Effects of fenoldopam on regional vascular resistance in conscious spontaneously hypertensive rats

The effects of fenoldopam, a selective dopamine-1 agonist, on regional blood flow and vascular resistance were examined in conscious unrestrained spontaneously hypertensive rats (SHR). Rats were instrumented chronically with pulsed Doppler flow probes to allow measurement of renal, mesenteric and hindquarters blood flow. Maximal changes in mean arterial pressure, heart rate and regional blood flow were recorded after i.v. administration of fenoldopam (1-1000 micrograms/kg). Fenoldopam produced a dose-dependent reduction in arterial pressure and increased heart rate in the conscious SHR. Significant increases in mesenteric (maximal = 69 +/- 10%) and renal (maximal = 42 +/- 4%) blood flows were observed at all doses of fenoldopam. In the hindquarters, vascular resistance was increased after low doses of fenoldopam (1-30 micrograms/kg), but decreased with higher doses (100-1000 micrograms/kg). After ganglionic blockade, hindquarter vasodilation was observed with fenoldopam at low (10 micrograms/kg) and high (500 micrograms/kg) doses. Pretreatment with metoclopramide (20 mg/kg) or SCH 23390 (30 micrograms/kg), a new selective dopamine-1 antagonist, significantly attenuated the vasodilator responses to fenoldopam in all three vascular beds. Pretreatment with propranolol failed to alter the vascular effects of fenoldopam, but reduced the tachycardia markedly. This study indicates that fenoldopam decreased regional vascular resistance in the renal, mesenteric and hindquarters vascular beds of the conscious SHR with the mesenteric vascular bed demonstrating the greatest reactivity. The vasodilation induced by fenoldopam in these vascular beds appeared to be due to stimulation of vascular dopamine-1 receptors.     

Renal hemodynamics in canine DOCA-salt hypertension: effect of calcium channel blockade.

Systemic arterial blood pressure (BP), renal blood flow (RBF), and renal vascular resistance (RVR) were followed for 3-4 wks during the progression of DOCA-salt hypertension in the conscious dog. Accompanying the gradual increase in BP was an increase in RBF; however, RVR was unchanged. The hypertension was totally reversed 5-7 days after cessation of DOCA-salt treatment, but the increase in RBF persisted, presumably as a result of renal hypertrophy. Renal adrenoceptor blockade with prazosin (6 dogs) and prazosin plus idazoxan (4 dogs) caused a comparable decrease in BP in the normotensive and DOCA-salt hypertensive dog; however, RVR was decreased only in the normotensive. Similar results were obtained during ganglionic blockade with hexamethonium. The i.v. infusion of diltiazem for 1 wk restored BP of the hypertensive dog to a normotensive level, and hexamethonium given i.v. had little further effect on either BP or RVR. These results suggest a non-neurogenically mediated mechanism of canine DOCA-salt hypertension that is susceptible to calcium channel blockade.     

Angiotensin II influences the renal hemodynamic response to blockade of thromboxane A2 and prostaglandin H2 receptors.

This study was designed to examine the influence of angiotensin II on the renal hemodynamic response to blockade of thromboxane A2 and prostaglandin H2 receptors with SQ29548 (2 mg/kg, i.v. bolus, plus 2 mg kg-1 hr-1 infusion) in anesthetized rats. In control rats without any pretreatment, SQ29548 did not change blood pressure, but increased renal blood flow from 7.0 +/- 0.4 to 7.7 +/- 0.4 ml min-1 g kidney weight-1 (P < .05) and decreased renal vascular resistance from 18.1 +/- 1.0 to 16.2 +/- 0.8 mm Hg/ml min-1 g kidney weight-1 (P < .05). In contrast, SQ29548 was without effect on renal blood flow or renal vascular resistance in rats pretreated with saralasin or captopril to block angiotensin II actions and formation, respectively. SQ29548 also increased renal blood flow and decreased renal vascular resistance in rats pretreated with captopril in which the plasma concentration of angiotensin II was fixed at elevated levels by concurrently infusing the peptide at doses ranging from 5 to 80 ng/min. In this experimental setting, the administration of SQ29548 reduced preglomerular vascular resistance selectively. Because, according to previous studies, SQ29548 does not interfere with the direct vasoconstrictor actions of angiotensin II, the renal vasodilatory effect of SQ29548 in rats with elevated plasma angiotensin II is attributable to interference with the operation of mechanisms of vasoconstriction mediated by activation of thromboxane A2-prostaglandin H2 receptors. We conclude that the status of the renin-angiotensin system is a determinant of the renal vasodilatory response to SQ29548.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Hemorrhage on Regional Blood Flow Distribution in Dogs and Primates

