Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Keeping pre-transplant patients alive while waiting for a suitable donor to be found is still a major challenge. New pharmacological agents which can provide improved hemodynamics are urgently needed in patients with severe heart failure who are on the waiting list for cardiac transplantation. Intravenous enoximone therapy (an initial 0.5 mg/kg bolus, then 1.25-5.0 mcg/kg/min infusion) was administered to 18 transplant candidates with heart failure progression despite optimal drug regimen including digoxin, diuretics, and ACE-inhibitors. Complete hemodynamic, echocardiographic, and neurohumoral studies were performed before and 24 h after intravenous enoximone infusion. Enoximone infusion increased cardiac index (1.78 +/- 0.45 l/min/qm vs. 3.04 +/- 0.83 l/min/qm; p < 0.001) and stroke volume index (22.33 +/- 9.45 ml/qm vs. 32.28 +/- 7.29 ml/qm; p < 0.05) and decreased wedge pressure (24.1 +/- 11.98 mmHg vs. 17.78 +/- 8.76 mmHg; p < 0.05) and systemic vascular resistance (1700.8 +/- 555.8 dyn x s x cm-5 vs. 952.8 +/- 384.0 dyn x s x cm-5; p < 0.001). Heart rate and mean arterial pressure were unchanged. Left ventricular ejection time (225.1 +/- 26.9 ms vs. 242.2 +/- 25.8 ms; p < 0.05) was increased, whereas other echocardiographic parameters were unchanged (left ventricular end-diastolic dimension, left ventricular end-systolic dimension, fractional shortening, early diastolic relaxation parameter Te). Plasma neurohumoral parameters did not change (aldosterone, epinephrine, renin, atrial natriuretic factor) except for a significant drop of norepinephrine (936.7 +/- 443.2 pg/ml vs. 522.4 +/- 287.6 pg/ml; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Low-dose enoximone therapy in pre-transplant patients: hemodynamic, echocardiographic, and neurohumoral findings. 809 24

1. There is evidence to suggest that essential hypertension is a polygenic disorder and that it arises from yet-to-be-identified predisposing variants of certain genes that influence blood pressure. The cloning of various hormone, enzyme, adrenoceptor and hormone receptor genes whose products are involved in blood pressure control and the identification of polymorphisms of these has permitted us to test their genetic association with hypertension. 2. Cross-sectional analyses of a number of candidate gene markers were performed in hypertensive and normotensive subjects who were selected on the basis of both parents being either hypertensive or normotensive, respectively, and the difference in total alleles on all chromosomes for each polymorphism between the hypertensive and normotensive groups was tested by chi 2 analysis with one degree of freedom. 3. A marked association was observed between hypertension and insertion alleles of polymorphisms of the insulin receptor gene (INSR) (P < 0.0040) and the dipeptidyl carboxypeptidase-1 (angiotensin I-converting enzyme; kininase II) gene (DCP1) (P < 0.0018). No association with hypertension was evident, however, for polymorphisms of the growth hormone, low-density lipoprotein receptor, renal kallikrein, alpha 2- and beta 1-adrenoreceptor, atrial natriuretic factor and insulin genes. 4. All but one of the hypertensive subjects had at least one of the hypertension-associated alleles, and although subjects homozygous for both were three times more frequent in the hypertensive group, examination of the nine possible genotypes suggested that the INSR and DCP1 alleles are independent markers for hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Independent, marked associations of alleles of the insulin receptor and dipeptidyl carboxypeptidase-I genes with essential hypertension. 810 54

Alatriopril is a dual inhibitor of two cell surface metallopeptidases which play important roles in the regulation of arterial blood pressure and renal function: the angiotensin I converting enzyme (ACE) which catalyses transformation of angiotensin I to angiotensin II, and the neutral endopeptidase (NEP; EC 3.4.24.11; atriopeptidase), responsible for the degradation of the atrial natriuretic factor (ANF). The purpose of the present study was to evaluate the systemic and regional hemodynamic effects of alatrioprilat, the active part of alatriopril, in 6 anesthetized, closed-chest beagle dogs instrumented for the measurement of arterial pressure (aortic catheter), cardiac output (thermodilution), as well as femoral and renal artery flows (Doppler). Animal received alatrioprilat at the doses of 1 and 10 mg/kg (i.v. bolus). Hemodynamic parameters were measured at baseline, then 15, 30, 45 and 60 min after administration of each dose. In addition, plasma ANF and ACE activity were determined at baseline and 30 min after administration. At the dose of 1 mg/kg, alatrioprilat dit not induce marked hemodynamic effects, except a transient hypotension which appeared within the first 10 min after administration and lasted less than 10 min. Neither plasma ANF nor angiotensin converting enzyme activity were affected by this dose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Systemic and regional hemodynamic effects of a new angiotensin converting enzyme and neutral endopeptidase mixed inhibitor, alatriopril, in the dog]. 812 43

