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

Angiotensin converting enzyme (ACE) inhibitors are used for the treatment of hypertension and congestive heart failure. However, ACE not only cleaves angiotensin I but is also responsible for the degradation of bradykinin. Therefore, renin inhibitors which block the system at an early step without influence on bradykinin should be devoid of side effects. Since renin has a very strong species specificity, it was necessary to develop new techniques to measure arterial pressure as well as hypertension models in primates in order to select orally active renin inhibitors. Remikiren (Ro 42-5892, CAS 126371-83-3) is a very potent renin inhibitor in vitro (IC50 for human renin = 0.7 nmol/l) and in vivo. Despite short lasting biochemical changes the arterial blood pressure decrease induced by remikiren is very long lasting (over 24 h). Several in vivo experiments have shown that remikiren is specific for renin and does not decrease arterial pressure by an unrelated mechanism. In sodium depleted monkeys, the blood pressure decrease induced by remikiren was similar to the blood pressure decrease induced by cilazapril, an ACE inhibitor. Clinical results seem to confirm the preclinical findings and show that remikiren is indeed a potent orally active renin inhibitor inducing a long lasting blood pressure decrease.
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PMID:Discovery of remikiren as the first orally active renin inhibitor. 849 74

Drug induced modification of the renin-angiotensin system is of established benefit in the treatment of hypertension and heart failure. The responses to the angiotensin converting enzyme (ACE) inhibitor enalapril (CAS 75847-73-3) have been studied in essential hypertension and normotensive controls. The kinetics and dynamics of enalapril have been characterised in an integrated concentration-effect model to identify factors underlying responsiveness to the ACE inhibitor. In addition models to predict the response to long-term treatment from changes after the first dose have been developed. Enalapril response could be described by a non linear (Emax) model defined by two parameters - the maximum response (Emax) and the drug concentration required to cause 50% of the maximum response (C50). Acute dosing accurately predicted the Emax after 6 weeks treatment. In addition to individual pharmacokinetics, pretreatment blood pressure was the most important determinant of response to enalapril. In caucasian salt-replete essential hypertension neither age nor plasma renin activity were major factors. However, in states of sodium restriction and/or diuretic treatment, the response to enalapril was greatly increased. The angiotensin II receptor antagonist, losartan has been reported to be without effect on blood pressure in salt-replete normals. Salt restriction together with furosemide for 3 days led to dose-related falls in blood pressure in normal subjects after losartan 25-100 mg. Concentration-effect analysis can be used to describe blood pressure responses, to predict the responses to long-term treatment and also to identify quantitatively important factors determining the response in individual patients.
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PMID:Inhibitors of the renin-angiotensin system. Clinical pharmacology studies on kinetics, dynamics and concentration-effect relationships. 849 75

The hemodynamic effects of celiprolol (CAS 56980-93-9), a betablocker with beta 1 antagonist and beta 2 agonist properties, were compared with those of atenolol (CAS 29122-68-7) in 12 patients with mild to moderately severe hypertension (diastolic BP 95-110 mmHg). Celiprolol and atenolol lead to a similar and significant reduction of systolic and diastolic blood pressure (p < 0.005). However, with celiprolol heart rate at rest was significantly less depressed then with atenolol (p = 0.004) and showed a distinctly less pronounced depression of heart rate with exercise (p = 0.004). Cardiac output at rest was reduced by 19% under atenolol, but was increased by 9% under celiprolol treatment; in this respect, the two medications differed significantly (p = 0.03). The adaptation of heart rate and cardiac output to exercise was better with celipropol as compared to atenolol treatment. The difference between arm arterial pressure and ankle occlusion pressure at rest was not significantly influenced by atenolol, whereas celiprolol treatment increased this difference by a mean of up to 16 mmHg (p = 0.009). This different effect on peripheral arterial circulation was even more pronounced after exercise. Both celiprolol and atenolol increased blood cell flow velocity in the nailfold capillaries, but this increases was statistically only significant with celiprolol (p = 0.047). These results demonstrate that the hemodynamic effects of celiprolol were significantly different from those of atenolol; celiprolol produces less bradycardia, increases cardiac output at rest and decreases peripheral arterial resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Different hemodynamic effects of celipropol and atenolol in patients with mild to moderate hypertension. 857 24

