Effect of indomethacin on the adrenal renin response to nephrectomy in the rat

The role of prostaglandins in the control of adrenal renin in vivo was evaluated in nephrectomized rats. Nephrectomy increased adrenal renin from 13.2 +/- 1.37 ng angiotensin I/mg protein/hr to 166.5 +/- 17.3 ng angiotensin I/mg protein/hr. Indomethacin treatment significantly suppressed the adrenal renin response to nephrectomy. (47.8 +/- 5.22 ng angiotensin I/mg protein/hr). Adrenal aldosterone was also suppressed by indomethacin. Adrenal prostaglandin E2 increased after nephrectomy and decreased after indomethacin. Plasma corticosterone and serum potassium did not change after indomethacin. These data indicate that inhibition of prostaglandin synthesis by indomethacin partially blocks the adrenal renin response to nephrectomy, suggesting that prostaglandins may play a role in the adrenal response to nephrectomy.     

Mechanism for the increase in plasma renin activity by pentobarbital anesthesia

The mechanism by which pentobarbital anesthesia causes increases in plasma renin activity (PRA) was examined in dogs infused with either propranolol or indomethacin, an inhibitor of prostaglandin synthetase. Infusion of propranolol at 1 mg/kg, (I.V.) followed by 0.6–0.7 mg/kg/hr decreased PRA from 6.98±2.49 ng/m1/hr during control periods to 1.58±0.79 ng/m1/hr 30 minutes after the injection of propranolol (P<0.025). Subsequent induction of anesthesia with sodium pentobarbital caused PRA to rise to 3.87±0.93 ng/m1/hr in 30 minutes. (P<0.01). Plasma potassium concentration decreased from 4.6±0.2 mEq/L to reach 4.0±0.1 mEq/L 30 minutes after induction of anesthesia (P<0.005). Infusion of indomethacin at 5 mg/kg, (I.V.) followed by 1.5 ? 3.1 mg/kg/hr into conscious dogs did not decrease PRA. In contrast to the report by Montgomery et al (Fed. Proc. 36: 989, 1977), we found that the increase in PRA after pentobarbital anesthesia could not be blocked by indomethacin. PRA was 5.3±1.2 ng/m1/hr(M ± SEM) during control periods and was 4.7±1.4 ng/m1/hr 30 minutes after the infusion of indomethacin (P<0.1). PRA increased to 10.9±2.3 ng/m1/hr, 9.2±2.2 ng/m1/hr, and 7.7±1.7 ng/m1/hr at 5, 15 and 30 minutes, respectively, after the administration of pentobarbital (P<0.005, P<0.025, P<0.05). PRA declined to 4.2±1.3 ng/m1/hr 60 minutes after pentobarbital anesthesia (P<0.1). It is concluded that the mechanism by which pentobarbital causes increases in PRA is independent of prostaglandins.     

Prostaglandin synthesis by murine mammary gland is modified by the state of the estrus cycle

Mammary glands were excised from female C₃H mice at various stages of their estrus cycle. Homogenates incubated at 37°C ± 10⁻⁵ M indomethacin synthesized prostaglandins (PG) E and F_2α at rates that varied as a function of the stage at estrus. The rate of PGF_2α synthesis was maximal at 1300 pg per mg protein per 2 hr in early diestrus and fell to undetectable levels in early estrus. PGE synthesis exhibited a similar pattern, being maximal at 83 pg per mg protein per 2 hr in early diestrus. These observations suggest that prostaglandins play a role in the cyclic changes observed within the mammary gland.     

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.     

