Hans-Michael Thiede

Antihypertensive and metabolic effects of diltiazem and nifedipine.

The antihypertensive effect of diltiazem (180-270 mg/day) and nifedipine (40-60 mg/day) in slow-release forms was assessed over 8 weeks in a double-blind parallel study in 40 subjects with essential hypertension at rest and during exercise. Blood pressure was comparably reduced in both groups at rest as well as during exercise. The responder rates (greater than or equal to 10% reduction in diastolic blood pressure) after 8 weeks of therapy were 53% at rest and 75% during exercise in the diltiazem group and 78% and 50%, respectively, in the nifedipine group. Diltiazem decreased heart rate by 8% (p less than 0.01), while nifedipine did not affect it. As a consequence, myocardial oxygen consumption, as judged by the pressure-rate product, was reduced by diltiazem. Resting plasma norepinephrine levels were increased significantly after 8 weeks of diltiazem therapy. Plasma epinephrine, renin, aldosterone, glucose, insulin, and lactate and routine laboratory parameters were unchanged at the end of the study. No significant changes in total cholesterol and triglyceride levels were observed after 8 weeks. Whereas therapy with diltiazem resulted in an 8% fall in low density lipoprotein cholesterol after 8 weeks (p less than 0.05), nifedipine induced a drop in very low density lipoprotein cholesterol (p less than 0.05) after 8 weeks of therapy. We conclude that both diltiazem and nifedipine are effective antihypertensive agents lacking undesirable metabolic side effect. Diltiazem, however, had the advantage of lowering heart rate and myocardial oxygen consumption.

Effects of sodium salts on pressor reactivity in salt-sensitive men.

Blood pressure in patients with essential hypertension is raised by sodium chloride but not by nonchloride sodium salts. Although a high sodium chloride diet is known to augment the pressor response to norepinephrine and angiotensin II, the effect of nonchloride sodium salts on pressor responsiveness has not been studied so far. To examine whether sodium chloride and nonchloride sodium salts evoke different pressor responses to these agonists, we performed graded norepinephrine and angiotensin II infusions in salt-sensitive (n = 7) and salt-resistant (n = 8) normotensive subjects. The subjects were given a low salt diet (20 mmol/day) for 3 weeks, to which a supplement of 200 mmol sodium per day, provided as either sodium chloride or sodium citrate, or a placebo was added for 1 week each. We found that, although sodium chloride raised mean arterial blood pressure in the salt-sensitive subjects (p less than 0.005), sodium citrate did not. However, under both sodium salts pressor response to norepinephrine and angiotensin II was significantly greater than under placebo (p less than 0.02). Furthermore, with both sodium salts, pressor response in the salt-sensitive subjects was greater than in the salt-resistant subjects (p less than 0.01). This study thus demonstrates that, although blood pressure in salt-sensitive individuals is raised by sodium chloride only, both sodium chloride and sodium citrate evoke similar increases in pressor response to norepinephrine and angiotensin II. Since pressor response increased with both sodium salts but resting blood pressure increased only with sodium chloride, enhanced pressor responsiveness alone cannot account for the sodium chloride-induced rise in resting blood pressure.

Crossover Comparison of Nitrendipine with Propranolol in Patients with Essential Hypertension

Summary The antihypertensive effect of nitrendipine (2 × 10 to 2 × 20 mg/day) was compared with that of propranolol (2 × 80 to 2 × 160 mg/day) in a randomized crossover study. Twenty-five patients were treated over two 4-week periods following a placebo period of 2 weeks. Three patients dropped out of the study because of side-effects (two on nitrendipine and one on propranolol). Arterial pressures decreased in a comparable manner from 171/107 mm Hg (measured in a sitting position) to 147/91 mm Hg after 4 weeks on nitrendipine and to 145/93 mm Hg after 4 weeks on propranolol. The frequency of side-effects possibly related to treatment was comparable for both drugs, but decreased with the duration of therapy with nitrendipine only. The antihypertensive effect of nitrendipine, but not of propranolol, correlated positively with age and plasma noradrenaline.

Effect of dietary salt restriction on urinary serotonin and 5-hydroxyindoleacetic acid excretion in man.