Antihypertensive Efficacy and Tolerability of Isradipine in Patients with Severe Hypertension/Results of an open multicenter study. In this open multicentre study 55 patients (mean age 51.2 years) with severe hypertension (diastolic blood pressure > 115 mmHg) were treated for seven weeks with the calcium antagonist of the dihydropyridine type isradipine (CAS 75695-93-1, Lomir). If necessary, metoprolol or enalapril were added to the regimen. Before inclusion into the active treatment phase, responsiveness of the patients to a single administration of isradipine (5 mg) was compared with placebo. Preexisting antihypertensive therapy (18 patients) was to be maintained during the study period. Blood pressure was recorded with an automatic device. During the 7-week period blood pressure decreased from 173.7/124.8 mmHg to 143.2/97.8 mmHg. Both the group with isradipine monotherapy (n = 32) and the combination group (n = 11) showed a significant reduction in systolic and diastolic blood pressure. Diastolic blood pressure response, defined as a decline of more than 15 mmHg, was noted in 87.5% (monotherapy) and 72.7% (combination group) of patients. On the whole, blood pressure was normalized in 27.9% of the participants. Nineteen patients experienced 43 adverse events, most of which were rated mild to moderate. Therapy was withdrawn in only one patient (due to ankle edema). The most frequent adverse event was headache (20.9%).
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PMID:[Antihypertensive effect and adverse effects of isradipine in patients with sever hypertension. Results of an open multicenter study]. 876 50

The pharmacodynamic and toxicological profile of the new angiotensin converting enzyme (ACE) inhibitor moexipril (CAS 82586-52-5) and its active diacid metabolite moexiprilat were studied in vitro as well as in vivo. In vitro, moexiprilat was a potent inhibitor of ACE in guinea pig serum as well as on purified ACE from rabbit lung with IC50 values of 2.6 and 4.9 nmol/l, respectively. Both, moexipril and moexiprilat inhibited the angiotensin I (ANG I)-induced contractions of rabbit aorta concentration-dependently, whereas contractions by other agents were not affected, indicating a high selectivity of both compounds for ACE. Similar results were obtained in vivo in experiments investigating the blood pressure increasing response to intravenous injection of ANG I or ANG II in conscious normotensive rats and dogs after oral or intravenous application of moexipril or moexiprilat, respectively. The antihypertensive effects of the oral application of moexipril were studied in models of hypertension in the rat as well as in renal hypertensive dogs. In renal hypertensive rats, moexipril (0.03-10 mg/kg p.o.) caused a dose-dependent decrease in blood pressure with a threshold dose of 0.3 mg/kg. Once daily treatment of the animals with 3 mg/kg/d for 5 days lowered mean blood pressure by about 70 mmHg and blood pressure was maintained on this low level for the experimental period. In spontaneously hypertensive rats, oral administration of moexipril (30 mg/kg/d) for 5 days caused a progressive lowering of mean blood pressure from pre-treatment values of 180 +/- 7 mmHg to a trough on day 4 of 127 +/- 4 mmHg. In perinephritic hypertensive dogs, oral administration of moexipril (10 mg/kg) in combination with hydrochlorothiazide (10 mg/kg) caused a drop of mean blood pressure by 25 mmHg from pre-treatment control, which persisted for 24 h. In all these models, the action was characterized by a rapid onset and a long duration of action. After cessation of treatment, a gradual return to baseline values was observed. In contrast, only slight blood pressure lowering effects were seen in normotensive rats at high doses (100 mg/kg p.o.). The general pharmacological properties of moexipril were also studied in generally accepted models in vitro and in vivo. In doses or concentrations more than 100 times higher than those causing ACE inhibition, no effects were observed on the central nervous system, on isolated smooth muscle preparations, the digestive system, the kidney or the lung. Additionally, moexipril is devoid of anti-inflammatory properties and has no effect on platelet function. On the cardiovascular system, the effects observed can be attributed to ACE inhibition by moexipril. Repeated dose toxicity studies in rats and dogs revealed the heart and kidneys as target organs. These effects, based on highly exaggerated pharmacological activity, are comparable to other ACE-inhibitors. No potential for mutagenic or carcinogenic activity and no evidence of reproductive toxicity was apparent for meoxipril. The preclinical data indicate that moexipril possesses a high degree of specifity as an ACE-inhibitor without relevant side effects or gross toxicity.
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PMID:Pharmacological and toxicological studies of the new angiotensin converting enzyme inhibitor moexipril hydrochloride. 907 32

