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

The effects of captopril on the response of cytosolic free Ca2+ concentration in cultured vascular smooth muscle cells of aortas from Wistar-Kyoto and spontaneously hypertensive rats to angiotensin II (Ang II) and bradykinin were studied using fura 2. Incubation with captopril for longer than 10 minutes caused a decreased response of cytosolic free Ca2+ to Ang II and bradykinin. Maximal effects of captopril were observed after a 40-minute incubation. The inhibitory effect of captopril was abolished in Ca(2+)-free medium, suggesting that captopril acts by blocking Ca2+ influx. Similar effects were observed with enalaprilat. Isometric contraction of aortic strips induced by Ang II in normotensive rats was reduced from 6.5 +/- 2.5 to 1.8 +/- 0.6 mN by a 40-minute incubation with 1 mumol/L captopril (P = .016). Enalaprilat similarly decreased the Ang II-induced contraction. Besides the inhibition of the angiotensin converting enzyme, direct effects of Ang II converting enzyme inhibitors on vascular contraction and Ca2+ influx in vascular smooth muscle cells may be of therapeutic relevance.
Hypertension 1993 Dec
PMID:Effect of captopril on vasoconstriction and Ca2+ fluxes in aortic smooth muscle. 824 13

We performed experiments to test the hypothesis that endogenous adenosine acts as an essential cofactor required for eliciting angiotensin II (Ang II)-induced afferent and/or efferent arteriolar vasoconstriction. Enalaprilat (2 mg IV) was administered to anesthetized rats to reduce endogenous Ang II levels. Kidneys and blood were harvested from these animals and used for study of renal microvascular function using the in vitro blood-perfused juxtamedullary nephron technique. Arteriolar inside diameter was monitored videomicroscopically in (1) normal kidneys, (2) kidneys subjected to adenosine receptor blockade (100 mumol/L 1,3-dipropyl-8-p-sulfophenylxanthine), and (3) kidneys continuously exposed to 1 mumol/L adenosine. Under resting conditions, arteriolar diameters were similar in all three groups of kidneys, averaging 24.8 +/- 1.0 microns (n = 23) in afferent arterioles and 24.0 +/- 0.9 microns (n = 16) in efferent arterioles. In normal kidneys, adenosine (10 mumol/L) decreased both afferent (10.2 +/- 2.0%) and efferent (6.5 +/- 0.8%) diameters, an effect that was absent in kidneys subjected to adenosine receptor blockade. Ang II (10 pmol/L to 100 nmol/L) elicited dose-dependent vasoconstriction of both vascular segments in normal kidneys. At a concentration of 100 nmol/L, Ang II decreased afferent diameter by 36.8 +/- 8.5% and efferent diameter by 30.8 +/- 9.6%. Neither afferent nor efferent arteriolar Ang II dose-response relations were significantly different in kidneys treated with low-dose adenosine or the adenosine receptor blocker. These observations refute the hypothesis that a receptor-mediated action of adenosine is required for Ang II-induced constriction of juxtamedullary afferent or efferent arterioles.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Jan
PMID:Renal arteriolar angiotensin responses during varied adenosine receptor activation. 828 42

To study the oxytocic effect of trypsin, we measured the force of isometric contraction in uteri isolated from estrogenized rats exposed to trypsin (8.8 x 10(-10) to 1.7 x 10(-6) mol/L) either alone or in the presence of receptor antagonists to angiotensin II [saralasin ([Sar1,Ala8]angiotensin II) or DuP 753 (losartan)] or to kinins (D-[Arg0,Hyp3,Thi5,8,D-Phe7]-bradykinin). We found that saralasin or DuP 753, but not the kinin antagonist, displaced the dose-response curve to the right. Exposure to exogenous angiotensin I desensitized the preparation to further doses of either angiotensin I or II or trypsin, without altering the effects of oxytocin or bradykinin. Enalaprilat (an angiotensin I converting enzyme inhibitor) or pepstatin A (a renin inhibitor) also displaced the dose-response curve to trypsin to the right, without altering the effects of oxytocin or angiotensin II. Our results indicate that the response to trypsin is mediated by an agent produced from a substrate present in the uterus and acting on the angiotensin II type 1 receptor and are consistent with both renin and angiotensin I converting enzyme being involved in its mechanism of action, thus supporting the notions that the renin-angiotensin system may be important in the late stages of pregnancy and that serine proteases existing in the uterus may contribute to its activation.
Hypertension 1994 Jan
PMID:Oxytocic effect of trypsin on the isolated rat uterus. 828 69

