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

Felodipine is a new dihydropyridine calcium channel blocker with a number of properties that enhance its suitability as a first-line antihypertensive drug for the elderly. Felodipine has a 100-fold selectivity for inhibiting the contribution of vascular smooth muscle compared with cardiac muscle. Negative inotropic action appears minimal while selectivity appears to increase with age. Felodipine has a minimal effect on smooth muscle of venous capacitance vessels, thereby greatly reducing the likelihood of orthostatic hypotension. Renal effects are favorable; the glomerular filtration rate is increased in some patients. The extended-release formulation of felodipine produces a smooth 24-hour plasma concentration curve and is effective when prescribed once daily. Felodipine appears to lower blood pressure effectively in the elderly patient with few, generally mild, adverse effects.

Hypertrophic adaptation of the left ventricle and blood vessels is a prominent feature of established essential hypertension. Presence of left ventricular hypertrophy in hypertension increases, independently of other risk factors, the risk for a number of the most important cardiovascular hypertensive complications. Available evidence indicates that left ventricular hypertrophy develops in close parallel with the peripheral vascular changes. Structural involvement can be detected already in early phases of borderline hypertension. The pathophysiology of structural changes in hypertension appears to be dependent on a complex interplay between genetic, hemodynamic, and humoral-metabolic factors.

The relationship between regular alcohol consumption and blood pressure elevation is now firmly established. Outstanding issues which will be discussed relate to the nature of the dose response curve, interactions between alcohol and other dietary and behavioural factors, mechanisms involved and the question of any protective influence of alcohol on atherosclerotic and ischaemic cardiovascular disease associated with hypertension. Alcohol is an important contributory to the prevalence of hypertension, and resistance to drug therapy in drinking communities. Heavy drinking and binge drinking increases the risk of stroke.

During the last decades the evidence that a genetic component contributes to the development of primary hypertension has been accumulating. The identification of the genes involved in blood pressure regulation, however, is only starting to emerge. The recent advances in recombinant DNA technology provide new molecular genetic strategies in cardiovascular research. In this review we will discuss the testing of candidate genes in vivo by transgenic techniques. Furthermore, we will describe the possibilities to identify the genes implicated in primary hypertension by genetic linkage analysis using polymorphic DNA markers.

Control of blood pressure usually has not, by itself, affected the incidence of heart attack in hypertensive patients. This suggests a need for cause-specific therapy targeted against mechanisms that engage the risks of myocardial infarction. Study of the renin system, the ongoing, long-term servo-control over blood pressure and electrolyte homeostasis may provide answers. Inappropriately high renin production, generating the powerful vasoconstrictor, angiotensin II, may cause ischemic vascular damage in the heart, kidney and brain, predisposing to infarction. Many clinical situations associated with high plasma renin levels are accompanied by striking vascular damage, heart attack, or stroke. A recent prospective study of 1,717 hypertensive patients shows an unequivocally positive relationship between myocardial infarction and high-renin status regardless of other risk factors such as smoking, hypercholesteremia, or diabetes. The data also suggest the possibility that renin is a continuous variable, since the risk of heart attack was significantly weaker in medium-renin than in high and significantly greater than in low renin subjects. These observations are in keeping with concept that any renin secretion in the face of arterial hypertension is abnormal, since the truly normal kidney completely turns off its renin secretion. Thus the renin-sodium profile appears to be especially useful for evaluating the large fraction of patients who develop heart attacks in the absence of these other risk factors. Although, these findings suggest that a renin test should be performed routinely in hypertensive patients, the better to assess prognosis and design appropriate anti-renin therapy.

Subjects with family history of hypertension represent a suitable model to investigate the mechanisms responsible for early cardiovascular structural and functional changes occurring in essential hypertension. In our study we have addressed the factors involved in determining the mild elevation in office blood pressure frequently observed in normotensive subjects with hypertensive parents. In 15 normotensive subjects with both parents hypertensive (FH++) and in 15 normotensive subjects with one parent hypertensive (FH(+)-) we found no evidence of a hyperreactivity to stress as compared to the responses of 15 normotensive subjects with no parental hypertension (FH--). On the contrary FH++ subjects were characterized by a significant although mild increase in their blood pressure values recorded either at rest and in ambulatory conditions over the 24 hours, including night sleep. FH++ and FH(+)- subjects also showed a greater left ventricular mass thickness and a greater minimal forearm vascular resistance than FH-- subjects. Thus, the elevation in blood pressure found in the pre-hypertensive stage in subjects with positive family history for hypertension does not reflect a hyperreactivity to the stress associated with physician's visit but indicates an early and persistent blood pressure elevation. This blood pressure elevation is accompanied by early cardiovascular structural changes which may indicate that these subjects are exposed to a higher risk even before developing overt hypertension.

