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The effects of early-stage hypertension on the macromolecular transport characteristics of the aorta have been investigated in rats 1 week after the ligature of the abdominal aorta between the two renal arteries. The animals were left untreated or treated for 1 week with an angiotensin converting enzyme inhibitor (enalapril, 6 mg/kg per day). Blood pressure of a subgroup of hypertensive rats was acutely lowered to a normal level by injection of enalaprilat (1.5 mg/kg) at the time of the experiment. 131I-Albumin and 125I-albumin were injected 90 minutes and 5 minutes, respectively, before the rats were killed. The transmural distribution of the relative tissue concentrations across the wall was obtained using a serial frozen-section technique. Short-term albumin uptake permitted calculation of apparent endothelial permeability coefficients, and 90-minute uptake was used to estimate the steady-state albumin distribution within the media. The effect of early-stage hypertension on the characteristics of the arterial macromolecular transport depended on the aortic site; the ascending aortic arch appeared not to be affected. In the thoracic and abdominal aorta, the endothelial permeability coefficients increased significantly in hypertensive rats. This increase was not a direct effect of the arterial pressure, since the values were not significantly different when the pressure was acutely normalized. The 90-minute albumin concentration in the media was enhanced in hypertensive rats and returned to the normal value by acutely lowering the blood pressure, indicating that the increase observed in hypertensive rats resulted from a direct effect of pressure, possibly increased pressure-driven convection and/or pressure-induced stretching of the wall. Treatment by angiotensin converting enzyme inhibitor prevented hypertension and protected against its effects in hypertensive animals.
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Oxidant stress is an important contributor to renal dysfunction and hypertension. We have previously demonstrated that regulation of renal oxygen consumption by nitric oxide (NO) is impaired in the kidney of spontaneously hypertensive rats (SHR) due to increased superoxide production. We further explored the mechanisms of enhanced oxidant stress in the kidney of SHR. Suppression of cortical oxygen consumption by bradykinin (BK) or enalaprilat (Enal), which act through stimulation of endogenous NO, was impaired in SHR (BK: -14.1 +/- 1.2%; Enal: -15.5 +/- 1.2%) and was restored by addition of apocynin, an inhibitor of assembly of the NAD(P)H oxidase complex (BK: -21.0 +/- 0.6%; Enal: -25.3 +/- 1.4%), suggesting this as the source of enhanced superoxide production. Addition of an angiotensin type 1 receptor blocker, losartan, also restored responsiveness to control levels (BK: -22.0 +/- 1.1%; Enal: -23.6 +/- 1.3%), suggesting that ANG II is responsible for enhanced oxidase activity. A similar defect in responsiveness to BK and Enal could be induced in Wistar-Kyoto kidneys by ANG II and was reversed by a superoxide scavenger (tempol), apocynin or losartan. Immunoblotting of cortical samples demonstrated enhanced expression of endothelial NO synthase (eNOS 1.9x) and NAD(P)H oxidase components (gp91(phox) 1.6x and Rac-1 4.5x). Expression of SOD-1 and -2 were unchanged, but SOD-3 was significantly decreased in SHR (0.5x). Thus NO bioavailability is impaired in SHR owing to an ANG II-mediated increase in superoxide production in association with enhanced expression of NAD(P)H oxidase components, despite increased expression of eNOS. Loss of SOD-3, an important superoxide scavenger, may also contribute to enhanced oxidant stress.
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Subjects with tetraplegia were tolerant of an acute bout of orthostatic stress after partial ACE inhibition. This may have clinical relevance because of the increased prevalence of type 2 diabetes mellitus in this population and the use of ACE inhibitors for the treatment of progressive renal and cardiovascular disease.
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The possibility of an impaired hepatic de-esterification of enalapril to enalaprilat due to hepatic dysfunction was assessed in seven patients with compensated liver cirrhosis and 10 normal control subjects. The peak serum concentration and time to the peak serum concentration of enalaprilat, as well as the suppression of serum angiotensin converting enzyme activity, following a single oral dose of enalapril maleate (10 mg) were not different in the two groups. The elimination half-life of enalaprilat was related to renal function. The results suggest that hepatic biotransformation of the drug may not be disturbed in a clinically significant manner in patients with moderate hepatic dysfunction due to compensated liver cirrhosis.
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Male rats were treated intragastrically with Per (2 mg.kg-1.d-1) or placebo (n = 18) for 6 wk. Aorta was isolated for experiment. Another set of isolated aortic rings with and without endothelium were incubated with Ena (0.1 mumol.L-1) for 30 min. Responses to acetylcholine, serotonin, phenylephrine, sodium nitroprusside (SN), and nitroglycerin (Nit) were observed.