The effects of hemorrhage on arterial pressure, blood flows, and resistances in the coronary, mesenteric, renal, and iliac beds of healthy, conscious dogs and intact, tranquilized baboons were studied. Mild nonhypotensive hemorrhage (14+/-2 ml/kg) increased heart rate and mesenteric and iliac resistances slightly but significantly, and decreased renal resistance (-13+/-2%). Moderate hypotensive hemorrhage, 26+/-2 ml/kg, reduced mean arterial pressure (-23+/-2 mm Hg) and blood flows to the mesenteric (-56+/-3%), iliac (-58+/-5%), and coronary (-39+/-4%) vascular beds, and increased heart rate (+89+/-9 beats/min) and resistances in the mesenteric (+73+/-15%), iliac (+102+/-19%), and coronary (+27+/-5%) beds. In contrast to the other beds, renal flow rose 11+/-6% above control and renal resistance fell 31+/-2% below control. Renal vasodilatation with hemorrhage was also observed in five baboons. The increases in mesenteric and iliac resistances were blocked almost completely by phentolamine, while the increase in coronary resistance was only partially blocked by phentolamine. The renal dilatation was not blocked by phentolamine, propranolol, atropine, or tripelennamine, but was prevented by indomethacin, suggesting that this dilatation was mediated by a prostaglandin-like compound.Thus the peripheral vascular responses to hemorrhage involve intense vasoconstriction in the mesenteric and iliac beds. In the normal conscious dog and the intact, tranquilized primate, the renal bed does not share in the augmentation of total peripheral resistance with nonhypotensive and moderate hypotensive hemorrhage, but does with more severe hemorrhage. In fact, renal vasodilatation occurs with nonhypotensive or moderate hypotensive hemorrhage, which can be prevented by blockade of prostaglandin synthetase with indomethacin.     

Muscarinic cholinergic and beta-adrenergic contribution to hindquarters vasodilation and cardiac responses to cocaine

Cocaine produces a pressor response associated with an initial hindquarters vasoconstriction followed by a prolonged vasodilation in conscious rats. Propranolol pretreatment prevented the vasodilation and enhanced the pressor response, whereas atropine methylbromide pretreatment reduced the increase in systemic vascular resistance. We studied the role of selective muscarinic and beta-adrenoceptor antagonists on responses to cocaine in rats with an increase in systemic vascular resistance to cocaine (vascular responders). Arterial blood pressure and ascending aortic and distal descending aortic blood flow using pulsed Doppler flowmetry were measured. In conscious rats, cocaine (5 mg/kg i.v.) elicited consistent pressor responses but variable systemic and hindquarters vascular resistance responses that were directly correlated, suggesting that skeletal muscle resistance responses comprise an important component of systemic vascular resistance. ICI 118551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)-amino]-2-butanol] (0.5 mg/kg i.v.) pretreatment prevented the hindquarters vasodilation, enhancing the increase in systemic vascular resistance and the pressor response while further depressing the cardiac output response, similar to the effects of propranolol. Atenolol (1 mg/kg) pretreatment attenuated the stroke volume and cardiac output responses while enhancing the increase in systemic vascular resistance without affecting the hindquarters responses. In contrast, M2 antagonist methoctramine (0.3 mg/kg) pretreatment had similar effects as atropine in reducing the decrease in cardiac output by reducing the increase in systemic vascular resistance, whereas the M1 antagonist pirenzipine (0.02 mg/kg) did not alter responses. Therefore, the cocaine-induced pressor response is ameliorated by beta2-adrenoceptor mediated skeletal muscle vasodilation, whereas the decrease in cardiac output and the increase in systemic vascular resistance are dependent on M2-cholinoceptor activation.     