Cigarette smoking as a risk factor for cerebro- and cardiovascular diseases was studied in a long-term prospective population survey which has been carried out in a Japanese rural community, Hisayama. In this population, the incidence of thrombotic brain infarction (TBI) was much higher than that of coronary heart disease (CHD) over a 26-year follow-up period. Cigarette smoking was strongly related to the occurrence of CHD but not to TBI. Comparing the incidence of CHD and TBI between first or early cohort (1961-74) and second or recent cohort (1974-87) during the 13-year follow-up, the incidence remained unchanged for CHD, while it significantly decreased for TBI in recent population. The prevalence of cigarette smoking as well as hypertension decreased in recent years, while hypercholesterolemia, obesity, and glucose intolerance increased. Smoking is a major contributor to CHD for men in both cohorts, but it is not any more for women in the recent cohort.

A practical new method for measuring serum guanosine-5'-monophosphate (GMP) was developed and three experiments were performed using this method. In the first, we observed the reduction of blood pressure (BP) and the elevation of serum GMP level persisting for 3 hours in male Japanese White Rabbits administered GMP, 50 mg/kg given as a single oral dose. In the second, 6-week-old male spontaneously hypertensive rats (SHR) received GMP, 200 mg/kg/day, orally for 8 weeks. The systolic BP in the GMP-treated rats, which averaged 170.2 mmHg, was lower than that of the control group, which averaged 188.0 mmHg. Arteriosclerotic findings were milder in the GMP-treated SHR as compared to the control. In the third experiment, the serum GMP level was measured in humans. We observed a significant negative correlation between the serum GMP concentration and systolic or diastolic BP. In conclusion, GMP reduced the BP in experimental animals, suggesting that it may be useful as an antihypertensive agent.

19-hydroxy-androstenedione (19-OH-A), a C19 steroid, is an amplifier of the sodium retaining action of aldosterone under the control of ACTH and renin-angiotensin system. These findings suggest that 19-OH-A may be involved in the regulation of hydroelectrolyte balance and blood pressure. Aim of the present study was to examine the behaviour of 19-OH-A in normal volunteers (N) and in patients with Essential Hypertension (EH) in basal conditions and after dynamic tests such as postural changes, physical exercise and ACTH administration. The significant increase in 19-OH-A after ACTH confirms its adrenal origin. During bicycle exercise the significant increase in plasma catecholamines, renin-activity, aldosterone, blood pressure and heart rate at maximum effort was not associated with a parallel increase in 19-OH-A. No significant differences were found in plasma 19-OH-A levels between N and EH patients both in basal conditions and after dynamic tests. Therefore, our findings seem to exclude an important role of 19-OH-A in the pathogenesis of EH.

We investigated the effect of insulin on the vascular reactivity to noradrenaline, serotonin and potassium chloride in rat mesenteric resistance arterioles in vitro. Mesenteric artery segments were placed in a myograph system. Sensitivity to noradrenaline, serotonin and KCl was tested after an equilibration at 37 degrees C. Thereafter, arteries were incubated with buffer alone or with insulin (40, 100, 250 and 400 mU/ml) for one hour at 37 degrees C. Sensitivity to the three vasoconstrictors was retested. Incubation with noradrenaline, serotonin and KCl resulted in a dose dependent increase in wall force. Exposure with buffer did not change the shape of the dose-response-curve. The same was true for the lowest dose of insulin (40 mU/ml). However, incubation with insulin at concentrations of 100, 250 and 400 mU/ml led to a reduction in wall force by 37-77%. The reduction in the slope of the curve and the maximal response suggest a non-competitive inhibition. Supraphysiological doses of insulin attenuate the vasoconstriction by noradrenaline, serotonin and KCl in rat mesenteric arteries in vitro.