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The development of highly sensitive and specific immunoassays allowed the characterization of bradykinin and desArg9-BK metabolism in vitro. The same methods were used to study the time course evolution of the tissue content of both kinins in an carragenan inflammatory model. Quantification of T-kininogen in the same animal model allowed to show an influence of BK on the neosynthesis of this acute phase protein.
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Sympathetic and angiotensinergic activation reduce splanchnic oxygen delivery during hypovolemia, which may lead to failure of the intestinal mucosal barrier and eventually multiple organ dysfunction. This study integrates sympathetic and angiotensinergic responses with splanchnic hemodynamics and duodenal mucosal function during hypovolemia and evaluates pharmacologic blockade of either system to ameliorate the impact of acute hypovolemia. Chloralose-anesthetized pigs subjected to 20 and 40% blood volume reductions were randomized to controls or administered guanethidine or enalaprilate to block sympathetic and angiotensinergic activation, as assessed by plasma norepinephrine spillover and angiotensin II levels, respectively. Mesenteric and hepatic oxygen delivery/consumption as well as duodenal mucosal alkaline secretion and potential difference were determined. Hypovolemia preferentially increased mesenteric sympathetic outflow and caused a vigorous angiotensinergic activation. Guanethidine and enalaprilate blocked effectively the sympathetic and angiotensinergic responses. Treatment with enalaprilate, but not guanethidine, prevented the reduction of mesenteric oxygenation and duodenal mucosal alkaline secretion and potential difference observed in control animals. The down-regulation of mesenteric oxygenation and duodenal mucosal function during hypovolemia can be prevented by administration of enalaprilate, whereas guanethidine is uneffective in this respect. Interference with the reninangiotensin system might be of clinical interest to support mesenteric perfusion and organ function in hypovolemia.
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Thirty-eight male patients chronically treated for arterial hypertension and scheduled for CABG randomly and double-blindly received either enalaprilat 30 micrograms.kg-1 or NaCl 0.9% at the time of skin incision. Intraoperatively, increases of mean arterial pressure (MAP) > 85 mmHg or > 80 mmHg during cardiopulmonary bypass (CPB) were treated by an urapidil bolus. The total intraoperative amount of urapidil was documented for both groups. Systemic and pulmonary hemodynamics as well as the plasma levels of epinephrine, norepinephrine, arginine vasopressin and renin were measured intraoperatively and up to 2 h after admission to the intensive care unit.
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1. Inhibition of neutral endopeptidase (NEP), the degradative enzyme for atrial natriuretic peptide, was studied in vitro and in vivo using a previously characterized NEP inhibitor radioligand, 125I-labelled RB104. 2. SCH 42354, the active di-acid of the ethylester prodrug, SCH 42495, caused a concentration-dependent displacement of 125I-labelled RB104 from rat renal NEP. The concentration of SCH 42354 that displaced 50% of radioligand bound to the enzyme NEP (IC50) was 3.3 +/- 0.1 nmol/l (mean +/- SEM). Enalaprilat, an angiotensin converting enzyme inhibitor, did not displace 125I-labelled RB104 in concentrations up to 10 mumol/l. 3. In adult normotensive Sprague-Dawley rats, oral SCH 42495 (3-300 mg/kg) caused significant inhibition of renal NEP (P < 0.001). SCH 42495 had no effect on renal or plasma angiotensin converting enzyme activity, but high-dose SCH 42495 (300 mg/kg) caused a significant increase in plasma renin activity (P < 0.01). 4. In a time course study, oral SCH 42495 (30 mg/kg) caused rapid (within 30 min) and significant inhibition of renal NEP for up to 48 h (P < 0.001). No changes in plasma atrial natriuretic peptide or plasma angiotensin converting enzyme activity were seen. 5. These data provide evidence that short-term administration of the NEP inhibitor SCH 42495 results in inhibition of renal NEP and does not inhibit the circulating or the tissue renin-angiotensin system. The NEP inhibitor radioligand 125I-labelled RB104, is a useful tool to study tissue NEP inhibition after administration of NEP inhibitors.
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We analyzed BP thresholds for ordering and administering IV antihypertensives, the types and frequencies of IV antihypertensives administered, and the effect of IV antihypertensive use on short-term BP and adverse outcomes. The BP change during hospitalization was contrasted in those receiving IV antihypertensives between those who did and did not receive subsequent intensification of chronic oral antihypertensive regimens.
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Ischemic/hypoxic myocardial damage and functional impairment of the myocardium occurs immediately after major burns. This experimental study investigated whether the prompt cardiac dysfunction initiates hepatic, renal, and intestinal injuries soon after a severe burn.
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We conclude that inhibition of the renin-angiotensin system at two distinct sites results in different MAP responses to phenylephrine infusion.
