[Insulin resistance and arterial hypertension]. / Insulinresistenz und arterielle Hypertonie.

Insulin resistance and reactive hyperinsulinemia occur not only in patients with obesity, impaired glucose tolerance or non-insulin-dependent (Type 2) diabetes mellitus, but also in many non-obese, non-diabetic individuals with essentiell hypertension and their normotensive, lean young offsprings. The common coexistance of a genetic predisposition for hypertension with insulin resistance helps to explain the frequent occurrence of hypertension as well as dyslipidemia, obesity and diabetes Type 2 in a given individual. In the pathogenesis of hypertension, inappropriate vasoconstriction and/or a structural vasculopathy appears to be an important and ultimate causative event. Several pressor mechanisms are discussed and a distinct sodium retention appears to be almost obligatory associated with diabetes mellitus, while essential and particularly obesity-associated hypertension involves predominantly a tendency for sympathetic activation. Acute hyperinsulinemia on one hand causes arterial vasodilation and on the other hand enhances renal sodium reabsorption and sympathetic activity. Chronically, hyperinsulinemia may promote cardiovascular muscle cell proliferation and atherogenesis. Insulin resistance affecting certain transmembrane cation transporters might lead to an elevation of intracellular cytosolic calcium levels thereby inducing inappropriate vasoconstriction. Nevertheless, whether insulin resistance and hyperinsulinemia contribute to the pathogenesis of hypertension per se is still unproven. Considering antihypertensive drugs, thiazide diuretics given in medium or high dosage as well as beta-blockers appear to promote insulin resistance, reactive hyperinsulinemia and dyslipidemia. Almost all calcium antagonists and the conventional sympthatolytics are metabolically neutral, while ACE-inhibitors and alpha 1-blockers tend to improve insulin resistance. In Type 2 diabetic patients, ACE-inhibitors exert in addition to their antihypertensive a potentially useful anti-diabetic effect. Nevertheless, the prognostic relevance of the metabolic side effects of antihypertensive drugs awaits further clarification.

Serum lipoproteins during treatment with antihypertensive drugs.

Several drugs used for antihypertensive therapy may modify the lipoprotein metabolism. Thiazides in high dosage and loop diuretics can increase serum low-density lipoprotein (LDL) cholesterol and/or very-LDL cholesterol and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio, while HDL cholesterol is largely unchanged; triglycerides (Tg) are also often elevated. Premenopausal women may be protected from this side effect. Whether diuretic-induced dyslipidemia is dose-dependent and low thiazide doses (i.e., hydrochlorothiazide < or = 12.5 mg daily) are interacting less, awaits clarification. beta-Blockers without intrinsic sympathomimetic activity increase serum triglycerides and tend to lower the potentially antiatherogenic HDL cholesterol. The diuretic-antihypertensive agent indapamide, given at a dose of 2.5 mg/day, is neutral with regard to serum lipoprotein and glucose metabolism. The potassium-sparing diuretic spironolactone, conventional sympatholytic agents, calcium-channel blockers, and probably the serotonin2-receptor antagonist ketanserin, exert no relevant effects on the lipoprotein profile. Angiotensin-converting enzyme inhibitors may slightly decrease serum triglycerides. alpha 1-Receptor blockers slightly decrease LDL cholesterol and Tg and increase HDL cholesterol. Drug-induced development or aggravation of dyslipidemia represents a potentially adverse influence. In the hypertensive population, effective blood pressure control with traditional drug therapy based on thiazide-type diuretics in high dosage led to a distinct decrease in cerebrovascular morbidity and mortality, but failed to satisfactorily reduce coronary complications. The prognostic relevance of drug-induced changes in serum lipoproteins, carbohydrate metabolism and other risk factors or correlates awaits further clarification.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive therapy in diabetic patients.

