Comparative effects of chronic ACE inhibition and AT1 receptor blocked losartan on cardiac hypertrophy and renal function in hypertensive patients.

The present study describes the effects of losartan and the angiotensin-converting enzyme inhibitor enalapril on blood pressure, echocardiographically calculated left ventricular mass, renal function evaluated by glomerular filtration rate and quality of life. The renin-angiotensin-aldosterone system is of importance for cardiovascular growth. There is substantial experimental documentation in animals that the angiotensin II antagonist, losartan, decreases the cardiac hypertrophy response caused by elevated arterial pressure as well as intravascular volume overload. However, data in humans is scarce. This is a 3-year, randomised, double-blind study with parallel group design in 50 patients with essential hypertension. The results show that both drugs reduced blood pressure equally effectively, and also left ventricular mass (P < 0.001). After 3 years of treatment glomerular filtration rate significantly increased with losartan (P < 0.005). Serum uric acid fell modestly although significantly, dose-dependent in losartan patients compared with an increase in enalapril patients. A fall in serum potassium from the pre-study period was observed in all patients. There was no difference between treatments in terms of patient satisfaction on quality of life. Both drugs have relatively similar hormonal and haemodynamic effect, with an excellent tolerability profile; they appear to induce comparable blood pressure falls in hypertensive patients in particular, therapy based on specific Ang II blockade may offer advantages in high risk hypertensives if left ventricular hypertrophy is present. Both enalapril and losartan, in improving the renal function attenuating the intrarenal effects of angiotensin II, might be able to reverse the pathophysiology of essential hypertensive kidney disease, and should be first-choice drugs in the treatment of essential hypertension.

Irbesartan effects on renal function in patients with renal impairment and hypertension: a drug-withdrawal study.

The blood-pressure lowering activity, tolerability, and safety of irbesartan was evaluated in 52 hypertensive patients with chronic renal insufficiency. After a 3-week placebo period, once-daily irbesartan was administered for 12 weeks at a daily dose of 150 mg titrated to 300 mg. A second, non-angiotensin-converting enzyme inhibitor, antihypertensive drug was added after 8 weeks as needed. Twenty-four-hour creatinine clearance was determined and renal clearance studies of inulin and para-aminohippurate were done in a subset of 11 patients. Trough sitting blood pressures were reduced at the end of the first week in all groups. At weeks 4, 8, and 12 the reductions in systolic blood pressure/diastolic blood pressure averaged -11.9/-8.7, -10.8/-9.4, and -14.7/-12.1 mm Hg in patients with mild renal insufficiency and -7.7/-6.3, -13.1/-11.8, and -14.1/-10.6 mm Hg in patients with moderate-to-severe renal insufficiency. Creatinine clearance, glomerular filtration rate, and effective renal plasma flow were stable. Irbesartan was withdrawn in only five patients because of adverse clinical or laboratory experience. Hyperkalemia (>6 mEq/l) requiring discontinuation of irbesartan occurred in only one patient. Once-daily irbesartan given as monotherapy at dose of 150-300 mg or in combination with other antihypertensive drugs is effective in reducing blood pressure in hypertensive patients with chronic renal disease. Irbesartan regimens are well tolerated in all groups. In addition, the blood pressure-lowering effect of irbesartan is accompanied by a significant reduction in proteinuria in patients with chronic renal insufficiency.

Effect of oral losartan potassium administration on intraocular pressure in normotensive and glaucomatous human subjects.

The effects of the type 1 angiotensin II receptor antagonist Losartan potassium on intraocular pressure (IOP) were studied. Four groups of subjects were analysed: group A, ten controls; group B, ten patients with essential arterial hypertension and with IOP within the normal range; group C, ten patients with primary open angle glaucoma (POAG), but without essential arterial hypertension; group D, ten patients with arterial hypertension and POAG. The study design was held in a randomized crossover double-blind fashion. Systolic and diastolic arterial pressure, heart rate, pupil diameter, IOP and total outflow facility were recorded at baseline and at 1 hr intervals up to 6 hr, following the oral administration of 50 mg of Losartan potassium and/or placebo. The alternative treatment was given a week later. Drug administration significantly reduced IOP in all subjects. No variation in heart rate and pupil diameter was observed during the follow-up period. Blood pressure dropped only in arterial hypertensive patients (groups B and D). Total outflow facility increased significantly in all groups. Placebo did not induce any variation in all groups. These findings demonstrate that the mechanism by which Losartan potassium reduces intraocular pressure is not mediated by a decrease in blood pressure, but rather it is more specific, confirming the role of the renin-angiotensin system also in the regulation of intraocular pressure in man.

