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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of penbutolol (Hoe 893 d), a new non-selective beta-receptor blocking agent, were studied in 5 patients with moderate hypertension. Initially, it was shown that 2-4 mg given orally once or twice daily tended to lower blood pressure and pulse rate, both at rest and following submaximal work. In prolonged trials (3-8 months) 4-60 mg/day were required to produce an acceptable antihypertensive effect. Penbutolol had no effect on the normal increase in plasma noradrenaline and adrenaline on standing, nor did it alter basal urinary catecholamine excretion. Submaximal work caused no significant change in plasma catecholamines before treatment, but there was a marked rise both in plasma noradrenaline and adrenaline during treatment with penbutolol. In short term studies there was a fall in plasma renin by 4 hours after oral administration of penbutolol 2-4 mg, which persisted for 24 hours. Prolonged treatment with penbutolol 20-30 mg twice daily inhibited renin production under basal conditions and following submaximal work, as well as lowered basal urinary aldosterone excretion. In one patient slight asthmatic symptoms appeared after treatment for 3 months with penbutolol. In other respects penbutolol was well tolerated.
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PMID:Long term treatment of moderate hypertension with penbutolol (Hoe 893d). I. Effects on blood pressure, pulse rate, catecholamines in blood and urine, plasma renin activity and urinary aldosterone under basal conditions and following exercise. 0 98

Ramipril, a converting enzyme inhibitor, was first studied in rats with aortic stenosis, an experimental model of reno-vascular hypertension. In this study, ramipril has an antihypertrophic cardiac effect, independently to its hypotensive effect. The co-administration of Hoe 140, a specific antagonist of bradykinin receptors blocked totally the effect of ramipril on blood pressure, cardiac hypertrophy and on concentration of cGMP. These effects can therefore be explained by an accumulation of bradykinins. Furthermore, we investigated the preventing effects of ramipril on left ventricular hypertrophy, on growth of cardiac capillaries using SHR rats, treated in utero and during the 20 weeks following birth with two doses: a relatively high dose (1 mg/kg/day) and a low dose (0.01 mg/kg/day). Animals treated with a low dose of ramipril presented a high blood pressure similar to that observed in the control group. At the end of the treatment, the converting enzyme activity was inhibited in both groups. An increase in the growth of cardiac capillaries and of the cardiac concentration of glycogen and a decrease in the cardiac concentration of citric acid was observed in both groups. The ventricular weight decreased only in the high dose treatment group. This results demonstrated that early treatment with converting enzyme inhibitor even with a low dose which was unable to prevent the development of hypertension and of left ventricular hypertrophy. We could therefore draw a hypothesis of an accumulation of bradykinin due to the converting enzyme inhibitor which could explain in part this effect through an improvement of cardiac metabolism.
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PMID:[Inhibition of the enzyme of conversion and cardioprotection: role of bradykinins]. 132 27

The goal of the present study was to compare the hemodynamic and biochemical effects of the renin inhibitor Ro 42-5892, the angiotensin converting enzyme inhibitor cilazapril, and the angiotensin II receptor blocker EXP132, the aldehyde derivative of DuP 753. The three drugs were evaluated in guinea pigs, previously treated with furosemide, using their maximal effective doses. Cilazapril decreased arterial blood pressure more than Ro 42-5892 and EXP132. In contrast, Ro 42-5892 and EXP132 had similar effects. The larger decrease of arterial pressure induced by cilazapril was not due to a larger decrease of angiotensin II in plasma and was not influenced by cyclooxygenase inhibition with indomethacin or by bradykinin antagonism with Hoe 140. After binephrectomy, most of the blood pressure-lowering effect of Ro 42-5892 disappeared. In contrast, cilazapril was still markedly effective, pointing to extrarenal effects. We conclude that in furosemide-treated guinea pigs, as opposed to previously published animal models, the decrease of arterial pressure induced by angiotensin converting enzyme inhibitors may be partly due to extrarenal effects not related to the renin-angiotensin system.
Hypertension 1992 Mar
PMID:Effects of renin-angiotensin system blockade in guinea pigs. 153 64

