Enhanced angiotensin-converting enzyme activity and impaired endothelium-dependent vasodilation in aortae from hypertensive rats: evidence for a causal link.

Endothelial vasomotor function is impaired in a variety of disorders representing both early and late stages of atherosclerosis. There is experimental evidence for enhanced vascular angiotensin-converting enzyme (ACE) activity in these disorders. We explored whether enhanced vascular ACE activity accounts for endothelial dysfunction in experimental hypertension. Hypertension was induced in rats by coarctation of the aorta. At 2 weeks post-operation, the animals were randomly divided into groups receiving the ACE inhibitor quinapril (2.0 mg.kg(-1).day(-1)), the angiotensin type-1 receptor antagonist losartan (3.0 mg.kg(-1).day(-1)), the B(2) kinin receptor antagonist icatibant (0.4 mg.kg(-1).day(-1)), quinapril plus icatibant, losartan plus icatibant, or no drug. Analyses were performed 4 weeks post-operation. None of the drug treatments had any significant effect on blood pressure. ACE activity was nearly doubled in aortae from untreated hypertensive rats as compared with sham-operated rats. Quinapril reduced ACE activity in aortae from hypertensive rats by 75%, losartan caused a 40% decrease, and icatibant had no effect. Endothelium-dependent, nitric oxide-mediated vasodilator responses studied in vitro were impaired by 40% in aortae from untreated hypertensive rats as compared with sham-operated rats. Both quinapril and losartan restored endothelial vasomotor function in aortae from hypertensive rats. Co-applied icatibant negated the effects of quinapril, but not those of losartan. The level of endothelial NO synthase (eNOS) mRNA determined by competitive RNA PCR was decreased by half in aortae from untreated hypertensive rats as compared with sham-operated rats. Quinapril induced an increase in the eNOS mRNA level of 350% in aortae from hypertensive rats, which was negated by co-applied icatibant. Losartan restored eNOS mRNA expression in aortae from hypertensive rats to normal levels, and this effect was not modified by co-applied icatibant. These findings suggest that enhanced vascular ACE activity accounts for endothelial vasomotor dysfunction by impairing the bioavailability of endothelium-derived NO. Both enhanced formation of angiotensin II and enhanced metabolism of bradykinin might account for a vascular deficiency of bioactive NO.     

Short-term effects of quinapril and nifedipine on early renal changes in streptozotocin-induced diabetes in rats

Summary— The effects on renal function of quinapril, an angiotensin I converting enzyme (ACE) inhibitor, and of nifedipine, a dihy-dropyridine calcium antagonist, were studied in the early stages of diabetes in rats. Wistar rats received one injection of streptozotocin (STZ) to induce diabetes; the hyperglycaemia was then controlled with daily insulin therapy (2–3 units NPH insulin/rat). One week after STZ injection, rats were treated orally with quinapril (0.3 or 3 mg/kg/d) or nifedipine (30 mg/kg/day) for 1 week, after which renal functions were compared with those of untreated diabetic rats or non-diabetic control rats. At the end of these two weeks, diabetic rats had gained less weight and had developed renal hypertrophy and glomerular hyperfiltration (3.21 ± 0.23 vs 2.36 ± 0.09 ml/min for non-diabetic rats, mean ± SEM, P < 0.01). Their urinary albumin excretion was higher, as was the urinary excretion of water, sodium, potassium, urea and glucose. One week treatment with quinapril or nifedipine had no significant effect on the increase in the glomerular filtration rate (respectively 2.97 ± 0.18 and 2.99 ± 0.15 ml/min). Quinapril and nifedipine differed with regard to their effects on urinary albumin excretion. Albuminuria was increased by nifedipine but not by quinapril (respectively 0.554 ± 0.158 and 0.149 ± 0.046 mg/day/100 g BW, P < 0.05). This difference between the effects of the dihydropyridine and the ACE inhibitor on albuminuria may be linked to different effects on the glomerular functions.     