Hypertension is a major risk factor for the development of heart failure. Despite significant progress in our knowledge of the physiopathology of heart failure, the cause for decompensation in patients with left ventricular hypertrophy (LVH) is still obscure. The angiotensin converting enzyme inhibitor enalaprilat has been found to improve electromechanical coupling of heart cells in animal models. To assess the effects of enalaprilat on ventricular electromechanical coupling in humans, we studied the His bundle electrograms and hemodynamics in 22 hypertensive patients with LVH. Patients received either 2.5 mg enalaprilat or saline placebo intravenously in a double-blind protocol. There were no significant changes in heart rate, and atrioventricular and His-Purkinje conduction times. Ventricular activity duration was reduced from 110 +/- 11 msec to 88 +/- 13 msec after enalaprilat administration (P < .01). Enalaprilat decreased peak-systolic and end-diastolic left ventricular pressures, and arterial and pulmonary pressures, as well as pulmonary and systemic vascular resistances. End-systolic wall stress decreased 18% (P < .01), ejection fraction increased 11% (P < .01), and end-diastolic pressure-volume ratio decreased 50% (P < .001) after enalaprilat administration. There were no significant changes in these parameters after saline infusion. It is concluded that enalaprilat reduces ventricular activation duration and improves ventricular performance in hypertensive patients with LVH. Data suggest that enalaprilat significantly improves excitation-contraction coupling in these patients.
 ...
PMID:Effects of enalaprilat on hemodynamics and ventricular activation duration in hypertensive patients with left ventricular hypertrophy: clinical evidence of improved excitation-contraction coupling with angiotensin converting enzyme inhibition in human hypertension. 839 97

As interactions between the renin-angiotensin and sympathetic nervous systems have been suggested in the pathogenesis of hypertension, we wanted to investigate the effect of chronic renin-angiotensin blockade with losartan and enalaprilat on the sympathetic reactivity to hypotension and on the cardiac beta-adrenergic-coupled adenylyl cyclase pathway in 12-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Both treatments, exerting equipotent shifts of angiotensin-pressure responses, lowered blood pressure and attenuated cardiac hypertrophy similarly in SHR. The nitroprusside-induced hypotension was similar in both strains, but the associated increases in plasma catecholamines and heart rate were higher in SHR. In SHR treated with losartan and enalaprilat, the nitroprusside-induced hypotension was greater and associated with markedly attenuated increases in norepinephrine and heart rate. The binding affinity of cardiac beta-adrenoceptors was significantly lower, and beta2-adrenoceptor subtype was dominant in untreated SHR in contrast to WKY, in which beta1-adrenoceptor subtype was dominant. Enalaprilat treatment increased total beta-adrenoceptor density, whereas both treatments restored the binding affinity and beta1- and beta2-adrenoceptor proportions to normal in SHR. Isoproterenol-, guanylylimidodiphosphate [Gpp(NH)p]-, and forskolin-stimulated adenylyl cyclase reactivity was increased in SHR. Enalaprilat restored adenylyl cyclase reactivity to normal in SHR and reduced the sensitivity (EC50) of Gpp(NH)p-induced cAMP formation in both strains. The present study supports the possibility that functional alterations of the renin-angiotensin and sympathetic systems are involved in hypertension in SHR. The antihypertensive action of losartan and enalaprilat in SHR may be partly mediated through the normalization of sympathetic hyperreactivity and the restoration of beta-adrenergic signaling pathway sensitivity.
Hypertension 1997 Aug
PMID:Effects of renin-angiotensin blockade on sympathetic reactivity and beta-adrenergic pathway in the spontaneously hypertensive rat. 926 Sep 93

