Acute neurohormonal and hemodynamic response to a new peak III phosphodiesterase inhibitor (ICI 153,110) in patients with chronic heart failure.

Peak III phosphodiesterase (PDE) inhibitors have combined positive inotropic and vasodilator effects. We studied 10 patients with chronic heart failure during and after infusion of intravenous (i.v.) ICI 153,110, an investigational peak III PDE inhibitor. Maximum hemodynamic response for the group occurred after cessation of infusion at a lower plasma drug concentration. At maximum hemodynamic response, cardiac index (CI) increased (2.4 +/- 0.5 vs. 3.2 +/- 0.37 L/min/m2, p less than 0.05) with a decrease in mean arterial pressure (MAP 91 +/- 5 vs. 80 +/- 3 mm Hg, p less than 0.05), pulmonary capillary wedge pressure (PCWP 25 +/- 2 vs. 17 +/- 3.1 mm Hg, p less than 0.01), systemic vascular resistance (SVR 1,422 +/- 106 vs. 983 +/- 97 dynes.s.cm-5, p less than 0.05) and pulmonary vascular resistance (PVR 227 +/- 39 vs. 16 +/- 31 dynes.s.cm-5, p less than 0.05). During the infusion, plasma renin activity (PRA) decreased from 6.34 +/- 2.53 to 3.6 +/- 3 ng/ml/h (NS). The five patients with high baseline PRA had a significant decrease (11.2 +/- 2.5 vs. 5.4 +/- 1.67 ng/ml/h, p less than 0.01) that preceded changes in CI and SVR by 1-2 h. These data suggest that reduction in PRA may have contributed to the hemodynamic effects of this peak III PDE inhibitor.     

Terbutaline infusion in cardiogenic shock: acute hemodynamic effects and clinical response

The effect of terbutaline infusion was studied in six patients with cardiogenic shock due to acute myocardial infarction. Terbutaline was initiated at 3 micrograms/kg/min, and the subsequent infusion rate was adjusted according to heart rate and blood pressure. At 3 hours after infusion arterial pressure increased from 62 +/- 13 mm Hg (mean +/- S.D.) to 89 +/- 13 mm Hg (P less than 0.001), cardiac index increased from 1.38 +/- 0.29 liter/min/m2 to 2.68 +/- 0.47 liter/min/m2 (P less than 0.001), and heart rate increased from 92 +/- 32 beats/min to 112 +/- 29 beats/min (P less than 0.005). Pulmonary artery wedge pressure fell from 24 +/- 7 mm Hg to 17 +/- 3 mm Hg (P less than 0.01), right atrial pressure fell from 12 +/- 4 mm Hg to 6 +/- 3 mm Hg (P less than 0.005), and systemic vascular resistance fell from 1880 +/- 641 dyn-sec/cm5 to 1515 +/- 418 dyn-sec/cm5 (P less than 0.05). In addition, urine flow increased from 4 +/- 6 ml/hr to 314 +/- 237 ml/hr (P less than 0.05), and subjective improvement was noted in all subjects. Undesirable effects observed were hypokalemia (all subjects), supraventricular tachycardia (one subject), and ventricular ectopic beats (three subjects), which responded to potassium replacement and other treatments. All patients required prolonged maintenance infusion to maintain adequate hemodynamic and clinical response. Four patients were weaned off from maintenance therapy after a mean duration of 4.8 days and eventually were discharged from the hospital.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasodilator properties of prostacyclin after coronary artery bypass surgery

The vasodilatory properties of prostacyclin were studied in 12 intubated patients who underwent coronary artery bypass surgery. When infused in doses of 2.5, 5, 10, and 20 ng/kg/min, prostacyclin produced a dose-dependent decrease in systemic vascular resistance from 2,702 +/- 143 to 1,654 +/- 106 dynes/cm5/m2 (p less than 0.05). Heart rate, right atrial pressure, and pulmonary arterial and capillary wedge pressures did not change. Cardiac function was improved, since stroke volume index increased from 29.5 +/- 1.4 to 35.5 +/- 2.0 ml/min/m2 (p less than 0.05) and the rate pressure product decreased from 13.3 +/- 1.3 to 10.9 +/- 0.9 X 10(3) mm Hg/beats/min (p less than 0.05), while stroke work index remained unchanged. These hemodynamic changes were associated with a dose-dependent decrease in arterial oxygen tension which occurred from 278 +/- 25 to 133 +/- 22 mm Hg; however, oxygen transport increased as a result of the prostacyclin-induced increase in cardiac index. This study demonstrates that prostacyclin is a potent arterial vasodilator that may be of interest in the treatment of postoperative vasoconstriction occurring after coronary artery bypass surgery.     