Hemodynamic effects of quinapril, a novel angiotensin-converting enzyme inhibitor

The hemodynamic effects of quinapril, a novel nonsulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, were assessed in 10 patients with mild-to-moderate essential hypertension. Compared with placebo, quinapril (20 mg) administered twice daily for 4 weeks significantly lowered blood pressure by decreasing total peripheral resistance without producing tachycardia, an increase in cardiac output, or a rise in plasma catecholamines. Quinapril significantly reduced renal, but not forearm, vascular resistance. Renal blood flow, glomerular filtration rate, and filtration fraction remained unchanged. Left ventricular wall stress was markedly reduced by quinapril, but during the relatively short treatment period, only a nonsignificant trend toward reduction in left ventricular mass was observed. These findings suggest that quinapril is an effective antihypertensive agent that lowers peripheral resistance without increasing cardiac output or disturbing autoregulation of renal hemodynamics.     

Low-dose angiotensin II reduces urinary cyclic AMP excretion in spontaneously hypertensive, but not normotensive, rats: independence from hypertension and renal hemodynamic effects of angiotensin.

The purpose of this study was to determine whether the greater inhibitory effect of angiotensin II (Ang II) on urinary cAMP excretion in spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto (WKY) rats is secondary to hypertension and/or renal hemodynamic changes induced by Ang II. SHRs and WKY rats were treated chronically from conception, 6 weeks of age, or 10 weeks of age (n = 8-10) with the angiotensin-converting enzyme inhibitor captopril (100 mg/kg/day). A fourth group was not treated chronically with captopril (n = 7). At approximately 13 weeks of age, all rats were anesthetized, given a bolus of captopril (30 mg/kg), and received an intrarenal infusion of a low dose of Ang II (1 ng/min). SHRs compared with WKY rats were normotensive, mildly hypertensive, and moderately hypertensive when treated with captopril from conception, 6 weeks of age, and 10 weeks of age, respectively, whereas untreated SHRs were severely hypertensive. In SHRs, Ang II decreased urinary cAMP excretion (p <.001), and this effect was independent of duration of captopril pretreatment (p = .696). In WKY rats, Ang II did not affect urinary cAMP excretion. Low-dose Ang II caused small and similar changes in renal blood flow and glomerular filtration rate in SHRs versus WKY rats and did not affect urine volume in either strain. We conclude that the greater effect of Ang II on urinary cAMP excretion in SHRs is not due to hypertension or to the renal hemodynamic effects of Ang II, but most likely to a greater effect of Ang II on some compartment of renal adenylyl cyclase activity in SHRs.     

Renal functional reserve in patients with essential hypertension: effect of inhibition of the renin--angiotensin system

1. Urinary albumin excretion and the effect of an acute oral protein load (a meat meal) on glomerular filtration rate ('renal functional reserve') were evaluated in 15 essential hypertensive patients with preserved renal function and compared with 12 normal subjects. 2. Seven patients had microalbuminuria (greater than 30 mg/day) that was not correlated with blood pressure values. 3. After an oral protein load, an average increase of 20% in glomerular filtration rate (from 91 +/- 19 to 110 +/- 27 ml min-1 1.73 m-2 was found in the hypertensive patients. This change was not statistically different from that observed in normal controls (from 102 +/- 7 to 124 +/- 9 ml min-1 1.73 m-2). The glomerular response in hypertensive patients was independent of age, duration of hypertension, blood pressure, plasma renin activity, urinary albumin excretion and retinal vascular alterations. 4. All patients were re-evaluated after 6 weeks treatment with a new orally active angiotensin-converting enzyme inhibitor, benazepril. Systolic, diastolic and mean blood pressures were lowered in all the patients, but the drug did not affect the glomerular response to acute protein ingestion or the magnitude of urinary albumin excretion. 5. The findings of a normal 'renal functional reserve' and a lack of change in both urinary albumin excretion and the glomerular response after angiotensin-converting enzyme inhibition cast doubt on the existence of increased intraglomerular pressure in hypertensive patients.     

