Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SCH 34826, i.e., (S)-N-(N-(2,2[(2,2-dimethyl-1,3-dioxolan-4- yl)methoxy]-2-oxo-1-(phenyl-methyl)ethyl)-phenylalanyl)-beta-alanine, is a potent and selective inhibitor of neutral endopeptidase 24.11 (NEP), an enzyme that degrades the atrial natriuretic peptide (ANP). The effects of SCH 34826 on hypertension and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs) were evaluated following 1 month of treatment by measuring the blood pressure, cardiac weight, and left ventricular fibrosis. Adult SHRs were treated with SCH 34826 at 10, 30, or 100 mg/kg given orally twice daily or with vehicle. The systolic blood pressure (SBP) and heart rate (HR) were recorded weekly by the tail-cuff method. Cardiac structural damage was determined by morphometric analysis. Over the dose range examined, the drug produced no significant changes in either blood pressure or heart rate. Despite the lack of antihypertensive activity, SCH 34826 at 100 mg/kg reduced both the cardiac mass (-10%) and the amount of fibrotic tissue present in the left ventricle (-42%). These data indicate that chronic inhibition of NEP by SCH 34826 interacts with mechanisms underlying myocardial hypertrophy and cardiac remodeling.
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PMID:The neutral endopeptidase inhibitor, SCH 34826, reduces left ventricular hypertrophy in spontaneously hypertensive rats. 127 98

We investigated the processing enzymes involved in the formation of circulating angiotensin-(1-7) after intravenous administration of angiotensin I to conscious spontaneously hypertensive and Wistar-Kyoto rats. Immunoreactive products, including angiotensin I, angiotensin II, and angiotensin-(1-7), were measured in arterial blood by three specific radioimmunoassays. Angiotensin I infusion (2 nmol) induced a rapid increase in immunoreactive angiotensin II and angiotensin-(1-7). Pretreatment with the angiotensin converting enzyme inhibitor enalaprilat (2 mg/kg) eliminated angiotensin II formation and augmented circulating levels of angiotensin I and angiotensin-(1-7) in spontaneously hypertensive and Wistar-Kyoto rats. The elevated levels of angiotensin-(1-7) in enalaprilat-treated rats were blocked by concurrent treatment with the neutral endopeptidase (EC 3.4.24.11) inhibitor SCH 39,370 (15 mg/kg) in both strains. Administration of SCH 39,370 alone decreased angiotensin-(1-7) levels in spontaneously hypertensive rats, whereas angiotensin II levels increased in both strains (p less than 0.01). Comparisons of the metabolism of angiotensin I in the two rat strains showed increased formation of angiotensin-(1-7) in spontaneously hypertensive rats not given any of the enzyme inhibitors. In addition, levels of angiotensin I were higher after administration of SCH 39,370 in hypertensive rats. These novel findings reveal that neutral endopeptidase EC 3.4.24.11 participates in the conversion of angiotensin I to angiotensin-(1-7) and in the metabolism of angiotensin II in the circulation of both spontaneously hypertensive and Wistar-Kyoto rats. Our results suggest that neutral endopeptidase EC 3.4.24.11 is a major enzymatic constituent of the circulating renin-angiotensin system.
Hypertension 1992 Jun
PMID:In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously hypertensive rats. 131 52

Our studies with the prototypical NEP inhibitor SCH 34826 indicate the potential role of this class of compounds in cardiovascular modulation. The data assembled to date indicate that NEP inhibition elicits significant ANF-like effects in animals and man. The early data generated to date on SCH 34826, when considered with those data generated on other NEP inhibitors, indicate that NEP inhibition may have therapeutic utility in some forms of hypertension and congestive heart failure.
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PMID:SCH 34826: an overview of its profile as a neutral endopeptidase inhibitor and ANF potentiator. 183 84