We studied whether inhibition of angiotensin converting enzyme stimulates the formation of nitric oxide and prostacyclin in cultured human and bovine endothelial cells by an enhanced accumulation of endothelium-derived bradykinin. Nitric oxide formation was assessed in terms of intracellular cyclic GMP accumulation, prostacyclin release by a specific radioimmunoassay. Inhibition of angiotensin converting enzyme by ramiprilat dose- and time-dependently increased the formation of nitric oxide and prostacyclin. These increases, peaking within 10 minutes, were maintained for at least 60 minutes. The ramiprilat-induced cyclic GMP increase was completely abolished by the stereospecific inhibitor of nitric oxide synthase, NG-nitro-L-arginine. The B2-kinin receptor antagonist, Hoe 140 (0.1 microM), markedly attenuated the cyclic GMP accumulation and abolished the increase in prostacyclin release. The supernatant of endothelial cells, incubated with ramiprilat (0.3 microM) for 15 minutes, elicited a significant nitric oxide release (as assessed by a guanylyl cyclase assay) in untreated endothelial cells used as detector tissue. Preincubation of the detector cells with Hoe 140 completely abolished this nitric oxide release. These data indicate that cultured endothelial cells from different species are capable of producing and releasing bradykinin into the extracellular space in amounts that lead to a sustained stimulation of nitric oxide and prostacyclin formation, provided that bradykinin degradation is prevented by angiotensin converting enzyme inhibition. Thus, the protective effect of angiotensin converting enzyme inhibitors observed on endothelial vasomotor function in hypertension may be explained by the local accumulation of endothelium-derived bradykinin that acts in an autocrine and paracrine manner as potent stimulus for endothelial autacoid formation.
Hypertension 1991 Oct
PMID:Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin. 165 53

To measure specifically angiotensin-(1-8)octapeptide, peptides were extracted from 2 ml of plasma by reversible adsorption to bonded-phase silica. The angiotensin-(1-8)octapeptide was then isolated by isocratic reversed-phase high-performance liquid chromatography and quantified by radioimmunoassay. The extraction recovery of 125I-angiotensin II added to 2 ml of plasma was 99 +/- 2% (mean +/- SD). The overall recovery of 5, 10, and 20 fmol unlabeled angiotensin II added to 1 ml of plasma was 80 +/- 10%. The coefficient of variation for within-assay precision was 0.06 and for between-assay precision 0.13. The detection limit was 0.4 fmol/ml. Buffer and plasma blanks were below the detection limit. Normal subjects on a free diet in supine position averaged 4.2 +/- 1.7 fmol/ml angiotensin-(1-8)octapeptide. Furosemide (40 mg p.o.) and standing increased these values to 22 +/- 7.6 fmol/ml. In four volunteers, immunoreactive "angiotensin II" (more or less angiotensin-like material) was measured serially before and after converting-enzyme inhibition (Hoe 498) with conventional Dowex extraction. At peak inhibition, plasma immunoreactive "angiotensin II" levels decreased by only 44%. In contrast, angiotensin-(1-8)-octapeptide isolated by high-performance liquid chromatography completely disappeared. In hypertensive patients receiving long-term treatment with enalapril, plasma levels of angiotensin-(1-8)octapeptide fell from 2.7 +/- 0.9 to 0.9 +/- 0.3 fmol/ml (mean +/- SEM) 2 hours after the morning dose, whereas levels of immunoreactive "angiotensin II" were not significantly changed. We found that this sensitive method specifically measured angiotensin-(1-8)octapeptide and demonstrated that true angiotensin II virtually disappears during converting-enzyme inhibition.
Hypertension
PMID:True versus immunoreactive angiotensin II in human plasma. 298 22