Diabetes mellitus (DM)-linked metabolic alterations and hypertension concomitantly accelerate or precipitate cerebrovascular and coronary heart disease, nephropathy, retinopathy and widespread macroangiopathy, thereby conferring to diabetic patients a very high risk of morbidity, disability and early death. Therefore, the long-term care for diabetic patients should be aimed at concomitant metabolic and blood pressure (BP) control. Dietary measures are indispensable; a high fibre, low fat, low salt diet is recommended, complemented with caloric restriction and physical exercise when body weight is above the ideal. Antidiabetic pharmacotherapy involves an unresolved dilemma. The desired achievement of euglycemia necessitates effective levels of insulin, but hyperinsulinemia (due to parenteral [over]treatment in insulin-dependent DM) is suspected to promote atherogenesis and represents a coronary risk factor and perhaps even facilitates hypertension. Considering antihypertensive pharmacotherapy, thiazide-type or loop diuretics are problematic drugs in DM because they can aggravate metabolic alterations. These agents also seem to exert only a limited preventive or regressive effect on left ventricular hypertrophy (LVH); beta-blockers are also not considered ideal, since they decrease the awareness of hypoglycemia and tend to promote glucose intolerance. Unselective beta-blockers in particular promote peripheral ischemia and insulin-induced hypoglycemia, while beta-blockers without intrinsic sympathomimetic activity lower serum HDL-cholesterol. Calcium antagonists and ACE inhibitors have equivalent antihypertensive efficacy, do not impair carbohydrate and lipid homeostasis or peripheral perfusion and can effectively improve LVH. Certain ACE inhibitors may even slightly ameliorate abnormal insulin sensitivity and plasma glucose levels. While alpha-blockers share most of these desirable properties, these agents are more prone to precipitate orthostatic hypotension in the diabetic patient. The non-thiazide diuretic indapamide and the serotonin2-antagonist ketanserin also combine antihypertensive efficacy with metabolic neutrality. The ultimate goal of therapy is to improve life prognosis. In essential hypertension, conventional drug treatment based on diuretics in high dosage satisfactorily reduced cerebrovascular but not coronary complications or sudden death. In diabetic patients, the influence of antihypertensive therapy on prognosis has not been assessed prospectively. Based on retrospective analyses, Warram et al reported a 3.8 times higher mortality in diabetics treated with diuretics alone, than in diabetics with untreated hypertension (Arch Intern Med. 1991;151:1350). H. H. Parving calculated that effective BP control in patients with diabetic nephropathy might reduce 10 year-mortality from about 65 to 20 percent (J Hypertension. 1990; 8[Suppl 7]:187).(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of diuretics on the plasma lipid profile.

Hypertension, dyslipidaemia, glucose intolerance (associated with insulin resistance and compensatory hyperinsulinaemia) and other abnormalities are complementary coronary risk factors which often occur in association. A familial trait for essential hypertension seems to coexist commonly with defects in carbohydrate and lipoprotein metabolism which can be detected before the appearance of hypertension. Diabetes mellitus as well as obesity promotes the development of hypertension and dyslipidaemia. Moreover, certain drugs used for antihypertensive therapy can further modify lipoprotein and glucose metabolism. Thiazides in high dosage and loop-diuretics can increase serum low-density-lipoprotein cholesterol (LDL-C) and/or very-LDL-C and the total C/high-density lipoprotein cholesterol (HDL-C) ratio, while HDL-C is largely unchanged; triglycerides (Tg) are also often elevated. Premenopausal women may be protected from this side effect. Whether diuretic-induced dyslipidaemia is dose-dependent and low thiazide doses (i.e. hydrochlorothiazide < or = 12.5 mg daily) are less active, awaits clarification. The diuretic-antihypertensive agent, indapamide, given at a dose of 2.5 mg.day-1, seems to exert no relevant effect on serum lipoprotein or glucose metabolism. The potassium-sparing diuretic, spironolactone, also may be largely neutral with regard to lipids. Moreover, potassium sparing diuretics may possibly counteract, at least in part, a dyslipidaemic influence of potassium-loosing diuretics in medium dose. Drug-induced dyslipidaemia, as well as glucose intolerance, represent potentially adverse influences. In the hypertensive population, effective blood pressure control with traditional drug therapy based on thiazide-type diuretics in high dosage led to a distinct decrease in cerebrovascular morbidity and mortality, but a lesser decrease in coronary events.(ABSTRACT TRUNCATED AT 250 WORDS)

[Monotherapy with the ACE-inhibitor ramipril or the calcium antagonist nitrendipine in essential hypertension]. / Monotherapie mit dem ACE-Hemmer Ramipril oder dem Calcium-Antagonisten Nitrendipin bei essentieller Hypertonie.

Angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists have, by reason of their potentially favourable pharmacological profile, become increasingly established in the treatment of hypertension in recent years. In a double-blind randomized study with an initial placebo phase, carried out by practising physicians and thus aimed at the "usual" practice patients with essential hypertension, we assessed (1) the antihypertensive effect and tolerability of an ACE inhibitor (ramipril, 5 mg/d) or a calcium antagonist (nitrendipine, 20 mg/d) given in a single daily dose, and (2) a possible age-dependent blood pressure (BP) effect of these therapies. In the 4 weeks' placebo phase, the two treatment groups were comparable as regards average age (49.6 and 49.4 years), age-range (27-67 and 25-64 years) and BP. Fifty-two patients completed the following 6 weeks' phase with active drug therapy. On ramipril (n = 26), the BP measured 24-25 hours after the last drug administration was reduced in the supine position from an average of 155/102 to 142/91 mmHg (mean reduction -10.1%) and in the upright position from 156/106 to 141/96 mmHg (-9.3%). Nitrendipine (n = 26) reduced the average BP from 155/102 to 147/94 mmHg (-6.8%) and from 155/106 to 146/99 mmHg (-6.6%) respectively. BP-lowering effects of both treatments were largely independent of age. Including the patients who discontinued the study prematurely because of side effects (1 on ramipril, 4 on nitrendipine), the "intention to treat analysis" shows BP normalization rates (diastolic < or = 90 mm Hg) of 55% (ramipril) and 30% (nitrendipine) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive agents, serum lipoproteins and glucose metabolism.

Effective blood pressure control with traditional high-dose diuretic therapy has led to a distinct decrease in cerebrovascular morbidity and mortality, but failed to achieve a satisfactory reduction of coronary complications and sudden death. The same applies also for beta blockers, although they have been shown to be effective in secondary prevention of myocardial infarction. It is suspected that conventional antihypertensive treatment has an unfavorable effect on coronary risk factors other than hypertension. For instance, thiazide-type diuretics can impair glucose tolerance and increase the potentially atherogenic serum low-density lipoprotein (LDL) cholesterol fraction and triglycerides. Beta blockers without partial intrinsic sympathomimetic activity increase serum triglycerides and tend to lower the potentially antiatherogenic high-density lipoprotein (HDL) cholesterol. Certain beta blockers may also impair glucose tolerance, particularly when they are combined with diuretics. Calcium channel blockers, angiotensin converting-enzyme inhibitors and alpha 1-receptor blockers do not adversely affect lipoprotein or carbohydrate profiles. The latter two drug classes may even increase insulin sensitivity, and alpha 1 blockers may also slightly improve lipid metabolism. The prognostic relevance of drug-induced dyslipidemia and/or glucose intolerance awaits further clarification. In the meantime, it is of clinical interest that several of the generally available antihypertensive drugs seem to be metabolically neutral or sometimes perhaps even potentially beneficial with regard to the lipoprotein and carbohydrate metabolism.

Antihypertensive and hypouricaemic effects of nitrendipine in chronic renal failure.

To evaluate the potential therapeutic value of calcium antagonists in hypertension associated with impaired renal function, blood pressure (BP), certain regulatory factors, and metabolic correlates of cardiovascular risk have been assessed in 15 patients with mild to marked chronic renal failure before and after 6 weeks of therapy with nitrendipine. Compared to placebo, nitrendipine (mean final dose 55 mg/day) decreased supine BP from 173/102 to 146/81 mm Hg and upright BP from 170/105 to 145/86 mm Hg. Heart rate, body weight (+0.8 kg) and exchangeable sodium (+176 mmol, not significant) were minimally increased, and plasma and whole blood volume, plasma angiotensin II and creatinine concentrations, and urinary electrolyte and creatinine excretion were not significantly changed. Nitrendipine increased uric acid excretion and lowered plasma uric acid by 24%; glucose, insulin, serum total lipids, and lipoprotein fractions were unchanged.

Pathogenetic and therapeutic relevance of cardiovascular pressor reactivity to norepinephrine in human hypertension.