Effects of alpha 2-adrenergic stimulation with UK 14,304-18 on the heart and peripheral circulation of intact dogs

To determine the extent of alpha 2-adrenoreceptor control of cardiovascular function, we studied the hemodynamic effects of the relatively selective alpha 2-adrenergic agonist UK 14,304-18 on the heart and peripheral circulation of intact dogs. Administration of increasing intravenous doses of UK 14,304-18 to conscious dogs given atropine to maintain heart rate (HR) resulted in a reproducible increase in mean aortic (AO) pressure (77.6 +/- 5.0 to 136.4 +/- 6.5 mm Hg, p less than 0.05) and reductions in stroke volume (31.7 +/- 2.9 to 17.9 +/- 1.9 ml/kg/min, p less than 0.05) and left ventricular (LV) dP/dt (2,120 +/- 280.0 to 1,463 +/- 196.1 mm Hg/s, p less than 0.05). In ganglion-blocked dogs UK 14,304-18 did not alter the slope of the LV end-systolic pressure-volume relationship when compared with angiotensin and nitroprusside (79.9 +/- 11.1 control vs. 73.3 +/- 8.7 mm Hg/ml/kg UK 14,304-18, p greater than 0.05), nor did it change the volume intercept (-0.46 +/- 0.12 control vs. -0.53 +/- 0.16 ml/kg UK 14, 304-18, p greater than 0.05) indicating no direct effect on LV contractile function. Changes in indices of diastolic function, including the time constant of isovolumic relaxation, time to peak filling, and chamber volume elasticity were similar to those of equipressor doses of angiotensin, indicating no direct effect on LV diastolic function. Effects on the peripheral circulation were studied in dogs undergoing transient acetylcholine-induced circulatory arrest. UK 14,304-18 increased mean circulatory filling pressure (7.9 +/- 0.3 to 10.3 +/- 0.2 mm Hg, p less than 0.05) and the pressure gradient for venous return (7.6 +/- 0.4 to 9.0 +/- 0.3 mm Hg, p less than 0.05). Central blood volume increased with UK 14,304-18 (15.6 +/- 1.1 to 18.7 +/- 1.5 ml/kg, p less than 0.05), but this increase was not sufficient to maintain cardiac output (CO) during the UK 14,304-18 infusion, which decreased from 157.4 +/- 11.1 to 131.5 +/- 8.9 ml/kg/min (p less than 0.01) in the presence of increased LV afterload. The time constant of relaxation of the arterial system increased and the arterial compliance decreased with increasing mean arterial pressure. Thus, this relatively selective alpha 2 agonist does not directly alter cardiac function but increased tone in arterial resistance vessels and in systemic veins. The fall in CO appears to be caused by a mismatch between preload and afterload, which is the net result of quantitatively different effects on systemic veins and arteries.     

Antihypertensive, enzymatic, and hormonal activity of cilazapril, a new angiotensin-converting enzyme inhibitor in patients with mild to moderate essential hypertension

