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.     

Regional hemodynamic effects of the N-(2-benzoylphenyl)-L-tyrosine peroxisome proliferator-activated receptor-gamma ligand, GI 262570 [(S)-2-(2-benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic acid], in conscious rats

This study provides novel data on the regional hemodynamic effects of the peroxisome proliferator-activated receptor-gamma activator, GI 262570 [(S)-2-(2-benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic acid], in conscious, male Sprague-Dawley rats. Administration of GI 262570 twice daily for 4 days caused a slowly developing, modest fall in mean arterial blood pressure, associated with a progressive, hyperemic hindquarters vasodilatation, but with no consistent changes in renal or mesenteric hemodynamics. The hindquarters vasodilator effect of GI 262570 was not inhibited by the beta2-adrenoceptor antagonist, ICI 118551 ((+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol hydrochloride), and was still apparent in the presence of the alpha-adrenoceptor antagonist, phentolamine. Neither the latter, nor antagonism of angiotensin (AT1) and endothelin (ETA and ETB) receptors unmasked vasodilator responses to GI 262570 in the renal or mesenteric vascular beds. In the presence of GI 262570, vasodilator responses to acetylcholine and vasoconstrictor responses to methoxamine were normal. Furthermore, the cardiovascular responses to nonselective nitric-oxide synthase inhibition were not influenced by GI 262570. Collectively, these results indicate that the vasodilator action of GI 262570 is specific to the hindquarters vascular bed (of those studied), does not involve alpha- or beta2-adrenoceptors, and is not associated with a change in basal or stimulated nitric oxide release.     

Regional hemodynamic effects of neutral endopeptidase inhibition and angiotensin (AT(1)) receptor antagonism alone or in combination in conscious spontaneously hypertensive rats

We tested the hypothesis that angiotensin (AT(1)) receptor antagonism (with losartan) would enhance the cardiovascular actions of neutral endopeptidase (NEP) inhibition [with candoxatrilat or (2S)-2-{[1-({[(1S)-1-carboxy-2-(5-phenyl-1,3-oxazol-2-yl)ethyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (UK-489,329)] in conscious spontaneously hypertensive rats (SHR). Four-day continuous intravenous infusion of candoxatrilat (1.9 microg kg(-1) min(-1)) or UK-489,329 (0.15 microg kg(-1) min(-1)) had no significant cardiovascular effects, whereas candoxatrilat (6.4 microg kg(-1) min(-1)) had a modest antihypertensive effect (-10.9 mm Hg on day 4) but no significant sustained effects on regional hemodynamics. Losartan caused a fall in blood pressure (maximum -29.2 mm Hg on day 4) that was associated with renal, mesenteric, and, to a lesser extent, hindquarters vasodilatation. The combination of losartan with either dose of candoxatrilat had no greater antihypertensive or vasodilator effects than losartan alone, with the exception of the increase in renal vascular conductance, which was greater with the combination of the drugs than with either drug alone (significant only in the lower dose study). Losartan combined with UK-489,329 showed a greater antihypertensive effect than losartan alone (-14.6 mm Hg greater on day 4), although the effects of the combination were not significantly greater than the sum of the effects of both agents administered separately. However, losartan combined with UK-489,329 caused increases in renal and hindquarters vascular conductance that were significantly greater with the combination than with either agent given alone. Thus, in conscious SHR, the renin-angiotensin system may act to oppose a vasodilator action of NEP inhibition, particularly in the renal vascular bed.     

Effect of destruction of the vascular endothelium upon pressure/flow relations and endothelium-dependent vasodilatation in resistance beds of spontaneously hypertensive rats.