Effects of 16,16-dimethyl prostaglandin E2 and indomethacin on leukotriene B4 and inflammation in rabbit colitis

The role of increased prostaglandin production and the effects of exogenous prostaglandins on inflammation of colitis are not established. We administered intramuscular 16,16-dimethyl prostaglandin E2 (DiM-PGE2) and indomethacin to rabbits with formalin immune-complex colitis and measured leukotriene B₄ (LTB4), prostaglandin E2 (PGE2) and severity of inflammation. DiM-PGE2 (100 ug/kg/BID) reduced LTB4 production (from 401±108 to 216±58 pg/ml) and infiltration of neutrophils, mucosal necrosis, inflammatory exudate and edema (all P<0.05). Other studies determined that parenteral DiM-PGE2 did not reduce the initial chemical damage induced by formalin, suggesting that cytoprotection of chemical insult was not the mechanism of suppressed inflamation in the immune colitis model. Indomethacin (10 mg/kg/d) reduced endogenous PGE2 by 80%, but did not reduce leukotriene production or inflammation. Exogenous prostaglandins cause a dose-dependent suppression of inflammation in experimental colitis, by a mechanism other than cytoprotection of chemical-induced mucosal injury.     

Prostaglandin-mediated hyperemia and renin-mediated hypertension during acute ureteral obstruction

Acute elevation of ureteral pressure to 100 mm Hg in anesthetized dogs (n=7) resulted in an increase (P<0.005) in systemic blood pressure from 151±7 to 163 ± 7 mm Hg, a transient (15 min) increase (P<0.05) in renal blood flow from 413 ± 27 to 465 ± 27 ml/min C and a rise (P<0.05) in plasma renin activity from 6.0 ± 1.6 to 10.3 ± 2.1 ng/ml/hr. Pretreatment with a competitive inhibitor of angiotensin II, i.e. sar¹gly⁸AII, abolished the hypertensive response to acute ureteral obstruction, and pretreatment with 2 mg/kg of either indomethacin (n=6) or meclofenamate (n=3), 15 min before obstruction, prevented the hyperemic response. These results suggest that acute ureteral obstruction leads to hypertension via activation of the renin-angiotensin system and hyperemia via a prostaglandin-initiated mechanism.     

Renal sodium handling and stimulation of medullary Na---K---ATPase during blockade of prostaglandin synthesis

The effect of suppression of prostaglandin synthesis on renal sodium handling and microsomal Na---K ATPase was studied in control and indomethacin treated intact rats maintained on a normal sodium diet (series A) and chronically salt loaded (series B). Indomethacin administration resulted in a decreased GFR and a significantly depressed urinary excretion and an increased fractional reabsorption of sodium in animals fed the normal sodium diet or chronically salt loaded. In rats maintained on a nomral Na diet, the activity of the renal medullary Na---K ATPase after indomethacin was 206.3±6.4 ug Pi./mg protein, i.e. significantly higher as compared with the enzyme activity in the medullary renal fraction from control animals in which it averaged 148±7.79 ug Pi/mg protein (p<0.001). While after chronic salt load a similar increment in the activity of renal medullary Na---K ATPase was observed, no additional stimulation was elicited by subsequent indomethacin administration. The addition of exogenous PGE₂, mM to microsomal fractions obtained from kidneys of normal rats, was associated with a moderate suppression of the medullary Na---K---ATPase activity, from a basal level of 170±16 to 151.3±13 umol Pi/mg protein/hr (p<0.005. In isolated segments of medullary thick ascending limb of Henle's loop (MTAL) addition of PGE₂ to the incubation medium resulted in a significant inhibition of Na---K--- ATPase from 37.2±2 to 21.25 ± 1.17 × 10⁻¹¹ mol/mm/min (p<0.0001.These findings suggest that the increased renal Na reabsorption after inhibition of PG synthesis might be related, at least partly, to stimulation of medullary Na---K ATPase. In parallel, the reported natriuretic effect of prostaglandins might imply a direct inhibitory effect of these mediators on renal Na---K ATPase.     