The antihypertensive activity of cilazapril, a new nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor was evaluated in 20 outpatients (13 women, 7 men; mean age, 49 +/- 2.4 years) with mild to moderate essential hypertension, by means of an open dose-finding study of 10 weeks' duration. Cilazapril, 0.5 mg/day, was given, and the dose increased up to 10 mg/day if sitting diastolic blood pressure (SDBP) was not normalized (less than or equal to 90 mm Hg). Blood pressure measurements were carried out every 2 weeks before and 2 h after dosing. Predose and 2-h postdose measurements of plasma renin activity (PRA), angiotensin II (AII), plasma aldosterone (PA), and enzyme converting activity (ECA) were performed on the 1st day of active treatment and after 2 weeks of therapy. The SDBP decreased from 107.6 +/- 2 to 97.2 +/- 3 mm Hg 2 h after the initial dose (p less than 0.01). At the same time, ECA was inhibited 84.2 +/- 5% (p less than 0.01), AII decreased from 21.2 +/- 3 to 13.6 +/- 2 pg/ml (p less than 0.05), and PA from 208 +/- 29 to 119 +/- 14 pg/ml (p less than 0.01). After 2 weeks of therapy, ECA remained markedly reduced, by 68 +/- 6%, 24 h after the preceding cilazapril dose (p less than 0.01). The mean SDBP decreased from baseline to the end of treatment by 14.6 +/- 3 mm Hg (p less than 0.01). Cilazapril seems to be an effective antihypertensive drug which exerts potent and long-lasting ACE inhibition.     

Hemodynamic and endocrine changes associated with hypotensive action of amosulalol in essential hypertension.

To clarify the hemodynamic and endocrine mechanisms of the hypotensive effect of amosulalol, an alpha- and beta-adrenoceptor antagonist, 19 patients with essential hypertension received amosulalol (20-80 mg/day; average 48.4 mg/day) for 16 weeks. Mean blood pressure (MBP) was significantly decreased (105 +/- 1 vs. 120 +/- 1 mm Hg, p less than 0.001), associated with a decrement in heart rate (HR). Although both cardiac index (CI, 3.68 +/- 0.09 vs. 3.91 +/- 0.09 L/min/m2, p less than 0.001) and total peripheral resistance index (TPRI, 2,271 +/- 78 vs. 2,441 +/- 79 dynes.s.cm-5.m2, p less than 0.001) were reduced, changes in TPRI positively correlated with those of MBP (r = 0.9155, p less than 0.001) but the change in CI did not (r = 0.3568, NS). Plasma renin activity (PRA, 0.55 +/- 0.09 vs. 0.95 +/- 0.14 ng/ml/h, p less than 0.05) and aldosterone concentration (4.6 +/- 0.4 vs. 8.6 +/- 0.5 ng/dl, p less than 0.001) were also decreased with amosulalol. Thus, the hypotensive effect of amosulalol may be due mainly to vasodilation by alpha 1-blocking action. In addition, this hypotensive effect may be facilitated by either beta-blocking action such as decreased cardiac output (CO), with suppression of reflex tachycardia or of the renin-angiotensin-aldosterone system.     

Oral nifedipine in the long-term management of severe chronic heart failure

We evaluated the hemodynamic effects of nifedipine in 10 symptomatic patients with chronic refractory heart failure due to idiopathic cardiomyopathy. Nifedipine significantly increased cardiac index (from 1.80 +/- 0.4 to 3 +/- 0.6 L/min/m2), stroke volume index (from 21 +/- 6 to 33 +/- 8 ml/beat/m2), and stroke work index (from 17.9 +/- 7 to 25.5 +/- 7 g-m/m2). The drugs also produced a significant decrease in left ventricular filling pressure (from 24.6 +/- 3 to 19 +/- 2 mm Hg), mean blood pressure (from 86 +/- 9 to 74 +/- 5 mm Hg), mean pulmonary arterial pressure (from 31.9 +/- 5 to 25.6 +/- 3 mm Hg), total systemic vascular resistance (from 2,104 +/- 329 to 1,088 +/- 249 dyn/s/cm-5), and pulmonary vascular resistance (from 200 +/- 71 to 107 +/- 50 dyn/s/cm-5). Heart rate remained unchanged. In all patients maintained on nifedipine therapy, repeat hemodynamic studies at 2 months revealed sustained effects, and all patients had symptomatic improvement of at least one New York Heart Association (NYHA) functional class. Long-term treatment was well tolerated. Forty-eight hours after discontinuation of nifedipine administration the hemodynamic benefits were lost. We conclude that nifedipine may be of value for long-term ambulatory therapy of severe chronic heart failure.     

