Blood pressure. Supplement最新文献

Epidemiological evidence suggests that optimal blood pressure control requires strategies that lower blood pressure consistently and fully throughout 24 h. In order to maximize compliance, antihypertensive agents also need to be well tolerated and effective when administered at a convenient once-daily dose. The new angiotensin II type 1 (AT1) receptor blocker candesartan binds tightly to, and dissociates slowly from, the AT1-receptor and thereby provides long-lasting suppression of the renin-angiotensin system. This is likely to explain its pronounced antihypertensive efficacy, which is maintained smoothly over 24 h. The trough-to-peak ratio is a useful measure of the persistence of antihypertensive efficacy at the end of the dosing interval. This ratio was found to be close to the ideal of 1.0 for candesartan cilexetil, 8 and 16 mg, whereas it was 0.7 for the prototype AT1-receptor blocker losartan, 50 mg. The antihypertensive effect of candesartan cilexetil, 16 mg, was also significantly greater than that of losartan, 100 mg, as demonstrated by ambulatory blood pressure measurements 0-36 h after dosing and by clinic measurements 48 h after dosing. By controlling blood pressure well beyond the normal dosing interval, candesartan cilexetil provides cardiovascular protection even in those patients who may occasionally miss doses.

Several types of calcium antagonists (CA) (verapamil, diltiazem, nifedipine and related drugs) may be used as antihypertensives. In practice, the dihydropyridines (nifedipine and related drugs) are the CA used most frequently as antihypertensives. Apart from the lowering of blood pressure CA may lead to other, theoretically beneficial, effects: regression of left ventricular and vascular hypertrophy, renal protection, weak natriuretic, weak antiplatelet, anti-ischaemic and antiatherogenic activity. Several new dihydropyridine CA have been introduced in recent years. The advantages of the newer compounds, such as amlodipine, felodipine, isradipine, lacidipine and lercanidipine, may include: vasoselectivity, hence little or no cardiodepressant activity; an improved kinetic profile, resulting in a slow onset and long duration of action, fewer side-effects such as reflex tachycardia and headache, owing to the slow onset of the antihypertensive action. For a few newer CA a predominant effect on specialized circulatory beds (renal, coronary and cerebral) has been claimed. The new CA, which are clearly lipophilic, deserve special attention. Owing to the lipophilic character of such compounds considerable concentration occurs in lipid-containing membrane depots. The CA thus concentrated are slowly released from these depots and, subsequently, reach their targets, the L-type calcium channels. This phenomenon explains both the slow onset and the long duration of action of these CA. Owing to the slow onset of action reflex tachycardia is virtually absent. The long duration of action allows satisfactory control of blood pressure in hypertensives by means of a single daily dose. A few lipophilic dihydropyridine CA are vasoselective. This property implies that at therapeutic, vasodilatory dosages no cardiodepressant activity occurs. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine CA. It is an effective vasodilator/antihypertensive drug, with a slow onset and long duration of action, which is associated with neither reflex tachycardia nor cardiodepressant activity. Other examples of recently introduced lipophilic CA are lacidipine, barnidipine and manidipine.

Adrenergic overactivity is a common hallmark of both essential hypertension and congestive heart failure. Indirect and direct measures of sympathetic function have clearly shown that sympathetic activation characterizes essential hypertension. This adrenergic overactivity appears to be related to the severity of the hypertensive state, being detectable in its early stages and showing a progressive increase with the severity of the disease. Essential hypertension is also associated with an impaired baroreflex control of vagal activity, whereas baroreceptor modulation of sympathetic nerve traffic remains unaltered, although undergoing a resetting phenomenon. In contrast, secondary hypertension is not associated with an increased adrenergic activity, thus suggesting that an enhancement in efferent sympathetic outflow is a peculiar feature of essential hypertension. Congestive heart failure is a condition also characterized by sympathetic activation, whose degree is proportional to the clinical severity of the disease. This is paralleled by an impairment in arterial baroreceptor modulation of both vagal and sympathetic activity, thus suggesting that the adrenergic overactivity in congestive heart failure is triggered by a reduced afferent restraint on the vasomotor centre. Chronic angiotensin-converting enzyme inhibition reduces the degree of both sympathetic activation and baroreflex dysfunction occurring in heart failure patients, a finding which documents that the neurohumoral abnormalities can be at least partially reversed by pharmacologic treatment.