The effect of angiotensin II and indomethacin on immunoreactive prostaglandin “A” levels in man

The effect of angiotensin II on peripheral levels of immunoreactive prostaglandin A₂ (IR-PGA) was determined in 17 normal male volunteers. IR-PGA rose from 338 ± 65 (SE) pg/ml to 635 ± 142 in response to pressor infusions of angiotensin II (p <0.05 on paired analysis). This increase was not observed when indomethacin, 75 mg p.o., was given to 8 patients two hours prior to a repeat infusion. Five patients of the original group were placed on a low sodium diet (10–20 mEq). The response to angiotensin was now exaggerated (278 ±52 pg/ml to 916 ± 284). These five patients were kept on a low sodium intake and given indomethacin 50 mg p.o. q 6 hourly for 4 days. There was no significant rise with angiotensin infusion (106 ± 31 pg/ml to 120 ± 70). Pressor infusions of angiotensin II raise peripheral levels of IR-PGA, and this response is exaggerated by a low sodium diet and blocked by either acute or chronic indomethacin administration. This data supports the concept that vasodilatory prostaglandins may be released by endogenous angiotensin and thus provide a dynamic antagonism to the renin angiotensin system in man.     

Effects of prostaglandins on adrenal steroidogenesis in the rat

To elucidate the role of prostaglandins in adrenal steroidogenesis, we studied aldosterone and corticosterone responses to

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of prostaglandin E₂ (PGE₂), prostaglandin F_2α (PGF_2α), prostacyclin (PGI₂), and arachidonic acid (AA) in collagenase dispersed rat adrenal capsular and decapsular cells. Whereas adrenocorticotrophic hormone (ACTH) and angiotensin II (AII) stimulated aldosterone production in capsular cells and ACTH stimulated corticosterone production in decapsular cells in a dose dependent fashion, aldosterone and corticosterone production were not stimulated significantly by PGE₂, PGF_2α, PGI₂, and AA. Although preincubation of dispersed adrenal cells with indomethacin ( ) markedly inhibited PGE₂ synthesis, ACTH- and AII-stimulated aldosterone production and ACTH-stimulated corticosterone production were not attenuated despite prostaglandin blockade. These results indicate that prostaglandins are unlikely to play an important role in adrenal steroidogenesis.     

Evidence from a dual action of converting enzyme inhibitor on blood pressure in normal man

We studied the effect of a converting enzyme inhibitor (CEI), Captopril SQ 14,225 50 mg p.o. in eight supine normal subjects under a high sodium (150 meq/d) and low sodium (25 mEq/d) diet. On high sodium, plasma renin (PRA) and aldosterone were basal and Saralasin did not lower mean blood pressure. However, CEI induced an 11.4±3.2 mm fall in blood pressure (p<0.02) and either indomethacin 50 mg or ibuprofen 800 mg (PI), when given simultaneously on another day, abolished the blood pressure response (2.5±0.9 mm Hg, p>0.5). In contrast, on a low salt diet where renin was increased, CEI induced a drop in blood pressure which was not significantly altered by PI (12.8±1.1 vs. 10.0±3.1 mm Hg, p>0.5). CEI increased plasma renin on both diets (1.7±0.5 to 3.5±0.8 and 2.8±0.6 to 12.5±3.1 ng/ml/hr respectively both p<0.05). Aldosterone did not change (high Na⁺) or fell (low Na⁺). Inhibition of prostaglandin synthesis did not significantly block the renin rise from CEI suggesting that the direct angiotensin II negative feedback is relatively independent of acute prostaglandin release. Our studies suggest that CEI has a dual hypotensive action. In a low renin state, the hypotensive action appears to be mediated through vascular prostaglandins.     

Metabolism of arachidonic acid in vitro by ovine conceptuses recovered during early pregnancy