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In rat serum, kininase I degraded 34% and kininase II 11% of bradykinin, no evidence for other activities being detected. In the awake rat, D,L-2-mercaptomethyl-3-guanidino-ethylthiopropionic acid, an inhibitor of kininase I, did not reduce the percentage of bradykinin inactivation in the pulmonary circulation. In the in situ perfused lung 65% of bradykinin was metabolized and the main products were BK1-7, BK1-5 and BK4-9. Enalaprilat (an inhibitor of kininase II) blocked the formation of BK1-7 and BK1-5 and increased the recovery of BK4-9. beta-Mercapto-ethanol, which inhibits aminopeptidase P, and diprotin A, a specific inhibitor of dipeptidylaminopeptidase IV, both reduced the formation of BK4-9. Diprotin A also allowed the recovery of BK2-9. Bradykinin degradation and BK4-9 recovery were not affected by endopeptidase inhibitors.
Enalaprilat was infused initially at 1 mg/ hour. The rate was doubled every 30 minutes until pulmonary capillary wedge pressure decreased at least 20% or until a maximum total dose of 10 mg was achieved.
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Vasopeptidase inhibitors are a new class of antihypertensive drugs that are single molecules having dual inhibitory action on angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The best known drug in this class is omapatrilat, which has been proposed to be more efficacious than ACE inhibitors because of its ability to inhibit NEP and prevent the breakdown of atrial peptides and bradykinin. However, survival of endothelin (ET) may also be enhanced and therefore, NEP inhibitors may have limited efficacy under conditions of low renin and high ET production. The purpose of the current study was to contrast the effects of the ACE inhibitor, enalapril, with omapatrilat in a model of established hypertension where ACE inhibitors are ineffective, the deoxycorticosterone acetate (DOCA)-salt-treated rat. Two weeks after starting DOCA-salt treatment, rats were given either enalapril (10 mg/kg/day) or omapatrilat (30 mg/kg/day) for 5 days. Mean arterial pressure (MAP) measured by radiotelemetry in untreated DOCA-salt rats increased from 102 +/- 2 to 181 +/- 12 mm Hg (P<.05) as a result of DOCA-salt treatment for 3 weeks. MAP was unaffected by either enalapril (189 +/- 3 mm Hg) or omapatrilat (184 +/- 8 mm Hg). DOCA-salt treatment significantly increased urinary ET excretion compared to baseline (1.6 +/- 0.2 vs. 0.5 +/- 0.1 pmol/day). Administration of omapatrilat significantly increased urinary ET excretion in DOCA-salt rats (2.9 +/- 0.4 pmol/day) compared to enalapril-treated (1.6 +/- 0.2 pmol/day) or untreated (1.5 +/- 0.1 pmol/day) rats. These results indicate that combined ACE/NEP inhibition does not lower blood pressure in a model of established hypertension with high ET activity. These results also support the hypothesis that combined ACE/NEP inhibition can increase renal ET production.
The authors recently reported the development of a new method for measuring angiotensin converting enzyme (ACE) by means of a highly sensitive angiotensin II RIA technique. We have carried out a comparative study of the pharmacological properties of captopril and MK-422, two ACE inhibitors recently developed as new antihypertensive agents. In this study, in vivo and in vitro animal experiments were performed using the Göttingen Mini-pig (Mini-pig G) animal model of the human disease. In the in vivo experimental system, each drug was administered by intravenous injection at a dose of 1 mg/kg, and a slight difference was found in the time-course of the per cent inhibition of ACE in the blood. In the in vitro system (cultured aortic endothelial cells), the ACE inhibitory activities of the two drugs were compared in terms of the 50%-inhibition point on the dose response curve, and it was found that MK-422 was about 100 times more potent than captopril. These results indicate that our newly-developed experimental system can be useful in the establishment of the clinical dose of vasoactive drugs that act on the renin-angiotensin system.
Several inhibitors of angiotensin converting enzyme were also found to inhibit aminopeptidase P, whereas inhibitors of other mammalian aminopeptidases were ineffective. Aminopeptidase P purified from pig kidney cortex was found to contain one atom of zinc per polypeptide chain, confirming its metalloenzyme nature. The concentrations of converting enzyme inhibitors required to cause 50% inhibition (I50) of aminopeptidase P were in the low micromolar range. The most potent converting enzyme inhibitors toward aminopeptidase P were the carboxylalkyl compounds, cilazaprilat, enalaprilat, and ramiprilat (I50 values of 3-12 microM). The sulfhydryl compounds captopril (I50 110 microM) and YS980 (I50 20 microM) were slightly less potent at inhibiting aminopeptidase P. In contrast, the carboxylalkyl compounds benazeprilat, lisinopril, and pentoprilat; the sulfhydryl compound rentiapril; and the phosphoryl compounds ceranopril and fosinoprilat had no inhibitory effect against aminopeptidase P. This compares with I50 values in the 1-6 nM range for these inhibitors with angiotensin converting enzyme. Inhibition of aminopeptidase P may account for some of the effects or side effects noted with the clinical use of converting enzyme inhibitors. These results may provide the basis for the design of more selective inhibitors of angiotensin converting enzyme or mixed inhibitors of aminopeptidase P and angiotensin converting enzyme, or both.
