Comparative effects of nitrendipine and hydrochlorothiazide on calciotropic hormones and bone density in hypertensive patients.

The effects of the calcium antagonist nitrendipine and the diuretic hydrochlorothiazide on plasma calciotropic hormone concentrations and lumbar bone density were compared during the treatment of hypertension in a randomized, double-blind, 8 week parallel study, followed by a 52 week open label study. There were 32 subjects with stable essential hypertension (sitting diastolic blood pressure > or = 95 mm Hg and < or = 115 mm Hg without medication) without evidence of renal insufficiency or active heart disease. They were randomly assigned to receive either 10 mg nitrendipine twice daily or 50 mg hydrochlorothiazide daily. In order to reach and maintain target blood pressure (diastolic blood pressure < or = 95 mm Hg) during the open label period, the nitrendipine dose was titrated up to 30 mg twice daily, and additional antihypertensive drugs, of differing classes, were added as necessary. Blood samples were analyzed for concentrations of calcium, parathyroid hormone, and calcitonin, and lumbar bone density was determined by dual photon absorptiometry, at the baseline and at 24 and 52 weeks of antihypertensive drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic and neurohumoral responses to intravenous nicorandil in congestive heart failure in humans.

Nicorandil is a vasodilator drug that combines potassium channel opening properties with nitrate effects. The resulting potent and unique vasodilating properties suggest a potential therapeutic role in congestive heart failure. We therefore studied the acute hemodynamic and neurohumoral responses to nicorandil, given as single intravenous bolus doses of 158, 251, 398, or 630 micrograms/kg, to 22 patients with chronic congestive heart failure (ejection fraction less than 40%). Hemodynamic responses occurred within 5 min of dosing and terminated within 240 min. The heart rate was significantly increased only at 5 min after the 158 micrograms/kg dose, and was unchanged after all other doses. The mean arterial pressure was reduced only by the 398 and 630 micrograms/kg doses. The pulmonary capillary wedge pressure and right atrial pressure were significantly reduced by all doses within the initial 30 min; this reduction in pulmonary capillary wedge pressure was better sustained over time by the two larger doses, whereas the reduction in right atrial pressure was sustained only by the 158 micrograms/kg dose. The cardiac index was reduced by the 158 micrograms/kg dose, but increased after 251, 398, and 630 micrograms/kg of nicorandil. Plasma nicorandil concentrations were positively correlated with changes in cardiac index, systemic arterial pressure, pulmonary capillary wedge pressure, heart rate, and systemic vascular resistance. When measured 1 h after dosing, plasma immunoreactive ANF decreased, norepinephrine concentrations did not change, and plasma renin activity increased, but only at the 630 micrograms/kg dose level.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged hemodynamic benefits from a high-dose bolus injection of human atrial natriuretic factor in congestive heart failure.

The physiologic and potential pharmacologic roles of atrial natriuretic factor in congestive heart failure have remained confusing. We have evaluated the hemodynamic responses to human atrial natriuretic factor [ANF (102-126)] given as bolus intravenous doses of 2.0 or 4.5 micrograms/kg to 12 patients with congestive heart failure. Responses were monitored with pulmonary and systemic arterial catheters in place. By 30 minutes after 4.5 micrograms/kg ANF (n = 6), heart rate decreased from 97 +/- 16 to 91 +/- 15 beats/min, right atrial pressure from 14 +/- 4 to 12 +/- 3 mm Hg, and pulmonary capillary wedge pressure from 33 +/- 3 to 23 +/- 2 mm Hg (all p less than 0.05); responses persisted for 120 minutes. Mean arterial pressure, cardiac index, stroke volume index, and pulmonic and systemic vascular resistances did not change significantly. The 2.0 micrograms/kg ANF dose produced similar responses, but only heart rate and right atrial pressure decreased significantly. No clinically important side effects were noted. High-dose ANF bolus doses can be administered simply and safely and improve hemodynamic parameters in chronic heart failure. Therefore ANF does have pharmacologic activity in heart failure and may have therapeutic potential.

Efficacy of nicardipine in angina pectoris.