Whole body clearance of atrial natriuretic factor is due to both receptor uptake and enzymatic degradation initiated by neutral endopeptidase 24.11. The effects of neutral endopeptidase inhibition have been studied in seven sodium-replete sheep using SCH 39370, a specific and potent inhibitor of neutral endopeptidase, in the presence or absence of exogenous hormone [rat ANF-(101-126), 2.4 pmol/kg/min for 2 hours]. SCH 39370 alone (2.5 mg/kg bolus) increased plasma atrial natriuretic factor and plasma cyclic GMP levels, lowered arterial pressure for periods beyond changes in plasma atrial natriuretic factor or cyclic GMP, and suppressed both plasma aldosterone and cortisol levels when compared with vehicle injections. The effects of SCH 39370 were similar to or exceeded those of atrial natriuretic factor infusions, which induced significantly greater increases in plasma atrial natriuretic factor (p = 0.01). Neither agent alone was natriuretic. When SCH 39370 and atrial natriuretic factor were given together, plasma cyclic GMP but not atrial natriuretic factor levels were increased (p = 0.013) compared with atrial natriuretic factor infusion alone, and the half-life was prolonged (p = 0.002) in the presence of SCH 39370. The hypotensive response was greater than that induced by atrial natriuretic factor alone (p = 0.03) but not different from SCH 39370 alone. Inhibitory effects of SCH 39370 on aldosterone levels were similar in the presence of absence of exogenous atrial natriuretic factor.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1991 May
PMID:Hemodynamic and hormonal effects of neutral endopeptidase inhibitor SCH 39370 in sheep. 185 Jul 15

Activation of renal dopamine-1 receptors decreases sodium transport. However, the spontaneously hypertensive rat retains sodium despite increased renal dopamine concentration. We tested the hypothesis that the abnormal sodium handling in spontaneously hypertensive rats (Okamoto-Aoki strain) is related to a decreased dopaminergic response by studying the effects of the intrarenal infusion of the dopamine-1 agonist SKF-38393 and the dopamine-1 antagonist SCH-23390 in hypertensive and in normotensive Wistar-Kyoto rats. Rats (9-16 weeks old) were studied with renal nerves intact under pentobarbital anesthesia (n = 5-6 in each group). Specificity of dopamine-1 effects of SKF-38393 was verified because its natriuretic effect was blocked in a dose-related manner by the dopamine-1 antagonist SCH-23390 (n = 5). Intrarenal but resulted in a dose-related natriuresis and diuresis in normotensive but not in hypertensive rats. Intrarenal arterial infusion of the dopamine-1 antagonist SCH-23390 alone induced an antinatriuresis, without affecting glomerular filtration rate, in normotensive but not in hypertensive rats. Addition of the dopamine-2 antagonist YM-09151 to the dopamine-1 antagonist infusion did not enhance the effect of the dopamine-1 antagonist. The lack of response to the dopamine-1 agonist or antagonist in hypertensive rats was not due to differences in renal dopamine-1 receptor density (1.3 +/- 0.3 pmol/mg protein for spontaneously hypertensive rats, n = 4; 1 +/- 0.2 for Wistar-Kyoto rats, n = 4) or affinity; distribution determined by autoradiography was also similar. The abnormal renal sodium handling in 9-16-week-old spontaneously hypertensive rats is in part due to decreased response distal to the dopamine-1 receptor.
Hypertension 1990 Jun
PMID:Attenuated renal response to dopaminergic drugs in spontaneously hypertensive rats. 197 11