The effects of two single oral doses (5 mg and 20 mg) of a new angiotensin I-converting enzyme inhibitor, imidapril, on a) systemic hemodynamics (arterial pressure, heart rate, cardiac output), b) brachial and common carotid arteries' hemodynamics (diameter and blood flow, pulsed Doppler technique), c) cerebral hemodynamics (middle cerebral artery mean blood flow velocity, transcranial Doppler technique), and d) biological parameters (plasma converting enzyme activity, active plasma renin, plasma aldosterone, catecholamines, and atrial natriuretic factor) were investigated and compared with those of a placebo during the 24 h period following administration in a randomized, double-blind, cross-over study performed in six healthy volunteers. Imidapril induced a strong, dose-dependent and sustained inhibition of plasma converting enzyme activity and at the 20 mg an increase in active plasma renin. Other investigated biological parameters were not drug-affected. Imidapril, whatever the dose, did not significantly affect systemic hemodynamic parameters. Imidapril, 20 mg, significantly increased common carotid artery blood flow and diameter and brachial artery diameter. Brachial blood flow also tended to increase but this was not significant. The middle cerebral artery mean blood flow velocity investigated in only five volunteers, underwent spontaneous variations after placebo, and these variations were not affected by imidapril, suggesting that imidapril, whatever the dose, does not influence cerebral blood flow. Thus, imidapril's vasodilating properties apparently affect only the muscular (brachial artery) and cutaneous (external carotid artery) territories, but do not influence the cerebral vascular bed.
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PMID:Systemic, regional and cerebral hemodynamic effects of a new angiotensin converting enzyme inhibitor, imidapril, in healthy volunteers. 818

The authors studied the responses of the main systems of sympathetic and hormonal regulation in valvular aortic stenosis, a special model of dissociation between arterial pressure and left ventricular function. The series comprised 14 patients with an average age of 70 +/- 9 years without diuretic therapy presenting with pure calcific aortic stenosis without other valvular or coronary disease. All were in sinus rhythm; 5 were taking an angiotensin converting enzyme inhibitor. Plasma concentrations of endothelin 1, atrial natriuretic factor (ANF), arginine vasopressin (AVP), catecholamines, plasma renin activity (PRA), angiotensin II and aldosterone were measured in resting, fasting patients, by blood samplings from a peripheral vein immediately before cardiac catheterisation. The results were compared with the severity of the aortic stenosis (aortic valve area greater or less than 0.7 cm2), the ratio of left ventricular work/myocardial mass (greater or less than 0.6) and treatment (with or without ACE inhibitors). Catecholamine levels were much higher in severe aortic stenosis (noradrenaline: 579 +/- 66 pg/ml when valve surface area > 0.7 cm2 versus 900 +/- 92 pg/ml when valve surface area < 0.7 cm2; p < 0.01). Endothelin -1 and AVP concentrations were normal. Whereas PRA was normal, aldosterone levels were increased in patients without treatment by ACE inhibitors. This treatment did not, however, normalise the noradrenaline levels. The increase in ANF concentration was large when left ventricular work decreased with respect to myocardial mass (190.8 +/- 42.3 pg/ml if W/M was decreased versus 82.7 +/- 15.4 pg/ml when W/M was normal): this could be related to the degree of left ventricular hypertrophy.
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PMID:[Neurohormonal profile in aortic valve stenosis]. 829 34