The dose-related efficacy and safety of nicardipine, a new calcium antagonist of the dihydropyridine class, was assessed by exercise tolerance testing in a randomized, double-blinded, placebo-controlled study in 19 patients with chronic, stable effort angina pectoris. Four patients were assigned to each of four treatment sequences receiving nicardipine three times daily in an extended Latin-Square study design. An increase in total exercise capacity, time to onset of angina and time to 1 mm ST segment depression was observed with nicardipine 90 mg/day compared to placebo (P less than .05). Gradual upward dose titration in 30 mg/day increments starting from 30 mg/day appeared to produce maximal increase in exercise capacity. Two patients developed adverse side effects attributable to the drug when administered nicardipine 90 mg/day directly from placebo.

Hemodynamic and renal effects of atrial natriuretic peptide in congestive heart failure.

The hemodynamic and renal effects of anaritide (human atrial natriuretic peptide 102-126), a synthetic analog of atrial natriuretic peptide, were evaluated in 35 patients with chronic New York Heart Association class II to IV heart failure. There were 32 men and 3 women, aged 33 to 75 (mean +/- standard error of the mean 56 +/- 2) years. In the first phase of the study, right-sided heart catheterization was performed, and anaritide was administered as 1-hour infusions. The rate of the infusion varied among patients from 0.03 to 0.3 micrograms/kg/min. In response to anaritide, there were decreases in mean systemic arterial (94 +/- 2 to 87 +/- 2 mm Hg), right atrial (10 +/- 1 to 8 +/- 1 mm Hg), mean pulmonary arterial (33 +/- 2 to 28 +/- 2 mm Hg) and pulmonary artery wedge (22 +/- 2 to 15 +/- 2 mm Hg) pressures (all p less than 0.05). Cardiac index increased (2.39 +/- 0.15 to 2.62 +/- 0.15 liters/min/m2, p less than 0.05) and heart rate was unchanged. Systemic vascular resistance decreased significantly, but pulmonary vascular resistance was unchanged. There were increases in urine volume (1.6 +/- 0.2 to 2.3 +/- 0.4 ml/min), sodium excretion (47 +/- 13 to 74 +/- 20 muEq/min) and fractional excretion of sodium (0.41 +/- 0.11 to 0.59 +/- 0.14%, all p less than 0.05), while potassium excretion and creatinine clearance did not change. In the second phase of the study, patients received 2-hour infusions of anaritide (0.03 to 0.6 micrograms/kg/min) and placebo with noninvasive monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic methionine-enkephalin evokes cardiostimulatory responses in the human.

The cardiovascular effects of bolus doses of methionine-enkephalin (Met5-ENK) (1 to 100 micrograms/kg) were studied in 9 subjects in whom, at cardiac catheterization for evaluation of chest pain, patent coronary arteries were found. Met5-ENK produced a simultaneous increase in blood pressure and heart rate beginning within 20 sec, reaching maximal values between 30 and 40 sec, and then terminating by 60 sec. Heart rate, systolic, diastolic, and mean arterial blood pressures increased significantly (p less than 0.0005); pulse pressure remained unchanged. Positive dose-effect relationships were observed for heart rate (p less than 0.002), systolic, diastolic, and mean arterial blood pressures (p less than 0.05). Naloxone (0.5 mg/kg), given to 4 subjects, prevented the heart rate and blood pressure changes associated with Met5-ENK administration, demonstrating that the cardiovascular changes were mediated by opiate receptors. Subjects also described cutaneous paresthesias which were not prevented by naloxone pretreatment. These data suggest a role for peripheral enkephalins in cardiovascular regulation.

Comparison of nitrendipine and hydrochlorothiazide for systemic hypertension.