1. Pressure/flow relationships were determined in the in situ blood-perfused superior mesenteric and hindquarters vascular beds of spontaneously hypertensive rats and Wistar-Kyoto normotensive rats before and after destruction of the endothelium with detergent. The effects of indomethacin on the regression of pressure on flow were also investigated in the spontaneously hypertensive rats, as were the endothelium-dependent relaxations in response to carbachol in the mesenteric bed. 2. In the spontaneously hypertensive rats the regression line of pressure on flow in the two vascular beds was both steeper and more elevated than in the Wistar-Kyoto rats, showing that there was greater resistance to flow in the hypertensive animals. Destruction of the endothelium significantly increased the slope of the regression in both Wistar-Kyoto and spontaneously hypertensive rats: the increases in the Wistar-Kyoto rats were 2.4 +/- 0.3 fold (mesenteric) and 2.0 +/- 0.5 fold (hindquarters) which were comparable with the respective increases of 1.6 +/- 0.3 fold and 1.8 +/- 0.3 fold in the spontaneously hypertensive rats. 3. Indomethacin (5 mg/kg, intravenously) had no effect on the pressure/flow relations in either of the vascular beds of the spontaneously hypertensive rats. 4. The dose-response curves for the endothelium-dependent vasodilatation in response to carbachol were not significantly different in spontaneously hypertensive and Wistar-Kyoto rats. 5. The results suggest that tonic release of endothelium-derived relaxing factor has similar effects in modulating resistance vessel tone in vivo in both hypertensive and normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional haemodynamic effects of captopril, enalaprilat and lisinopril in conscious water-replete and water-deprived Brattleboro rats

1. The regional haemodynamic effects of intravenous bolus doses of captopril, enalaprilat and lisinopril were assessed in conscious Brattleboro (i.e. vasopressin-deficient) rats, chronically instrumented with miniaturized pulsed Doppler probes and intravascular catheters. 2. Responses to incremental doses of each drug (spanning the median effective dose for the inhibition of the pressor response to angiotensin I) were examined in both water-replete and water-deprived states. 3. In the water-replete state, the haemodynamic profiles of captopril, enalaprilat and lisinopril were generally similar, with incremental doses causing rises in mesenteric and renal flow and, to a lesser extent, hindquarters flow. There were small tachycardias and only slight falls in mean blood pressure. 4. In the water-deprived state, the effects of all three drugs were greatly enhanced; tachycardic and hypotensive effects occurred together with increases in mesenteric, renal and hindquarters flows. However, for renal flow and renal vascular conductance the effectiveness of the drugs decreased in the order enalaprilat greater than captopril greater than lisinopril, whereas for mesenteric flow and mesenteric vascular conductance the order was captopril greater than enalaprilat greater than lisinopril. 5. Since marked haemodynamic actions were seen with doses one-tenth of the median effective dose for the inhibition of the pressor effect of angiotensin I, it is likely these effects were due to inhibition of angiotensin-converting enzyme, although not necessarily to inhibition of angiotensin II production.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of phosphodiesterase 5 and angiotensin-converting enzyme inhibition alone or in combination in conscious SHR

The regional hemodynamic responses to continuous 4-day infusion of UK-357,903 [1-ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-2-(2-methoxyethoxy)-5-pyridylsulphonyl}piperazine] (266 microg kg(-1) h(-1)) alone and in combination with a low dose of enalapril (10 microg kg(-1) h(-1)) were measured in conscious spontaneously hypertensive rats to test the hypothesis that the renin-angiotensin system may influence the cardiovascular consequences of inhibition of phosphodiesterase 5 (PDE5) by UK-357,903 or vice versa. UK-357,903 alone caused a fall in mean blood pressure (-12.1 mm Hg) associated with vasodilatation in the mesenteric and hindquarters vascular beds. The only way in which the effects of enalapril given alone differed significantly from those of the vehicle was in causing mesenteric vasodilatation, which developed over the 4 days of infusion. UK-357,903 given in combination with enalapril caused hypotension (-17.8 mm Hg) and vasodilatation in the renal, mesenteric, and hindquarter vascular beds. There was evidence of a significant interaction between the effects of the two compounds on renal Doppler shift and vascular conductance with the combined action of the two compounds being greater than the sum of their individual effects. However, although there was a trend for the combination to have greater effects than either of the individual agents on blood pressure and mesenteric vascular conductance, there was no statistical evidence of an interaction. The results indicate that inhibition of the renin-angiotensin system uncovers additional renal vasodilator effects of UK-357,903, and/or inhibition of PDE5 enhances the renal vasodilator effects of angiotensin-converting enzyme inhibition.     