Depressor and natriuretic effects of M&B 22,948, a guanosine cyclic 3',5'-monophosphate-selective phosphodiesterase inhibitor

We examined the effects of an acute infusion of M&B 22,948 (2-o-propoxyphenyl-8-azapurin-6-one), a (cGMP)-selective phosphodiesterase inhibitor, on mean arterial pressure (MAP) and urinary sodium excretion in anesthetized rats. M&B 22,948 (at doses of 0.34-2.72 mg/kg/min for 30 min) lowered MAP in a dose-dependent manner, with a 60 mm Hg fall in pressure produced at the highest dose. Despite large decreases in MAP, a profound natriuresis was observed at all doses. Plasma concentrations of cGMP increased in parallel with the depressor action of M&B 22,948, whereas increases in the urinary excretion of cGMP temporally correlated with the natriuresis. The concentration of cyclic AMP in plasma increased transiently in rats treated with M&B 22,948 but the urinary excretion of cyclic AMP was not elevated in these animals. Because changes in cGMP correlated with the physiological effects of M&B 22,948, and the increase in cyclic AMP did not, it is likely that the depressor and natriuretic actions of M&B 22,948 are mediated by increases in cGMP. M&B 22,948 administered chronically at an oral dose of 200 mg/kg/day normalized MAP in spontaneously hypertensive rats; whereas MAP in vehicle-treated spontaneously hypertensive rats remained at hypertensive levels. cGMP-selective phosphodiesterase inhibitors (like M&B 22,948) could be more effective antihypertensive drugs than currently available vasodilators because, when administered acutely, M&B 22,948 simultaneously lowers blood pressure and promotes sodium excretion in the anesthetized rat.     

The antiproteinuric action of enalapril in stroke-prone spontaneously hypertensive rats is unrelated to alterations in urinary prostaglandins.

We examined whether the renal protective effect of the angiotensin I converting enzyme inhibitor enalapril in stroke-prone spontaneously hypertensive rats (SHRSP) is dose-related and associated with alterations in the urinary excretion of prostaglandin (PG) E2 and 6-keto-PGF1 alpha, a stable breakdown product of prostacyclin. Enalapril maleate at 1.5, 5 and 15 mg/kg/day or vehicle was chronically administered to saline-drinking SHRSP (six per group) starting at 8.1 weeks of age. Vehicle-treated SHRSP developed severe hypertension, proteinuria and strokes (age at death, 14 +/- 1 weeks; mean +/- S.E.). Enalapril prolonged survival dose-dependently and reduced proteinuria; all SHRSP given 15 mg/kg/day lived beyond 23 weeks of age without evidence of stroke or proteinuria. There was no effect of enalapril at any dose on systolic arterial blood pressure in spite of variable levels of urinary protein excretion and onset of stroke in the different groups. Likewise, urinary 6-keto-PGF1 alpha and PGE2 excretion did not differ among the groups except for an increase in 6-keto-PGF1 alpha in the 15 mg/kg/day group at one week after initiation of enalapril therapy. These results are consistent with a dose-related renal protective action of enalapril in saline-drinking SHRSP that is not closely associated with sustained alterations in urinary excretion of renal vasodilatory PGs.     