Atherosclerosis results from multiple factors and involves several mechanisms, including endothelial monocyte and smooth muscle cell (SMC) changes, cholesterol accumulation, plaque rupture and thromboembolism. Calcium ions play a role in the initial and chronic development of atherosclerotic lesions. Several studies in experimental animal models have demonstrated the potential direct antiatherosclerotic effects of calcium antagonists. In this study the antiatherogenic activity of lercanidipine, a new lipophilic, second-generation calcium antagonist, was investigated. Lercanidipine and its enantiomers inhibited the replication and migration of arterial myocytes in concentrations ranging from 10 to 50 microM. The antiproliferative effect of lercanidipine was dose dependent, with a potency similar to that of lacidipine and nifedipine, and was unrelated to the stereoselectivity of enantiomers to bind L-type calcium channels. Lercanidipine and its enantiomers (25 microM) decreased the serum-induced elevation of [Ca2+]i in SMC, with the (S)-enantiomer (69% inhibition) being 2.4-fold more active than the (R)-counterpart (29% inhibition). The studies performed with enantiomers of lercanidipine suggest that the observed effects are not related to the blockade of voltage-dependent Ca2+ channels and confirm, at least in vitro, the pharmacological potential of the compound to influence negatively the process of atherogenesis.

It is estimated that 40 million people in the USA have hypertension, 14 million are diabetic and 4 million suffer congestive heart failure. Since all three conditions are age-related, as the longevity in industrialized societies continues to improve, the overall burden of congestive heart failure, hypertension and diabetes will increase. These major diseases of civilization are characteristically associated with an increased autonomic cardiovascular drive. In our terminology the output that emanates from the central nervous system via sympathetic and parasympathetic efferents is referred to as "tone". The overall "drive" depends on the balance between inhibitory (parasympathetic) and excitatory (sympathetic) tone and the organ's responsiveness to that tone. The responsiveness, in turn, depends on the receptors' properties as well as on the intrinsic functional or anatomic properties of the responding organs. These components can change independently. For example, in the course of hypertension the alpha-adrenergic responsiveness increases whereas the beta-adrenergic responses are down-regulated. Another example is: plasma noradrenaline and sympathetic tone are increased in elderly subjects but their circulation does not show any tell-tale response of increased sympathetic tone, presumably because the responses to sympathetic tone decrease with aging. These complex interactions between the autonomic tone and organ responsiveness determine to a great extent the overall clinical impact of the autonomic abnormality in hypertension, non-insulin-dependent diabetes mellitus and in congestive heart failure. The major thesis of this review is that, whether primary or secondary, whether easily discerned or hidden, an enhanced autonomic drive, independent of the underlying condition, greatly increases the risk of poor cardiovascular outcomes. It follows that targeting the underlying autonomic imbalance in congestive heart failure, hypertension and diabetes may not only be pathophysiologically sound but such an approach may also lead to better outcomes.

Treatment of arterial hypertension is known to reduce cardiovascular morbidity and mortality and has a positive effect against stroke, where benefit is strongly linked to reduction in blood pressure per se. The protective effects against coronary heart disease (CHD) have also been significant but numerically less impressive than the effect against stroke. It is conceivable that this due to the fact that not just blood pressure, but also a number of metabolic variables need to be considered in this context. The insight that hypertension is often just one of the components of the so-called metabolic syndrome suggests that a modern antihypertensive drug should not only lower blood pressure; to exert optimal cardioprotective properties it should also have a neutral or even positive metabolic profile as regards its effects on lipids, glucose and insulin in order to achieve a better protection against CHD. Against this background the centrally acting selective imidazoline receptor (I1) agonist moxonidine is of considerable interest. Moxonidine has been shown to improve glucose tolerance in man, probably by two different mechanisms, i.e. by augmenting insulin sensitivity in peripheral tissues and by enhancing glucose-stimulated insulin release from the pancreas. By employing a therapeutic intervention against hypertension that not only lowers elevated arterial pressure but also positively affects some of the frequently occurring concomitant metabolic disturbances, it appears that today's standard of antihypertensive therapy may be surpassed in tomorrow's perspective.