Coronary and systemic hemodynamic effects of tetramethylpyrazine in the dog

The hemodynamic effects of tetramethylpyrazine were examined in 27 anesthetized open chest dogs with electromagnetic flowmeter probes on the left circumflex coronary artery and ascending aorta. Tetramethylpyrazine, 2-15 mg/kg i.v., caused prominent systemic and coronary vasodilation, with a maximum reduction of mean aortic pressure from 92 +/- 5 mm Hg during control conditions to 62 +/- 7 mm Hg (p less than 0.01), a peak increase in cardiac output from 3.0 +/- 0.4 to 4.1 +/- 0.7 L/min (p less than 0.05), and a peak reduction of systemic vascular resistance from 2,450 +/- 400 to 1,210 +/- 329 dyne X s X cm-5 (p less than 0.01). Simultaneously, heart rate increased from 143 +/- 9 to 174 +/- 8 beats/min (p less than 0.01), and maximum left ventricular dP/dt increased from 2,410 +/- 120 to 4,020 +/- 60 mm Hg/s (p less than 0.01). Dose-related increases of coronary blood flow occurred from 37.3 +/- 3.7 to a maximum of 74.1 +/- 6.6 ml/min (p less than 0.01), while mean coronary vascular resistance decreased from 1,770 +/- 240 to 700 +/- 260 dyne X s X cm-3 (p less than 0.01). Myocardial oxygen consumption increased in proportion to the increase in coronary blood flow. Following beta-adrenergic blockade with propranolol (1 mg/kg, i.v.), ganglionic blockade with hexamethonium, or catecholamine depletion with reserpine (1.0 mg/kg, i.p.), the systemic and coronary vasodilator effects of tetramethylpyrazine persisted, but the increases in heart rate, maximum left ventricular dP/dt, and myocardial oxygen consumption were markedly attenuated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive effect of canrenone in a model where endogenous ouabain-like factors are present

The effect of canrenone, an antialdosterone and partial ouabain-agonist drug, was studied in rats that developed volume expansion and hypertension after renal mass reduction and excess Na+ intake (RRM-salt). The RRM-salt was characterized by: (1) increased endogenous "digitalis-like" compounds in plasma [cross reactivity with digoxin-antibodies (57.5 +/- 5.0 vs. 42.1 +/- 3.8 pg/ml, p less than 0.02); inhibition of kidney Na+, K+-ATPase activity (135 +/- 5 vs. 154 +/- 5 mumol/mg/h, p less than 0.01); and inhibition of Na+ extrusion from normal erythrocytes (5.96 +/- 0.40 vs. 7.68 +/- 0.34 mmol/L cells/h, p less than 0.01)]; (2) reduced Na+, K+-pump activity (7.34 +/- 0.29 vs. 10.88 +/- 0.41 mmol/L cells/h, p less than 0.001) and increased Na+ content (4.66 +/- .08 vs. 4.16 +/- 0.11 mmol/L cells, p less than 0.01) in erythrocytes; and (3) low plasma renin activity (2.1 +/- 0.9 vs. 12.6 +/- 1.6 ng/ml/h). Ninety minutes after the administration to RRM-salt of a single oral dose of 60 mg/kg of canrenone, the systolic blood pressure decreased by 36 +/- 4 mm Hg (mean +/- SEM). Chronic canrenone administration (60 mg/kg/day) resulted in a marked antihypertensive effect associated to a correction of volume expansion, a decrease in endogenous "digitalis-like" compounds, and a partial recovery of Na+, K+-pump activity and Na+ content in erythrocytes. Our results suggest that the antihypertensive effect in RRM-salt rats results, at least in part, from antagonism with endogenous "digitalis-like" compounds.     

Beneficial effects of the calcium antagonist PN 200-110 in patients with congestive heart failure