In normotensive humans with a positive family history of essential hypertension, blood pressure (BP) is often dysregulated. Body sodium, blood volume, plasma angiotensin II (AngII), epinephrine and norepinephrine (NE), their responses to changes in sodium intake or posture, as well as baroreflex function, beta-receptor-mediated cardiac responsiveness, and the responsiveness of BP to AngII appear to be largely unaltered. However, the responsiveness of BP to NE is commonly exaggerated. An increase in potassium intake may improve the NE hyperreactivity and concomitantly lower BP within the "normotensive" range. Therefore, a selective vascular NE hyperreactivity relative to existing sympathetic activity seems to be a common familial abnormality predisposing for the development of essential hypertension. In borderline or established essential hypertension, an inappropriate vascular reactivity relative to sympathetic activity probably complements other mechanisms contributing to the maintenance of hypertension. Various antihypertensive treatments may lower BP at least in part by improving cardiovascular NE (hyper)reactivity without provoking an equivalent rise in sympathetic activity. These include dietary potassium supplementation, thiazide-type agents, indapamide, calcium channel blockers, postsynaptic alpha 1-blockers, and AngII converting enzyme inhibitors.

Metabolic effects of calcium antagonists in humans, with emphasis on carbohydrate, lipid, potassium, and uric acid homeostases.

Since metabolic side effects of conventional antihypertensive drugs could be one reason for the lack of improvement of cardiac morbidity and mortality, metabolic neutrality has become an important postulate of newer products such as the calcium antagonists (CA). Carbohydrate homeostasis--in spite of an anticipated deterioration derived from early in vitro experiments--has mostly been unaffected by CA therapy in humans, nondiabetic and diabetic. This was found in long-term studies in particular, whereas in acute or short-term trials with high dosages, minor alterations of insulin secretion and/or action were sometimes noted. These are negligible from a clinical point of view. Serum lipid profiles also were generally not disturbed by CA treatment, since most of the controlled long-term trials showed no change or even a potentially beneficial change. Minor lowering of plasma potassium levels during a CA regimen was exceptional and a rise of plasma uric acid values never reported; the latter may even decrease under certain circumstances. Thus, after reviewing more than 150 pertinent publications, we can state that the benefit of antihypertensive or antianginal treatment with a CA is in all likelihood not compromised by introducing known untoward metabolic cardiovascular risks.

Serum lipoproteins during treatment with antihypertensive drugs.

Hypertension and certain alterations in serum lipoproteins such as a decrease in high density lipoprotein-cholesterol (HDL-C), an increase in low density lipoprotein-cholesterol (LDL-C) and perhaps also elevated triglycerides (Tg), are complementary coronary risk factors. Moreover, it has become evident that several of the drugs used for standard antihypertensive therapy may also interact with lipoprotein metabolism. The following has been observed after 1 to 12 months of treatment. Various diuretics can significantly increase LDL-C and/or very LDL-C and total C/HDL-C ratio, while HDL-C is often largely unchanged; Tg also are often elevated. LDL-C increased in diuretic-treated men and in chlorthalidone-treated postmenopausal women but not in chlorthalidone-treated premenopausal women. The latter may be protected from this side effect. Drug dosages were usually high in these studies. Indapamide, given at a dose of 2.5 mg/day, seems to exert no relevant effect on the lipoproteins. It is not established whether this difference is related to the nature of the drugs or the doses used. There is little doubt that the dose of chlorthalidone used was greater than that required for a full antihypertensive effect of this drug. Several beta-blockers given as monotherapy induce significant increases in Tg and a tendency for decreases in HDL-C. These changes are most prominent on non-selective beta 1+2-blockers without partial intrinsic sympathomimetic activity (ISA), less pronounced on highly selective beta 1-blockers without ISA, and even more discrete or absent on beta-blockers with distinct ISA. Other sympatholytics such as reserpine, methyldopa, debrisoquine, urapidil, clonidine, labetalol, or postsynaptic alpha-blockers (prazosin, trimazosin, doxazosin etc.) did not affect or, postsynaptic alpha-blockers in particular, sometimes even slightly decreased Tg or LDL-C and very LDL-C values. During combination therapy, diuretic-induced increases in LDL-C were at short term prevented or reversed by the concomitant administration of certain beta-blockers, but not by sympatholytics such as reserpine, methyldopa or clonidine. With combined diuretic-prazosin treatment, a tendency for slightly higher HDL-C was reported. Angiotensin converting enzyme inhibitors (captopril, enalapril) and calcium channel blockers (verapamil, nifedipine, nitrendipine, diltiazem) seem to be largely devoid of undesirable effects on serum lipoproteins. Monotherapy with the potent direct vasodilator carprazidil improved blood pressure and significantly increased HDL-C. Whether and to what extent the observed variations in lipoproteins may persist beyond 1 year of treatment is as yet unclear.(ABSTRACT TRUNCATED AT 400 WORDS)