Recent clinical reports have suggested that hypertension accelerates the progress of diabetic nephropathy and retinopathy, whereas antihypertensive treatments may retard them. Thus, the effect of antihypertensive treatment in diabetes mellitus with hypertension was evaluated in rats. A model of diabetes mellitus with hypertension has been developed in spontaneously hypertensive (SHR) rats by unilateral nephrectomy and streptozotocin (STZ, 30 mg/kg, i.v. treatment). The rats were treated with four antihypertensive drugs orally for 12 weeks thereafter. STZ treatment induced chronic hypeglycaemia (300-400 mg/dl), decreased body weight and heart rate, and caused vascular changes of ophthalmic fundi and cataracta. The kidney of these rats showed proliferative changes such as periarteritis nodosa, hyperplasia, or fibronecrosis of the arterioles, exudative changes, mesangial proliferation, or thickening of the basement membrane of the glomeruli. Enalapril (10 mg/kg per day) and remipril (Hoe 498) (1 mg/kg per day), converting enzyme inhibitors, or arotinolol (20 mg/kg per day), a beta-adrenoceptor blocking drug, decreased blood pressure, prevented the development of renal and ocular lesions, and tended to increase creatinine clearance. Nisoldipine (3 mg/kg per day), a calcium-entry blocking drug, tended to decrease blood glucose, and prevented the decrease of body weight and development of ocular lesions. In conclusion, antihypertensive treatments were effective in preventing the progress of diabetic retinopathy and nephropathy, and renal insufficiency in this animal model.
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PMID:Antihypertensive treatment in spontaneously hypertensive rats with streptozotocin-induced diabetes mellitus. 329 54

The cardiovascular and antihypertensive activities of the novel orally active non-sulfhydryl converting enzyme (CE) inhibitor 2-[N-[(S)-1-Ethoxycarbonyl-3-phenyl-propyl]-L-alanyl] -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) were evaluated in several experimental preparations. The hemodynamic profile of Hoe 498 in anesthetized animals was characterized by a reduction in systemic blood pressure which was associated with a decrease in total peripheral and renal vascular resistance. These effects were enhanced upon sodium depletion. In conscious normotensive rats a single oral administration of Hoe 498 reduced systemic blood pressure for more than 5 h. The development of acute renovascular hypertension in anesthetized rats was prevented by oral pretreatment with Hoe 498. In conscious rats with renovascular hypertension (two-kidney, one clip) single oral doses of Hoe 498 induced a long lasting antihypertensive effect. Chronic oral treatment of spontaneously hypertensive rats with Hoe 498 lowered arterial blood pressure more effectively than enalapril. The threshold antihypertensive dose for Hoe 498 was 0.01 mg/kg/d, for enalapril 1 mg/kg/d. In conscious hypertensive dogs (two-kidney, two wrapped) Hoe 498 at a single oral dose of 10 mg/kg reduced systemic blood pressure for more than 6 h. Oral administration of Hoe 498 in a dose of 1 mg/kg/d for 5 d normalized systemic blood pressure in conscious hypertensive dogs. These findings demonstrate that in various models of experimental hypertension the novel orally active converting enzyme inhibitor Hoe 498 exerts marked cardiovascular and potent prolonged antihypertensive activities, which merit exploration with respect to possible therapeutic benefits.
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PMID:Cardiovascular and antihypertensive activities of the novel non-sulfhydryl converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498). 609 68

The short chemical half-life limits the potential therapeutic value of Prostacyclin (PGI2). Replacement of the acid-labile enolether structure of PGI2 by a beta-thia-imino group resulted in the orally active and chemically stable analogue Hoe 892. Incubation of rabbit platelet rich plasma with PGI2 and Hoe 892 caused a dose dependent inhibition of collagen and arachidonic acid (AA) induced platelet aggregation with ID50 of 4.2 and 20.1 ng/ml for PGI2 respectively 43.3 and 170.2 ng/ml for Hoe 892. These effects could be potentiated by the phosphodiesterase inhibitor theophylline. Single oral administration of Hoe 892 in conscious rabbits inhibited platelet aggregation for more than 3 hrs with an ID50 of 0.2 mg/kg using collagen and 1.5 mg/kg using AA. These doses were without influence on systemic blood pressure (BP) in conscious rabbits. Intravenous injection of Hoe 892 induced a dose dependent decrease of systemic BP in anesthetized rats (ED25 of 2.2 micrograms/kg) and in the rats with acute renal hypertension. Hoe 892 stimulated renin release in anesthetized rats. The hemodynamic profile in anesthetized dogs (0.5 micrograms/kg/min i.v.) was characterized by a decrease of systemic BP, left ventricular pressure, pulmonary artery pressure, total peripheral resistance and in increase in heart rate, cardiac output and dp/dt max, thus demonstrating arteriolar vasodilation. In conscious dogs with two kidney, two wrapped hypertension oral treatment for 1 or 5 days resulted in a marked reduction of BP.
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PMID:The orally active thia-imino-prostacyclin Hoe 892: antiaggregatory and cardiovascular activities. 640 94

