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

Effects of a newly developed Ca2+ channel antagonist, (4R)-(-)-2-(nicotinoylamino)ethyl 3 nitrooxypropyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) 3,5-pyridine-dicarboxylate (CD-832), on hypertensive complications in stroke-prone spontaneously hypertensive rats (SHRSPs) were compared with effects of diltiazem. We examined changes in histological and hematological parameters in SHRSPs given the following treatments at 8 to 20 weeks of age: (a) CD-832; (b) diltiazem; (c) no treatment. CD-832 and diltiazem were added to the diet, in doses of 0.05 and 0.15% (approximately 30 and 100 mg/kg per day), respectively, throughout the experimental period. In untreated control SHRSPs, systolic blood pressure increased and severe renal lesions such as fibrinoid necrosis, smooth muscle proliferation, glomerular and tubular lesions and some cardiac fibrosis were observed at age 20 weeks. 12-week repeated-administration of CD-832 and diltiazem led to a comparable hypotension and decreased heart rate. CD-832 and diltiazem decreased the ratios of weights of kidney and heart to body weight and the concentration of blood urea nitrogen and creatinine in serum, compared to values in controls. In SHRSPs treated with CD-832 and diltiazem, the incidence of renal lesions and myocardial fibrosis was significantly reduced when compared with control SHRSPs. These results suggest that 12-week repeated-administration of CD-832 prevents the development of hypertension and the incidence of organ damage in SHRSPs. CD-832 and diltiazem were equally efficacious in preventing organ damage but this organ-protective effect was obtained at a lower dose for CD-832 (30 mg/kg per day) than that of diltiazem (100 mg/kg per day).
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PMID:Protective effects of CD-832 on organ damage in stroke-prone spontaneously hypertensive rats. 927 79

Abnormal smooth-muscle contractility may be a major cause of disease states such as hypertension, and a smooth-muscle relaxant that modulates this process would be useful therapeutically. Smooth-muscle contraction is regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myofilaments: the former activates myosin light-chain kinase and the latter is achieved partly by inhibition of myosin phosphatase. The small GTPase Rho and its target, Rho-associated kinase, participate in this latter mechanism in vitro, but their participation has not been demonstrated in intact muscles. Here we show that a pyridine derivative, Y-27632, selectively inhibits smooth-muscle contraction by inhibiting Ca2+ sensitization. We identified the Y-27632 target as a Rho-associated protein kinase, p160ROCK. Y-27632 consistently suppresses Rho-induced, p160ROCK-mediated formation of stress fibres in cultured cells and dramatically corrects hypertension in several hypertensive rat models. Our findings indicate that p160ROCK-mediated Ca2+ sensitization is involved in the pathophysiology of hypertension and suggest that compounds that inhibit this process might be useful therapeutically.
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PMID:Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. 935 12

The new loop diuretic torasemide belongs to the pyridine sulfonylurea class. It is well absorbed and yields a bioavailablity of about 80% in healthy individuals, even higher in patients with oedema. This is roughly double that of the 'classical' loop diuretic furosemide (frusemide) [26 to 65%]. Torasemide is highly bound to protein (99%) as is furosemide. The volume of distribution of torasemide was determined as 0.2 L/kg as compared with 0.11 to 0.18 L/kg for furosemide. Torasemide undergoes extensive hepatic metabolism; only 20% of the parent drug is recovered unchanged in the urine. For comparison only 10 to 20% of furosemide undergoes phase II metabolisation (to the glucuronide). In chronic renal failure the renal clearance of torasemide decreased in proportion to the decrease of the patients' glomerular filtration rate, whereas the total plasma clearance (3 times that of the renal clearance) appeared to be independent of renal function. As expected, the renal excretion of torasemide metabolites is significantly retarded in renal disease. The pharmacokinetics of torasemide are significantly influenced by liver disease. Total plasma clearance of torasemide was reduced to about half of that found in the control group, yielding an increase in elimination half-life. A greater than normal fraction of torasemide was recovered in the urine of patients with cirrhosis. In contrast, the kinetics of furosemide appeared to depend more on kidney function than on liver disease. The pharmacodynamics of torasemide are principally the same as those reported from conventional loop diuretics due to their interference with one binding site in the thick ascending limb of Henle's loop, the Na+:K+:2Cl- carrier. The maximum natriuretic effect of all loop diuretics amounts to about 3 mmol Na+/min. Members of this class differ, however, with respect to their intravenous potency or affinity for the receptor, respectively: bumetanide > piretanide > torasemide > furosemide. So far, the only loop diuretic which has been shown to effectively lower high blood pressure is torasemide. This effect occurs at the low dose of 2.5 mg/day.
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PMID:Clinical pharmacokinetics and pharmacodynamics of torasemide. 947 71