Potassium and norepinephrine- or angiotensin-mediated pressor control in pre-hypertension.

Blood pressure (BP), plasma electrolytes, renin, aldosterone, angiotensin II (AII) or catecholamines, the chronotropic effects of intravenous isoproterenol, norepinephrine (NE) or AII, the pressor responses to NE or AII, and the relationship between plasma AII and aldosterone concentrations were studied before and after 10 days of dietary supplementation with potassium 100 mmol/day, in normotensive members of normotensive (N = 12) or hypertensive (N = 12) families, and 11 patients with borderline essential hypertension. Under control conditions, the pressor responsiveness to NE was significantly enhanced in normotensive with positive family history for hypertension and hypertensive subjects; the other variables were comparable in the groups. After potassium supplementation, plasma potassium, renin, aldosterone or AII, and the relationship between AII and aldosterone levels increased significantly, while body weight, plasma catecholamines, the chronotropic effects of isoproterenol, AII or NE, the pressor effects of AII and plasma clearance of AII or NE were unchanged in all groups. In normotensive members of hypertensive families and patients with hypertension, BP was decreased and the exaggerated pressor responsiveness to NE was normalized; these variables were not modified in normotensive members of normotensive families. These observations are consistent with a potassium-remediable disturbance in NE- but not AII-dependent regulation of BP in the pathogenesis of essential hypertension.

Comparative acute effects of the calcium channel blockers tiapamil, nisoldipine, and nifedipine on blood pressure and some regulatory factors in normal and hypertensive subjects.

To clarify the pharmacological profile of the two new calcium channel blockers tiapamil and nisoldipine in humans, their acute effects as compared with those of the reference agent nifedipine were assessed in 10 normal subjects and 10 patients with essential hypertension. Blood pressure (BP), heart rate (HR), plasma and urinary catecholamine, sodium and potassium, plasma renin and aldosterone levels, and urinary prostaglandin E2 and F2 excretion rates were determined before and up to 4 or 5 h (urine values) after intravenous injection of placebo (20 ml 0.9% NaCl), tiapamil 1 mg/kg body weight, nisoldipine 6 micrograms/kg, or nifedipine 15 micrograms/kg. The four studies were performed at weekly intervals according to Latin square design. All three calcium channel blockers significantly (p less than 0.05 or lower) lowered BP and distinctly increased sodium excretion in hypertensive patients, but had only little influence on these parameters in normal subjects. HR was increased in both groups. Changes in BP and HR were maximal at 5 min and largely dissipated 3 h after drug injection. Effects on BP and HR, as well as concomitant mild increases in plasma norepinephrine and renin levels that occurred in both groups, tended to be more pronounced (about double) following nisoldipine than following tiapamil or nifedipine at the dosages given. Plasma aldosterone, epinephrine levels, and prostaglandin excretion rates were not consistently modified. These findings demonstrate that tiapamil and nisoldipine possess distinct antihypertensive properties in humans. Different chronotropic and renin-activating effects of different calcium channel blockers may be determined, at least in part, by a different influence on sympathetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Pressor factors and responsiveness in hypertension accompanying diabetes mellitus.