We studied the acute hemodynamic effects of PN 200-110, a newly available calcium antagonist, in 12 patients with severe congestive heart failure. Measurements of cardiac performance were obtained by a right heart catheter before and after administration of 5 and 15 mg of PN. Peak drug effects occurred 1-2 h following the administration of PN 200-110 and were dose related. The 15-mg dose reduced mean arterial pressure (MAP) from 90 +/- 11 to 75 +/- 6 mm Hg (mean +/- SD) (p less than 0.001) and decreased systemic vascular resistance (SVR) from 1,740 +/- 500 to 995 +/- 300 dynes X s X cm-5 (p less than 0.01). Stroke volume index (SVI) increased from 26 +/- 7 to 36 +/- 10 ml/m2 (p less than 0.001), and cardiac index (CI) rose from 2.1 +/- .3 to 2.8 +/- .6 L/m2 (p less than 0.01). Pulmonary arterial wedge pressure (PAW) changed insignificantly. Seven patients performed graded supine exercise at identical workloads before and after treatment. When peak exercise values were compared, the addition of PN 200-110 further reduced SVR from 1,282 +/- 461 to 936 +/- 356 dynes X s X cm-5 (p less than 0.01) and increased CI from 3.3 +/- 1.1 to 4.3 +/- 1.3 L/m2 (p less than 0.01). Only minor, self-limiting side effects were noticed during acute administration. Of the seven patients discharged on PN 200-110 and followed for at least 6 months, six reported substantial relief of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiischemic and hemodynamic effects of intravenous isradipine, a new calcium antagonist, in coronary heart disease: a comparative double-blind cross-over study with nifedipine.

In a double-blind cross-over study, 10 patients with stable angina pectoris owing to coronary heart disease were investigated in supine position during rest and bicycle exercise for the effect of 0.4 mg of intravenous (i.v.) isradipine in comparison to 2 mg i.v. nifedipine on cardiac hemodynamics and myocardial ischemia. At rest, both drugs significantly decreased total peripheral resistance (TPR) and mean arterial blood pressure (MAP), whereas heart rate (HR) increased. The pressures and resistance of the pulmonary circulation remained uninfluenced at rest. During symptom limited-exercise, both medications reduced TPR despite an unchanged MAP. Mean pulmonary artery pressure decreased significantly after both medications, whereas right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR) decreased significantly only after nifedipine. The improvement of mean ischemic ST-segment depression averaged 44 +/- 6% (mean +/- SEM, p less than or equal to 0.01) after nifedipine and 45 +/- 7% (p less than or equal to 0.01) after isradipine. The time until angina appeared increased after isradipine by 89 +/- 28% (p less than or equal to 0.05) and after nifedipine by 105 +/- 42% (p less than or equal to 0.01). Significant differences between the two medications appeared only for cardiac output (CO) at rest (p less than or equal to 0.05), during which state the increase after isradipine was higher than after nifedipine, and for exercise HR (p less than or equal to 0.01), during which state only nifedipine induced a significant increase in frequency. We conclude that at the chosen dosages the hemodynamic and antiischemic effects of isradipine are similar to the effects that occur after nifedipine.     

Enhanced acute antihypertensive effect of propranolol in the absence of circulating epinephrine in the rat

beta-Adrenoceptor blocking agents might reduce blood pressure, in part, by blocking presynaptic beta-adrenoceptors. Absence of circulating epinephrine should then reduce the antihypertensive effect of propranolol. Biadrenalectomized Wistar-Kyoto rats were made hypertensive with methylprednisolone (20 mg/kg s.c. weekly), given for 2 weeks, and supplemented with deoxycorticosterone pivalate (10 mg/kg weekly). Sham-operated controls received the same treatment. Baseline weight, mean intraarterial blood pressure, and heart rate of the groups were the same. After propranolol (5 mg/kg s.c.) was administered to the unanesthetized rats, blood pressure fell within 90 min from 151 +/- 4 by 23 +/- 4 mm Hg (mean +/- SEM) in the adrenalectomized animals and from 153 +/- 4 by only 7 +/- 3 mm Hg in the sham-operated controls (p less than 0.001); heart rate fell by 91 +/- 13 beats/min in the adrenalectomized animals and by 40 +/- 11 beats/min in the controls (p less than 0.01). Propranolol's vehicle had no effect. At the end of the experiment, plasma epinephrine levels were less than 40 pg/ml for adrenalectomized rats, and 420 +/- 60 pg/ml for controls. Norepinephrine levels were approximately equal in the two groups. Since blood pressure fell despite virtual absence of circulating epinephrine, these results suggest that propranolol reduces blood pressure, at least in part, by mechanisms other than presynaptic beta-adrenoceptor blockade.     