The effects of SCH 34826, an orally active neutral metalloendopeptidase inhibitor, on responses to atrial natriuretic factor-(103-125) or -(99-126) and on blood pressure were evaluated in rats. SCH 34826 (10, 30, and 90 mg/kg s.c. and 90 mg/kg p.o.) potentiated the antihypertensive action of atrial natriuretic factor (30 micrograms/kg i.v.) in conscious spontaneously hypertensive rats. SCH 34826 (90 mg/kg) also potentiated the diuretic and natriuretic responses to atrial natriuretic factor (30 micrograms/kg i.v.) as well as the plasma levels achieved after peptide injection. SCH 34826 significantly reduced blood pressure in the conscious deoxycorticosterone acetate-salt hypertensive rat, at doses of 90 mg/kg s.c. (-35 +/- 12 mm Hg), 10 mg/kg p.o. (-30 +/- 7 mm Hg), and 90 mg/kg p.o. (-45 +/- 6 mm Hg). SCH 34826 was devoid of acute antihypertensive activity in the spontaneously hypertensive rat but reduced blood pressure by day 3 of a 5-day treatment schedule. SCH 34826 (90 mg/kg s.c.) enhanced urine volume output in the deoxycorticosterone acetate-salt rat (2.78 +/- 0.6 vs. 1.27 +/- 0.3 ml/100 g/3 hr in vehicle-control rats, p less than 0.05). SCH 34826 (90 mg/kg s.c.) increased plasma levels of atrial natriuretic factor at 1 hour (753 +/- 89 vs. 451 +/- 79 pg/ml in vehicle-treated rats, p less than 0.05) but not 3 hours after dosing. The renal excretion of atrial natriuretic factor (3,092 +/- 1,089 vs. 21 +/- 6 pg/100 g/3 hr in vehicle-treated rats, p less than 0.05) and cyclic guanosine monophosphate (2,131 +/- 509 vs. 879 +/- 168 pg/100 g/3 hr in vehicle-treated rats, p less than 0.05) was markedly elevated by SCH 34826 in deoxycorticosterone acetate-salt rats. These studies suggest that neutral endopeptidase inhibition may represent a new approach to treatment of some forms of hypertension.
Hypertension 1990 Feb
PMID:Atrial natriuretic factor-potentiating and antihypertensive activity of SCH 34826. An orally active neutral metalloendopeptidase inhibitor. 215 4

Brain catecholamines may play a role in the development of hypertension in the spontaneously hypertensive rat (SHR). To investigate central dopaminergic function in this strain, the effect of various dopaminergic drugs on open-field activity was assessed. In general, basal levels of ambulation were similar in SHRs and their controls, the Wistar-Kyoto rats (WKY). Exploratory rearing activity was increased in SHRs, however. Haloperidol inhibited open-field ambulation in SHRs and WKY, but higher doses were needed in the SHR. Apomorphine inhibited ambulatory activity in WKY but had virtually no effect in SHRs. Amphetamine and the dopamine uptake inhibitor GBR-12909 increased ambulation in SHRs and WKY to a similar extent. Central administration of haloperidol or sulpiride decreased ambulatory activity in WKY, but had no effect in SHRs at the doses used. SCH-23390 decreased ambulation scores both in SHRs and WKY, with the effect being slightly greater in the latter strain. In all cases exploratory rearing was affected as well by the drugs used. The large difference in base-line scores has to be taken into account when interpreting these data, however. Also, for comparison the noradrenergic drugs clonidine and desipramine were tested. Both elicited decreases in activity which were identical in SHRs and WKY. These results show that a number of dopaminergic drugs have differential effects on open-field activity of SHRs as compared to WKY. Ambulatory activity appeared more resistant to inhibition in SHRs than in WKY. The possibility that these results could reflect altered dopaminergic function in SHR involved in the development of hypertension in this strain is discussed.
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PMID:Differential effects of dopaminergic drugs on open-field behavior of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. 256 90

Direct effects of dopamine on renin release were examined using static incubations and perifusions of rat renal cortical slices. Dopamine (10(-5)M) significantly stimulated renin release compared with control. To determine which receptors are involved in dopamine-elicited renin release, studies were performed with specific dopamine-1 and dopamine-2 receptor agonists and antagonists, as well as with alpha- and beta-adrenergic antagonists. Fenoldopam, a dopamine-1 receptor agonist, dose dependently stimulated renin secretion both in static incubations and perifusions; whereas quinpirole (10(-7)-10(-5)M), a dopamine-2 receptor agonist, was ineffective. Phentolamine (10(-4)M), an alpha-adrenergic antagonist, did not alter dopamine- or fenoldopam-induced renin release. Similarly, propranolol, a beta-blocker, did not interfere with the renin stimulation of dopamine (10(-5)M) or fenoldopam (10(-6)M) incubations or perifusion experiments; whereas propranolol significantly blocked isoproterenol action. SCH 23390 (10(-5)M), a specific dopamine-1 antagonist, blocked dopamine- and fenoldopam-induced renin. In contrast, pimozide, a dopamine-2 receptor antagonist, was ineffective. These studies indicate that dopamine is a direct renin secretogogue, and its effects seem to be mediated by specific dopamine-1 receptor activation, as neither alpha- nor beta-adrenergic blockers nor dopamine-2 receptor antagonists altered dopamine actions. The results suggest that dopamine produced locally in the kidney may stimulate renin secretion directly by dopamine-1 receptor activation.
Hypertension 1989 May
PMID:Evidence that specific dopamine-1 receptor activation is involved in dopamine-induced renin release. 256 77