The objective of this study was to compare the effectiveness of three treatment methods available for treatment of previously medicated patients with mild to moderate hypertension. The comparison was made between adjusting or increasing previous medication and switching the previous drug treatment to lisinopril (CAS 76547-98-3) or lisinopril hydrochlorothiazide (CAS 58-93-5) therapy and in both of these treatment groups the effect of additional intensified health education was tested. An open, randomised, controlled multi-centre study lasting 36 weeks involving 189 doctors and 69 nurses was carried out in 155 centres of primary health care and occupational health care system in Finland. The study population consisted of 1156 patients, age 30-70 years, (mean DBP 95-115 mmHg in the last three to five measurements during follow-up). The number of patients achieving target pressure (DBP < 90 mmHg) at the end of the study, defined daily doses (DDD) of antihypertensive drugs and side-effects in different treatment groups were regarded as the main outcome measures of the study. After exclusions and drop-outs the final analysis was carried out with 900 patients, 419 women (46.6%) and 481 men (53.4%). Patients receiving lisinopril treatment achieved target pressure significantly more often (p < 0.001) than those continuing their previous or adjusted medication at 36 weeks (59.2 and 55.5% vs 40.3 and 42.7%). Only a small additional but statistically non-significant blood pressure lowering effect was achieved with intensified non-pharmacological treatment at weeks 12 and 24, but this difference had disappeared at week 36. The mean DDDs of different antihypertensive drugs did not differ between groups except for female patients on previous or adjusted medication not receiving health education, the mean DDD being significantly (p < 0.05) higher at weeks 24 and 36 in this group. The profile of adverse effects at the end of the study clearly favoured patients on lisinopril treatment except for cough which was reported in 18% of patients vs 10% in the control groups. 81 patients on lisinopril treatment were withdrawn from the study because of cough. The results showed that hypertensive patients with poor treatment control benefit from all three approaches. A greater proportion of patients on lisinopril treatment achieved target pressure and also experienced fewer side effects than those continuing on adjusted previous medication. Intensified personal health education given once a month during six months had only a small additional beneficial effect on reaching the target pressure and this effect was lost in three months after the health education period.
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PMID:Effects of lisinopril or lisinopril/hydrochlorothiazide compared with adjusting of previous medication and intensifying non-pharmacological treatment in patients with mild to moderate hypertension. 907 33

Acute hepatic porphyrias can be induced by several drugs and acute attacks of porphyrias are often associated with severe hypertension. Therefore it is important to know if an antihypertensive drug used has porphyrogenic potency or not. As previously demonstrated in normal rats the alpha-receptor blocker clonidine (CAS 4205-90-7) has no significant influence on the porphyrin metabolism. Pretreatment of rats with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or allyl-isopropyl-acetamide (AIA) induces hepatic delta-aminolaevulinic acid synthase (ALA-S) and increases the urinary excretion of porphyrin precursors (ALA and PBG) comparable to the latent phase of acute hepatic porphyrias in humans. Clonidine did not induce hepatic ALA-S or urinary excretion of ALA or PBG in normal as well as in DDC or AIA pretreated rats. Moreover the induction of P4501A1 (7-ethoxyresorufin-O-deethylase) by DDC was abolished by simultaneous application of clonidine. From these findings one can probably conclude that clonidine is a safe drug in human acute hepatic porphyria.
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PMID:Effects of clonidine in a primed rat model of acute hepatic porphyria. 923 51

These studies were designed to investigate the protective effects of the new angiotensin II receptors antagonist BAY 10-6734 (6-n-butyl-4-methoxycarbonyl-2-oxo-1[(2'-(1H-tetrazol-5-yl) -3-fluorobiphenyl-4-yl)methyl] 1,2-dihydropyridine, CAS 156001-18-2) on haemodynamic, hormonal, renal, and structural parameters in renin transgenic rats (TGR(mRen2)27), salt-loaded Dahl S and R rats, and salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) in long-term trials. Study 1: In SHR-SP the development of blood pressure, cardiac hypertrophy, and the deleterious effects of salt loading on kidney structure and kidney function was prevented by BAY 10-6734. Study 2: In salt-loaded Dahl S rats with a suppressed plasma renin activity treatment with BAY 10-6734 did not delay the increase in blood pressure but prevented cardiac hypertrophy and the increase in plasma ANP (Atrial natriuretic peptide). Study 3: TGR develop malignant hypertension associated with cardiac hypertrophy, elevated left-ventricular end-diastolic pressure and increased plasma ANP. After 6 weeks of treatment with BAY 10-6734 (30 mg/kg p.o. bid) cardiac pump function was improved and cardiac hypertrophy was reversed in this angiotension dependent form of hypertension. The beneficial effects of BAY 10-6734 in these different animal hypertension models are also emphasized by a reduction in mortality.
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PMID:Long-term blockade of the angiotensin II receptor in renin transgenic rats, salt-loaded Dahl rats, and stroke-prone spontaneously hypertensive rats. 934 14