Azotemia during chronic converting enzyme inhibition with enalapril in sodium-depleted rats: role of renal circulatory changes

Chronic administration of the angiotensin-converting enzyme inhibitor enalapril to sodium-restricted rats causes azotemia and elevations in serum creatinine. This study was undertaken to determine the contribution of altered systemic and renal hemodynamics to the reductions in renal function in sodium-restricted rats treated with enalapril. Animals were maintained for 21 days on a sodium-restricted diet (0.04 +/- 0.01 mEq Na+/24 h). Enalapril was administered in the drinking water (300 mg/L) to half the rats. Regional blood flows were measured in animals anesthetized with pentobarbital (50 mg/kg, i.p.) using the radioactive microsphere technique. Converting enzyme inhibition (CEI) reduced mean arterial pressure (130.8 +/- 5.9 vs 60.3 +/- 6.1 mm Hg, p less than 0.001), and increased cardiac index (346 +/- 33 vs. 437 +/- 28 ml/min/kg, p less than 0.05). Total peripheral resistance was significantly lower in enalapril-treated rats [0.406 +/- 0.049 vs. 0.166 +/- 0.013 arbitrary resistance units (RU), p less than 0.001]. Renal blood flow was maintained (control, 2.93 +/- 0.21 vs. enalapril, 2.55 +/- 0.28 ml/min/100 g, p = NS) despite a 54% decrease in perfusion pressure due to decreased renal vascular resistance (42.6 +/- 1.7 vs. 25.2 +/- 2.9 RU, p less than 0.001). CEI reduced coronary blood flow (2.76 +/- 0.22 vs. 1.59 +/- 0.19 ml/min/100 g, p less than 0.001), but did not change coronary vascular resistance (50.2 +/- 4.6 vs. 44.0 +/- 4.3 RU, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive therapy with ketanserin: metabolic and hemodynamic effects

Ketanserin, a serotonin-2-receptor antagonist, was administered to 12 subjects with mild to moderate hypertension in a randomized, double-blind, placebo-controlled crossover trial. After 6 weeks of ketanserin (40 mg every 12 h), blood pressures measured 12 h after dosing were not significantly different from those obtained during the placebo period. However, 2 h after ketanserin administration, supine systolic and diastolic blood pressures declined 11 +/- 10 mm Hg (p less than 0.01) and 6 +/- 5 mm Hg (p less than 0.005) from predose values, whereas placebo caused no change in either systolic or diastolic blood pressure. At the time of peak antihypertensive activity, plasma renin activity, aldosterone, growth hormone, and prolactin levels were unchanged. Prolactin levels decreased slightly (4.1 +/- 3.0 vs. 3.7 +/- 2.9 ng/ml, p less than 0.05) during ketanserin therapy when measured 12 h after dosing. Other pituitary hormones, serum testosterone, plasma catecholamines, and plasma lipids showed no changes. Heart rate was also unchanged. Stroke volume, measured 2 h after dosing, increased (70 +/- 22 vs. 85 +/- 31 ml, p less than 0.05) with ketanserin therapy, but cardiac output did not change significantly. Ketanserin has a moderate antihypertensive effect and neutral metabolic-hormonal profile when used as monotherapy for the treatment of hypertension. However, further studies are needed to define the frequency of dosing that will provide 24-h antihypertensive activity.     

First-step treatment of mild to moderate uncomplicated essential hypertension by a new calcium antagonist: nicardipine

Nicardipine, a new calcium antagonist, was tested in a 14-week double-blind trial including 15 outpatients with uncomplicated essential hypertension. They were randomly assigned to nicardipine (20-30 mg three times daily) or placebo as first-step treatment. When necessary but always after a minimum of 4 weeks, pindolol (15 mg/day) was combined with nicardipine or placebo. At the end of step 1 (85 +/- 6 days with nicardipine vs. 58 +/- 6 days with placebo, p less than 0.01), nicardipine induced larger drops in supine systolic and diastolic blood pressure (SBP and DBP) than the placebo (21 +/- 2.5 vs 1.4 +/- 3 mm Hg, p less than 0.001, and 13 +/- 2 vs. 3.5 +/- 1.5 mm Hg, p less than 0.001, respectively). In the nicardipine group (n = 57), 53% of patients had controlled blood pressure (SBP less than 160 mm Hg and DBP less than 95 mm Hg) versus 17% in the placebo group (n = 47), p less than 0.001. There was no significant correlation between the decrease in blood pressure and the age of patients. The most common side effects in the nicardipine group were flushes (12%), headache (8%), ankle edema (5%), and asthenia (4%). When blood pressure was not brought under control and pindolol was prescribed as the second-step treatment, the nicardipine group (n = 52) displayed larger drops in SBP and DBP than the placebo group (n = 40) (27 +/- 5 vs. 15 +/- 3 mm Hg, p less than 0.01, and 18 +/- 1 vs. 9 +/- 2 mm Hg, p less than 0.001, respectively). These results show that a calcium antagonist is useful for first-step treatment of hypertension.     