Dilevalol (SCH 19927) is a potent, long-acting, nonselective beta-blocker with marked vasodilator actions. Unlike classical beta-blockers, dilevalol promptly lowers blood pressure and vascular resistance in animal models of hypertension. The present studies address the peripheral vascular effects of dilevalol and explore the role of beta-receptor agonism in the acute vasodilator and antihypertensive effects of the compound. In the denervated dog hindlimb preparation, dilevalol (0.1, 0.3, 1.0 and 3.0 micrograms, i.a.) significantly increased femoral blood flow by 12 +/- 6, 27 +/- 6, 84 +/- 31 and 132 +/- 41 ml/min, respectively. In contrast, celiprolol, a beta-blocker with purported vasodilator activity, caused a significant increase in flow of 31 +/- 9 ml/min at a dose of 30 micrograms i.a. Systematic pretreatment with the selective beta 2-antagonist ICI 118,551 virtually abolished dilevalol's vasodilator effect in the dog hindlimb. In conscious spontaneously hypertensive rats, 3 mg/kg i.v. dilevalol reduced blood pressure by 58 +/- 8 mmHg (P less than 0.05) and vascular resistance by 171 +/- 27 dyne.sec.cm-5/100 g (P less than 0.05) but did not change cardiac output significantly. Pretreatment of spontaneously hypertensive rats with ICI 118,551 significantly reduced both dilevalol's antihypertensive and resistance-lowering effects. Oral doses of 10 and 25 mg/kg dilevalol lowered blood pressure by 19 +/- 3 (P less than 0.05) and 37 +/- 5 mmHg (P less than 0.05) in spontaneously hypertensive rats with chronically implanted Doppler flow probes. The lower dilevalol dose reduced mesenteric vascular resistance 38 +/- 6% (P less than 0.05) while the higher dose significantly lowered vascular resistance in the hindlimb, mesenteric and renal vascular beds of spontaneously hypertensive rats by 18 +/- 8, 33 +/- 2 and 43 +/- 4%, respectively. Propranolol lowered neither blood pressure nor regional vascular resistances at the above doses in spontaneously hypertensive rats. Thus, dilevalol promotes a generalized fall in vascular resistance. Furthermore, the present studies illustrate that beta 2-receptor stimulation plays an obligatory role in both the vasodilatory and antihypertensive actions of dilevalol.
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PMID:Role of beta 2-receptor stimulation in the peripheral vascular actions of the antihypertensive dilevalol. 257 92

It has been postulated that endogenously produced dopamine (DA) may play a role in the regulation of renal sodium excretion. In the present study, experiments were designed to test the hypothesis that acute volume expansion with isotonic sodium chloride stimulates the production of DA within the kidney, which in turn acts on specific DA1 receptors to promote sodium excretion. In pentobarbital-anesthetized rats, acute volume expansion over a period of 1 hour evoked a pronounced increase in urine output and urinary sodium excretion. These diuretic and natriuretic effects were not accompanied by any significant changes in blood pressure or heart rate. However, there was a significant elevation in central venous pressure and a transient rise in glomerular filtration rate. The natriuretic and diuretic response was accompanied by a significant increase in urinary DA excretion, and this effect was clearly dissociated from the rise in glomerular filtration rate. In a separate group of rats, the effects of acute volume expansion were studied in the presence of selective DA1 receptor antagonist SCH-23390 (50 micrograms/kg i.v. bolus; 10 micrograms/kg/min). During DA1 receptor blockade, there was a marked attenuation in the diuretic and natriuretic response throughout the period of volume expansion, when compared with that in the control group. The changes in central venous pressure and glomerular filtration rate were identical in the two groups. In another group of rats, the renal effects of exogenously administered DA were studied. DA (0.5 micrograms/kg/min) produced significant increases in urine output and urinary sodium excretion, without causing any alterations in blood pressure or glomerular filtration rate, suggesting a tubular site of action.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1989 Jun
PMID:Role of kidney dopamine in the natriuretic response to volume expansion in rats. 266 32


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