Patients with severe stenoses of the carotid and renal arteries define a population at high risk but most of them are asymptomatic. Here arises the question of who must be tested and what would be the actual utility of a screening program in the general or selected populations. The aim of this study was to assess the efficacy of a duplex-based screening for carotid and renal arteries stenoses, in a subset of patients with aortoiliac arterial disease, in terms of: (1) prevalence of occlusive disease of the carotid and renal arteries detected and surgical procedures generated; (2) analysis of clinical variables that could be useful to increase the suspicion index for the disease; and (3) predictive values of duplex scanning adjusted for the observed prevalence. One hundred sixty eight consecutive patients selected for elective aortoiliac surgery were included. Carotid duplex scanning, renal duplex scanning and/or aortorenal angiography, and recording of clinical predictive variables were obtained in all the patients. The statistical analysis included prevalence rates, multivariate analysis, and predictive values of carotid and renal duplex scanning adjusted for the observed prevalence. Greater than 50% asymptomatic stenosis in at least one of the internal carotid arteries (CAS > 50%) was detected in 47 (28%) patients [95% confidence interval (CI): 21.2%-34.8%]; 67 (39.9%) patients showed greater than 60% stenosis in one or both renal arteries (RAS > 60%) (95% CI: 32.5%-47.3%). Based on current surgical indications, carotid endarterectomy was performed in 24 (14.3%) patients and a bypass to the renal artery in 30 (17.8%) patients. Logistic regression analysis accepted the following variables, in this order: carotid bruit, age, and ankle/brachial index for predicting carotid artery stenosis; and hypertension and CAS for predicting renal artery stenosis. Based on previous validation studies of duplex scanning accuracy, estimated positive predictive values for significant stenosis of the carotid and renal arteries showed a range of 80.5%-89.1% and 82.3%-89.7%, respectively. Routine screening of the carotid and renal arteries may be justified in those patients with aortoiliac aneurysmal and occlusive disease, provided there is a high prevalence of clinically significant lesions and sufficient predictive values of duplex scanning are obtained.
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PMID:Screening for carotid and renal artery stenoses in patients with aortoiliac disease. 945 91

Experiments were performed to characterize the pharmacology of Sch 50971 ((+)-trans-4-(4(R)-methyl-3(R)-pyrolidinyl)-1H-imidazole dihydrochloride, CAS 167610-28-8), a novel histamine H3 receptor agonist. The activity of Sch 50971 was compared with that of (R)-alpha-methylhistamine (CAS 75614-87-8), a potent and moderately selective agonist of histamine H3 receptors, in a series of in vitro and in vivo assays. Sch 50971 is a high affinity, selective H3 receptor agonist in vitro and in vivo. Sch 50971 inhibits [3H]-N-alpha-methylhistamine (CAS 673-50-7) binding to the histamine H3 receptor in human brain (Ki = 5.0 nmol/l) and guinea pig brain (Ki = 2.5 nmol/l). Sch 50971 also inhibits electric field stimulated guinea pig ileum contractions (pD2 = 7.47) and decreases [3H]-norepinephrine (CAS 51-41-2) release (pD2 = 7.48) from guinea pig pulmonary artery by activation of presynaptic inhibitory H3 receptors. The in vitro effects of Sch 50971 are antagonized by low concentrations of a selective H3 antagonist, thioperamide (CAS 106243-16-7). Sch 50971 has low affinity (IC50's > 10 mumol/l) for histamine H1, dopamine D1 and D2, serotonin 5-HT2 and muscarinic cholinergic receptors. It also does not exhibit histamine H2-antagonist activity. In guinea pigs and cats, Sch 50971 exhibits in vivo H3 agonist activity. Sch 50971 inhibits sympathetic hypertension evoked by stimulation of the medulla oblongata in anesthetized guinea pigs (ED30 = 0.3 mg/kg i.v., ED30 = 1.0 mg/kg i.d.). Sch 50971 also inhibits the effects of sympathetic nerve stimulation on nasal resistance in cats. In these assays, Sch 50971 exhibits an efficacy and potency comparable to H3-agonist (R)-alpha-methylhistamine. However, under in vivo conditions, Sch 50971 does not exhibit histamine H1-mediated responses that are seen with (R)-alpha-methylhistamine at doses close to those that produce H3 effects. Therefore, Sch 50971 is a novel, potent and selective agonist of histamine H3 receptors with an improved in vitro and in vivo receptor profile selectivity compared with (R)-alpha-methylhistamine.
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PMID:Studies on the pharmacology of the novel histamine H3 receptor agonist Sch 50971. 979 13


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