Keeping pre-transplant patients alive while waiting for a suitable donor is still a major challenge. New pharmacological agents which can provide improved hemodynamics are urgently needed in patients with severe heart failure who are on the waiting list for cardiac transplantation. Intravenous enoximone therapy (an initial 0.5 mg/kg bolus, then 1.25-5.0 mcg/kg/min infusion) was administered to 35 transplant candidates with progressive heart failure despite optimal drug regimen including digoxin, diuretics, and ACE-inhibitors. In 18 out of 35 patients complete hemodynamic, echocardiographic, neurohumoral, and Holter-ECG studies were performed before and 24 hours after intravenous enoximone infusion. Patients were then continued on chronic oral therapy of 100 mg twice a day. Enoximone infusion increased the cardiac index (CI) (1.78 +/- 0.45 l/min/m2 vs 3.04 +/- 0.83 l/min/m2; p < 0.001) and stroke volume index (SVI)(22.33 +/- 9.45 ml/m2 vs 32.28 +/- 7.29 ml/m2; p < 0.05) and decreased wedge pressure (PCP)(24.1 +/- 11.98 mmHg vs 17.78 +/- 8.76 mmHg; p < 0.05) while mean arterial pressure (MAP) was unchanged. Left ventricular ejection time (LVET)(225.1 +/- 26.9 ms vs 242.2 +/- 25.8 ms; p < 0.05) was increased whereas other echocardiographic parameters were unchanged (Left ventricular end-diastolic dimension LVEDD, left ventricular end-systolic dimension LVESD, fractional shortening FS, early diastolic relaxation parameter Te). Plasma neurohumoral parameters did not change (Aldosterone, epinephrine, renin, atrial natriuretic factor) except for a significant drop in norepinephrine (936.7 +/- 443.2 pg/ml vs 522.4 +/- 287.6 pg/ml; p < 0.05). Holter-ECG parameters (ventricular premature beats VPB, couplets, ventricular tachycardia VT) were not influenced by enoximone infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enoximone therapy as pharmacological bridging to cardiac transplantation. 837 84

We tested the effect of renal insufficiency, with and without angiotensin (Ang) converting enzyme (ACE) inhibition, on blood and brain atrial natriuretic factor (ANF) in rats. Two ACEs, one which penetrates into the CNS and one which does not, were used to distinguish between peripheral and central ACE effects. Rats underwent 5/6 nephrectomy (5/6-NPX) by ligation of renal arterial branches. After seven days, 28 5/6-NPX rats received lisinopril 20 mg/kg/day and 28 5/6-NPX rats received quinapril 30 mg/kg/day orally for five days, while 28 5/6-NPX control rats and 28 sham rats did not. Body weight, blood pressure, drinking and urine volume were monitored. At sacrifice, urine, plasma, and brain tissue was collected. ANF in 16 brain areas was measured by radioimmunoassay. 5/6-NPX resulted in increased blood pressure, increased urine volume, proteinuria, and increased drinking. Both ACEs lowered blood pressure to sham values and decreased proteinuria. Both ACEs increased plasma renin activity and decreased plasma ANF. However, only lisinopril decreased drinking and urine volume. 5/6-NPX increased ANF values in six brain areas, namely the periventricular preoptic nucleus, the arcuate nucleus, the perifornical nucleus, the periventricular hypothalamic nucleus, the paraventricular nucleus, and the dorsal raphe nucleus compared to sham rats. These same increases in brain ANF were also observed in 5/6-NPX rats given quinapril, compared to shams. However, lisinopril lowered ANF to sham levels in the periventricular preoptic nucleus, the arcuate nucleus, and the perifornical nucleus. In the three additional brain areas, namely the periventricular hypothalamic nucleus, the paraventricular nucleus, and the dorsal raphe nucleus, lisinopril did not effect the elevated ANF concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of ACE inhibitors on atrial natriuretic factor in the brains of rats with reduced renal mass. 839 52

