Reduction of left ventricular hypertrophy after longterm antihypertensive treatment with doxazosin.

The aim of this study was to evaluate the effect of antihypertensive treatment with doxazosin on left ventricular anatomy and function. Therefore, after 4 weeks of washout with placebo (phase 1), doxazosin (dosage range from 1 to 16 mg, plus hydrochlorothiazide when necessary) was given to 11 essential hypertensive patients (6 M, 5 F, age range 34-63 years) for 8 weeks (phase 2) in order to achieve diastolic blood pressure values less than 90 mmHg; this dosage was then maintained for a further 20 weeks up to the end of the study (phase 3). Blood pressure was significantly reduced (Anova P less than 0.05), while heart rate did not change. A significant reduction of left ventricular mass index (from 128.5 +/- 26 to 114 +/- 23 g/m2, at the end of phase 1 and 3 respectively, P less than .001)) was observed. Before and during treatment left ventricular systolic function, both at rest and during stress (handgrip and cold pressor tests), evaluated by fractional shortening as related to end-systolic stress, in every case within 95% confidence limits, was calculated in normal subjects. Diastolic function, as evaluated by the ratio between peak early and atrial velocities of transmitral flow examined by pulsed doppler was significantly improved. Plasma catecholamine concentrations, plasma renin activity and plasma aldosterone did not change. A significant reduction of plasma cholesterol concentration was observed. These results confirm that doxazosin is a well tolerated and effective antihypertensive drug, with a favourable effect on blood lipids and they indicate that its longterm administration can induce a significant reduction of left ventricular mass.     

Felodipine compared to nifedipine as "third-line drug" in resistant hypertension

Felodipine is a new dihydropyridine calcium antagonist, and in hypertension it is a much more effective "third-line" drug than hydralazine. Nifedipine, on the other hand, is the established dihydropyridine calcium antagonist that has been increasingly used to treat hypertension. Information is now needed on the relative merits and demerits of these two drugs. This study appraised, therefore, the therapeutic utility of twelve months' treatment with nifedipine 20-60 mg twice daily in 55 patients with previous drug-resistant hypertension who had been successfully treated for the previous year with felodipine 5-20 mg twice daily, each calcium antagonist being used in combination with atenolol 100 mg daily with or without chlorthalidone 25 mg daily. Initially, nifedipine maintained comparable blood pressure control to that which had been achieved by felodipine, although in the longer term (over eight months) nifedipine proved less effective than felodipine had (p less than 0.02) and more patients became uncontrolled (supine diastolic blood pressure, Phase V, greater than or equal to 90 mmHg) on the maximum tolerated dose of the calcium antagonist (chi 2 = 4.13, p less than 0.05 greater than 0.025). The former degree of blood pressure control was, however, reestablished by increasing the dose of nifedipine or reintroducing the diuretic as necessary, and this control was maintained over the next four months. Minor side effects were less common on nifedipine than they had been during the preceding felodipine treatment phase. Felodipine thus has more pronounced and sustained antihypertensive effects than nifedipine, though its side effect burden may appear to be greater.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of alpha 1-blocker, bunazosin on a murine model of congestive heart failure induced by viral myocarditis.

The purpose of this study was to investigate the therapeutic effect of an alpha 1-blocker, bunazosin, using an experimental murine model of congestive heart failure induced by viral myocarditis. This model is characterized by a high incidence of severe myocarditis and subsequent congestive heart failure, and is suitable for the evaluation of the effect of drugs. To estimate myocardial damage objectively and quantitatively, we used antimyosin monoclonal antibody in addition to histopathological grading. Four-week-old BALB/c mice were inoculated with encephalomyocarditis virus. The mice were injected daily with bunazosin or saline as a placebo from the day of viral inoculation until day 7 (protocol-I) or day 14 (protocol-II), or from day 4 to day 14 (protocol-III). They were then injected with 1.5 microCi of indium-111 labeled antimyosin antibody and were killed 24 h later. The antimyosin cardiac uptake was counted and histopathological grading was performed. The heart-weight to body-weight ratio, left ventricular dimension, histopathological grades and antimyosin cardiac uptake were significantly lower in the bunazosin group than in the placebo group in protocol-II, but not in protocol-I or protocol-III. Bunazosin showed a protective effect against viral myocarditis only when it was started early after infection and continued until the stage of congestive heart failure.     