Hypertension accompanying diabetes mellitus may involve abnormalities in at least two major blood pressure-regulating systems: the body sodium-fluid volume state and cardiovascular reactivity. In metabolically stable nonazotemic diabetes, exchangeable sodium is increased by 10% on average, regardless of age, insulin dependence or nondependence, or the presence or absence of diabetic retinopathy or clinical nephropathy (proteinuria greater than or equal to 0.3 g/24 hr). Possible contributing mechanisms include renal sodium retention and an extravascular shift of fluid and sodium; intracellular accumulation is not excluded. Circulatory volume is normal or low and the total exchangeable sodium/blood volume ratio increased. In hypertensive diabetes, the latter abnormality is particularly pronounced; systolic pressure tended to correlate with exchangeable sodium (r = 0.47, p less than 0.001) and diastolic pressure with the plasma sodium/potassium ratio (r = 0.25, p less than 0.05). Plasma aldosterone, renin, epinephrine, and norepinephrine levels are generally normal or sometimes low in metabolically stable nonazotemic diabetic patients with normal or high blood pressure; the plasma clearance of norepinephrine also appears to be unaltered. The cardiovascular pressor responsiveness to norepinephrine is often exaggerated relative to concomitant plasma concentrations, regardless of age, type of antidiabetic treatment, or presence or absence of diabetic retinopathy, peripheral neuropathy, or high blood pressure. Pressor responsiveness to angiotensin II also may sometimes be increased relative to plasma renin levels. Sodium retention and diabetic vasculopathy of resistance vessels could be important complementary mechanisms of hyperreactivity. In diabetes with mild hypertension, diuretic treatment restored exchangeable sodium, norepinephrine pressor responsiveness, and blood pressure toward normal. Thus sodium retention and cardiovascular hyperreactivity tend to occur even at the normotensive, nonazotemic stage of diabetes and may concomitantly predispose for the frequent development of hypertension in the diabetic population.

Body-sodium and blood volume in a patient with licorice-induced hypertension.

A 68-year-old man a nine-year history of licorice ingestion had moderate hypertension and low plasma potassium. Exchangeable sodium and blood volume were increased to 128 and 111%, respectively of the expected values; plasma renin and aldosterone levels were suppressed. Plasma norepinephrine concentration was distinctly elevated but the pressor response to infused norepinephrine was normal. After licorice withdrawal, blood pressure, plasma potassium and blood volume reverted to normal levels within three weeks, exchangeable sodium and plasma renin within four months. Exchangeable sodium in our patient with licorice-induced hypertension was increased to a comparable extent as in primary hyperaldosteronism. Moreover, blood pressure in relation to body sodium or plasma potassium did not differ between the exogenous or the endogenous types of mineralocorticoid excess. This observation does not support the possibility that in primary hyperaldosteronism excess aldosterone secretion per se could play an important pressor role independently from sodium retention.

Correction of cardiovascular hypersensitivity to norepinephrine by potassium supplementation in normotensive members of hypertensive families and patients with essential hypertension.

Blood pressure (BP), plasma levels of norepinephrine (NE) and epinephrine, the chronotropic effect of isoproterenol, and the relationship between variations in BP and concomitant plasma NE levels obtained during NE infusion were studied under control conditions and after 10 days of dietary potassium supplementation (100 mmol/day) in 12 normotensive subjects with negative family history (FH) of hypertension (mean BP 111/70 +/- 9/7 mmHg), 11 normotensive subjects with positive FH (112/73 +/- 8/6 mmHg), and 10 subjects with untreated borderline to mild essential hypertension (131/89 +/- 15/9 mmHg). Under control conditions, the increase in circulating NE required to elevate mean BP by 20 mmHg was significantly lower in hypertensive subjects (6.1 +/- 4.0 nmol/l) or normotensive subjects with positive FH (5.0 +/- 2.4 nmol/l) than in normal subjects with negative FH (9.9 +/- 6.4 nmol/l); the other study parameters were similar. After potassium supplementation, plasma and urinary potassium increased and body weight decreased slightly in all groups; basal plasma NE and epinephrine levels and cardiovascular effects of isoproterenol were unchanged. However, in normotensive subjects with positive FH and hypertensive subjects, the increase in plasma NE required to elevate mean BP by 20 mmHg was normalized (to 8.9 +/- 5.9 and 9.9 +/- 6.9 nmol/l, respectively), while BP tended to decrease slightly. These findings indicate that dietary potassium supplementation may favorably modify noradrenergic BP-regulation in hypertension prone individuals.

Pressor factors and cardiovascular pressor responsiveness after short-term antihypertensive therapy with the calcium antagonist nifedipine alone or combined with a diuretic.