Systemic, pulmonary, and renal hemodynamic effects of endothelin ET(A/B)-receptor blockade in patients with maintained left ventricular function

Endothelin-1 (ET-1) regulates vascular tone in congestive heart failure and modulates renal function. Its role in patients with normal left ventricular (LV) function and its renal effects are unclear. Cardiac and renal hemodynamics were studied in 24 patients with normal LV function and coronary arteries after single-dose, double-blind, randomized administration of TAK-044 (25, 50, or 100 mg, i.v.), an ET(A/B)-receptor antagonist, or placebo. Hemodynamics were monitored using Swan-Ganz and arterial catheters, and ET levels were measured. Renal function was assessed by clearance techniques. In the absence of a dose-response relation, TAK-044 patients were analyzed as a single group. Most hemodynamic effects occurred during the first 4 h. TAK-044 reduced mean arterial (-9.3 mm Hg, p < 0.001), pulmonary (-1.8 mm Hg, p = 0.01), and pulmonary capillary wedge pressure (-1.6 mm Hg, p < 0.001) between 30 min and 4 h. Mean reduction in systemic vascular resistance was 279 dyne/s/cm2 (p < 0.001), whereas heart rate increased 6.1 beats/min (p < 0.001) and cardiac index by 0.37 L/m2 (p = 0.01). Stroke volume index, right atrial pressure, and pulmonary vascular resistance did not change. TAK-044 increased renal plasma flow in proportion to the increase in cardiac output (+119 ml/min, 4 h after TAK-044; p < 0.05) and ET-1 levels (2.5-fold; p < 0.05). No serious side effects were noted. In patients with normal cardiac function, ET-receptor blockade causes vasodilation and reduces systemic but not pulmonary vascular resistance and increases cardiac index and renal plasma flow.     

Short-term hemodynamic effects of intravenous methyldopa in patients with congestive heart failure

The acute hemodynamic effects of intravenous methyldopa were studied in six patients with chronic congestive heart failure (New York Heart Association class IV) at 4-6 hours after a 750-mg bolus (period A) and 6-12 hours after a maintenance infusion of 1-2 mg/minute (period B). For period A, the most consistent and striking finding was a significant (48%) fall in pulmonary wedge pressure (33 +/- 6 to 17 +/- 2 mm Hg; p less than 0.05). Stroke volume increased 39% (23 +/- 3 to 32 +/- 4 ml/m2; p less than 0.05), while peripheral vascular resistance decreased 15% (3331 +/- 363 to 2841 +/- 241 dynes.s.cm-5; p less than 0.05). Heart rate fell from 97 +/- 7 to 76 +/- 3 beats/minute (p less than 0.05) with a nonsignificant decline in mean right atrial pressure (18 +/- 4 to 9 +/- 1 mm Hg). These hemodynamic changes were either sustained or enhanced during period B. Concomitant clinical improvement was also noted. As an agent with potent vasodilatory and antiadrenergic properties, methyldopa permitted a rise in stroke volume by virtue of unloading and possible inhibition of sympathetic activity that led to increased density of beta-adrenergic receptors of the heart (up-regulation). Significant reduction of ventricular filling pressure was attributed to venodilation and probable improved diastolic function. In selected patients with severe congestive heart failure, particularly underscored by excessive sympathetic tone, methyldopa may be considered as an alternative agent to improve cardiac performance and clinical symptomatology.     