Allylmercaptocaptopril: a new antihypertensive drug

Allylmercaptocaptopril (CPSSA) was synthesized by reacting captopril with pure allicin. Fructose-induced hypertensive groups of rats were fed a fructose-rich diet for 3 weeks, and then received the diet plus either CPSSA (40 to 56 mg or 138 to 194 micromol/L/kg/d) or captopril (80 mg or 369 micromol/L/kg/d) for 2 more weeks. CPSSA (both doses) significantly lowered blood pressure (BP) from 153.4 to 120.8 mm Hg (P <.005). Captopril gave similar results, lowering BP from 150.7 to 123 mm Hg (P <.005). CPSSA also decreased the high levels of triglycerides to normal. The new stable compound allylmercaptocaptopril combines the beneficial properties of captopril and allicin and is a potential candidate for antihypertensive drug therapy.     

Plasma lipid lowering effects of doxazosin, a new selective alpha1 adrenergic inhibitor for systemic hypertension

Hypertension and hypercholesterolemia are 2 major risk factors for atherosclerotic coronary artery disease (CAD). Elevations of both blood pressure and serum cholesterol levels should be reduced to control CAD risk. Doxazosin is a once-daily, long-acting, selective alpha 1-adrenergic inhibitor that is effective for the treatment of essential hypertension. During controlled studies of doxazosin's antihypertensive efficacy, 3 serum lipid parameters were measured; total cholesterol, total triglyceride and high density lipoprotein (HDL) cholesterol. In 10- to 12-week placebo-controlled studies, 142 doxazosin-treated patients were compared with 155 placebo-controlled subjects. Doxazosin patients had an increase of 8.9% in the HDL/total cholesterol ratio (p less than 0.05), whereas total cholesterol, HDL cholesterol and triglyceride levels were not significantly different between the 2 study groups. During a 52-week comparison of doxazosin versus atenolol, doxazosin treatment was associated with a significant decrease in total triglyceride levels (5%; p less than 0.001) and increases in HDL cholesterol levels (3.9%; p less than 0.01) and HDL/total cholesterol ratio (5.4%; p less than 0.0001). Doxazosin is an effective antihypertensive agent that has a favorable impact on serum lipid levels, thereby promoting a beneficial effect on 2 major CAD risk factors.     

Selective alpha 1-adrenergic antagonists: therapeutically relevant antihypertensive agents

Alpha-adrenergic antagonists were the first substances to receive serious consideration as antihypertensive agents. However, their therapeutic potential in the management of essential hypertension was not realized until prazosin, a highly selective alpha 1-adrenergic antagonist, became available. A number of analogs of prazosin have now been synthesized, as have several structurally distinct alpha 1-adrenergic antagonists. Preliminary investigations suggest that these agents may also be clinically useful antihypertensive drugs. The alpha 1 receptor of arteriolar smooth muscle is the predominant adrenergic subtype determining sympathetically mediated vascular tone. Therefore, its selective blockade by an agent such as prazosin is a relevant approach to the major pathophysiologic defect in hypertension: an elevation of peripheral vascular resistance. Because prazosin has little selectivity for the alpha 2 receptor, the negative feedback control of norepinephrine release from sympathetic nerve terminals remains intact. This unique action of prazosin may explain why it effectively lowers arterial pressure without markedly increasing cardiac output, heart rate and plasma renin activity. An additional factor in the favorable therapeutic effects of this agent is its ability to induce a balanced reduction in both arteriolar and venous tone, with little change or even improvement in renal hemodynamics. The antihypertensive effects of prazosin, when used as a single agent, may be modest. However, it may be useful as initial as well as adjunctive therapy for the management of hypertension because of its high toxic to therapeutic ratio, coupled with a sustained reduction in arterial blood pressure, a low incidence of side effects, and a potentially favorable metabolic profile.     

