rise to an increase in ATP overflow in the absence of prazosin and suramin. No evidence for a differential modulation of neural noradrenaline versus ATP release was found. Correspondence to: B. Driessen at the above address     

Inhibition of captopril-induced renin release by angiotensin II

The angiotensin-converting enzyme inhibitor (CEI) captopril has been shown to elevate plasma renin activity (PRA) and prostaglandin E2 levels, and to lower blood pressure and angiotensin II (AII) levels. Renin is secreted in both active and inactive forms; however, the interrelationship of these forms and responses to captopril are unclear. We proposed to determine if PRA rise induced by captopril is due primarily to release from AII inhibition, and if inactive renin is converted to active renin when PRA increases. Seven normal volunteers were given captopril, 50 mg orally, while on a moderately sodium-restricted diet (35 mEq/day). Changes in PRA and total and inactive renin, as well as prostaglandin E2, were measured. Then, on two different occasions, the captopril dose was preceded or followed by infusion of AII, to negate changes in AII induced by CEI. The dose of AII was obtained by dose-response infusion until a minimal increase in blood pressure occurred. Active renin increased with captopril alone, from 8.2 to 48.3 ng/ml/h by 90 min (p less than 0.01). AII completely blocked the rise in PRA induced by captopril, whether given before or after captopril. Inactive renin did not decline as active renin increased over the 90-min study. Therefore, the PRA rise induced by captopril is mediated through a fall in AII levels and loss of feedback on renin-secreting cells. The rise in PRA comes from secretion of active renin rather than conversion from inactive renin.     

Effects of clonidine on the experimental hypertension by abdominal aortic coarctation in rats.

Cardiovascular baroreflex mechanisms and sympathetic tone could be involved in the arterial hypertension by coarctation of abdominal aorta artery (CoA). The present work analyzes the effect on the arterial pressure and heart rate (HR) of the clonidine, an alpha(2)-adrenergic central acting antihypertensive agent, after intravenous (i.v.), intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration in rats anesthetized with pentobarbital (40 mg/kg i.p.).Wistar rats of both sexes (240-270 g) were used to the 7 days of the CoA or a sham operation (SO). Values of mean arterial pressure (MAP) and of HR were calculated from intraarterial recordings of blood pressure.The MAP of the CoA rats (161.5+/-5.3 mmHg, n=20) was significantly higher (P<0.01) than that of the SO rats (101.6+/-3.3 mmHg, n=20).The i.v. injection of clonidine (3-30 microg/kg) produced an increase of blood pressure in the rats SO and in the CoA animals, followed by a fall of arterial pressure in both groups of rats. Clonidine showed a small pressor effect but also a great depressor action in the hypertensive rats. Except for with the dose of 10 microg/kg, differences in cardiac response to clonidine were not seen in both groups of rats.Injection of clonidine by the i.c.v. via (10 microg) like by the i.t. (3 microg) also produced a greater fallen of the MAP in the hypertensive rats than in the controls SO animals.In conclusion, these hypertensive animals would be sensitive to the antihypertensive action of central acting alpha(2)-adrenoceptor agonist clonidine administered by different ways, suggesting a great sensitivity of the post-synaptic alpha(2)-adrenoceptor of central nervous system.     

Interaction between norepinephrine release and intrarenal angiotensin II formation during renal nerve stimulation in dogs

We examined possible interactions between intrarenal angiotensin II (ANG II) formation and norepinephrine (NE) release during renal sympathetic nerve stimulation (RNS) in anesthetized dogs. During 10 min of continuous RNS (1.5-2 Hz), the ANG II formation rates (ANG II-FR) and NE secretion rates (NE-SR) were determined at 1 and 10 min. Under control conditions, almost the same extent of increase in the NE-SR was observed at 1 and 10 min of RNS, whereas a significant increase in ANG II-FR was observed at 10 min but not at 1 min. During intrarenal arterial infusion of enalaprilat or losartan, the increase in NE-SR and reduction in renal blood flow at 10 min of RNS were suppressed, whereas the NE release and vasoconstriction responses at 1 min remained unaffected. The RNS-induced increases in ANG II-FR were completely abolished during infusion of enalaprilat. These results suggest that NE release on continuous RNS is enhanced by concomitantly formed ANG II, and this interaction depends on the time-related changes in intrarenal ANG II formation during RNS in the canine kidney.     