Effects of enalapril and isradipine alone and in combination on blood pressure, renal function and echocardiographic parameters in mild hypertension.

AIMS AND METHODS: A study was carried out to evaluate the influence of antihypertensive treatment with combined low doses of enalapril plus isradipine (5+5 mg daily) compared with those of either drug at a higher dose level (10 mg daily) by double-blind, three-way crossover study (balanced Latin square design) in 102 subjects (mean age 51.9 +/- 7.42 years) with essential hypertension. Left ventricular mass and function were evaluated by M-B mode echocardiography, renal function by glomerular filtration rate (GFR) and by serum and 24-h urinary Na+ and K+ during wash-out period and after 24 weeks of treatment. RESULTS: The supine blood pressure for subjects given placebo was 171/103 mmHg. After 24 weeks of treatment, systolic and diastolic supine blood pressure were significantly lower with 5 mg isradipine plus 5 mg enalapril (134/84 mmHg) than with 10 mg enalapril (137/84 mmHg) or with 10 mg isradipine (144/85 mmHg). Left ventricular posterior wall and septal thickness were significantly and similarly reduced in all groups. Left ventricular systolic and diastolic end diameters were not significantly changed. Left ventricular mass (LVM) was significantly reduced in E plus I group and enalapril group. GFR was not significantly altered. The 24-h urinary Na+ significantly increased with enalapril, more so than isradipine. The combination was tolerated better than either monotherapy. We observed no clinically significant changes in laboratory variables including blood lipoproteins. CONCLUSIONS: The combination of isradipine plus enalapril reduced blood pressure more effectively and was better tolerated than other drug alone. All three groups showed similar changes in echocardiographic indices and no change in renal function.

Reversal of left ventricular hypertrophy following once daily administration of felodipine for two years to elderly subjects with isolated systolic hypertension.

Left ventricular mass sometimes decreases during the treatment of hypertension. In a two-year open study, we investigated the ability of extended release (ER) felodipine (5 or 10 mg), plus chlorthalidone (25 mg), given once daily, to reduce left ventricular mass in 84 elderly patients with isolated systolic hypertension. Drug dosage was determined in an initial stepped-care titration phase lasting six weeks. Mean systolic blood pressure decreased after two years of treatment with 5 or 10 mg of felodipine (p < 0. 001) and the left ventricular mass index decreased too (p < 0.0001). One or two weeks after withdrawal of therapies, blood pressure returned to pretreatment values. We concluded that left ventricular mass can be reduced in elderly patients with isolated systolic hypertension and ventricular hypertrophy who receive felodipine 5-10 mg once daily. This treatment was generally well tolerated.

Antianginal efficacy over 24 hours and exercise hemodynamic effects of once daily sustained-release 300 mg diltiazem and 240 mg verapamil in stable angina pectoris.

The antianginal efficacy of 240 mg sustained release verapamil once daily doses and 300 mg diltiazem was studied in 20 normotensive patients with chronic stable angina pectoris, using a randomized, double-blind crossover design. Patients received a blinded therapy of verapamil placebo and diltiazem placebo for six weeks than only sustained-release diltiazem (SRD) for a long-term phase of three weeks, after a two-week placebo baseline period. Symptom-limited bicycle exercise was longer with the verapamil (510+/-129.9 s) and diltiazem (540+/-124.6 s) than with placebo at baseline (396+/-152.2 s, P<0.005). Verapamil and diltiazem reduced the weekly rate of anginal attacks from 5.1+/-8.6 during placebo to 4.4+/-4.1 with verapamil and 1.9+/-3.2 with diltiazem (P<0.05). The antianginal effects of the two agents are probably mediated by reduction of myocardial oxygen demand at submaximal exercise. In addition, diltiazem appears to provide more symptomatic relief and reduces the weekly number of anginal attacks significantly more than verapamil. Therefore its once-daily administration simplifies the treatment schedule and should improve patients' compliance.

Influence of autonomic tone on QT interval duration.