Intra-erythrocyte sodium and (Na+,K+-activated)-ATPase concentration and urinary aldosterone excretion in spontaneously hypertensive rats

1. Intra-erythrocyte sodium, potassium, ATP and (Na+,K+-activated)-ATPase concentrations and urinary aldosterone excretion were compared in 3-month-old spontaneously hypertensive rats (n = 11) and normotensive Wistar-Kyoto control rats (n = 11). 2. Spontaneously hypertensive rats exhibited significantly higher intra-erythrocyte sodium concentration (5.5 +/- 1.3 vs 4.0 +/- 1.1 mmol/l of erythrocytes, P less than 0.01). No significant difference was found in intra-erythrocyte potassium. ATP or (Na+,K+-activated)-ATPase concentration. 3. Mean urinary aldosterone excretion was significantly lower in spontaneously hypertensive rats (66.3 +/- 6.5 pmol/24 h) than in Wistar-Kyoto rats (90.5 +/- 10.6 pmol/24 h, P less than 0.01). No significant relationship between urinary aldosterone and intra-erythrocyte sodium concentration was found in spontaneously hypertensive or Wistar-Kyoto rats or in the pooled group. 4. These results are thus consistent with previous findings of an increased intracellular sodium concentration in spontaneously hypertensive rats, but do not support the hypothesis that aldosterone is a dominant regulator of intracellular sodium concentration.     

Effect of sodium intake on brain angiotensin-converting enzyme activity in spontaneously hypertensive rat

The effect of sodium intake on angiotensin-converting enzyme activity in five areas of the brain (the cerebral cortex, midbrain, striatum, thalamus and hypothalamus) was studied in normotensive, spontaneously hypertensive and stroke-prone spontaneously hypertensive rats. The enzyme activity was significantly higher in the hypothalamus than in other areas of the brain of spontaneously hypertensive rats. Sodium intake resulted in a significant rise of the enzyme activity in the midbrain of spontaneously hypertensive rats and also in the midbrain and the striatum of stroke-prone spontaneously hypertensive rats. In normotensive rats, however, there was no significant difference in the enzyme activity in any area of brain between the control and the salt-treated group. It is likely therefore that a high circulating sodium level increases angiotensin-converting enzyme content of the brain in spontaneously hypertensive rats, and it is suggested that the increased converting-enzyme activity may play a role in development of hypertension induced by sodium loading.     

Effects of chronic administration of an angiotensin-converting enzyme inhibitor on angiotensin-converting enzyme activity in the pars recta of rabbits

1. To determine whether chronic angiotensin-converting enzyme inhibition induces a decrease in proximal tubular angiotensin-converting enzyme activity, urine and blood samples were collected in conscious New Zealand rabbits before and after 16 days administration in drinking water of low doses of captopril (2.6 +/- 0.6 mg 24 h-1 kg-1), high doses of captopril (7.6 +/- 0.9 mg 24 h-1 kg-1) or no captopril (controls). The kidneys were then removed and angiotensin-converting enzyme activity was determined in isolated pars recta of microdissected nephrons as pmol of tritiated hippurylglycylglycine substrate hydrolysed min-1 of incubation and mm-1 of tubule. 2. Both low and high doses of captopril significantly decreased plasma angiotensin-converting enzyme activity and increased plasma renin activity, thus indicating an effective inhibition of circulating angiotensin-converting enzyme. Both low and high doses of captopril also significantly decreased mean arterial pressure and increased water intake and urine flow rate. Neither dose modified creatinine clearance and absolute and fractional sodium excretion. 3. None of the doses altered urinary kallikrein excretion. Urinary excretion of kinins was increased by 98.7% compared with control rabbits by the high dose of captopril (402 +/- 152 vs 251 +/- 104 ng/24 h, P less than 0.01) but was unchanged by the low dose of captopril. 4. Angiotensin-converting enzyme activity in the pars recta was lower in rabbits given the high dose of captopril than in control rabbits (17.6 +/- 7.2 vs 37.3 +/- 9.0 pmol min-1 mm-1, P less than 0.01) but was not decreased in rabbits given the low dose of captopril (40.4 +/- 5.0 pmol min-1 mm-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective and nonselective inhibition of thromboxane formation