Pharmacogenetics of antihypertensive drug response

Pharmacogenetics is a discipline of molecular medicine that investigates the genetic basis of individual variation of drug responses. Before the era of the human genome project and the subsequent progress in genomic research, this field was primarily restricted to the investigation of the genetics of drug-metabolizing enzymes as they account for individual differences in pharmacokinetics and tolerability of drugs. In the current genomic era, pharmacogenetic research is applied to all fields of drug treatment in clinical medicine, including hypertension research. In contrast to the traditional approach, however, the influence of individual genetic variation on the efficacy of a drug (ie, the pharmacodynamic response) is the major focus of pharmacogenetic research and its clinical applicability. Therefore, the identification of individual genetic variation influencing the blood pressure-lowering effect of an antihypertensive compound and the implementation of this knowledge into clinical practice is the major goal of pharmacogenetic research in the field of hypertension. In this article, some important, recent research work and progress on the pharmacogenetics of antihypertensive drug responses are reviewed and evaluated.     

Principles of antihypertensive drug treatment

The main objectives of chronic drug treatment in essential hypertension are to decrease blood pressure, improve prognosis, reduce the number and severity of adverse effects to a minimum, and use simple treatment schedules. Simple treatment schedules may be easily maintained with monotherapy (i.e., beta blockers, diuretics, calcium antagonists and angiotensin-converting enzyme inhibitors). If monotherapy is insufficiently effective, antihypertensive drugs can be combined. Combination therapy makes use of the synergistic effects of most antihypertensive drugs. Further considerations of combination therapy of antihypertensive agents are the inhibition of compensatory mechanisms working against blood pressure reduction and the decrease of the frequency and severity of adverse effects. Combinations of 2 antihypertensive agents usually contain a diuretic or a calcium antagonist.     

Interaction of alcohol and an alpha1-blocker on ambulatory blood pressure in patients with essential hypertension

Ingestion of alcohol acutely decreases vascular resistance and blood pressure (BP) with activation of the sympathetic nervous system in Orientals. Although alpha1-blockers are widely used in the treatment of hypertension, the possible interaction between alcohol and alpha1-blockers has not been clarified. We examined the effects of prazosin on the alcohol-induced BP changes in Japanese men with mild hypertension. Ten hypertensive patients (54 +/- 3 years, mean +/- SE) were given 1 mL/kg of alcohol or isocaloric control drink with a light meal in the evening before and 5 to 7 days after treatment with prazosin (1 mg three times daily). Ambulatory BP monitoring was carried out every 30 min for 24 h in each period using Colin ABPM-630. Blood samples were obtained before and 2 h after intake of alcohol or control drink. Before prazosin treatment, alcohol ingestion decreased BP for several hours with a significant reduction in average 24-h BP, whereas it increased heart rate, plasma norepinephrine, and plasma renin activity. Treatment with prazosin caused a significant decrease in 24-h BP (136.3 +/- 4.0/82.8 +/- 2.5 v 131.6 +/- 3.2/80.0 +/- 2.3 mm Hg). The alcohol-induced hypotension at 2-4 h after ingestion was enhanced by prazosin (-18.0 +/- 3.7/-11.8 +/- 2.7 v -24.4 +/- 4.9/-17.8 +/- 2.8 mm Hg, P < .05 for diastolic BP). These results suggested that inhibition of the sympathetic nervous system with alpha1-blockers accentuates alcohol-induced hypotension. Ingestion of alcohol may cause a marked BP reduction in hypertensive Orientals treated with alpha1-blockers.     

Melatonin as a potential antihypertensive treatment

The number of patients with well-controlled hypertension is alarmingly low worldwide and new approaches to treatment of increased blood pressure (BP) are being sought. Melatonin has a role in blood pressure regulation. The nighttime production of melatonin is found to be reduced in hypertensive individuals. Administration of melatonin decreased BP in several animal models of hypertension, in healthy men and women, and in patients with arterial hypertension. Most promising results were achieved in patients with non-dipping nighttime pressure, in which the circadian rhythm of BP variation is disturbed. Several potential mechanisms of BP reduction are considered. Melatonin can, via its scavenging and antioxidant nature, improve endothelial function with increased availability of nitric oxide exerting vasodilatory and hypotensive effects. Melatonin seems to interfere with peripheral and central autonomic system, with a subsequent decrease in the tone of the adrenergic system and an increase of the cholinergic system. Melatonin may act on BP also via specific melatonin receptors localized in peripheral vessels or in parts of central nervous system participating in BP control. With a large clinical trial using melatonin in hypertension treatment, many important questions could be answered, such as the dose of melatonin and regimen of its application, the choice of patients with greatest possible benefit from melatonin treatment, the potential of anti-remodeling effect of melatonin and the interaction of melatonin with other antihypertensive drugs.     