Abnormalities in the response of atrial natriuretic factor (ANF) to volume expansion have been reported in hypertensive-prone animals and men as well as in hypertensive patients undergoing ACE-inhibition. To investigate some of the mechanisms affecting ANF release in borderline hypertensive patients (BHT) we have studied 16 subjects by assessing their neuro-humoral and hemodynamic response to a two-hour isotonic i.v. NaCl infusion carried out during short-term administration of either placebo or captopril. ACE-inhibition increased baseline venous distensibility (VV30:1.4 vs 1.6 ml/100 ml; p < .05) and reduced the prompt (45') ANF response to saline loading (10.3 +/- 13 vs 42.7 +/- 15%; p < .05)) without affecting the overall ANF release (120':92 +/- 25 vs 65.8 +/- 20%; NS)). A significant pressor increase in response to NaCl loading was observed exclusively after ACE-inhibition (SBP: 5.2 +/- 2 vs 2.4 +/- 1%; p < .05--DBP: 7.1 +/- 3 vs 2 +/- 3%; p < .025) and occurred along with a peripheral arterial and venous constriction and with an increase in plasma levels of an endogeneous Na+/K+ATPase inhibitor (8.8 +/- 4 vs -2 +/- 4%; p < .05). We conclude that the ANF response to saline infusion is delayed by ACE-inhibition in borderline hypertensives. The abnormalities observed in ANF response could follow the changes in peripheral venous distensibility and contribute to the pressor and neuro-humoral derangements described in borderline hypertensives during volume expansion.
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PMID:Atrial natriuretic factor response to acute volume expansion in borderline hypertension. Role of ACE-inhibition and changes in peripheral venous tone. 846 21

Neutral metalloendopeptidase (NEP) inhibitors delay atrial natriuretic factor (ANF) catabolism and potentiate biological responses to ANF. We describe biochemical and pharmacological profiles of a novel NEP inhibitor, SCH 42354 (N-[2(S)-(mercaptomethyl)-3-(2-methylphenyl)-4-oxopropyl]-L-methionine and its orally active ethylester prodrug, SCH 42495. SCH 42354 selectively inhibited hydrolysis of leu-enkephalin and ANF (IC50 of 8.3 and 10.0 nmol/L, respectively) in vitro. Plasma levels of exogenous ANF were augmented and ANF clearance from plasma was delayed by oral SCH 42495 (3 to 30 mg/kg) in normotensive rats. Plasma ANF levels in volume expanded rats were higher in SCH 42495-treated rats. Diuretic and natriuretic effects of ANF were increased in rats treated with SCH 42495. Oral doses of 1, 3, or 10 mg/kg of SCH 42495 produced significant reductions in blood pressure in DOCA-Na hypertensive rats of 22 +/- 6, 43 +/- 7, and 62 +/- 12 mm Hg, respectively, which were not associated with increases in heart rate. These doses did not alter urine flow, salt excretion, or plasma ANF. SCH 42495 produced significant elevation of urinary excretion of ANF and cGMP. In Dahl-S hypertensive rats, SCH 42495 (1 to 10 mg/kg orally) produced falls in blood pressure of a magnitude similar to that observed in DOCA-Na hypertensive rats. Significant hypotensive activity was observed 18 h after a single 10 mg/kg oral dose in Dahl-S hypertensive rats. In DOCA-Na hypertensive rats, a single dose of SCH 42495 significantly decreased cardiac output and did not lower systemic vascular resistance, a profile similar to that of ANF. The hypotensive response to SCH 42495 was not ascribable to ACE inhibition. Pithed rat preparations revealed no interaction of the drug with autonomic cardiovascular function. The antihypertensive effect of SCH 42495 likely results from potentiation of endogenous ANF via NEP inhibition.
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PMID:Atrial natriuretic factor potentiating and hemodynamic effects of SCH 42495, a new, neutral metalloendopeptidase inhibitor. 851 60

1. Current therapy of heart failure relies on diuretics, positive inotropic compounds and vasodilators. The short-term haemodynamic benefits, especially of the cAMP generators, may be compromised by long-term limitations leading to an increased mortality. In contrast, some vasodilators, especially angiotensin converting enzyme inhibitors, improve survival even in severe heart failure. 2. Modulation of Na(+)- or K(+)-channels and calcium sensitization are positive inotropic mechanisms whose promise in treatment of heart failure needs to be fully explored. 3. The introduction of vasodilator therapy has been a significant advance. Newer compounds act to inhibit the endogenous vasoconstrictors angiotensin II and endothelin, or to potentiate the endogenous vasodilators atrial natriuretic factor and nitric oxide. The full potential of these compounds is yet to be realised.
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PMID:New drugs in the treatment of heart failure. 859 38


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