Cardiovascular effects of adenosine A2 agonists in the conscious spontaneously hypertensive rat: a comparative study of three structurally distinct ligands.

The hemodynamic responses to 5'-N-ethylcarboxamide adenosine (NECA), a nonselective adenosine agonist, were compared to those elicited by the sodium salt of 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido adenosine (CGS 21680C) and N6-2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl adenosine (CGS 24012), two structurally dissimilar selective A2 agonists in conscious spontaneously hypertensive rats (SHR). Dose-related reductions in mean arterial pressure occurred after bolus administration of NECA, CGS 21680C and CGS 24012. Dose-dependent tachycardia was seen with both CGS 21680C and CGS 24012, whereas NECA produced a biphasic response on heart rate. At high doses (3 and 10 micrograms/kg), NECA evoked an immediate and dramatic fall in heart rate, followed by a more gradual and long-lasting tachycardia. At equihypotensive doses, both CGS 21680C and CGS 24012 produced significant increases in cardiac output, but NECA had no effect. Although each of the adenosine agonists reduced total peripheral resistance, the greatest change was produced by CGS 21680C. Hindquarter, renal and mesenteric vascular resistances were significantly reduced by both CGS 21680C and CGS 24012, whereas only mesenteric vascular resistance was reduced with NECA. CGS 24012 reduced renal vascular resistance to the greatest extent and produced a concomitant significant increase in renal blood flow. Marked elevation in plasma renin activity occurred with CGS 24012 and CGS 21680C, whereas no change was seen after NECA. The hemodynamic responses to NECA, CGS 21680C and CGS 24012 were significantly reduced by the adenosine antagonist, 8-(p-sulfophenyl) theophylline, suggesting that these agents act through stimulation of adenosine receptors in the conscious SHR. Furthermore, blockade of the beta adrenergic receptor with metoprolol (1 mg/kg, i.v.) significantly attenuated the increase in heart rate produced by NECA, CGS 21680C and CGS 24012. The cardiovascular pattern of responses to the two selective A2 agonists, CGS 21680C and CGS 24012, are distinct from those of NECA, the nonselective adenosine agonist. The responses to both CGS 21680C and CGS 24012 indicate that systemic vasodilation, with resultant cardioexcitation and stimulation of renin release, are the predominant hemodynamic effects of selective A2 agonists in the conscious SHR. In contrast, the cardiovascular effects produced by NECA are mediated by activation of both A1 and A2 receptors.     

Graded regional vasodilation with converting enzyme inhibitors in conscious spontaneously hypertensive rats

The present study was designed to examine the effects of two different converting enzyme inhibitors on regional hemodynamics in conscious spontaneously hypertensive rats. Rats were chronically instrumented with miniaturized pulsed Doppler flow probes for measurement of renal, mesenteric and hindquarters blood flow. Equidepressor doses of captopril (10 mg/kg) or a potent new converting enzyme inhibitor, Wy-44,221 [(-)-(S)-2,3-dihydro-1-[(S)-3-mercapto-2-methyl-1-oxypropyl]-1 H-indoline-2-carboxylic acid] (2 mg/kg) were administered by i.a. bolus injection. The converting enzyme inhibitors caused a reduction in mean arterial pressure, which was accompanied by a tachycardia. Renal blood flow was significantly increased by approximately 30 to 37% within 5 min after administration of the converting enzyme inhibitors, and renal vascular resistance was reduced. The renal hemodynamic effects were sustained for the 45-min duration of the experiment. Pretreatment with an angiotensin II receptor antagonist markedly attenuated the renal vasodilator effects of Wy-44,221, whereas antagonism of kinin or prostaglandin synthesis failed to diminish the renal effects of Wy-44,221. Both converting enzyme inhibitors also caused a significant but transient reduction in mesenteric vascular resistance, but had no significant effect on hindquarter hemodynamics. These data indicated that the converting enzyme inhibitors in conscious spontaneously hypertensive rats caused a prolonged increase in renal blood flow as a result of removing the renal vasoconstrictor effects of angiotensin II. These data further suggest that converting enzyme inhibitors exerted graded actions on regional vascular resistance with renal greater than mesenteric greater than hindquarters dilation.     