Thromboxane A2, the predominant cyclooxygenase product of arachidonic acid in the platelet, is a potent vasoconstrictor and stimulus of platelet aggregation. Prostacyclin, the principal cyclooxygenase metabolite formed in the vascular endothelium, inhibits platelet aggregation and dilates blood vessels. A therapeutic objective in the treatment of human vascular occlusive disease has been the inhibition of thromboxane formation without coincident reduction in prostacyclin biosynthesis. We compared the biochemical selectivity and platelet inhibitory actions of single doses of aspirin, a cyclooxygenase inhibitor, with imidazo(1,5-2)pyridine-5-hexanoic acid (CGS 13080), an inhibitor of thromboxane synthase. Aspirin, 325 mg, prolonged the bleeding time markedly, inhibited aggregation and nucleotide release in whole blood and platelet-rich plasma, and maximally inhibited thromboxane generation in serum. The effects of aspirin, 20 mg, were considerably less marked but, as with the higher dose, persisted throughout the study period (24 hr after dosing). CGS 13080 also prolonged bleeding time and inhibited thromboxane formation. In contrast to aspirin, these effects were reversible and inhibition of aggregation was less marked. Endogenous prostacyclin biosynthesis was measured by excretion of the major urinary metabolite 2,3-dinor-6-keto-PGF1 alpha (PGI-M). Whereas aspirin, 325 mg, reduced PGI-M excretion a mean 29%, excretion increased 48% and 100% after CGS 13080, 100 mg and 200 mg. Aspirin, 20 mg, did not alter prostacyclin biosynthesis. Inhibition of thromboxane synthase permits selective inhibition of thromboxane formation in man. Although drugs of greater potency and longer duration of action are desirable, enhanced prostacyclin synthesis may be an important component of the platelet inhibitory actions of thromboxane synthase inhibitors in man.     

Effect of angiotensin-converting enzyme inhibitors on glomerular eicosanoid production in normotensive and spontaneously hypertensive rats.

1. This study was designed to examine the production of certain eicosanoids (prostaglandin E2), prostacyclin (as 6-keto-prostaglandin F1 alpha) and thromboxane A2 (as thromboxane B2) by glomeruli isolated from normotensive Wistar-Kyoto and spontaneously hypertensive rats both before and after the administration of one of three angiotensin-converting enzyme inhibitors, captopril, enalapril or fosinopril, for 10 days. 2. Measurements of glomerular eicosanoid production were made under basal conditions and in the presence of excess exogenous arachidonic acid. 3. The production of prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 was greater by glomeruli from untreated spontaneous hypertensive rats (prostaglandin E2 2.24 +/- 0.41, 6-keto-prostaglandin F1 alpha 1.20 +/- 0.13 and thromboxane B2 2.75 +/- 0.43 ng 10 min-1 mg-1 of protein) than by those from Wistar-Kyoto rats (prostaglandin E2 1.41 +/- 0.28, 6-keto-prostaglandin F1 alpha 0.98 +/- 0.11 and thromboxane B2 1.29 +/- 0.24 ng 10 min-1 mg-1 of protein) under basal conditions. However, these differences only achieved statistical significance for thromboxane B2 (P less than 0.01). Similar strain-related differences were noted in the presence of arachidonic acid. 4. The ratio of glomerular (prostaglandin E2 + prostacyclin)/thromboxane A2 production was significantly lower in spontaneously hypertensive rats than in their normotensive counterparts under basal conditions with values of 1.3 +/- 0.18 and 2.2 +/- 0.20, respectively (P less than 0.01). 5. Angiotensin-converting enzyme inhibitors induced significant changes in the glomerular production of some eicosanoids, which differed both between strains and with the nature of the inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dexamethasone effect on prostanoid formation in healthy man