A comparison between the prostaglandin releasing effects of angiotensin II and angiotensin III

Angiotensin II and its natural fragment (des-aspartic acid)1-angiotensin II (angiotensin III) induced a dose-dependent contraction in the isolated rat stomach fundus strip and rat colon. 1-Acetyl-2-(8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10, carbonyl) hydrazine (SC 19220), a widely used competitive-blocker of prostaglandins and acetyl salicylic acid, a well-known inhibitor of prostaglandin biosynthesis, partially abolished the contraction induced by both peptides in the rat stomach fundus but not in the rat colon. The inhibition induced by SC 19220 and acetyl salicylic acid was found to be higher for angiotensin III than angiotensin II when the dose-response curves and equipotent concentrations of the peptides were compared before and after the drugs. These results were taken as evidence that some component of the contractile effects of angiotensin II and angiotensin III on the isolated rat stomach fundus involves the release of prostaglandins by the peptides and in this respect angiotensin III has higher potency than angiotensin II.     

Sustained release verapamil in renal hypertension

Summary In 14 patients with arterial hypertension secondary to chronic renal parenchymal disease and impaired renal function, 24-h ambulatory and casual blood pressure readings plasma, angiotensin II, aldosterone, arginine vasopressin and atrial natriuretic peptide, creatinine clearance, plasma lipids and lipoproteins, and body weight were determined after consecutive 3-week periods on placebo and sustained release verapamil 240 mg/day.Verapamil reduced the mean 24-h ambulatory blood pressure from 152/104 to 142/97 mm Hg. Blood pressure was significantly reduced during the daytime and the evening, but not at night. Casual blood pressure was also significantly reduced from 176/106 mm Hg to 154/96 mm Hg. No significant changes were found in the hormones, creatinine clearance, plasma lipids and lipoproteins, heart rate or body weight. The atrial natriuretic peptide level was significantly correlated with the calculated creatinine clearance (r=–0.797).Thus, sustained release verapamil 240 mg as a single daily dose had a moderate hypotensive effect in patients with chronic renal disease without inducing tachycardia, activation of the renin-angiotensin-aldosterone system, or increasing body weight, and without altering renal function and plasma lipids and lipoproteins. The negative correlation between atrial natriuretic peptide and glomerular filtration rate supports the hypothesis that the extracellular volume increases during progression of renal disease.     

Effects of sepiapterin infusion on renal oxygenation and early acute renal injury after suprarenal aortic clamping in rats

Acute kidney injury (AKI) can occur after aortic clamping due to microvascular dysfunction leading to renal hypoxia. In this rat study, we have tested the hypothesis that the administration of the precursor of the nitric oxide synthase essential cofactor tetrahydrobiopterin (BH4) could restore renal oxygenation after ischemia reperfusion (I/R) and prevent AKI. We randomly distributed rats into 4 groups: sham group; ischemia-reperfusion group; I/R + sepiapterin, the precursor of BH4; and I/R + sepiapterin + methotrexate, an inhibitor of the pathway generating BH4 from sepiapterin. Cortical and outer medullary microvascular oxygen pressure, renal oxygen delivery, renal oxygen consumption were measured using dual-wavelength oxygen-dependent quenching phosphorescence techniques during ischemia and throughout 3 hours of reperfusion. Kidney injury was assessed using myeloperoxidase staining for leukocyte infiltration and urine neutrophil gelatinase-associated lipocalin levels. Ischemia reperfusion induced a drop in microvascular PO2 (P < 0.01 vs. Sham, both), which was prevented by the infusion of sepiapterin. Sepiapterin partially prevented the rise in renal oxygen extraction (P < 0.001 vs. I/R). Finally, treatment with sepiapterin prevented renal infiltration by inflammatory cells and decreased urine neutrophil gelatinase-associated lipocalin levels indicating a decrease of renal injury. These effects were blunted when adding methotrexate, except for myeloperoxidase. In conclusion, the administration of sepiapterin can prevent renal hypoxia and AKI after suprarenal aortic clamping in rats.     