Renin-Angiotensin System Inhibition in Conscious Sodium-Depleted Dogs: EFFECTS ON SYSTEMIC AND CORONARY HEMODYNAMICS

The role of the renin-angiotensin system in the regulation of the systemic and coronary circulations during sodium depletion was studied in conscious normotensive dogs by i.v. administration of teprotide (0.5 mg/kg), an angiotensin-converting enzyme inhibitor, and saralasin (0.05-5 μg/kg per min), an angiotensin-receptor antagonist. Sodium depletion was produced by administering a low sodium diet and furosemide for 5 days. Administration of both teprotide and saralasin lowered systemic arterial blood pressure and total peripheral vascular resistance. Simultaneously, cardiac output increased, but left ventricular end-diastolic pressure, dP/dt, and dP/dt/P did not change significantly. Furthermore, both agents reduced diastolic coronary vascular resistance and increased coronary blood flow, but did not affect myocardial oxygen consumption, left ventricular work, or myocardial efficiency. These systemic and coronary vasodilator effects of teprotide and saralasin, however, were not observed in normal dogs on a regular sodium diet; in this group, the only effect noted was a slight increase in arterial pressure during saralasin infusion. Arterial plasma concentration of norepinephrine did not differ between normal and sodiumdepleted dogs, nor did it change significantly after teprotide administration. These results suggest that, during salt depletion, angiotensin II exerts an active vasoconstrictor action on the systemic and coronary vessels, but has no significant effects on myocardial contractility or energetics. It also appears likely that the increase in cardiac output observed in sodiumdepleted dogs after angiotensin inhibition was caused, at least in part, by the decrease in systemic arterial pressure.     

Hemodynamic effects of adenosine agonists in the conscious spontaneously hypertensive rat

The present studies examined the underlying hemodynamic mechanisms contributing to the reduction in blood pressure observed in conscious spontaneously hypertensive rats after systemic administration of adenosine agonists. The effects produced by i.v. and i.a. injections of 2-phenylaminoadenosine [CV-1808, adenosine (A2) selective agonist], 5'-N-ethylcarboxamide adenosine (NECA, nonselective agonist), 2-chloroadenosine (2-CADO, A1 selective agonist) and cyclopentyladenosine (CPA, A1 selective agonist) were evaluated and compared to those of hydralazine. All agents produced hypotensive effects after bolus i.v. injection. Although CPA, NECA and 2-CADO elicited dose-dependent bradycardia, CV-1808 and hydralazine increased heart rate. These effects, with the exception of the hydralazine-evoked responses, were attenuated by prior treatment with 8-(p-sulfophenyl)theophylline (2 mg/kg/min), whereas both CV-1808 and hydralazine produced regional vasodilation, significant increases in blood flow occurred only after CV-1808 (3-30 micrograms/kg). The regional hemodynamic responses to NECA were more complex; low doses (0.1-1 microgram/kg) produced consistent reductions in regional vascular resistance, whereas at the highest dose renal vasoconstriction occurred. Although regional vasodilation occurred after 2-CADO, mesenteric vasoconstriction was observed subsequent to CPA administration. Whereas a significant increase in renin release was evident in animals treated with CV-1808 and hydralazine, no change occurred in response to the NECA-, 2-CADO- or CPA-induced hypotension. We conclude that the predominant hemodynamic response after selective activation of A2 receptors is one of regional vasodilation and hypotension leading to a reflex increase in heart rate and renin release.(ABSTRACT TRUNCATED AT 250 WORDS)     

