Clinical and experimental hypertension. Part A, Theory and practice最新文献

The question whether some classes of antihypertensive drugs have an antiatherogenic action independent of the antihypertensive one has been investigated through a large series of experimental studies; on the other hand, clinical evidence is still rather scanty. Most experimental investigations have shown a significant antiatherogenic action of the antihypertensive compounds, but only when the drug is administered simultaneously with the atherogenic stimulus (mostly cholesterol feeding). When the drug is administered weeks or months after the beginning of atherosclerosis (as in the Watanabe heritable hyperlipemic rabbit), no antiatherogenic effect has been shown, with a single exception. Although the most numerous data available are on calcium antagonists, almost all antihypertensive classes tested have shown some favorable effect on some experimental model. The few clinical studies completed so far as on coronary patients; they have provided arteriographic evidence that various calcium-antagonists have little effect on well-developed lesions and display a beneficial action on new or early lesions only. Ultrasound studies are now underway to compare the effects of calcium-antagonists and diuretics on asymptomatic carotid atherosclerotic lesions in hypertensive patients.

On the basis of six randomized primary intervention trials, major changes in the diagnosis and treatment of relatively mild hypercholesterolemia have been strongly advocated. This paper examines the data from these six trials which show a significant reduction in morbidity and mortality from coronary heart disease but no decrease in overall mortality because of concomitant increases of cancer and violent deaths in the treated half. These adverse effects cannot be decisively proven to be related to the reduction in cholesterol levels but they also cannot be disregarded as biological or statistical quirks. In view of the limited positive evidence and the serious reservations about negative effects, caution is advised in the advocacy of more widespread therapy of all people with even minimal degrees of hypercholesterolemia. In particular, the limited effectiveness and the large expense of such broad therapy threaten to aggravate further the critical health care cost crisis.

During recent years there has been growing interest in the possibility that dietary fish confers some protection against ischaemic heart disease. In four prospective studies, people who ate moderate amounts of fish tend to have a lower mortality from heart disease than persons who ate little or no fish. A randomized controlled trial showed that mortality after myocardial infarction was less among men who were advised to increase their intake of fatty fish than in a control group. Studies of fish oil administered to volunteers suggest that it is the omega-3 fatty acids which are responsible. The effects of fish oil include a reduction in serum triglyceride concentration, a reduction in platelet activity, a reduction in blood pressure, and (in animals) prevention of arrhythmias. Some of these effects require doses much larger than those that would normally be supplied by dietary fish.

The acute increase in blood pressure and heart rate that accompanies cigarette smoking is associated with a rise in plasma catecholamines and it is thus believed to result from stimulation of the adrenergic nervous system. We have employed direct recording of efferent post-ganglionic sympathetic nerve activity by the microneurographic technique from the peroneal nerve to determine whether this stimulation occurs centrally or peripherally. It was shown that during cigarette smoking blood pressure, heart rate, plasma norepinephrine and epinephrine do increase markedly. Sympathetic nerve activity, however, shows a concomitant specular reduction. Thus peripheral (adrenal gland stimulation, reduction in norepinephrine reuptake, reduction in catecholamine clearance, etc.) rather than central mechanisms explain the adrenergic involvement in the acute hemodynamic effect of smoking, the central sympathetic drive being inhibited rather than excited probably as a result of arterial baroreceptor stimulation.

Arterial hypertension can badly affect coronary circulation through several mechanisms that are not mutually exclusive, namely, coronary artery disease, left ventricular hypertrophy, and microvascular disease. Theoretical and experimental data suggest that coronary microvascular disease may exist in hypertensives, in whom it can cause both a reduction of coronary flow reserve and a shift to the right of the coronary flow autoregulation curve. To address this issue, we used dipyridamole- echocardiography test, which causes ischemic-like ST segment depression with no detectable changes in left ventricular function in different subsets of patients with microvascular disease (Syndrome X; Hypertrophic cardiomyopathy; acute heart rejection). We found that dipyridamole infusion can cause a similar pattern of response (i.e., echocardiographically silent ST segment depression) in mild-moderate essential hypertensives with normal epicardial coronary arteries, without left ventricular hypertrophy, with increased forearm minimal vascular resistances and with a reduced coronary reserve. This pattern of response identifies hypertensives with higher risk of ventricular arrhythmias, is amplified by acute reduction of diastolic blood pressure and can be reversed, together with the reduction of forearm vascular resistances by chronic antihypertensive treatment. Taken together these findings suggest that microvascular coronary disease can exist in hypertensives with two adverse consequences, consistent with the experimental background: the reduction of coronary flow reserve as well as a shift to the right of the coronary flow autoregulation curve.

The purpose of this study was to determine if alpha 1-adrenergic receptor blockade alters the hemodynamic response to exercise in young (less than 25 yr) male borderline hypertensives differently than in young normotensives. Five hypertensive (HTN, MAP greater than 105 mmHg) and 7 normotensive (NTN, MAP less than 95 mmHg) college-age males underwent two 30 min bouts of cycle ergometry exercise at 50% VO2pk in a warm (25 degrees C, 50% rh) environment; one following alpha 1-receptor blockade with prazosin (PRAZ) and the other following placebo administration (PLAC). During resting PLAC and compared to NTN, HTN exhibited an elevated cardiac index (CI, p = .002), similar HR and elevated total peripheral resistance index (TPRI, p = .015). During resting PRAZ, CI and TPRI were similar but HR was higher (p = .013) in HTN than NTN. While reduced during PRAZ, resting MAP was higher in HTN than NTN (p = .007) for both trials. With exercise and PLAC, CI was higher (p = .029) while HR and TPRI were similar for HTN compared to NTN. With PRAZ, the exercise CI, TPRI and HR responses were similar for both groups. Exercise MAP was blunted in both groups with PRAZ. While not differing significantly between groups for each treatment, MAP was stable for NTN while it declined after 10 min of exercise in HTN. The elevated CI seen in exercising HTN with PLAC was removed with PRAZ; the exercise response was otherwise unaltered by alpha 1-blockade. Consequently, these data suggest that young male hypertensives have an elevated blood pressure due to an elevated CI incompletely offset by a reduced TPRI. While alpha 1-blockade lowers MAP by lowering CI, the MAP response to exercise remains unaltered.

The mechanisms of anti-hypertensive effect of diuretics remain unknown. The purpose of this study was to test the hypothesis that long-term treatment with chlorthalidone decreases the responsiveness of resistance vessels to neurohormones. The study was performed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats with and without treatment with chlorthalidone (Chlor. 8 mg/day, for 20 days). Resting mean arterial pressure in freely moving state was significantly reduced in DOCA-salt-Chlor rats when compared to DOCA-salt rats (116 +/- 3 vs 147 +/- 7 mmHg, respectively). Chlorthalidone treatment reduced the high plasma sodium content observed in DOCA-salt rats to the same levels observed in normotensive control groups. Results obtained in isolated perfused mesenteric arteries showed: a) the increase in perfusion pressure elicited by norepinephrine (NE), serotonin (SE) and vasopressin (VP) was significantly greater in DOCA-salt than in DOCA-salt + Chlor rats or control normotensive rats; b) the endothelium removal increased the pressor responses to NE, SE and VP in a similar way in all groups. These data provide evidence that long-term chlorthalidone treatment reduces vascular hyperresponsiveness to these neurohormones. In addition, these results indicate that this reduction in vascular hyperresponsiveness, associated with a decrease in extracellular sodium level, could be a possible mechanism by which the diuretics reduce the high blood pressure.