Hemodynamic, neural, and humoral mechanisms of aortic coarctation hypertension in the rat

The present study was designed: (a) to examine the contribution of the renin-angiotensin system (RAS) to elevated regional vascular resistance during the onset of aortic coarctation hypertension, and (b) to determine the role of angiotensin II (Ang II)-neural interactions during the maintenance of high arterial pressure (AP). In the first study, rats were instrumented chronically with miniaturized pulsed Doppler flow probes on the right renal and superior mesenteric arteries 3 days prior to complete aortic ligation. After ligation, AP and renal and mesenteric vascular resistances increased significantly. In sham-ligated rats, small increases in AP and decreases in regional vascular resistances were observed. Captopril, administered 6 h postligation, reduced AP and regional vascular resistance in ligated rats to preligation levels, indicating that the RAS was responsible for these acute increases. In the second study, Ang II-neural interactions were examined by treating 12- to 14-day postligation hypertensive rats with captopril or with hexamethonium, a ganglionic blocker, followed by captopril. Depressor responses to captopril were also examined in aortic-ligated rats pretreated with hydralazine. Captopril alone and captopril after hydralazine caused similar reductions in AP (-26 +/- 2% and -27 +/- 1%, respectively). After ganglionic blockade, the depressor responses to captopril were attenuated (-13 +/- 2%). The marked differences in the efficacy of captopril to lower AP in the ganglionic-blocked group of rats suggested that the pressor actions of Ang II were mediated, in part, through indirect actions on the sympathetic nervous system.     

Prostaglandin release from vasculature by angiotensin II: dissociation from lipolysis

Prostaglandin (PG) was released from the perfused splenic fat pad (with the spleen removed) by angiotensin (AII) and not by epinephrine or ACTH. The angiotensin antagonist, cysteine-8-AII blocked the AII induced PG release both in the spleen and the splenic fat pad. ACTH stimulated lipolysis from the rabbit spleen fat pad, but catecholamines and AII were ineffective. Thus, the release of PG from the rabbit splenic fat pad does not seem to require enhanced lipolysis nor do lipolytic agents cause the release of bioassayable PG.     

Prevention and reversal by enalapril of target organ damage in angiotensin II hypertension.

Angiotensin-converting enzyme inhibitors (ACE-Is) prevent target organ damage in several models of hypertension. The aim of this study was to assess the influence of the ACE-I enalapril (10 mg/kg(-1) per day, gavage) on the cardiovascular alterations and production of free radicals induced by chronic infusion of angiotensin II (Ang II, 200 ng/kg(-1) per minute, s.c.) in Sprague-Dawley rats. Enalapril was given concomitantly for the 10 days of Ang II infusion (prevention) or from day 10 to 17 of Ang II infusion (intervention). The influence of the NADPH oxidase inhibitor apocynin (600 mg/L(-1) in drinking water) was evaluated. Enalapril and apocynin had no effect on hypertension in the prevention and intervention studies. Enalapril prevented the increase in heart weight index (HWI), carotid cross-sectional area (CSA) and albuminuria induced by Ang II. Enalapril reduced HWI and albuminuria whereas CSA was not affected in the intervention study. Apocynin had effects comparable to enalapril. Both enalapril and apocynin reduced the overproduction of superoxide anion by the left ventricle and rise in advanced oxidation protein products induced by Ang II. Therefore, the antioxidant but not the antihypertensive effect of enalapril may participate in the prevention and treatment of the Ang II-induced cardiovascular and renal alterations.     