It is well-known that cardiac hypertrophy and arterial and renal dysfunction are serious complications of hypertension. Therefore, we investigated the chronic effects of 606A (2-propyl-3-[2'(1H-tetrazole-5-yl)biphenyl-4-yl]methyl-5-acetyl-4,5,6,7- tetrahydro imidazo [4,5-c]pyridine-4-carboxylic acid disodium salt), a novel AT1-receptor antagonist, on these complications of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP) using Wistar Kyoto rats (WKY) as the control. After 8 weeks treatment from 16 weeks of age with 606A by a subcutaneously implanted osmotic pump, cardiac function, cardiac weight, acetylcholine-induced endothelium-dependent relaxation in the isolated aorta and renal function were estimated. Furthermore, wall thickness of the left ventricle was studied morphologically. We found that 606A (0.3 mg, 1 mg and 3 mg/head/day) dose-dependently lowered blood pressure without any effects on heart rate in SHRSP. Long-term treatments with 606A significantly reduced cardiac weight, left ventricular wall thickness and left ventricular end diastolic pressure, whereas it did not affect cardiac contractility. Endothelium-dependent relaxation of the aorta was recovered, and total protein excretion as well as total protein excretion/creatinine excretion ratio was reduced to the level of WKY by the treatment. These results suggest that 606A not only has a hypotensive effect but also protects cardiac, renal and vascular tissues from complications of hypertension. Thus, 606A could be an useful drug for treatment of hypertension.
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PMID:A novel angiotensin II-receptor antagonist, 606A, induces regression of cardiac hypertrophy, augments endothelium-dependent relaxation and improves renal function in stroke-prone spontaneously hypertensive rats. 954 Dec 81

This study was carried out to characterize a novel angiotensin II-receptor antagonist, TA-606, (3-pentyloxy) carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2'(1H-tetrazole-5-yl) biphenyl-4-yl]methyl-4,5,6,7-tetrahydro imidazo [4,5-c] pyridine-4-carboxylate hydrochloride, which is a newly synthesized prodrug of 606A. In anesthetized rats, 606A inhibited angiotensin II-induced pressor response with a median inhibitory concentration (IC50) of 6 microg/kg, i.v., and was 8 times more potent than EXP3174, an active metabolite of losartan. Bioavailability of TA-606 was 11 times higher than that of 606A in Sprague-Dawley rats, with consistent hypotensive potencies in spontaneously hypertensive rats (SHRs). In conscious renal hypertensive rats (RHRs) and conscious SHRs, TA-606 lowered the blood pressure without any effects on the heart rate, and its effective dose for 30 mm Hg (ED30) values were 0.14 and 0.21 mg/kg, p.o., respectively. The effect of TA-606 lasted > 10 h in both models. Moreover, the effect of TA-606 was approximately 30 and 10 times more potent than those of losartan in RHRs and SHRs, respectively. TA-606 did not affect the blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. TA-606 given for 12 weeks attenuated the development of hypertension in stroke-prone SHRs. These results indicate that TA-606 is a potent angiotensin II-receptor antagonist with antihypertensive efficacy. Thus TA-606 is suggested to be a possible useful agent in the treatment of hypertension.
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PMID:Pharmacologic profile of TA-606, a novel angiotensin II-receptor antagonist in the rat. 955 6