The peripheral vascular response to severe exercise in untethered dogs before and after complete heart block

The peripheral vascular response to severe exercise was studied in 11 healthy conscious dogs instrumented with Doppler ultrasonic flow probes on the mesenteric, renal, and iliac arteries, and miniature pressure gauges in the aorta. The response to severe exercise was restudied in six of these dogs after recovery from a second operation producing complete heart block by the injection of formalin into the atrioventricular (AV) node. Three of these dogs also exercised while their ventricles were paced at rates of 100/min and 200/min. The untethered normal dogs ran at speeds of 15-25 miles/hr behind a mobile recording unit for a distance averaging 1.5 miles, while continuous measurements of arterial blood pressure and blood flow were telemetered and recorded on magnetic tape. Severe exercise in normal dogs increased heart rate from 84 to 259/min, arterial pressure from 89 to 140 mm Hg, flow resistance in the mesenteric and renal beds by 59 and 52% respectively, and iliac blood flow 479% above control, while mesenteric and renal blood flows remained constant and iliac resistance decreased by 73%.In dogs with complete AV block, severe exercise at speeds of 10-18 miles/hr increased heart rate from 47 to 78/min, mean arterial pressure from 81 to 89 mm Hg, iliac flow 224%, resistance in the renal bed by 273%, and mesenteric bed by 222% while it decreased blood flow in mesenteric and renal beds by 61 and 65% respectively, and iliac resistance by 62%. A similar response occurred during exercise with pacing at 100/min, but when paced at 200/min a more normal exercise response reappeared. Thus, in normal dogs the peripheral vascular response to severe exercise involved increases in heart rate, arterial pressure and visceral resistance but visceral blood flow did not decrease. In dogs with heart block, where the ability to increase heart rate is severely compromised, compensatory reduction of mesenteric and renal blood flows occurred.     

Interaction between alpha 2-adrenergic and angiotensin II systems in the control of glomerular hemodynamics as assessed by renal micropuncture in the rat.

The hypothesis that renal alpha 2 adrenoceptors influence nephron filtration rate (SNGFR) via interaction with angiotensin II (AII) was tested by renal micropuncture. The physical determinants of SNGFR were assessed in adult male Munich Wistar rats 5-7 d after ipsilateral surgical renal denervation (DNX). DNX was performed to isolate inhibitory central and presynaptic alpha 2 adrenoceptors from end-organ receptors within the kidney. Two experimental protocols were employed: one to test whether prior AII receptor blockade with saralasin would alter the glomerular hemodynamic response to alpha 2 adrenoceptor stimulation with the selective agonist B-HT 933 under euvolemic conditions, and the other to test whether B-HT 933 would alter the response to exogenous AII under conditions of plasma volume expansion. In euvolemic rats, B-HT 933 caused SNGFR to decline as the result of a decrease in glomerular ultrafiltration coefficient (LpA), an effect that was blocked by saralasin. After plasma volume expansion, B-HT 933 showed no primary effect on LpA but heightened the response of arterial blood pressure, glomerular transcapillary pressure gradient, and LpA to AII. The parallel results of these converse experiments suggest a complementary interaction between renal alpha 2-adrenergic and AII systems in the control of LpA.     

Effect of fenoldopam on the acute and subacute nephrotoxicity produced by amphotericin B in the dog.