Effects of cadralazine on contractions induced by norepinephrine, serotonin, angiotensin II and K+ in rabbit aortic and renal arterial strips

Antagonistic effects of the new antihypertensive agent cadralazine (ethyl(+/-)-6-[ethyl(2-hydroxypropyl)-amino]-3-pyridazinecarbazate ) and its metabolite ISF-2405 [+/-)-6-[ethyl(2-hydroxypropyl)amino]-3-hydrazinopyridazine) on norepinephrine (NE), 5-hydroxytryptamine (serotonin), angiotensin II (angio II) and KCl induced contractions of rabbit abdominal aortic and renal arterial strips were compared with those of hydralazine. Substantially, cadralazine does not exert any effect on cumulative dose-response curves of these agonists in both vessel preparations even with the highest concentration of 10(-4) mol/l. ISF-2405 and hydralazine at concentrations of 10(-5) and 10(-6) mol/l showed non-competitive antagonism, depending not only on the dose but also on the length of the pretreatment time, on NE-induced contractions of abdominal aorta and renal artery. The two drugs attained maximal pD2 values with 60 min pretreatment without showing significant difference between the two vessel preparations, suggesting that the inhibitory effect of these drugs does not show vascular bed-related difference against NE-induced contractions. 60 min pretreatment with 10(-6) and 10(-5) mol/l of ISF-2405 and hydralazine also manifested non-competitive antagonism on contractile responses to serotonin, angio II, and K+ for both compounds. The degree of antagonistic effects of ISF-2405 and hydralazine on these agonists is similar, the order being angio II greater than serotonin greater than NE greater than K+. These results suggest that ISF-2405 and hydralazine exert direct vasodilating effects by the same mode of action at a site other than receptors against Ca2+ mobilization.     

Neural control of the renal vasculature in angiotensin II-induced hypertension

1. Chronic administration of angiotensin (Ang) II causes an increase in blood pressure via a multitude of actions, including direct vasoconstriction, hypertrophy and increased sympathetic nerve activity. In the present study, we assessed whether the hypertension resulting from chronic Ang II alters the ability of the renal vasculature to respond to sympathetic activity. 2. Angiotensin II was administered for 7 weeks via an osmotic minipump at a dose of 50 ng/kg per min, i.v., to a group of six rabbits. Blood pressure, measured at 0, 1, 2 and 6 weeks after insertion of the pump, increased from 76 +/- 2 to 104 +/- 6 mmHg at the end of 6 weeks, without any significant change in heart rate. The blood pressure in the control group remained constant at 76 +/- 2 mmHg. 3. After 7 weeks, rabbits were anaesthetized and the renal nerves were stimulated at 0.5, 1, 1.5, 2, 3, 5 or 8 Hz for 3 min at their supramaximal voltage (5.5 +/- 1.0 V in the normotensive group and 6.5 +/- 1.5 V in the hypertensive group) while the renal blood flow (RBF) response was recorded. Under anaesthesia, there was no difference in mean arterial pressure between the normotensive and hypertensive animals (77 +/- 2 and 80 +/- 7 mmHg, respectively). The resting RBF under these conditions was not significantly different in the hypertensive group (30 +/- 4 vs 26 +/- 5 mL/min in the normotensive vs hypertensive group, respectively). 4. Stimulation at increasing frequencies was associated with increasing reductions in RBF (e.g. 36 +/- 8% at 2 Hz in normotensive rabbits and 48 +/- 7% at 2 Hz in hypertensive rabbits). However, there were no significant differences between RBF responses in normotensive and hypertensive rabbits. 5. We conclude that hypertension associated with chronic Ang II administration does not alter the response in RBF to electrical stimulation of the nerves.     

Etomidate alters calcium mobilization induced by angiotensin II in rat aortic smooth muscle cells

Etomidate is widely used for induction of anesthesia in the hemodynamically compromised patient, because of its moderate direct effect on arterial vasomotoricity and cardiac function, but its effect on blood pressure regulatory systems is not known. We studied the effect of etomidate (10(-8) to 10(-4) mol.L) on Ca++ mobilization elicited by angiotensin II (Ang II) in cultured aortic smooth muscle cells (VSMC) from 6-week-old Wistar Kyoto rats. Intracellular Ca++ (Cai++) variation was assessed in Fura 2-loaded VSMC, using fluorescent imaging microscopy. Ang II (10(-6) mol.L(-1))-induced transient Cai++ mobilization from internal stores was assessed in the absence of external Ca++. Ca++ influx was assessed upon reintroduction of external Ca++ (10(-3) mol.L(-1)). Etomidate moderately decreased both the amplitude (etomidate 10(-4) mol.L(-1): 68% of control value, P < 0.001) and the slope of Cai++ increase (56% of control, P < 0.001) from internal stores induced by Ang II. PD2 values (PD2 = -log(EC50)) for amplitude and slope were 6.4 +/- 0.7 and 6.0 +/- 0.3, respectively. Ang II-elicited Ca++ influx was also significantly decreased (45% of control, P < 0.001; PD2 = 5.5 +/- 0.3). Etomidate alters the Ca++ mobilization elicited by Ang II in rat aortic VSMC, suggesting that the vascular response to Ang II may be altered during etomidate anesthesia. However, this effect was observed at high concentration of etomidate, and may be limited when low doses of etomidate are used.     