The beneficial therapeutic effects of angiotensin-converting enzyme (ACE) inhibitors are the result of reduced angiotensin II formation and possibly also of an accumulation of bradykinin that is inactivated by ACE. In particular, recently developed ACE inhibitors with tissue-penetrating properties, such as quinaprilat, may exert vascular effects via the bradykinin B2-receptor. To test direct arterial effects of quinaprilat and enalaprilat and to study their effects on vasodilation induced by bradykinin, venous occlusion plethysmography was used during local intra-arterial drug administration into the brachial artery in healthy volunteers. The response to bradykinin was augmented by both ACE inhibitors, but the effect of quinaprilat (3.9 nmol/min) was exclusively attributable to its direct vasodilator action. Enalaprilat (13 nmol/min) did not change baseline blood flow in the human forearm circulation. In contrast, quinaprilat significantly increased arterial flow from 3.5 +/- 0.5 to 4.6 +/- 0.7 mL/100 mL tissue/min, which was inhibited by N(G)-monomethyl-L-arginine (8 micromol/min IA). Moreover, the effect of sodium nitroprusside (0.023 to 22.9 nmol/min) was substantially attenuated during concomitant administration of quinaprilat. These results suggest that quinaprilat induces vascular effects beyond the inhibition of angiotensin II formation; it causes vasodilation by increasing vascular nitric oxide production and thereby attenuates the relaxing effect of the nitric oxide donor sodium nitroprusside.
Hypertension 1997 Oct
PMID:Quinaprilat induces arterial vasodilation mediated by nitric oxide in humans. 933 92

We studied the enhancement of the effects of bradykinin B2 receptor agonists by agents that react with active centers of angiotensin-converting enzyme (ACE) independent of enzymatic inactivation. The potentiation and the desensitization and resensitization of B2 receptor were assessed by measuring [3H]arachidonic acid release and [Ca2+]i mobilization in Chinese hamster ovary cells transfected to express human ACE and B2 receptor, or in endothelial cells with constitutively expressed ACE and receptor. Administration of bradykinin or its ACE-resistant analogue desensitized the receptor, but it was resensitized (arachidonic acid release or [Ca2+]i mobilization) by agents such as enalaprilat (1 micromol/L). Enalaprilat was inactive in the absence of ACE expression. La3+ (100 micromol/L) inhibited the apparent resensitization, probably by blocking the entry of extracellular calcium. Enalaprilat resensitized the receptor via ACE to release arachidonic acid by bradykinin at a lower concentration (5 nmol/L) than required to mobilize [Ca2+]i (1 micromol/L). Monoclonal antibodies inhibiting the ACE N-domain active center and polyclonal antiserum potentiated bradykinin. The snake venom peptide BPP5a and metabolites of angiotensin and bradykinin (angiotensin-[1-9], angiotensin-[1-7], bradykinin-[1-8]; 1 micromol/L) enhanced arachidonic acid release by bradykinin. Angiotensin-(1-9) and -(1-7) also resensitized the receptor. Enalaprilat potentiated the bradykinin effect in cells expressing a mutant ACE with a single N-domain active site. Agents that reacted with a single active site, on the N-domain or on the C-domain, potentiated bradykinin not by blocking its inactivation but by inducing crosstalk between ACE and the receptor. Enalaprilat enhanced signaling via ACE by Galphai in lower concentration than by Galphaq-coupled receptor.
Hypertension 1999 Mar
PMID:Enhancement of bradykinin and resensitization of its B2 receptor. 1008 96

1. Endothelial dysfunction is seen in patients with essential hypertension or congestive heart failure (CHF). The present study aimed to evaluate the direct effect on endothelium- dependent vasodilation (EDV) of different pharmacological drugs commonly used in the treatment of these conditions. 2. Forearm blood flow (FBF) was measured in 37 young healthy normotensive subjects with venous occlusion plethysmography during local intra-arterial infusions of methacholine (MCh; 2-4 microg/min), evaluating EDV, and sodium nitroprusside (SNP; 5-10 microg/min), evaluating endothelium-independent vasodilation (EIDV). The measurements of EDV and EIDV were undertaken under baseline conditions and were repeated after 1 h intra-arterial infusion of digoxin (0.1 mg/h), furosemide (5.0 mg/h), enalaprilat (2,4 mg/h), metoprolol (1.2 mg/h) or saline (controls). 3. Enalaprilat and digoxin improved the FBF response to MCh at 4 microg/min (from 22.7+/-2.3 to 25.5+/-2.1 mL/min per 100 mL tissue (P < 0.01) and from 18.2+/-2.4 to 22.2+/-2.0 mL/min per 100 mL tissue (P < 0.05), respectively). No significant changes where induced by furosemide or metoprolol in response to MCh at 4 microg/min (from 19.4+/-2.0 to 22.9+/-2.8 and from 15.3+/-2.4 to 14.7+/-1.1 mL/min per 100 mL tissue, respectively). No significant changes in basal FBF or EIDV were induced by the different drugs. When the endothelial function index was calculated as the MCh: SNP FBF ratio, a significant improvement was seen only with enalaprilat (1.1+/-0.1 to 1.2+/-0.1; P < 0.01) and furosemide (1.0+/-0.1 to 1.3+/-0.4; P < 0.05). 4. In conlusion, the results of the present study show that enalaprilat and furosemide improve endothelial vasodilatory function, while no major effect was induced by digoxin or metoprolol. Thus, different direct effects on the endothelium in young normotensive subjects were induced by drugs commonly used in the treatment of hypertension or CHF.
 ...
PMID:Effects of digoxin, furosemide, enalaprilat and metoprolol on endothelial function in young normotensive subjects. 1138 May 10