The effect of the selective dopamine DA1 receptor agonist fenoldopam (1 microgram/kg/min i.v.) on the acute nephrotoxic response to amphotericin B (2 mg/kg i.v.) has been studied in the anesthetized dog. Animals were prepared for the measurement of blood pressure, renal blood flow, urine flow, glomerular filtration rate and sodium and potassium excretion. Amphotericin B was given over 20 min and the animals were followed for an additional 160 min. The fenoldopam infusion was started 20 min before amphotericin B and was continued for the duration of the experiment. In control animals, amphotericin B markedly increased renal vascular resistance without affecting blood pressure and thus produced a significant reduction in renal blood flow. The renal vasoconstrictor response to amphotericin B was not attenuated by fenoldopam. Concomitant with the renal vasoconstriction produced by amphotericin B was a marked reduction in glomerular filtration rate, sodium excretion and urine flow rate, which lasted for at least 160 min after amphotericin B treatment. Fenoldopam did not have any effect on the initial reductions in glomerular filtration rate, sodium excretion and urine flow rate but did produce a significant return of these parameters toward control levels by 160 min, despite the continued renal vasoconstriction. The effect of fenoldopam (0.5 microgram/kg/min) given continuously by i.v. infusion on the subacute nephrotoxic response produced by amphotericin B given every other day for 8 days was also investigated. One day after the start of the fenoldopam infusion, venous samples were drawn for the analysis of serum creatinine and blood urea nitrogen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular responses to cocaine are initially mediated by the central nervous system in rats.

Cocaine produces a pressor response reportedly resulting from both potentiation of peripheral catecholamine activity and a centrally mediated sympathoexcitation. In the present study we sought to differentiate the central nervous system and peripheral contributions to the hemodynamic effects of cocaine. In conscious rats, cocaine (5 mg/kg i.v.) produced a pressor response with two distinct components consisting of a brief, substantial increase in mean arterial pressure (MAP) associated with hindquarters and mesenteric vasoconstriction followed by a sustained, modest response associated with mesenteric vasoconstriction and bradycardia. Pentolinium (7.5 mg/kg i.v.) or adrenal demedullation attenuated the peak increase in MAP by attenuating increases in mesenteric and hindquarters vascular resistance, but did not affect the sustained increase in MAP. Methyl atropine (0.5 or 1 mg/kg i.v.) pretreatment reduced the cocaine-induced increase in systemic vascular resistance and enhanced the hindquarters vasodilation during the sustained MAP response. In contrast, adrenal demedullation abolished the hindquarters vasodilation. The bradycardic response was prevented by pentolinium and reduced by methyl atropine. Sympathetic nerve activity was reduced dramatically after cocaine or procaine administration for several minutes in conscious and in chloralose-anesthetized rats. In several anesthetized rats, the sympathoinhibition was preceded by a brief (3-8 sec) increase in renal sympathetic nerve activity. Procaine or cocaine produced little change in cortical cerebral blood flow as estimated by using a laser Doppler flowmeter. These data suggest that cocaine produces an initial, brief centrally mediated sympathoexcitation, but the sustained, modest pressor response is dependent upon peripheral actions that are diminished by baroreflex activation.     

ACE Inhibitors and Renal Vascular Responses in the Spontaneously Hypertensive Rat

BACKGROUND: Substantial evidence has accumulated for the intrarenal generation of functionally important quantities of angiotensin II (Ang II). To assess the possibility that Ang II generation occurs beyond a barrier to diffusion from the vascular compartment, six angiotensin-converting enzyme (ACE) inhibitors varying widely in their lipid solubility were employed in the spontaneously hypertensive rat (SHR) and their normotensive controls (WKY). The biological end points were renal blood flow and its response to Ang II. RESULTS: Two ACE inhibitors, ramipril and captopril, induced a larger increase in renal blood flow and enhanced the renal vascular response to Ang II substantially more than did enalapril and lisinopril. The two prodrugs, enalapril and ramipril, which are substantially more lipophilic than the respective active drugs, enalaprilat and ramiprilat, showed equivalent responses. The partial agonist saralasin virtually abolished the renal vasodilator response to ramipril. The pattern of response was similar in WKY, but the responses were substantially smaller. CONCLUSIONS: The results support the concept that a functionally important compartment for intrarenal Ang II formation exists in the healthy rat and that this process is amplified in the SHR.     