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Blood pressure and heart rate were measured in conscious, chronically instrumented sodium-replete (n = 3-5) and sodium-depleted (n = 4) cynomolgus monkeys (Macaca fascicularis). Plasma renin activity (PRA), active renin and angiotensin II plasma concentrations were determined.
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Alpha-adrenergic, cholinergic, and serotonergic receptor-mediated contractile responses have been well characterized in the genitourinary tissues of several mammalian species. The present study characterizes the in vitro contractile responsiveness of canine bladder and prostate to the peptides, bradykinin, angiotensin I, and angiotensin II. All preparations contracted to 0.15 M KCl. Bradykinin elicited contractile responses in both prostate (10(-10) to 10(-7) M) and bladder (10(-10) to 10(-6) M). In both tissues, angiotensin II produced minimal responses and angiotensin I failed to elicit contractions. The potent angiotensin converting enzyme (ACE) inhibitor, enalaprilic acid [MK-422] (10(-6) M) increased the contractile response to the prostate to bradykinin two-fold while having no effect on bradykinin-induced contractions in the bladder. Enalaprilic acid did not affect the contractile responses of the two tissues to angiotensin I or angiotensin II. The canine urogenital tissue contractile responses to bradykinin, angiotensin I, and angiotensin II may have relevance to human physiology. Previous studies have demonstrated that human prostatic tissue, specifically benign prostatic hyperplasia (BPH), has the highest concentration of ACE activity of tissues evaluated. Bradykinin is a potent peptidergic contractile agent in canine bladder and prostate. The activity of enalaprilic acid to amplify the bradykinin-induced contractions in the canine prostate is consistent with high levels of ACE in the tissue. These data confirm the sensitivity of the canine prostate to bradykinin and report for the first time, the ability of bradykinin to induce contractions in the prostate. These studies support the possibility that bradykinin may be involved in mediating micturition under normal and pathological states such as infravesical obstruction secondary to BPH. Furthermore, the results from these investigations in canine urogenital tissues, if applicable to humans, suggest that urinary function be closely monitored in patients receiving ACE inhibitor therapy.
To study potency, efficacy, development of tolerance, and mechanism of action of substance P, an endothelium-dependent vasodilator neurokinin, in human hand veins in vivo.
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Haemodynamic parameters in conscious rats were assessed. Release of noradrenaline from isolated atria and cardiac beta-adrenergic-adenylyl cyclase pathway in rats of sham-treated and L-NAME-treated groups, with or without losartan or enalaprilat treatment, were assessed.
Enalaprilat protects the cardiomyocyte from the stress by cold.
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Evidence for effects of angiotensin converting enzyme (ACE) on isolated human glomeruli was provided using specific binding of tritium-labeled ramiprilat, a potent inhibitor of ACE. [3H]ramiprilat bound to isolated glomeruli, depending on time and temperature, displaying a KD of 3.8 nmol/L and a Bmax of 853 fmol/mg protein. Specific binding represented more than 90% of total binding. Dissociation occurred rapidly after dilution of the sample with incubation buffer or after addition of an excess of unlabeled inhibitor. Binding of [3H]ramiprilat was also inhibited by increasing concentrations of enalaprilat, another ACE inhibitor. ACE is a zinc-containing enzyme. Addition of EGTA to the assay, which chelates zinc ions, completely prevented binding. This was reversed by divalent Zn2+ and Ca2+ ions, but not by magnesium. Binding of [3H]ramiprilat to isolated glomeruli was maximal at pH 8, which also is optimal for ACE activity. The binding of [3H]ramiprilat to isolated human glomeruli is specific, and resembles the characteristics which have been found earlier for enzyme activity of ACE. Thus, binding of [3H]ramiprilat to isolated glomeruli can be assumed to be directed to ACE.
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Primary cultures of human proximal tubular cells (PTC) and renal cortical fibroblasts (CF) were exposed for 24 h to CyA in the presence or absence of enalaprilat. Parameters of tubulo-interstitial nephrotoxicity were then measured including collagen synthesis (proline incorporation), tubular viability and function (thymidine incorporation, lactate dehydrogenase release, and apical sodium-hydrogen exchange), and secretion of insulin-like growth factor I, transforming growth factor beta 1 (TGFbeta1), and platelet-derived growth factor.