Leukotrienes C4 and D4 induce prostaglandin and thromboxane release from rat peritoneal macrophages.

The present study examined the effect of leukotrienes C4 and D4, the products of the 5'lipoxygenase pathway on prostaglandins and thromboxane release from rat peritoneal macrophages. Incubation of rat peritoneal macrophages with leukotrienes C4 and D4 enhanced the release of prostaglandin E2 (PGE2), 6-keto PGF1 alpha and thromboxane B2 (TxB2) in a dose-dependent manner. The increase of PGE2 was more pronounced than that of 6-keto-PGF1 alpha and TxB2. Lipopolysaccharide, a known stimulator of these cells elicited a similar pattern of increase of the arachidonate metabolites assayed. These results suggest that leukotrienes C4 and D4 are potential activators of macrophages. Since leukotrienes C4 and D4 are produced by these cells, it is suggested that endogenous leukotrienes may be involved in activation of macrophages.     

Vasopressin release induced by intracranial injection of eledoisin is mediated by central angiotensin II

Pulse intracerebroventricular injection of eledoisin, but not of substance P, markedly increases plasma vasopressin levels in the rat. Intracerebroventricular pretreatment with sarcosine1, alanine8-angiotensin II, 1 microgram/rat, completely suppresses the effect of eledoisin, suggesting that it is mediated by angiotensin release and angiotensin II receptor activation. The vasopressin releasing effect of eledoisin is neither due to peripheral haemodynamic alterations, nor to activation of the peripheral renin-angiotensin system. It is apparently related to central angiotensin release in a specific neuronal pathway subserving vasopressin release. This effect is not secondary to inhibition by tachykinins of the brain mechanisms for angiotensin-induced drinking, but is probably expression of direct activation of specific tachykinin receptors controlling vasopressin release.     

Regulation of renal proximal fluid uptake by luminal and peritubular angiotensin II.

INTRODUCTION: Angiotensin II (Ang II), when administered to either tubular lumen or peritubular capillary, exerts a biphasic action on proximal fluid uptake rate. At low concentrations, (10(-12)-10(-10) M) Ang II stimulates fluid transport, whereas higher doses (>10(-9) M) inhibit. Ang II is secreted into the lumen in the proximal tubule and the concentration of Ang II in the proximal lumen has been reported to be in the nanomolar range, 100-1,000 times higher than in peritubular blood. We investigated the regulation of renal proximal fluid transport by luminal (predominantly locally produced) and peritubular capillary (circulatory) Ang II in anaesthetised rats, using a selective AT(1)-receptor antagonist, candesartan. METHODS: Experiments were performed in inactin-anaesthetised male Wistar rats. Proximal fluid uptake rate was measured using computerised capture and analysis of shrinking-split droplet microperfusion in response to either luminal addition or luminal addition with simultaneously peritubular capillary perfusion of 10(-8) M candesartan. RESULTS: Luminal addition of candesartan (10(-8) M) decreased fluid absorption by 19-25%. Perfusion of the peritubular capillaries with an electrolyte solution (containing no Ang II) reduced fluid uptake by 27%, and blockade of the peritubular actions of Ang II by addition of candesartan (10(-8) M) resulted in 33% decrease in fluid uptake. However, when candesartan (10(-8) M) was added to both luminal and capillary perfusates, there was a 43% reduction in fluid transport when compared with initial values. CONCLUSION: These results suggest that the presence of endogenous Ang II in both peritubular blood and luminal fluid is important for maximal expression of the stimulatory influence of this peptide on proximal tubule fluid uptake.