Nonpeptide angiotensin II receptor antagonists. VIII. Characterization of functional antagonism displayed by DuP 753, an orally active antihypertensive agent

In the spinal pithed rat, DuP 753, 2-n-butyl-4-chloro-5-hydroxy-methyl-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4-yl) methyl] imidazole potassium salt, inhibited competitively the pressor response to angiotensin II (AII), whereas saralasin showed a noncompetitive pattern of interaction. It did not alter the pressor responses to vasopressin and norepinephrine as well as the heart rate response to isoproterenol. In the anesthetized rat, DuP 753 did not affect the vasodepressor response to bradykinin. Given p.o. or i.v., DuP 753 did not lower blood pressure in conscious normotensive rats, but it inhibited the pressor response to AII but not to vasopressin. It lowered blood pressure in furosemide-treated normotensive rats. Unlike saralasin, DuP 753 did not cause a transient increase in blood pressure even at 100 mg/kg i.v. DuP 753 at 3.5 micrograms i.c.v. inhibited the pressor response to i.c.v. AII, whereas DuP 753 at 10 mg/kg p.o. did not, suggesting that a single p.o. administration of DuP 753 does not affect brain AII receptors which are accessible by i.c.v. injection. Our study indicates that DuP 753 is a p.o. active, nonpeptide, selective, competitive AII receptor antagonist.     

Nonpeptide angiotensin II receptor antagonists. IX. Antihypertensive activity in rats of DuP 753, an orally active antihypertensive agent

In conscious renal artery-ligated rats, a high renin hypertensive rat model, DuP 753, a p.o. active nonpeptide angiotensin II (AII) receptor antagonist, decreased blood pressure at 0.1 to 3 mg/kg given i.v. or at 0.3 to 10 mg/kg given p.o. with an i.v. ED30 of given i.v. or at 0.3 to 10 mg/kg given p.o. with an i.v. ED30 of 0.78 mg/kg and a p.o. ED30 of 0.59 mg/kg. The antihypertensive efficacy of DuP 753 was similar to that of captopril. Unlike the peptide AII antagonist saralasin, DuP 753 did not cause a transient increase in blood pressure, suggesting absence of agonistic activity. At 3 mg/kg p.o., DuP 753 lowered blood pressure for at least 24 hr and did not change heart rate, suggesting a long duration of antihypertensive effect. At 3 mg/kg i.v., DuP 753 inhibited the pressor response to AII but not to norepinephrine or vasopressin. Pretreatment of renal artery-ligated rats with captopril, saralasin or propranolol, but not with prazosin, hydralazine or indomethacin, abolished or reduced the antihypertensive effect of DuP 753. In the deoxycorticosterone acetate hypertensive rat, a low renin model, DuP 753 did not lower blood pressure. These results suggest that DuP 753 is a p.o. active, antihypertensive agent in renal artery-ligated rats with a similar antihypertensive efficacy as captopril. The antihypertensive effect of DuP 753 is most likely related to the blockade of the vasoconstrictor effect of AII. Unlike saralasin, DuP 753 does not have agonistic activity.     

Vasoactive intestinal peptide: a direct renal natriuretic substance

To establish whether or not vasoactive intestinal peptide (VIP) acts directly on the kidney and also to define the renal responses to it, we compared the natriuretic and haemodynamic responses to VIP (10(-4)-100 pmol min-1 kg-1) infused intravenously with those obtained by direct infusion into the renal artery in seven conscious male rabbits. VIP had significant effects on the renal circulation without changing systemic arterial pressure or pulse rate. There was a significant fall from control in effective renal plasma flow (P less than 0.05 renal infusion, P less than 0.01 intravenous infusion) and glomerular filtration rate (P less than 0.01 renal, P less than 0.05 intravenous). The derived renal vascular resistance rose significantly from control (P less than 0.01 renal, P less than 0.01 intravenous). Despite the significant decline in filtered sodium load (P less than 0.01 renal, P less than 0.001 intravenous), there was a significant log dose-related increase in fractional sodium excretion (P less than 0.005) with intrarenal infusion of VIP. We conclude that the actions of VIP on intrarenal blood vessels and renal tubules are direct, leading to increases in renal vascular resistance and fractional sodium excretion.     