Metabolism of [³H] arachidonic acid ([³H] AA) and synthesis of prostaglandins were examined with ovine conceptuses and endometrial slices collected on various days after mating. Tissues were incubated for 24 hr with or without 5 μCi of [³H] AA and with 200 μg radioinert AA. In experiment 1, results of chromatography indicated that conceptuses collected on days 14 and 16 after mating metabolized [³H] AA to PGE₂, PGF_2α, PGFM, 6-keto-PGF_1α, and to unidentified compounds in three chromatographic regions. One of these regions (region 1) contained triglycerides. Endometrial slices metabolized only small amounts of the [³H] AA to prostaglandins. In experiment 2, results of radioimmunoassays indicated that day 14 conceptuses released somewhat similar amounts (ng/mg tissue) of PGF_2α (32.1 ± 17.9), PGFM (8.4 ± 6.2), PGE₂ (12.3 ± 7.5) and 6-keto-PGF_1α (41.4± 4.8), whereas day 16 conceptuses released more (P<.05) PGF_2α (9.0 ± 4.1) and 6-keto-PGF_1α (15.9 ± 2.7) than PGE₂ (0.9 ± 0.2) or PGFM (0.5 ± 0.08). Day 14 and 16 endometrial slices released (ng/mg tissue) more (P<.05) PGFM (3.0 ± 0.2) and 6-keto-PGF_1α (4.0 ± 0.4) than PGF_2α (0.5 ± 0.08) or PGE₂ (0.05 ± 0.02). In experiment 3, conceptuses were recovered on days 16, 20 and 24 of pregnancy and incubated with [³H] AA to determine the effects of indomethacin on [³H] AA metabolism. In general, indomethacin (Id; 4 × 10⁻⁴ M) reduced (P<.05) the percentage of total dpm recovered as prostaglandins, but Id increased the release of chromatographic region I. Experiment 4 was conducted with day 16, 20 and 24 conceptuses to evaluate the time course of metabolism of [³H] AA, and the appearance of region I and of prostaglandins. In general, the percentage of total dpm in region I increased as the percentage of dpm as [³H] AA decreased. The percentage of dpm as prostaglandins increased as the percentage of dpm in region I decreased. Prostaglandins, probably essential for embroynal survival and development, were synthesized in vitro by ovine conceptuses.     

Modulation of prostaglandin of the renal vascular action of arginne vasopressin

To determine whether the renal vascular effect of arginine vasopressin (AVP) is modulated by renal prostaglandin E₂ (PGE₂) were determined during the infusion of AVP in dogs during control conditions and after the administration of the inhibitor of prostaglandin synthesis, indomethacin. During control conditions, intrarenal administration for 10 min of a dose of AVP calculated to increase arterial renal plasma AVP concentration by 75 pg/ml produced a slight renal vasodilation (p<0.01) and an increase in renal venous plasma concentration of PGE₂. Renal venous PGE₂ concentration during control and AVP infusion averaged 33 ± 7 and 52 ± 12 pg/ml (p<0.05), respectively. After administration of indomethacin, the same dose of AVP induced renal vasoconstriction (p<0.05) and failed to enhance renal venous PGE₂ concentration (9 ± 1 to 8 ± 1 pg/ml). Intrarenal administration of 20 ng/kg. min of AVP for 10 min induced a marked renal vasoconstriction (p<0.01) and increased renal venous plasma PGE₂. Renal venous PGE₂ during control and AVP infusion averaged 31 ± 10 and 121 ± 31 pg/ml (p<0.01), respectively. Administration of the same dose of AVP following indomethacin produced a significantly greater and longer lasting renal vasoconstriction (p<0.01) and failed to increase renal venous plasma PGE₂ (10 ± 1 to 9 ± 1 pg/ml). These results indicate that a concentration of AVP comparable to that observed in several pathophysiological conditions induces a slight renal vasodilation which is mediated by renal prostaglandins. The results also indicate that higher doses of AVP induce renal vasoconstriction and that prostaglandin synthesis induced by AVP attenautes the renal vasoconstriction produced by this peptide.     

Pentobarbital anesthesia: Lack of effect on venous prostaglandins in dogs

Venous prostaglandins A, E, and F were determined by radioimmunoassay in 10 dogs before and one hour after administration of sodium pentobarbital (35 mg/Kg, iv). In the conscious state, PGA was 0.34 ± 0.04 ng/ml (mean ± SE), PGE 0.20 ± 0.01 ng/ml, and PGF 0.25 ± 0.03 ng/ml. During pentobarbital anesthesia, these levels were unchanged (p >0.05). Thus, pentobarbital anesthesia had no effect on peripheral venous prostaglandin levels.     