Objective: To determine the effect of dietary salt restriction on urinary excretion of serotonin and its principal metabolite 5-hydroxyindoleacetic acid (5-HIAA) in man Design: We studied 16 healthy male volunteers (age range 20-28 years) who ate a standard diet containing 20mmol/day NaCl, to which either 220mmol/day NaCl or placebo was added as a supplement for 1 week each, according to a randomized, single-blind crossover design Methods: Urinary excretion of serotonin, 5-HIAA, noradrenaline and vanillylmandelic acid (VMA) were measured during the low- and high-salt periods using reverse-phase high-performance liquid chromatography Results: During the low-salt diet, 24-h urinary excretion of serotonin increased by 42%, accompanied by a 52% rise in the excretion of 5-HIAA. Salt restriction also increased noradrenaline excretion by 77% and VMA excretion by 40%. Regression analysis revealed a strong positive relationship between the excretion of serotonin and of noradrenaline (r=0.84, P< 0.001) and between that of 5-HIAA and of VMA (r=0.74, P< 0.001) Conclusions: Salt restriction stimulates the serotonergic system in man. Stimulation of this system, in conjunction with the sympathetic nervous system, may contribute to renal sodium conservation during dietary salt restriction in man

Alpha 2- and beta 2-adrenoceptor downregulation in marathon runners.

The regulation of platelet alpha 2- and lymphocyte beta 2-adrenoceptor densities by alterations in endogenous catecholamines was examined. In order to activate the sympathetic nervous system eight trained male normotensive subjects carried out a marathon run. Adrenoceptor densities and plasma catecholamine concentrations were measured before and immediately after the run. Platelet alpha 2-adrenoceptor density and lymphocyte beta-adrenoceptor density decreased after the run (P less than 0.05), whereas both plasma noradrenaline and adrenaline concentrations increased (P less than 0.01). Mean arterial pressure decreased (P less than 0.05), and the heart rate increased (P less than 0.001). The data suggest that increases in endogenous catecholamine concentrations cause downregulation of both alpha- and beta-adrenoceptor densities on human blood cells.

Somatostatin-Induced Hyperkalemia in a Patient on Maintenance Hemodialysis

A 65-year-old man, who had been undergoing maintenance hemodialysis for 20 years, suffering from severe postprandial hypotension was studied on 2 consecutive interdialytic days. The drop in blood pressure resulting from the oral administration of 75 g glucose was prevented by the concomitant infusion of somatostatin (350 micrograms/h), but this was accompanied by severe hyperkalemia (7.4 mmol/l). Suppression of insulin by somatostatin may have contributed to the hyperkalemia by impairing cellular potassium uptake. We conclude that although somatostatin prevents postprandial hypotension, hyperkalemia may limit its use in patients with end-stage renal failure.

Combined beta 1-adrenoceptor blockade and/or beta 2- or beta 1/2 adrenoceptor stimulation as treatment of essential hypertension.

Single and combined therapy with terbutaline (10 mg/day) and metoprolol (200 mg/day) and single therapy with orciprenaline (30 mg/day) were assessed over 8 weeks in a total of 45 patients with essential hypertension. Blood pressure at rest was comparably reduced by metoprolol + terbutaline and metoprolol alone, but with terbutaline and orciprenaline only after 4 weeks. The responder rates (greater than or equal to 10% reduction in diastolic blood pressure) at rest were 58% (metoprolol + terbutaline), 63% (metoprolol) and significantly lower with terbutaline alone at 42% and orciprenaline alone at 45%. The heart rate was affected only by metoprolol monotherapy, which caused a significant decrease. The beta-adrenoceptor stimulators terbutaline and orciprenaline in the chosen doses slightly decreased blood pressure and did not increase the heart rate. Metoprolol was an effective antihypertensive agent but decreased the heart rate. Under combined therapy with terbutaline, there was no additional blood pressure decrease, but the heart rate remained unaffected.

Studies on the Blood Pressure Increasing Mechanism of Mineralocorticoids

The precise mechanism of mineralocorticoid-induced hypertension is still unclear. However, it has been well established that the pressor effect of the mineralocorticoid hormones is mediated by sodium, since it has been shown that their pressor action can be prevented by sodium restriction [1, 2]. Further evidence that sodium and volume retention play an important role in the pathogenesis of mineralocorticoid hypertension comes from the observation of an increased exchangeable sodium [1, 3] and extracellular fluid volume [1, 4] in patients with primary aldosteronism. Thus, mineralocorticoid hypertension represents a sodium- and volume-dependent type of hypertension.