The anodic and cathodic behavior of nisoldipine, 3-isobutyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3 ,5-dicarboxylate, are reported. This drug belongs to the nitroaryl-1,4-dihydropyridine family, known as calcium channel antagonist and employed in therapeuticalls as peripheral and cerebral vasodilators, in the treatment of the arterial hypertension. The cathodic response corresponds to the reduction of the nitroaromatic group to generate the hydroxylamine derivative. The study by dc and d.p.p. reveals the appearance of four signals depending on pH: Signal I (pH 1-11.5) R - NO2 + 4H+ + 4e- --> R - NHOH + H2O; Signal II (pH 1-5) R - N+H2OH + 2H+ + 2e- --> RN+H3 + H2O; Signal III (pH > 11.5) R - NO2 + e- <--> R - NO2.-; Signal IV (pH > 11.5) R - NO2.- + 3e- + 4H+ --> R - NHOH. In contrast, the anodic response corresponds to the oxidation of the 1,4-dihydropyridine ring to generate the corresponding pyridine derivative. Both, cathodic (d.p.p.) and anodic signals (d.p.v.) were employed to develop analytical methodology for the determination of the drug. The repeatability of the measurements for both methods was adequate with R.S.D. of 1.4% (n = 10) and 2.1% (n = 10) for d.p.p. and d.p.v., respectively. Also recovery studies, 103.8% (R.S.D. 2.65%) by d.p.p. and 98.7% (R.S.D. 2.1%) by d.p.v. show that the accuracy and precision of the developed methods were adequate. The analytical methods were successfully applied to the determination of nisoldipine in both tablets and capsules. In addition, a preliminary study of the photostability of nisoldipine (using both UV and artificial day light) was completed. The identity of the main electroactive photodegradation products by GC with spectrometry detection is provided.
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PMID:Electrochemical study of nisoldipine: analytical application in pharmaceutical forms and photodegradation. 958 Mar 40

The antihypertensive action of KRN4884 (5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine ), a newly synthesized 3-pyridine derivative was examined in conscious spontaneously hypertensive rats (SHRs). A single administration of KRN4884 (0.5, 1.5 mg/kg, p.o.) produced a dose-dependent and long-lasting antihypertensive effect. The 7-day repeated administration of KRN4884 (0.5, 1.5 mg/kg, p.o.) did not diminish antihypertensive activity during the treatment period or induce rebound hypertension after the discontinuation of treatment. To examine the mechanism of the antihypertensive effect of KRN4884, we studied its vasorelaxing effects in rat isolated aortae precontracted with 25 mM KCl. Single application of KRN4884 showed a slower onset of inhibitory action than that of levcromakalim. KRN4884 was approximately 26-fold more potent than levcromakalim and 10-fold less potent than nilvadipine. KRN4884- and levcromakalim-induced vasorelaxation were antagonized by glibenclamide. Furthermore, we observed the recovery of the contraction inhibited by these drugs after repeated washing. The inhibitory effect of KRN4884 was restored only after four washes, whereas that of levcromakalim was completely restored after one wash. The nilvadipine-induced inhibitory effect was the most resistant to washing among these drugs. These results suggest that KRN4884 shows a long-lasting antihypertensive effect based on its potent potassium channel-opening action. The long-lasting action may be due to a slow association/dissociation with/from the binding sites on vascular smooth muscle.
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PMID:Antihypertensive properties of KRN4884, a novel long-lasting potassium channel opener. 1002 39