1. Dexamethasone was administered to six healthy female volunteers for 4 days, resulting in plasma levels of 4.8 +/- 1.4 x 10(-8) mol/l. Urinary excretions of six prostanoids as well as collagen-induced platelet thromboxane formation and aggregation were determined before, during and 1 month after administration of dexamethasone. 2. Dexamethasone had no effect on urinary thromboxane B2 (77 +/- 22 ng/day vs 63 +/- 16 ng/day during dexamethasone), dinor-thromboxane B2, the major urinary metabolite of thromboxane B2 (406 +/- 84 ng/day vs 380 +/- 90 ng/day), dinor-6-keto-prostaglandin F1 alpha, the major urinary metabolite of prostacyclin (199 +/- 41 ng/day vs 237 +/- 53 ng/day), tetranor-5,11-diketo-7 alpha-hydroxy-prostane-1,16-dioic acid, the major urinary metabolite of prostaglandins E1 and E2 (7712 +/- 1677 ng/day vs 7886 +/- 2565 ng/day) and tetranor-11-keto-5 alpha,7 alpha-dihydroxy-prostane- 1,16-dioic acid, the major urinary metabolite of prostaglandins F1 alpha and F2 alpha (14,394 +/- 2053 ng/day vs 18,288 +/- 2251 ng/day). Prostaglandin E2 excretion slightly but significantly increased from 217 +/- 48 ng/day to 294 +/- 55 ng/day. Collagen-induced platelet thromboxane formation and aggregation were not altered. 3. These results suggest that glucocorticoids do not regulate renal, platelet or total body prostanoid formation in healthy man.     

In vivo kinetics of indoxyl sulfate in humans and its renal interaction with angiotensin-converting enzyme inhibitor quinapril in rats

Indoxyl sulfate (IS) is an organic anion uremic toxin that accumulates in patients with chronic kidney disease (CKD). The aims of this study were to examine the kinetic profiles of IS in humans at a steady state after multiple doses of L-Trp, a precursor of IS, and the in vivo interaction of IS with the angiotensin-converting enzyme inhibitor quinapril, whose active metabolite is a substrate of organic anion transporter 3 (OAT3) in rats. First, 12-h kinetics after single doses of Trp (2, 4, and 8 g) were examined in two healthy volunteers. Second, 24-h kinetics after a single dose of 2 g of Trp was studied in six volunteers. Third, 35-h kinetics after single and multiple doses of 2 g of Trp were examined in five volunteers. In anesthetized rats, quinapril or probenecid, an inhibitor of OATs, was given intravenously before IS, and blood and urine samples were taken until 90 min. Trp and IS concentrations were determined by high-performance liquid chromatography. Ultrafiltration was used to measure serum unbound IS concentrations. Renal tubular secretion of IS accounted for more than 90% of its renal clearance in the steady state of serum IS levels after multiple doses in humans. In animals, the serum area under the curve of IS increased in conjunction with a decrease in renal clearances after coadministration of IS with quinapril or probenecid. It is concluded that quinapril may inhibit the urine excretion of IS via OAT3-mediated renal tubular transport in patients with CKD.     

Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans.

We studied the incorporation and metabolism of eicosapentanoic (EPA) and docosahexaenoic acid in six human volunteers who supplemented their normal Western diet for 5 mo daily with 10-40 ml of cod liver oil, rich in omega-3 polyunsaturated fatty acids. EPA and docosahexaenoic acid were incorporated into the total phospholipids of plasma, platelets, and erythrocytes in a dose- and time-dependent manner. During omega-3 fatty acid ingestion serum triacylglycerols were lowered and platelet aggregation upon low doses of collagen was reduced. Concomitantly, formation and excretion of prostanoids showed a characteristic change. As measured in serum from whole clotted blood, thromboxane A3 was formed in small amounts, whereas thromboxane A2 formation was reduced to 50% of control values. Excretion of the main urinary thromboxane A metabolites was unaltered in subjects with low basal excretion rates, but decreased markedly in two subjects with high control values. As determined from the main urinary metabolite, prostaglandin I3 was formed from EPA at rates up to 50% of unaltered prostaglandin I2 formation. The biochemical and functional changes observed lasted for the entire supplementation period of 5 mo and were reversible within 12 wk after cessation of cod liver oil intake. Favorable changes induced by long-chain omega-3 fatty acids include a dose-related and sustained shift of the prostaglandin I/thromboxane A balance to a more antiaggregatory and vasodilatory state.     