We examined whether the excretory effect of atrial natriuretic peptide could be antagonized by intravenously administered bradykinin or by elevated endogenous kinin levels attained during converting enzyme inhibition. Urinary volume and sodium and potassium excretion were determined every 20 minutes in female, anesthetized Sprague-Dawley rats (weight, 0.19 to 0.22 kg) infused with 10 microL/min isotonic glucose. In some experiments, urinary cGMP content was measured by radioimmunoassay. Two intravenous boluses of 209 pmol (0.5 micrograms) atrial natriuretic peptide were given before and after the injection of test substances, and the response ratio was used to quantify inhibition. Single injections of 94.3 or 142 pmol (100 or 150 ng) bradykinin, 3 minutes prior to atrial natriuretic peptide, inhibited the excretion of water, sodium, and potassium by 70%, 75%, and 50%, respectively. Larger (236 to 472 pmol) or smaller (23.6 to 47.2 pmol) bradykinin doses were ineffective. None of the bradykinin doses tested affected basal urinary output, systemic pressure, or the modest depressor effect of atrial natriuretic peptide. The anti-atrial natriuretic peptide effect of bradykinin was completely prevented by the kinin receptor antagonist Hoe 140. Converting enzyme inhibition with ramipril (96 nmol IV) also blunted atrial natriuretic peptide diuresis and natriuresis by 70% and reduced urinary cGMP excretion by 50%. These effects of ramipril were mediated by endogenous kinin accumulation, since they were abolished by pretreatment with Hoe 140. It is concluded that intrarenal kinins modulate the renal actions of atrial natriuretic peptide, and at a precise concentration bradykinin strongly antagonizes atrial natriuretic peptide by preventing its transduction mechanism.
Hypertension 1995 Dec
PMID:Inhibition of atrial natriuretic peptide excretory action by bradykinin. 749 89

Angiotensin-converting enzyme (ACE) inhibitors can improve cardiac function independent of their blood pressure (BP)-lowering actions. We investigated the effect of chronic subantihypertensive ACE inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRSP). Animals were treated in utero and subsequently to age 20 weeks with the ACE inhibitor perindopril (0.01 mg/kg/day). The contribution of endogenous bradykinin (BK) potentiation to the actions of the ACE inhibitor was assessed by cotreatment with the BK beta 2-receptor antagonist Hoe 140 (500 micrograms/kg/day subcutaneously, s.c.) from age 6 to 20 weeks and by measurement of myocardial prostacyclin and cyclic GMP concentrations. Chronic low-dose perindopril treatment had no effect on development of hypertension and left ventricular hypertrophy (LVH), but perindopril improved cardiac function, as demonstrated by increased LV pressure (LVP) (19.4%) and LVdp/dtmax (27.8%) but no change in heart rate (HR). The activities of lactate dehydrogenase (LDH) and creatine kinase (CK) as well as lactate concentrations in the coronary venous effluent were reduced by 39.3, 50, and 60.6%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and CK were increased by 16.3, 33.1, and 28.2%, respectively. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by concomitant chronic BK receptor blockade. Cardiac prostacyclin concentrations were threefold elevated in perindopril-treated animals whereas cardiac cyclic GMP concentration remained unchanged as compared with that of controls. Our data demonstrate that chronic low-dose ACE inhibitor treatment can improve cardiac function and metabolism by potentiating endogenous BK.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of low-dose treatment with perindopril on cardiac function in stroke-prone spontaneously hypertensive rats: role of bradykinin. 752 3


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