Effect of enalapril (MK-421), an orally active angiotensin I converting enzyme inhibitor, on blood pressure, active and inactive plasma renin, urinary prostaglandin E2, and kallikrein excretion in conscious rats

The angiotensin I converting enzyme (ACE) inhibitor enalapril (MK-421), at a dose of 1 mg/kg or more by gavage twice daily, effectively inhibited the pressor response to angiotensin I for more than 12 h and less than 24 h. Plasma renin activity (PRA) did not change after 2 or 4 days of treatment at 1 mg/kg twice daily despite effective ACE inhibition, whereas it rose significantly at 10 mg/kg twice daily. Blood pressure fell significantly and heart rate increased in rats treated with 10 mg/kg of enalapril twice daily, a response which was abolished by concomitant angiotensin II infusion. However, infusion of angiotensin II did not prevent the rise in plasma renin. Enalapril treatment did not change urinary immunoreactive prostaglandin E2 (PGE2) excretion and indomethacin did not modify plasma renin activity of enalapril-treated rats. Propranolol significantly reduced the rise in plasma renin in rats receiving enalapril. None of these findings could be explained by changes in the ratio of active and inactive renin. Water diuresis, without natriuresis and with a decrease in potassium urinary excretion, occurred with the higher dose of enalapril. Enalapril did not potentiate the elevation of PRA in two-kidney one-clip Goldblatt hypertensive rats. In conclusion, enalapril produced renin secretion, which was in part beta-adrenergically mediated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of indomethacin on cardiac output distribution in normal and asphyxiated piglets

We determined the effect of breathing 9% CO₂/10% O₂/81% N₂ (asphyxia) on cardiac output distribution (microspheres) in 4–5 day old unanesthetized, chronically instrumented piglets prior to and following intravenous indomethacin administration. Thirty minutes of asphyxia caused Pa_CO2 to increase from 35 ± 2 mmHg to 66 ± 2 mmHg, Pa_O2 to decrease form 73 ± 4 mmHg to 41 ± 1 mmHg, and pH to decrease from 7.52 ± 0.05 to 7.21 ± 0.07. Arterial pressure was increased slightly but cardiac output was not changed significantly. Asphyxia caused blood flow to the brain, diaphragm, liver, heart, and adrenal glands to increase while causing decreases in blood flow to the skin, small intestine, and colon. Blood flows to the stomach and kidneys tended to decrease, but the changes were not significant. Treatment with indomethacin during asphyxia did not alter arterial pressure or cardiac output but decreased cerebral blood flow to the preasphyxiated level and decreased adrenal blood flow about 20%. Indomethacin did not alter blood flow to any other systemic organ. At this time the piglet was allowed to breathe air for 2.5 hr undisturbed. Two and a half hours after indomethacin administration, blood flows to all organs returned to the preasphyxia control levels with the exception of cerebral blood flow which was reduced (93 ± 13 to 65 ± 5 ml/100 g·min. Three hours after indomethacin administration, the cerebral hyperemia caused by asphyxia was less (134 ± 17b ml/100 g·min) than prior to indomethacin (221 ± 15 ml/100 g·min. Indomethacin did not alter the asphyxia-induced changes to any other systemic organ. We conclude that in newborn pigs, systemic treatment with indomethacin decreases cerebral blood flow and cerebral hyperemia in response to asphyxia, without affecting blood flow to any other systemic organ.     

Role of prostaglandins in the mediation of systemic tachyphylaxis to angiotensin II

Angiotensin-induced prostaglandin release has been implicated in the development of tachyphylaxis to angiotensin $\text{in vitro}$. Based on these findings and evidence that prostaglandins modulate the angiotensin response locally, experiments were done to investigate the role of prostaglandins in the systemic tachyphylaxis to angiotensin. Rats were given intravenous infusions of 1-asparaginyl-5-valyl and 1-aspartyl-5-isoleucyl angiotensin II at two different doses. Using systemic blood pressure as a parameter, varying degrees of tachyphylaxis were produced and the aspartyl analog was found to be more tachyphylactic. When rats were given indomethacin, a prostaglandin synthesis inhibitor, the response to intravenous infusion of aspartyl angiotensin was not significantly altered.     