Preferential renal vasodilator effects of CGP 22979A in conscious spontaneously hypertensive rats

CGP 18137A (2-hydrazino-5-n-butyl-pyridine) and its prodrug CGP 22979A [N-acetyl-L-glutamic acid-N-[N2-(5-n-butyl-2-pyridyl)hydrazide]] were evaluated for their blood pressure-lowering potency and regional hemodynamic actions in conscious spontaneously hypertensive rats. The effects were compared to those of hydralazine. Animals were instrumented with miniaturized pulsed Doppler flowprobes to allow continuous simultaneous measurement of renal, mesenteric and hindquarter blood flow. From changes in mean arterial pressure and the respective flows, changes in renal, mesenteric and hindquarter resistance were calculated. After i.v. administration, hydralazine and CGP 18137A were equally potent with regard to their blood pressure-lowering effect in a dose range of 0.1 to 1 mg/kg. Hydralazine was more effective than CGP 18137A in lowering renal and hindquarter resistance. Neither of the two drugs, however, caused preferential dilation in any of the three beds studied. CGP 22979A in doses of 1 to 30 mg/kg caused a much smaller acute blood pressure-lowering response. However, already at low doses (1-10 mg/kg) it caused a significant reduction of renal resistance, without affecting either hindquarter or mesenteric resistance. At the highest dose (30 mg/kg), selectivity was no longer retained, which is probably due to excessive leakage of the active vasodilator into the peripheral circulation. These findings suggest that CGP 22979A is a renal-selective prodrug for CGP 18137A and thereby is capable of preferentially dilating the renal vasculature in conscious unrestrained spontaneously hypertensive rats.     

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.     

Vascular areas where clonidine induces vasodilation in hypertensive and normotensive rats

The aim of this study was to find vascular areas where clonidine decreases the regional vascular resistance when this drug lowers arterial pressure in conscious spontaneously hypertensive rats and normotensive control rats. Arterial pressure was observed with an indwelling catheter at a carotid. Blood flow was measured with an electromagnetic flow probe implanted around the renal artery or the superior mesenteric artery. Regional vascular resistance was calculated as arterial pressure divided by blood flow. Intravenous bolus injection of clonidine at a dose to decrease arterial pressure decreased renal resistance and superior mesenteric resistance. Quantitatively, the combined effect of the decrease in these two resistances was enough to account for the decrease in arterial pressure. Although clonidine is thought to inhibit sympathetic nerve activity centrally, the above vasodilator effect is not ascribable to this inhibitory mechanism: Sympathetic activity to be inhibited does not seem to be present in the superior mesenteric area and clonidine similarly decreased renal vascular resistance even after renal denervation.     

Regional hemodynamic effects of rilmenidine and clonidine in the conscious spontaneously hypertensive rat

Rilmenidine is an oxazoline analogue that has antihypertensive properties that resemble those of clonidine. Since rilmenidine has recently been described to have a relatively greater affinity for imidazoline receptors than clonidine, it was of interest to study whether this has functional consequences with regard to the regional hemodynamic responses. We investigated regional hemodynamics in conscious spontaneously hypertensive rats, equipped with miniature Doppler flow probes on the renal and mesenteric arteries and on the abdominal aorta. Clonidine (3-30 micrograms/kg) and rilmenidine (0.2-3 mg/kg) induced similar, dose-dependent reductions in heart rate. Both also induced an early hypertensive response, which was greater with rilmenidine, and similar later blood pressure reductions, which were maintained over 3 h. The early hypertensive response was associated with generalized vasoconstriction. Rilmenidine caused slightly greater mesenteric and hindquarter constriction than clonidine, whereas renal effects did not differ significantly. During the hypotensive phase, rilmenidine was a less potent mesenteric and hindquarter vasodilator than clonidine. During this phase, renal blood flow was at control levels, probably indicating autoregulation of renal flow. The minor differences in regional hemodynamic effects suggest that clonidine and rilmenidine can both be used as potent antihypertensives. The fact that rilmenidine has been suggested to possess less sedative side-effects suggests that, on this basis, it may be superior for antihypertensive drug therapy.     