The autonomic tone has been shown to influence the duration of the QT interval, however the independent contribution of sympathetic and parasympathetic tone is not fully elucidated. The influence of autonomic tone on QT duration was studied in 10 young healthy volunteers by evaluating the changes in QT and RR duration induced by i.v. isoproterenol infusion and by standing before and after i.v. administration of propranolol or atropine. Furthermore, the relationship between RR interval and QT duration was evaluated during nocturnal sinus arrhythmia and submaximal exercise test. Low doses of isoproterenol reduced RR (p < 0.01) but not QT interval duration, while higher doses influenced both RR (p < 0.0001) and QT (p < 0.001) duration. Propranolol did not influence standing-induced shortening of RR and QT intervals; on the contrary, atropine administration abolished standing-induced QT interval shortening, without influencing RR changes. QT duration resulted significantly related to preceding RR interval at peak exercise (r = 0.87, p < 0.001) and during nocturnal sinus arrhythmia (r = 0.73, p < 0.0005), however, the regression lines showing the correlation between QT and preceding RR interval were different. Both sympathetic and parasympathetic tone appear to contribute to heart rate-independent changes in QT duration. In the basal state parasympathetic more than sympathetic tone influences the relation QT-heart rate. Major increases of sympathetic nervous system activity may change the relation QT-heart rate. Thus, in case of abrupt autonomic changes, any proposed formula for heart rate correction of QT may result inappropriate, also in the normal range of heart rate.

Effects of age and hypertension on adrenoceptor-sensitivity evaluated with CD25 and QT/QS2.

BACKGROUND: We studied the effects of age and hypertension on responses to chronotropic dose (CD25) and standing-induced changes in the ratio of electrical systole (QT) to electromechanical systole (QS2) in order to identify their role on beta adrenoceptor sensitivity and to verify the value of QT/QS2 ratio as a noninvasive parameter of beta-adrenoceptor sensitivity. METHODS: We enrolled 33 normal subjects and 37 hypertensive patients (WHO stage I and II) (age range 21-82 years). RESULTS: CD25 was significantly age-related in normotensive and hypertensive subjects, whereas standing-induced QT/QS2 changes were age-related in normotensive subjects only When we divided subjects into three age groups, beta-adrenoceptor sensitivity was found to be lower in hypertensives than normotensives in the two groups under age 60, but was not affected in those over age 60. This suggests that hypertension influences beta-adrenoceptor sensitivity in younger subjects, but not in elderly patients, whose beta-adrenoceptor sensitivity is already reduced. CONCLUSIONS: CD25 does not predict standing-induced QT/QS2 ratio changes; therefore, during autonomic stimulation, QT/QS2 ratio seems not to be significantly related to beta adrenergic sensitivity.

Regression of left ventricular hypertrophy and improvement of renal hemodynamics in hypertensive patients treated with quinapril.

Of 17 patients with mild to moderate essential hypertension, 8 showed echocardiographic evidence of left ventricular hypertrophy. Cardiac and renal function evaluated by glomerular filtration rate (GFR) were studied in all patients before and after 20 weeks of quinapril treatment. Systolic pressure decreased from 174.7 +/- 16.7 to 131.7 +/- 7.7 mmHg (p < .0001) and diastolic pressure decreased from 101.8 +/- 9.8 to 80 +/- 4.3 mmHg (p < .0001). Left ventricular mass index decreased in the eight patients with left ventricular hypertrophy (p < .01). Basal values of GFR were lower than normal in 41% of all patients; GFR increased significantly after 20 weeks of treatment (from 96.5 +/- 32.3 to 108.6 +/- 31.12 ml/min, p < .01); it decreased in only one patient. Patients reported few adverse effects to quinapril, and no important clinical laboratory abnormality was observed. Quinapril not only lowered arterial pressure, but it had a distinct effect on regression of left ventricular hypertrophy and favorable effects on renal function.

[Comparison of nisoldipine and diltiazem in the treatment of effort angina pectoris]. / Confronto tra nisoldipina e diltiazem nel trattamento dell'angina da sforzo.