Left ventricular (LV) hypertrophy with associated LV systolic and diastolic dysfunction is frequently found in patients with systemic hypertension, and is multifactorial in origin. Although a reduction in blood pressure (BP) often results in regression of hypertrophy, the pharmacologic profiles of the antihypertensive agents used may determine the probability of such regression despite similar levels of BP reduction. Thiazide diuretic drugs may actually result in increased LV hypertrophy; calcium channel antagonists may cause regression or no change. The effects of treatment with nitrendipine (20 mg/day) or hydrochlorothiazide (50 mg/day) were compared in an 8-week, double-blind study of 18 hypertensive subjects aged 50 years or older. BP was significantly reduced (p less than 0.05) by both nitrendipine (from 161 +/- 29/102 +/- 4 to 145 +/- 24/92 +/- 7 mm Hg; mean +/- standard deviation) and hydrochlorothiazide (from 162 +/- 15/105 +/- 6 to 143 +/- 20/95 +/- 7 mm Hg). Plasma norepinephrine increased in the nitrendipine group, from 202 +/- 110 to 332 +/- 220 pg/ml at 8 weeks of therapy and in the hydrochlorothiazide group, from 147 +/- 130 to 313 +/- 277. Plasma renin activity changed from 3.2 +/- 2.4 to 3.5 +/- 2.1 during nitrendipine treatment, but from 2.1 +/- 2.1 to 10.5 +/- 10.8 ng angiotensin l/ml/90 min (p less than 0.05) during treatment with hydrochlorothiazide. Left ventricular mass index did not change significantly with either therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha-adrenergic mechanisms in the pathophysiology of left ventricular heart failure--an analysis of their role in systolic and diastolic dysfunction.

Alpha-adrenoceptor (alpha-AR) mechanisms may contribute to systolic and diastolic dysfunction of the left ventricle. Centrally acting alpha 2-AR agonist drugs, including methyldopa, clonidine, and guanabenz, activate brainstem alpha 2-AR and this activation results in a decrease in overall sympathetic tone and an increase in parasympathetic tone. Peripherally acting alpha 1-AR antagonists, such as prazosin, inhibit the actions of catecholamines at post-synaptic receptor sites. Heart failure is characterized by hyperactivity of sympathetic pathways and parasympathetic withdrawal. In this situation, alpha 2-agonists reduce sympathetic activity and improve hemodynamic parameters of cardiac function; both acute and chronic administration of alpha 2-AR have been demonstrated to reduce serum catecholamine levels, heart rate, and arterial blood pressure, and to improve exercise performance. Diastolic dysfunction of the left ventricle is characterized by a marked decrease in ventricular compliance, often a result of hypertension and left ventricular hypertrophy; the end result is an increase in left ventricular filling pressure and pulmonary venous pressure. Treatment with alpha 2-AR, by decreasing sympathetic tone and blood pressure, and alpha 1-AR antagonists, by reducing blood pressure and by directly inhibiting the actions of catecholamines at alpha 1-AR, may produce a reduction in the degree of ventricular hypertrophy and improve diastolic performance of the left ventricle. Thus, therapeutic intervention in heart failure with either alpha 2-AR agonists or alpha 1-AR antagonists may favorably modulate these alterations in sympathetic tone and improve ventricular function.

Antianginal effects of clonidine.

The effects of clonidine, a central alpha-adrenoceptor agonist, were studied in 12 patients with chronic stable effort angina pectoris in an 18-week randomized, double-blind, two-period (6 weeks each) crossover study with a 3-week inter-period washout phase. Clonidine (200 micrograms as a single dose) produced a decrease in rate-pressure product at rest and during exercise and an increase in exercise tolerance, at 1 and 2 h after administration. Chronic administration of clonidine produced a decrease in rate-pressure product at rest and during exercise and an increase in exercise tolerance after 3 weeks (200 micrograms twice a day) and 6 weeks (400 micrograms twice a day) of treatment.

Central alpha-adrenergic agonists in chronic heart failure and ischemic heart disease.

Central alpha-adrenoceptor agonists (methyldopa, clonidine, guanabenz) decrease sympathetic outflow and renin and vasopressin secretion as well as increase parasympathetic activity. These drugs are commonly employed as antihypertensives. Two other conditions, chronic heart failure and ischemic heart disease, may also benefit from central alpha-adrenergic stimulation. In both acute and chronic heart failure, central alpha-adrenoceptor agonists reduced cardiac work load by decreasing heart rate, systemic arterial pressure and reducing venous tone. Also, plasma catecholamines were decreased. Exercise at comparable work loads was achieved at a lower pressure-rate product and effort capacity was sometimes increased. Central alpha-adrenoceptor agonists increased effort capacity in patients with ischemic heart disease and angina pectoris. Again, the benefits are thought to be decreased heart rate, systemic arterial blood pressure and rate-pressure products during exercise; catecholamines are reduced in these patients as well. Central alpha-adrenoceptor agonists offer another avenue of approach to alter neurohumoral factors in congestive heart failure and ischemic heart disease and thereby produce beneficial hemodynamic response.