Regional vascular selectivity of angiotensin II

To examine the actions of angiotensin II on regional vascular resistances, we monitored regional blood flows and cardiac output with transit-time flow probes and thermodilution, respectively, in anesthetized rats. To remove the influence of endogenous angiotensin II, rats were pretreated with captopril (30 mg/kg intravenously). Intravenous infusions of angiotensin II were used to produce circulating angiotensin II, and these infusions caused marked dose-related (3, 30, and 300 pmol/min) and sustained (2 h) increases in renal vascular resistance, with lesser effects on mesenteric vascular resistance, little effect on carotid vascular resistance, and no effect on hindquarter or calculated "other tissue" vascular resistances. In contrast, vasopressin caused similar increases in renal, mesenteric, carotid, hindquarter, and other tissue vascular resistances. Infusions of angiotensin II (3, 10, and 30 pmol/min) into the local arterial blood were used to increase selectively local angiotensin II levels. Intrarenal artery infusions of angiotensin II increased renal, but not mesenteric, vascular resistance; and intramesenteric artery infusions of angiotensin II increased mesenteric, but not renal, vascular resistance. Infusions of angiotensin II into the hindquarter and carotid vascular beds caused little change in hindquarter and carotid vascular resistances, respectively, but sufficient angiotensin II escaped the hindquarter and carotid vascular beds to cause increases in renal and mesenteric vascular resistances. In conclusion, angiotensin II constricts primarily the renal vascular bed and to a lesser extent the gut circulation, and those tissues that are most responsive to angiotensin II also metabolize angiotensin II better than tissues that are less responsive to angiotensin II.     

Renal response to pentobarbital anesthesia in rats: effect of interrupting the renin-angiotensin system

The influence of interrupting the renin-angiotensin system on the renal hemodynamic response to barbiturate anesthesia was assessed in conscious, trained, chronically catheterized rats. Anesthesia induced by pentobarbital caused a marked reduction in mean arterial pressure, heart rate, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Pretreatment of rats with captopril, an inhibitor of angiotensin I converting enzyme, prevented the impairment of renal hemodynamics by pentobarbital without restoring blood pressure. GFR remained at 100 to 110% of control values in captopril-pretreated rats receiving pentobarbital, but was reduced by pentobarbital (90-120 min after induction) to 75 +/- 5% in rats which did not receive captopril. ERPF showed similar changes. An antagonist of angiotensin II receptors, 1-sarcosine-8-isoleucine-angiotensin II, did not prevent the anesthesia-induced decrements in GFR and ERPF (GFR was reduced to 78 +/- 6% and ERPF to 68 +/- 4% at 90-120 min after pentobarbital). This failure of the antagonist of angiotensin II receptors to protect renal hemodynamics may have been due to its intrinsic agonist activity on the renal vasculature. This is suggested by the fact that, in captopril-pretreated rats, which maintained renal hemodynamics in response to pentobarbital, addition of 1-sarcosine-8-isoleucine-angiotensin II caused a reduction in GFR and ERPF and an elevated blood pressure. At 100 min after administration of pentobarbital, plasma renin activity was elevated compared to a conscious control group (3.57 +/- 0.42 vs. 1.94 +/- 0.34 ng angiotensin l/ml X hr, P less than .05). It is concluded that the renin-angiotensin system mediates an impairment of renal hemodynamics during pentobarbital anesthesia.(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.     

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.     

Comparison of systemic and regional hemodynamic effects of a diuretic, an angiotensin II receptor antagonist, and an angiotensin-converting enzyme inhibitor in conscious renovascular hypertensive rats.