Ca2+ channels of the L-type were assayed in human peripheral blood lymphocytes of normotensive control subjects and of essential hypertensives using radioligand binding assay techniques. The dihydropyridine Ca2+ channel blocker [3H](+)-PN 200-110 [isopropyll-4-(2,1,3-benzoxadiazol-4-yl)1,4-dihydro-5-methox ycarbonyl-2,6-dimethyl-3-pyridine carboxylate] was used as a ligand. [3H](+)-PN 200 110 was bound specifically to human peripheral blood lymphocytes in a manner consistent with the labeling of Ca2+ channels of the L-type. No significant differences in the dissociation constant (Kd), in the maximum density of binding sites (Bmax) or in the pharmacological profile of [3H](+)-PN 200 110 binding were found between normotensive subjects and different degree essential hypertensives. Analysis of the intralymphocytic free Ca2+ concentration did not reveal differences between normotensive subjects and essential hypertensives. Although hypertension is associated with altered membrane handling of Ca2+, no changes in the expression of peripheral blood lymphocyte Ca2+ channels of the L-type or in intralymphocytic Ca2+ concentrations were found in essential hypertensives. Human peripheral blood lymphocytes therefore cannot represent a peripheral marker of altered Ca2+ handling in hypertension.
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PMID:Ca2+ channels of the L-type in peripheral blood lymphocytes of essential hypertensives. 1007 83

Cicletanine ((+/-)3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c ] pyridine) 3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c] pyridine) is a novel antihypertensive agent that has been shown to possess vasorelaxant, natriuretic, and diuretic properties in preclinical and clinical studies. The mechanism(s) by which cicletanine induces these biological effects has not been definitely established, although it appears to differ from that of other classes of antihypertensive drugs. The salidiuretic activity appears to be the result of an action of the sulfoconjugated metabolite of cicletanine, which inhibits the apical Na+-dependent Cl-/HCO3- anion exchanger in the distal convoluted tubule. The mechanism of the vasodilating effect of cicletanine seems to be complex; it may include stimulation of vascular prostaglandin synthesis, inhibition of the low Km cyclic GMP phosphodiesterases, and blockade of Ca2+ channels either directly or indirectly through a K+-channel opening effect. The drug has also been shown to interact with alpha-adrenergic, vascular histamine, and muscarinic receptors. We have also reviewed the other vascular effects of the drug, such as stimulation of nitric oxide synthesis and inhibition of both myosin light chain kinase and protein kinase C. Cicletanine protects cardiovascular and renal systems against the injuries induced by hypertension, in addition to its lowering of arterial pressure. Similarly to the vasorelaxant action of cicletanine, the various properties of the drug likely contribute to its protective effect against injury in hypertension.
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PMID:Cicletanine: new insights into its pharmacological actions. 1042 10

Losartan is a prodrug type Angiotensin II (Ang II) AT1-receptor antagonist whose efficacy depends on the oxidase activity of individuals. In addition, losartan affects the normal blood pressure and can potentially cause orthostatic hypotension. In this report, we examined effects of TA-606 [(3-pentyloxy)carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2'(1H -tetrazole-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydro imidazo[4,5-c]pyridine-4-carboxylate hydrochloride], a prodrug type AT1-receptor antagonist, on the Ang II-induced pressor response and hypertension in a dog model, which is known to have lower oxidase activity than other species, and orthostatic hypotension in the rat tilting model. The results indicated that TA-606 was immediately converted to its active form, 606A, after oral administration, and it demonstrated potent inhibition of the Ang II-induced pressor response in conscious normotensive dogs (0.3-3 mg/kg, p.o.). It also had a potent hypotensive effect in conscious 2K,1C-renal hypertensive dogs (0.3-10 mg/kg, p.o.). These effects of TA-606 were 32 and 30 times more potent than those of losartan, respectively. In addition, EXP3174 (1, 10 mg/kg, i.v.), an active metabolite of losartan, but not 606A (1-30 mg/kg, i.v.) showed an orthostatic hypotensive effect in the rat tilting model. These results suggest that TA-606 is an effective Ang II receptor antagonist without the drawbacks of losartan.
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PMID:Comparative study of TA-606, a novel angiotensin II receptor antagonist, with losartan in terms of species difference and orthostatic hypotension. 1058 Mar 72


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