Functional and structural determinants of glomerulosclerosis in the fawn-hooded rat

The effect of uninephrectomy (UN) at 4 months of age was studied on several parameters involved in the development of glomerulosclerosis (GS) in male spontaneously hypertensive Fawn-Hooded rats. Protein excretion per animal was significantly more increased in UN rats at 2 months after operation compared to sham operated controls (202 +/- 104 vs. 88 +/- 37 mg 24 h-1, P = 0.005) and remained significantly higher throughout the rest of the observation period. At 11 months of age UN rats had a marked increase in the incidence of GS, 37 +/- 16% compared to 5 +/- 3% (P less than 0.001) in controls. No differences were observed in mean arterial blood pressure. Functional studies in separate groups of rats at 5 months of age showed an increase in single kidney glomerular filtration rate in UN rats (0.40 +/- 0.07 vs. 0.28 +/- 0.09 ml min-1 100 g, P = 0.006). Single kidney renal plasma flow and filtration fraction were not altered. Mean glomerular volume was increased 1 month after UN (1.86 +/- 0.25 vs. 1.39 +/- 0.25 x 10(6) microns 3, P = 0.003). Urinary noradrenaline excretion per animal (24-h) showed a high sympathic nervous tone in both sham and UN rats. Total urinary dopamine and kallikrein excretion per animal were not influenced by UN. These data indicate that after UN the development of GS in this rat strain is accelerated in association with compensatory hyperfiltration and glomerular volume expansion, which may play a role in the pathogenesis of GS.     

Quinapril versus atenolol in the treatment of mild to moderate essential hypertension.

A randomized, double-blind, parallel-group study was conducted to compare the safety and efficacy of the angiotensin-converting enzyme inhibitor quinapril with that of the beta-blocker atenolol. Fifty-six outpatients with mild to moderate hypertension were enrolled in the trial. After a 4-week washout period, 27 patients were treated with quinapril 20 mg once daily and 29 patients were treated with atenolol 50 mg once daily for 4 weeks. During a third 4-week period, the daily doses were adjusted on an individual basis. At the end of the 8-week treatment period, the systolic and diastolic blood pressures were significantly reduced in both groups of patients. Heart rate was significantly reduced only in the atenolol group. Adverse effects were inconsequential and comparable in both groups. Quinapril was shown to be a safe and effective treatment for patients with mild to moderate hypertension.     

Evidence for a functional tissue renin-angiotensin system in the rat mesenteric vasculature and its involvement in regulating blood pressure

Electrical stimulation of the isolated rat mesenteric vascular bed resulted in a frequency-dependent pressor response, which could be potentiated by increasing concentrations of renin substrate (synthetic tetradecapeptide). This potentiating effect appeared to be mediated by tissue conversion of renin substrate to angiotensin II because the response 1) could be mimicked by angiotensin II, 2) was accompanied by an increase in angiotensin II production and 3) was blocked by the angiotensin converting enzyme (ACE) inhibitor quinaprilat and the angiotensin II receptor antagonist saralasin ([Sar1,Ile5,Ala8]angiotensin II). To assess the role of this tissue renin-angiotensin system in contributing to blood pressure regulation, spontaneously hypertensive rats were administered the prodrug ACE inhibitor quinapril at a dose of 10 mg/kg/day for 7 days. Such administration resulted in a reduction in systolic blood pressure of 48 +/- 3 mm Hg, a greater than 95% inhibition of serum ACE activity, and a significant attenuation of the potentiating effect of renin substrate on electrically evoked contractions of isolated mesenteric beds. Significant reductions in blood pressure and the potentiating effect of renin substrate on the isolated mesenteric vasculature were still observed 24 and 48 hr after the last dose of quinapril. In contrast, serum ACE activity returned to normal levels within 48 hr after the last dose of quinapril. These results suggest that the changes in tissue renin-angiotensin system, and not the circulating system, are closely related to the blood pressure lowering effect of the ACE inhibitor, quinapril.     