Time-dependent antihypertensive effect of carteolol--a beta-adrenoceptor antagonist with partial agonist activity.

The antihypertensive effect of carteolol (0.5 to 60 mg daily), a beta-adrenoceptor antagonist with partial agonist activity, was studied in a double-blind parallel protocol. A 3-wk placebo period was followed by an 8-wk treatment period during which patients received 0.5, 2.5, 20, and 60 mg in an increasing (group 1) or decreasing (group 2) manner for successive 2-wk intervals, followed by a 2- to 6-wk withdrawal period. Resting supine and standing blood pressures (BP) and heart rates (HR) were measured at each visit. Isometric handgrip exercise and treadmill exercise were used to evaluate beta-blockade. Plasma carteolol concentration was measured by radioimmunoassay. Recumbent BP fell from 154 +/- 10/100 +/- 2 to 143 +/- 10/84 +/- 11 mm Hg for group 1 and from 153 +/- 10/100 +/- 3 to 138 +/- 14/78 +/- 8 mm Hg for group 2 after 8 wk of treatment. HR was unchanged. The greater reduction in BP for each dose was observed with the later administrations, but was not related to serum concentration. beta-Blockade was evident at all doses of carteolol. Carteolol is an effective antihypertensive. Duration of carteolol therapy, independent of dosage, is important in its effectiveness.

The effect of intravenous clonidine hydrochloride on the isolated forearm venous segment in heart failure.

The effects of intravenous (IV) clonidine (150 micrograms) on the isolated forearm venous segment of ten patients with heart failure were studied. Clonidine reduced pressure in the isolated venous segment of all patients (12.8 +/- 2.1 to 10.6 +/- 1.4 mm Hg, p less than 0.005). In addition, IV clonidine decreased the pressor response to mental arithmetic (2.9 +/- 0.3 mm Hg to 1.8 +/- 0.3 mm Hg, p less than 0.05), while the pressor response to deep breath was slightly enhanced (4.5 +/- 0.8 mm Hg to 6.1 +/- 0.7 mm Hg, p less than 0.05).

The prolonged effect of pentaerythritol tetranitrate on exercise capacity in stable effort angina pectoris.

We studied the effect of a single oral dose of 40 mg of pentaerythritol tetranitrate (PETN) on the exercise capacity of ten patients with angina pectoris. The study design was a randomized double-blind crossover comparing the effects of 40 mg of oral PETN with placebo on exercise tolerance. Patients were exercised to moderate angina pectoris before and 2 1/2 and 4 1/2 hours after receiving the placebo or PETN at seven-day intervals during the double-blind crossover period. Exercise tolerance time was measured using a multistage, progressive treadmill test. Exercise times were greater 2 1/2 hours and 4 1/2 hours following PETN compared with placebo (P less than 0.05). Heart rate, systolic and diastolic blood pressure, and double product at rest (supine and standing) and at point of angina pectoris did not change significantly.

Cardiopulmonary pharmacology of enkephalins in the conscious dog.

Various enkephalins (ENK) have been reported to alter heart rate, systemic blood pressure, and respiratory function but with variable results. We previously found that pentobarbital anesthesia reversed the increases in heart rate and systemic arterial blood pressure produced by Leu5-ENK in the dog. We have now studied the cardiopulmonary responses to systemically injected enkephalins in the awake, chronically instrumented dog. In these unanesthetized dogs, Leu5-ENK, Met5-ENK, and an ENK dimer increased heart rate, systemic arterial pressure, and respiratory rate in a dose-dependent fashion. D-Phe4, Met5-ENK, an analog with behavioral activity but without analgesic or in vitro opiate effects was inactive. Leu5-ENK was studied in detail; typically, heart rate and systemic pressure increased within 20 sec and returned to baseline in less than 180 sec. Intra-arterial injections produced a smaller increase in heart rate than did intravenous injections, but similar increases in systemic arterial blood pressure were recorded. These cardiovascular responses suggest that systemically injected enkephalins suppress baroreceptor reflexes and may have a role in cardiopulmonary regulation.