Inhibition of compensatory renal growth by indomethacin

Renal prostaglandins may be important in the modulation of compensatory renal growth. Reductions in renal mass are associated with increased synthesis of these substances by the remaining kidney, and inhibition of prostaglandin synthesis diminishes renal function in partially nephrectomized animals and in patients with reduced functioning renal mass. We examined the effects of uninephrectomy and treatment with indomethacin on renal prostaglandin E₂ and 6-keto prostaglandin F_1α concentrations in adult male Sprague Dawley rats. The renal content of these prostaglandins was significantly increased in the remaining kidney two days following uninephrectomy (p<0.01). Treatment with 5 mg/kg/day of indomethacin over this period abolished the compensatory increase in renal prostaglandin synthesis and significantly attenuated compensatory increases in renal mass, protein and RNA concentration (p<0.05). No alterations in kidney weight, protein or RNA concentrations were found in intact animals treated with the same dose of indomethacin. These findings suggest renal prostaglandins may participate in the biological events leading to compensatory renal growth.     

Effect of indomethacin and propranolol on the blood pressure and renin response to atriopeptin III in conscious rats

The effect of prostaglandin synthesis inhibition and of beta-adrenoceptor blockade on the blood pressure and renin response to the synthetic atrial natriuretic peptide atriopeptin III was assessed in unanesthetized normotensive rats. This peptide was infused i.v. for 30 min at a rate of 1 microgram/min in rats pretreated either with indomethacin (5 mg i.v.) or propranolol (1 mg i.v.). The blood pressure reducing effect of atriopeptin III was attenuated neither by indomethacin nor by propranolol. Atriopeptin III per se did not modify plasma renin activity. Both the administration of indomethacin and of propranolol had a suppressing effect on renin release during atriopeptin III infusion. These data suggest that the vasodilating properties of atrial natriuretic peptides do not depend in the conscious normotensive rats on the production of prostaglandins. They also provide evidence that during infusion of such peptides, both prostaglandins and beta-adrenergic mechanisms are still involved in the regulation of renin secretion.     

Indomethacin inhibits the uptake of sodium by ovine trophoblastic tissue in vitro

Blastocysts from several species synthesize prostaglandins in vitro, but the exact functions of the prostaglandins are unknown. The purpose of this study was to determine if indomethacin, an inhibitor of prostaglandin synthesis, would inhibit the uptake of ²²sodium ([²²Na]) by ovine trophoblastic tissue. To determine the concentration of indomethacin that would inhibit the synthesis of PGF_2α and 13,14-dihydro-15-keto-PGF_2α (PGFM) by blastocysts, blastocysts were collected from ewes 16 days after mating, sliced into pieces approximately 2 mm in length and incubated for 48 h at 37°C in 2 ml of medium containing either 0, 0.2, 0.4, 0.8 or 1.6 mM of indomethacin. Concentrations of indomethacin mM reduced (P<.01) trophoblastic release (ng/μg DNA) of PGF_2α from

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, reduced PGFM from

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, and inhibited formation of trophoblastic vesicles. In a second experiment, blastocysts were recovered from ewes 16 days after mating and pieces of trophoblast were incubated with [²²Na] and either 0 or 0.4 mM of indomethacin. Indomethacin reduced the uptake of [²²Na], which is an indirect measure of the transport of water across epithelia, from 3680 ± 1118 to 934 ± 248 cpm/μg DNA (P<.03) and prevented formation of trophoblastic vesicles. Prostaglandins produced by ovine blastocysts might be involved in controlling uptake of water, which is essential for expansion of blastocysts.     

Indomethacin potentiates the vasoconstrictor actions of angiotensin II in normal man

The blood pressure response to graded infusions of angiotensin II was assessed under control conditions and following short term (16 hour) indomethacin treatment utilizing normal men equilibrated on a constant diet of normal sodium and potassium content. Although basal mean blood pressure was unchanged, the increase in blood pressure with all rates of angiotensin II infusion ranging from 200 to 1000 ng/min was significantly greater with indomethacin treatment. Pre-infusion body weight and plasma renin activity were similar under the two conditions. These results suggest that prostaglandins modulate the systemic vasoconstrictor effects of angiotensin II.