Pharmacokinetic interaction between cefdinir and two angiotensin-converting enzyme inhibitors in rats.

The pharmacokinetic interaction between cefdinir and an angiotensin-converting enzyme inhibitor (captopril or quinapril) was investigated in rats. The linearity of cefdinir pharmacokinetics was demonstrated in three groups of rats receiving 10, 20, or 40 mg of cefdinir per kg of body weight intravenously. Then, three other groups of rats were established as follows: group 1 (n = 5) received cefdinir (10 mg/kg) intravenously, and 12 blood samples per rat were drawn between 0 and 8 h after injection of the dose; group 2 (n = 5) was treated in the same way as group 1, but captopril (0.8 mg/kg) was coadministered by intraintestinal injection into all animals; group 3 (n = 6) was treated in the same way as group 2, but quinapril (0.8 mg/kg) replaced captopril. Plasma cefdinir concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method. Finally, three groups of four or five rats each were set up as described above, but the cefdinir dose was 20 mg/kg and the animals were sacrificed 1 h after drug injection to collect blood to determine the unbound cefdinir fraction (fu) by ultrafiltration. The angiotensin-converting enzyme inhibitors increased the mean cefdinir area under the concentration-time curve up to 8 h by a factor of 1.8 (captopril; P < 0.05) and a factor of 3.5 (quinapril; P < 0.05). With captopril, mean cefdinir clearance was decreased by a factor of 2, and the volume of distribution increased by the same factor, while the fu increased from 15.4% +/- 3.0% (cefdinir alone) to 22.8% +/- 10.9% (cefdinir plus captopril). Captopril increased the cefdinir half-life from 0.62 +/- 0.17 to 2.92 +/- 0.95 h. With quinapril, the interaction was so strong that no elimination phase was detectable in four of the six rats, and therefore, no pharmacokinetic parameter values other than the cefdinir fu could be calculated; the cefdinir fu increased to 25.1% +/- 11.1%. It is concluded that captopril and quinapril (and/or their metabolites) have a major impact on the disposition of cefdinir in rats, probably by competition at the plasma protein-binding level and at the tubular anionic carrier level. This latter mechanism should also be relevant in humans.     

Influence of food on the pharmacokinetics of perindopril and the time course of angiotensin-converting enzyme inhibition in serum

Food has been shown to reduce the bioavailability of the angiotensin-converting enzyme inhibitor captopril, but not the bioavailability of inhibitors administered as ester prodrugs. Perindopril is the ester pro-drug of the angiotensin-converting enzyme inhibitor perindoprilat. The influence of food on the pharmacokinetics of perindopril (4 mg administered orally) and the time course of angiotensin-converting enzyme inhibition in serum was studied in a randomized crossover short-term study of 12 healthy subjects. Food significantly decreased the relative availability of perindoprilat by 35% +/- 42%, the fractional urinary excretion of perindoprilat from 19% +/- 7% to 13% +/- 4% (p less than 0.05), and the partial metabolic clearance of perindopril to perindoprilat from 102 +/- 57 ml.min-1 to 72 +/- 32 ml.min-1 (p less than 0.05). These changes were associated with a significant decrease in the area under the percent angiotensin-converting enzyme inhibition-versus-time curve by 15% (p less than 0.05). Food did not alter the total amount of drug recovered in urine as perindopril and its metabolites, and it did not alter perindoprilat renal clearance. We concluded that food alters the conversion of perindopril to its active metabolite perindoprilat after single-dose administration of perindopril.