The present experiments were designed to compare the antihypertensive action and the systemic and regional hemodynamic effects of a diuretic (furosemide), an angiotensin II (AngII) receptor blocker (Dup 753), and an angiotensin converting enzyme (ACE) inhibitor (enalapril) in conscious, two-kidney, one-clip renovascular hypertensive rats by the radioactive microsphere technique. Measurements were done 3 hours after a single dose treatment. Furosemide (20 mg/kg) produced a marked diuresis and tachycardia with no change in blood pressure; in comparison with control rats, furosemide-treated rats had total peripheral vascular resistance increased by 46.55% (p less than 0.01) and local vascular resistance increased in most organs, to a significant degree in the spleen, muscle, stomach, intestine, and skin (p less than 0.05 to 0.01). Dup 753 (20 mg/kg) and enalapril (10 mg/kg) decreased mean blood pressure by 41.89 +/- 7.17 mm Hg and 47.13 +/- 8.67 mm Hg, respectively (p less than 0.01), with tachycardia only in the Dup 753 group. Total peripheral and local vascular resistances in several tissues were significantly lower in both the Dup 753 and enalapril groups than in the furosemide group. In particular, both antiangiotensin agents, in contrast to furosemide, produced significant decrease in renal vascular resistance by 42.28% and 38.81%, respectively (p less than 0.01), with a tendency to increase the renal blood flow (of the intact kidney). No detectable differences were found in systemic and regional hemodynamic changes between the Dup 753 and enalapril group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absence of adrenergic mediation of agonist response to [Sar1,Ala8]angiotensin II in conscious normotensive and hypertensive dogs.

1. In the conscious normotensive and two-kidney Goldblatt hypertensive dog a transient agonist response to the intravenous infusion of saralasin (1 microgram min-1 kg-1)was manifested by a small increase in blood pressure (6-12) mmHg) and 28-30% increase in renal vascular resistance. 2. These increases in blood pressure and renal vascular resistance were unaffected by administration of either phentolamine or guanethidine. 3. The agonist response in the conscious dog is most likely accounted for by a direct action of saralasin on vascular angiotensin receptors.     

The acute renal actions of angiotensin converting enzyme inhibitors in the sodium-depleted conscious primate are mediated by inhibition of the renin-angiotensin system.

The purpose of this study was to determine if the changes in renal function acutely produced by an inhibitor of angiotensin converting enzyme (ACE) in the sodium-depleted conscious marmoset can be explained primarily by blockade of the renin-angiotensin system. Intravenous injection of a dose of the ACEI, enalaprilate (2 mg/kg), that produced a maximal lowering of blood pressure (BP), also decreased renal vascular resistance and increased renal blood flow. Glomerular filtration rate was unchanged by enalaprilat, leading to a fall in the filtration fraction. In comparison, a dose of the renin inhibitory monoclonal antibody, R-3-36-16 (0.1 mg/kg), that also produced a maximal fall in BP, produced similar changes in renal hemodynamics to those observed after administration of the ACEI. Combined administration of 2 mg/kg enalaprilat and 0.1 mg/kg R-3-36-16 produced changes in BP and renal hemodynamics similar to those produced by the same doses of either agent administered alone. Enalaprilat (2 mg/kg) significantly increased urine volume (UV) and urinary sodium excretion (UNaV). In contrast, these parameters were not significantly altered by 0.1 mg/kg R-3-36-16. However, when given at a 10-fold higher dose, the monoclonal antibody produced an increase in UNaV and UV identical to that produced by the ACEI alone. Enalaprilat did not increase UV and UNaV excretion to a greater extent than the high dose of the renin inhibitory antibody. These results demonstrate that acute administration of an ACEI affects BP and renal function in the sodium-depleted conscious primate primarily by inhibition of the renin-angiotensin system.     

Effect of inhibition of converting enzyme on renal hemodynamics and sodium management in polycystic kidney disease