Previous studies have indicated that angiotensin II (Ang II) concentrations in renal interstitial fluid are much higher than plasma levels. In the present study, we performed experiments to explore renal interstitial fluid concentrations of Ang I and Ang II further and to determine whether these levels are altered by acute arterial infusion of an ACE inhibitor (enalaprilat) or by volume expansion. Microdialysis probes (molecular weight cutoff point: 30 000 Da) were implanted in the renal cortex of anesthetized rats and were perfused at a rate of 2 microL/min. Using relative equilibrium rates, the basal renal interstitial fluid Ang II concentration averaged 3.07+/-0.43 nmol/L, a value much higher than the plasma Ang II concentration of 107+/-8 pmol/L (n=7). Interstitial fluid Ang I concentrations (0.84+/-0.04 nmol/L) were consistently lower than the Ang II concentrations but higher than the plasma Ang I concentrations (112+/-14 pmol/L). Intra-arterial infusion of enalaprilat (7.5 micromol/kg/min, n=5) for 120 minutes resulted in a significant decrease in mean arterial pressure (from 114+/-4 to 68+/-4 mm Hg) along with reductions in plasma and renal ACE activity (by -99% and -52%, respectively). Enalaprilat resulted in a significant increase in plasma Ang I from 133+/-21 to 1167+/-328 pmol/L and a decrease in plasma Ang II from 110+/-12 to 67+/-9 pmol/L. During enalaprilat infusion, interstitial fluid concentration of Ang I was significantly increased from 0.78+/-0.06 to 0.97+/-0.08 nmol/L; however, Ang II concentrations were not altered significantly (3.67+/-0.28 versus 3.67+/-0.25 nmol/L). Acute volume loading with Ringer's solution containing 1% bovine serum albumin at a rate of 150 microL/min for 2 hours (6% to 7% of body weight) lowered plasma concentrations of Ang I from 110+/-23 to 16+/-2 pmol/L and Ang II from 100+/-23 to 36+/-6 pmol/L; however, renal interstitial fluid concentrations of Ang I and Ang II were not altered significantly during volume expansion (Ang I, from 0.77+/-0.05 to 0.69+/-0.03 nmol/L; Ang II, from 3.76+/-0.43 to 3.59+/-0.39 nmol/L, n=5). These data indicate that renal interstitial fluid concentrations of Ang I and Ang II are substantially higher than the corresponding plasma concentrations. Furthermore, the fact that the high interstitial fluid concentrations of Ang II are not responsive to acute ACE inhibition or volume expansion suggests the compartmentalization and independent regulation of renal interstitial fluid Ang II.
Hypertension 2002 Jan
PMID:Renal interstitial fluid concentrations of angiotensins I and II in anesthetized rats. 1179 91

This study examined the proposition that kinins are involved in the renal hemodynamic effect of an ACE inhibitor in Goldblatt (GB) hypertension. The effects of the ACE inhibitor enalaprilat were compared in two groups of anesthetized two-kidney one-clip GB rabbits. One group (n = 11) was given enalaprilat (10 mg/kg, i.v.) while a second group (n = 10) received the kinin B2 receptor antagonist, icatibant (2.5-5 microg/kg/min, i.v.) prior to enalaprilat. Enalaprilat caused a 40% rise in renal blood flow and 11 mm Hg decrease in blood pressure in the untreated, but no significant renal effect in the icatibant-treated group. Blood pressure was reduced to the same degree in both groups. The results indicate that kinins play a major role in the renal hemodynamic, but not the blood pressure effect of ACE inhibition in the GB rabbit.
 ...
PMID:Icatibant blocks but does not reverse ACE inhibitor renal effect in Goldblatt rabbit. 1210 73


<< Previous 1 2 3 Next >>