Usefulness of exertion tests in the evaluation of the effectiveness of antihypertensive therapy

Aim of this study was to assess the reliability of blood pressure (BP) response to exercise compared with the occasional BP measurements in evaluating the efficacy of an antihypertensive therapy. We have studied 40 subjects (22 M, 18 F mean age 33.3 +/- 6.6) with essential hypertension (19 with mild hypertension, 8 with moderate hypertension, 13 with severe hypertension). Every patient underwent a maximum graded exercise test in the supine position on a bicycle ergometer before starting the antihypertensive treatment. An exercise test was repeated with the same procedure after resting BP had been normalized for at least six months. Both systolic and diastolic BP at peak exercise were significantly reduced (systolic BP from 212.13 +/- 25.79 mmHg to 194.38 +/- 21.58 mmHg; diastolic BP from 128.00 +/- 16.52 to 114.1 +/- 11.02 mmHg) during the second test. An excessive BP increase (above the 95% confidence limits of the BP response to exercise in a group of normotensives) was observed in 32 subjects during the first test. A "hypertensive" response to stress persisted in 13 subjects during the second test even if the resting BP values were normalized. Our data support the value of stress testing in both the evaluation of the hypertensive patient and the assessment of the individual response to treatment.     

Concentration-effect analysis of antihypertensive drug responses

It is now widely recognized that a rigid stepped-care approach to antihypertensive therapy is not universally appropriate. Individualized treatment may result in good or better blood pressure control and a simpler regimen without troublesome side effects. Successful development of such a strategy depends on accurate characterization of a dose-response relation and quantitative assessment of the response in each individual. In the past such relations have proved to be hard to identify for antihypertensive drugs, often because of inappropriate study design during drug development. Despite failure of earlier studies to identify drug concentration-antihypertensive response relations, use of concentration-effect modeling, which recognizes and characterizes the temporal discrepancy between drug concentration and effect, has proved more successful. By using such approach, it has been possible to characterize the concentration-effect relations after acute and steady-state antihypertensive therapy with prazosin, doxazosin, nifedipine, verapamil, and enalapril. With enalapril and nifedipine, it has been demonstrated that the mathematical parameters of effect derived from the first dose can predict the response to these drugs after 4-6 weeks of treatment. These findings suggest that the definition of individual concentration-effect relations may be of value in the rational choice of antihypertensive drug therapy and optimization of dose and dose frequency. In particular, the approach can provide valuable information on dose-effect relations and should optimize choice of dose intervals in drug development and practice.     

Nifedipine as an antihypertensive drug in patients with renal failure--pharmacokinetics and effects

Pharmacokinetics and pharmacodynamics of nifedipine were studied in 12 patients with renal failure and hypertension, after a single dose and during an 18-week treatment period. The plasma concentrations of nifedipine and its first pyridine metabolite were measured by gas chromatography mass spectrometry. The oral plasma clearance of nifedipine was 1189 +/- 876 ml min-1, and the mean plasma half-life (t1/2) was 5.99 +/- 3.05 h. The pyridine metabolite was not retained. Plasma concentrations of nifedipine were found to be significantly correlated with the effects on blood pressure, forearm blood flow and peripheral resistance, and these effects did not vary with the degree of renal failure. Normotension was achieved in eight of the nine patients observed over a period of 4 months with doses in the range 20-40 mg, administered twice daily. The mean Cr-EDTA clearance remained unchanged during the study (initial value 31.4 +/- 12.3 ml min-1; final value 32.7 +/- 14.4 ml min-1), and in three patients it increased. Nifedipine induces a slight increase in metabolic rate in patients with renal failure, but it is not necessary to modify the dose. It is effective in lowering blood pressure, has mild side-effects and may improve renal function in some patients.