Exchangeable sodium, blood volume, plasma norepinephrine, epinephrine, renin levels, and pressor responses to infused norepinephrine or angiotensin II were assessed in 10 patients with essential hypertension on placebo, following six to eight weeks of monotherapy with nifedipine, 3 X 10-20 mg/day, and after six to eight weeks on nifedipine combined with the diuretic chlorthalidone, 25 to 50 mg/day. Supine blood pressure was decreased after nifedipine alone (P less than 0.05) and even further after nifedipine + chlorthalidone (P less than 0.01). Body weight and exchangeable sodium increased after nifedipine (P less than 0.05), but were decreased after adding chlorthalidone. Blood volume was unchanged after nifedipine, but was reduced on nifedipine + chlorthalidone (P less than 0.05). Heart rate, supine plasma renin, catecholamine levels, and pressor responses to norepinephrine or angiotensin II were not consistently changed on nifedipine alone or combined with chlorthalidone. These findings indicate that in the established phase of treatment, nifedipine may exert its antihypertensive effect without necessarily altering cardiovascular responsiveness to norepinephrine and angiotensin II. Moreover, mild sodium retention may develop on nifedipine at least in some hypertensive patients.

Serum lipoproteins in patients with mild renal disease treated with the diuretic muzolimine.

Patients with renal functional impairment are prone to develop hypertension and hyperlipidemia, and both abnormalities tend to occur already at an early stage of kidney disease. In 18 patients with mild renal disease (glomerular filtration rate 65 +/- 5 ml/min) and hypertension (mean blood pressure 126 +/- 4 mm Hg), the effect of six weeks of treatment with the loop-diuretic muzolimine on serum lipoproteins was assessed. Compared to placebo values, the diuretic significantly increased serum low-density lipoprotein cholesterol (LDL-C) and apoprotein B (+ 18 and 11%, respectively, P less than 0.005) in 13 men or postmenopausal women, but not in 5 premenopausal women. Serum high-density lipoprotein cholesterol (HDL-C), and total triglycerides or lipoprotein triglyceride fractions were not consistently changed in both subgroups. Thus, the ratio LDL-C/HDL-C was increased from 3.2 +/- 0.3 to 3.9 +/- 0.3 (P less than 0.05) in the men or postmenopausal women, while no such tendency occurred in the premenopausal women (4.1 +/- 0.6 to 3.7 +/- 0.6). Changes in serum LDL-C were not associated with hemoconcentration or alterations in carbohydrate metabolism and were not related to variations in serum potassium or blood pressure. Increased serum levels of the atherogenic LDL-C fraction during diuretic treatment in men or postmenopausal women with renal disease may represent a potentially undesirable effect, particularly since such patients may tend to have hyperlipidemia in the untreated state.

Sodium, renin, aldosterone, catecholamines, and blood pressure in diabetes mellitus.

Interrelations among plasma renin activity (PRA), aldosterone and cortisole levels, 0lood volume, exchangeable sodium, urinary catecholamines, and blood pressure were studied in 35 normal subjects and 60 age-matched non-azotemic patients with diabetes mellitus (60% with hypertension, 15% with orthostatic hypotension). Basal PRA, plasma aldosterone, cortisol, blood volume, plasma potassium, and urinary electrolytes were comparable in diabetic and normal subjects. Diabetic patients, however, had a 10% increase in body sodium (P less than 0.01), and 8% of them showed normal postural PRA responses and subnormal aldosterone responses; 22% had subnormal PRA and normal aldosterone responses, and 17% had subnormal responses of PRA and aldosterone. Non-PRA-related aldosterone responses could not be explained by ACTH or electrolytes. Orthostatic decreases in blood pressure correlated (P less than 0.01) with both catecholamine excretion and basal PRA. This suggests that in diabetes mellitus, body sodium is increased. Basal PRA and plasma aldosterone are usually normal, but their postural responses are frequently impaired. Absent aldosterone responses, despite normal PRA responsiveness, may reflect an adrenal abnormality or an ineffective form of renin. Marked postural aldosterone stimulation, unrelated to PRA, ACTH, or electrolytes, points to a potent unknown factor in aldosterone control. Low levels of free peripheral catecholamines and PRA may be complementary factors contributing to postural hypotension.