Haemodynamic consequences of experimental papillary necrosis in the rat

Experimental renal papillary necrosis induced by 2-bromoethylamine hydrobromide (BEA) results in hypertension in the rat. The haemodynamics of this increase in blood pressure were investigated with radiolabelled microspheres, thus enabling individual organ blood flows to be evaluated. Total peripheral resistance was raised in BEA-treated rats (3.6 +/- 0.3 mmHg ml-1 min X 100 g) compared with control rats (2.87 +/- SEM 0.2, P less than 0.05) whilst cardiac index remained similar (39.9 +/- 3.6 vs 39.2 +/- 3.1 ml min-1 100 g-1). Heart and brain from BEA rats demonstrated a significant rise in vascular resistance with a normal blood flow. In the kidneys vascular resistance increased still further and here there was a reduction in renal blood flow despite an increase in kidney size. These findings are compatible with a loss of renomedullary vasodepressor mechanisms acting directly or indirectly on the resistance vessels.     

Antihypertensive effects of CI-907 (indolapril): a novel nonsulfhydryl angiotensin converting enzyme inhibitor

CI-907 is a new orally active nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor. Monoester (prodrug) and diacid forms produced concentration related ACE inhibition in guinea-pig serum (IC50 for monoester, 1.7 X 10(-7) M and for diacid, 2.6 X 10(-9) M). In isolated rabbit aortic rings and in rat and dog autonomic studies, CI-907 is highly specific in suppressing the contractile or pressor responses to angiotensin I. In two-kidney, one-clip Goldblatt hypertensive rats, single daily doses (0.03-30 mg/kg p.o.) produced dose-dependent decreases in blood pressure; 3 mg/kg lowered blood pressure to normotensive levels. In the spontaneously hypertensive rat, subacute administration of CI-907 (30 mg/kg/day for 5 days) produced the same decrease in blood pressure as that obtained in the renal hypertensive rat. In diuretic-pretreated renal hypertensive dogs, 10 mg/kg normalized blood pressure. For equivalent drops in blood pressure, heart rate increases were less in CI-907 than in enalapril-treated renal hypertensive dogs. No side effects were observed with CI-907 in any of the conscious animals. The antihypertensive response to CI-907 (0.03-1.0 mg/kg p.o.) was found to correlate with inhibition of vascular tissue ACE, but not plasma or brain ACE in two-kidney, one-clip renal hypertensive rats. These studies indicate that CI-907 is a potent antihypertensive agent with a heart rate profile different from enalapril.     

5-Hydroxytryptamine3 receptors mediate tachycardia in conscious instrumented dogs

Intravenously administered 5-HT and the 5-HT3 selective agonist, 2CH3-5-HT, and the 5-HT2 selective agonist, alpha-CH3-5-HT, transiently increased heart rate in conscious, instrumented dogs. 5-HT, alpha-CH3-5-HT and 2CH3-5-HT increased systolic blood pressure in conscious dogs. The increase in blood pressure produced by alpha-CH3-5-HT was blocked by the 5-HT2 selective antagonist, LY53857, supporting a role for vascular 5-HT2 receptors in the pressor response to these amines. In contrast, LY53857 did not antagonize tachycardia produced by 2CH3-5-HT. Furthermore, propranolol also did not block 2CH3-5-HT-induced tachycardia, indicating that an indirect neuronal effect to release norepinephrine cannot explain the increase in heart rate to 2CH3-5-HT. Tachycardia to 2CH3-5-HT (as well as to isoproterenol) was modestly inhibited, but never abolished by interruption of the autonomic nervous system with atropine or hexamethonium. 5-HT3 receptor antagonists, zacopride, ICS 205-930 and GR38032F, dose-dependently blocked the tachycardia and pressor response to 2CH3-5-HT. These data establish the presence of a 5-HT3 receptor mediating a direct positive chronotropic effect of 5-HT in conscious dogs, an effect that depends, only minimally, on the presence of an intact autonomic nervous system.