We compared the tubular transport of sodium and the erythrocyte sodium-lithium countertransport activity in hypertensive patients with autosomal dominant polycystic kidney disease (ADPKD) and in normotensive control subjects. In addition, we assessed the effects of inhibition of converting enzyme on renal hemodynamics and sodium excretion in hypertensive patients with ADPKD to provide information on mechanisms responsible for the increased renal vascular resistance and filtration fraction and the adjustment of the pressure-natriuresis relationship during saline expansion, observed in patients with ADPKD, hypertension, and preserved renal function. In comparison with normotensive control subjects, the hypertensive patients with ADPKD had lower renal plasma flows, higher renal vascular resistances and filtration fractions, and similar proximal and distal fractional reabsorptions of sodium. The administration of enalapril resulted in significant increases in the renal plasma flow and significant reductions in mean arterial pressure, renal vascular resistance, and filtration fraction, but the glomerular filtration rate remained unchanged. Despite the significant reduction in mean arterial pressure during inhibition of converting enzyme, the distal fractional reabsorption of sodium decreased while the total fractional excretion of sodium remained unchanged or increased slightly. No significant differences were detected between the normotensive control subjects and the hypertensive patients with ADPKD in erythrocyte sodium-lithium countertransport activity, plasma renin activity, plasma aldosterone concentration, or atrial natriuretic factor. These results suggest that the renal renin-angiotensin system plays a central role in the alterations in renal hemodynamics and sodium management associated with the development of hypertension in ADPKD.     

Role of renal sympathetic nerves in regulating renovascular responses to angiotensin II in spontaneously hypertensive rats

The purpose of this study was to test the hypothesis that renal sympathetic nerves modulate angiotensin II-induced renal vasoconstriction in kidneys from genetically hypertensive rats via Y1 receptors activating the Gi pathway. In isolated, perfused kidneys from spontaneously hypertensive rats, the naturally occurring renal sympathetic cotransmitter neuropeptide Y at 6 nM enhanced angiotensin II (0.3 nM)-induced changes in perfusion pressure by 47 +/- 7 mm Hg, and this effect was inhibited by BIBP3226 [N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-D-arginine amide)], a selective Y1 receptor antagonist (1 microM). We next examined whether periarterial nerve stimulation (5 Hz) enhances renal vascular responses to a physiological level of angiotensin II (100 pM). Kidneys were pretreated with prazosin (a selective alpha1-adrenoceptor antagonist) to block nerve stimulation-induced changes in perfusion pressure. In kidneys from spontaneously hypertensive rats, but not normotensive rats, periarterial nerve stimulation significantly augmented angiotensin II-induced changes in perfusion pressure (177 +/- 26% of response in absence of stimulation). BIBP3226, but not rauwolscine (a selective alpha2-adrenoceptor antagonist), abolished periarterial nerve stimulation-induced enhancement of angiotensin II-mediated renal vasoconstriction. Pretreatment of hypertensive animals with pertussis toxin 3 days prior to kidney perfusion significantly (p < 0.000001) decreased mean blood pressure (203 +/- 2 versus 145 +/- 6 mm Hg in nonpretreated versus pertussis toxin-pretreated spontaneously hypertensive rats) and abolished periarterial nerve stimulation-induced enhancement of angiotensin II-mediated renal vasoconstriction. We conclude that, in spontaneously hypertensive rats but not normotensive rats, sympathetic nerve stimulation enhances renal vascular responses to physiological levels of angiotensin II via a mechanism mainly involving Y1 receptors coupled to Gi proteins.     

MC-838 (altiopril calcium): a novel orally active angiotensin converting enzyme inhibitor

MC-838, calcium (-)-N-[(S)-3-(N-cyclohexylcarbonyl-D-alanyl) thio]-2-methylpropionyl]-L- prolinate, is a new orally active angiotensin converting enzyme (ACE) inhibitor in which the mercapto-group is taken up in a stable thiolester linkage. The linkage was relatively resistant against enzymatic hydrolysis by rat liver homogenates. The ACE prepared from rabbit lung was inhibited by MC-838 in a concentration-dependent manner. In isolated rat aortic ring and guinea-pig ileum preparations, MC-838 was highly specific in suppressing the contractile response to angiotensin-I (A-I) an in augmenting the contractile one to bradykinin. However, the ACE inhibitory activity of MC-838 was 30-100 times less potent than that of captopril. In conscious two-kidney (2 KG), renal hypertensive rats and spontaneously hypertensive rats (SHRs), MC-838 (3 and 10 mg/kg) given orally caused a long-lasting hypotensive effect with a slow onset. When compared on a weight basis (3 mg/kg), the antihypertensive effect of MC-838 was comparable to that of captopril in magnitude, but the duration of action of MC-838 was approximately 2 times longer than that of captopril.