BACKGROUND: In order to evaluate the benefits of a calcium-antagonist medium-term treatment, 20 patients with effort stable angina pectoris were treated with nisoldipine in comparison to diltiazem. METHODS: Twenty patients with stable effort angina completed a double-blind, placebo controlled trial, comparing 10 twice daily nisoldipine per os and diltiazem 120 three times daily per os for 28 days. After wash-out, placebo and drug period, ergometer stress tests were performed. Exercise tolerance, angina frequency, nitrate consumption and side effects were evaluated. RESULTS: Our results showed that both drugs significantly increased exercise tolerance. Exercise duration was 330 +/- 107 sec after placebo, 397 +/- 106 sec after nisoldipine (p < 0.05) and 378 +/- 99 sec after diltiazem (p < 0.05). Effort angina episodes decreased from 20 after placebo to 8 after nisoldipine and diltiazem. Both drugs reduced rate-pressure product at submaximal exercise in comparison to placebo. There were no differences at peak exercise between placebo or drug periods. Both drugs similarly reduced nitrate consumption and weekly effort angina attacks. No patients referred serious side-effects. CONCLUSIONS: nisoldipine, like diltiazem, is an effective drug in the treatment of stable effort angina. Moreover, the therapeutic effects of nisoldipine during medium-term treatment are probably related to decrease in oxygen consumption.

[Acute effects of propranolol and its association with nifedipine in aged patients with effort stable angina. Randomized double-blind crossover study, under placebo control]. / Effetti acuti del propranololo e sua associazione con nifedipina in pazienti anziani con angina stabile da sforzo. Studio a doppio cieco, randomizzato, cross-over, controllato con placebo.

Calcium-antagonist and B-blockers are effective in improving exercise tolerance in patients with effort angina. We studied the short effects of oral administration of nifedipine (10 mg) and propranolol (80 mg) alone and in combination in 15 elderly patients with chronic exertional angina pectoris in a double-blind, randomized, cross-over study. The 15 patients (13 men and 2 women, mean age 69 years) performed symptoms-limits bicycle exercise stress test 3 h after placebo or active substance administration. Maximal work load, exercise duration, real time to 1 mm ST segment depression were significantly increased and ST depression at peak exercise was significantly decreased by drug alone and in combination. Propranolol and nifedipine improved exercise duration in combination; however, a different response to the three pharmacologic interventions was found in patients treated with single drug. The improvement in exercises tolerance was associated with rate-pressure product values at peak exercise tolerance was associated with rate-pressure product values at peak exercise, unchanged after placebo and significantly reduced after both propranolol alone and in combination. After placebo all patients had exercise-induced angina, in 50% and in 40% after propranolol and the combination of the two drugs, respectively. In aging patients nifedipine and propranolol are effective in the treatment of effort angina and they are superior in patients who show poor response to mono therapy, although this combination will be conditioned by different patient sensibility to the three pharmacologic interventions and then therapeutic choice would be evaluated and verified individually.

[Medical therapy of portal hypertension due to liver cirrhosis]. / Terapia medica dell'ipertensione portale da cirrosi epatica.

Several vasoactive agents are known to reduce portal pressure and therefore are potentially useful in the treatment of portal hypertension. These drugs act in different ways and seem to have several actions. In most cases, their exact mechanisms have not yet been elucidated and more investigations are required. Different pharmacologic treatments of portal hypertension may result from these hemodynamic studies but more trials are required in the forthcoming years.

[Comparative evaluation using an ergometric test of the efficacy of the 3 major calcium antagonists on exertion stable angina]. / Valutazione comparativa mediante test ergometrico dell'efficacia dei tre maggiori calcio-antagonisti sull'angina stabile da sforzo.

Nifedipine, diltiazem and verapamil are three effective calcium-antagonists in the treatment of angina pectoris. We compared their effects on effort angina to evaluate whether one of them is more efficacious. The data were collected from 42 patients (37 males, 5 females; mean age 51 +/- 4) entering one of 3 different trials; the beginning of all trials comprised a two-week, single blind, placebo run-in phase. An exercise stress test was performed at the end of this period and it was considered as basal test for the statistical analysis. Then the 42 patients were divided in 3 groups of 14 and entered a double-blind, randomized phase of drug treatment. The 3 groups started 3 parallel trials: 1) placebo/nifedipine 60 mg/day; 2) placebo/verapamil 360 mg/day; 3) placebo/diltiazem 240 mg/day. The duration of each trial was of 6 weeks (3 weeks of treatment with placebo and 3 weeks with active substance). Exercise stress tests were performed at the end of each phase of the trials, and the resulting data were compared with the data of the test performed at the end of run-in period. Parameters evaluated were: heart rate, blood pressure and rate pressure product at basal conditions, at submaximal and peak exercise; moreover we considered workload, maximal ST segment depression, total exercise duration and frequency of exercise-induced angina. Verapamil reduced rate pressure product at basal condition; all three drugs reduced rate pressure product at submaximal exercise, but a significant statistical difference was found only for verapamil and diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)