Acute vasodilator test in pulmonary arterial hypertension: evaluation of two response criteria

The rationale for the acute vasodilator test in idiopathic pulmonary arterial hypertension (IPAH) is to identify patients who have a vasoreactive component that justifies the use of non-selective vasodilators. We tested the ability of two different response criteria to identify such patients studying 34 patients with IPAH. The hemodynamic data from the right heart catheterization were collected at baseline and post-administration of inhaled nitric oxide. We describe the results obtained by two different response criteria: (A) a 20% decrease in indexed pulmonary vascular resistance (PVRi) and in mean pulmonary artery pressure(PAPm)(classic criterion); (B) a fall in PAPm of at least 10 mm Hg to a pressure level of 40 mm Hg or lower (revised criterion). Patients who responded according to the revised criterion showed a higher cardiac index (CI) (3.45+/-1.94 vs. 1.99+/-0.44 L/min/m2; p=0.05) and lower PVRi (1247+/-746 vs. 2437+/-1105 dyn cm-5 s m2; p=0.02) compared to non-responders. Responders according to the classic criterion had a statistically significant lower CI (1.59+/-0.40 vs. 2.43+/-1.14 L/min/m2; p=0.03) and higher PVRI (3130+/-1173 vs. 1958+/-980 dyn cm-5 s m2; p=0.04) also compared to non-responders. We conclude that the revised criterion seems to reflect the degree of vascular remodeling more accurately, identifying patients with better preserved cardiac function, possibly in an earlier phase of the disease.     

Influence of metoprolol and cilazapril on blood pressure and on sleep apnea activity.

Up to 50% of hypertensive men are subject to sleep apnea (SA). With a prevalence in men of up to 10%, SA is a common illness and hypertension (HT) one of its early symptoms. It is important to have available a drug treatment that will effectively control blood pressure (BP) without exacerbating symptoms of SA. Twelve patients with SA and HT were investigated in a double-blind, comparative trial. Patients were randomly allocated to either metoprolol (M) 100 mg daily or cilazapril (C) 2.5 mg daily. Polysomnographic measurements under standardized conditions including intraarterial BP monitoring were taken on two consecutive nights each before and after the 1-week treatment. Values in the M group were (mean +/- 95% CI) systolic BP 161 +/- 2.1 vs. 148 +/- 2.2 mm Hg (p less than 0.01); diastolic BP 98 +/- 1.8 vs. 93 +/- 1.8 mm Hg (p less than 0.01); and HR 73 +/- 1.2 vs 65 +/- 1.1 beats/min (p less than 0.01). Corresponding figures for the C group were systolic BP 140 +/- 2.1 vs. 127 +/- 2.1 mm Hg (p less than 0.01); diastolic BP 95 +/- 1.7 vs. 78 +/- 1.7 mm Hg (p less than 0.01); and HR 82 +/- 1.1 vs. 79 +/- 1.2 beats/min (p less than 0.01). Whereas C reduced both BP and HR in all sleep phases, M produced no changes during REM sleep. SA activity was 45 (range 15-91) vs. 34 (range 2-57) apneas per hour of sleep in the M group and 54 (range 21-84) vs. 40 (range 8-72) apneas per hour in the C group (p less than 0.01). There were no changes in total sleep time or in the proportions of non-REM to REM sleep. Both M and C reduce nocturnal BP in SA patients, but the effect of C is seen in all sleep phases. C has a more favorable effect on the disturbed nocturnal blood pressure of SA patients.     

Hemodynamic response to intracoronary infusion of atrial natriuretic factor in patients with normal or altered left ventricular function.

To assess the effects of atrial natriuretic factor (ANF) on cardiac function, synthetic human ANF was infused directly into the left main coronary artery of eight patients with congestive heart failure (CHF) and six subjects with normal left ventricular (LV) function (controls) who underwent cardiac catheterization. ANF infusion at the incremental rates of 60, 125, 400, and 800 ng/min induced a dose-related increase in plasma ANF concentrations in the coronary sinus, from 1,223 +/- 590 to 3,923 +/- 1,123 pg/ml in patients with CHF (p less than 0.01) and from 1,041 +/- 605 to 2,710 +/- 1,741 pg/ml in controls (p less than 0.01). Peripheral plasma ANF concentrations (femoral artery) increased from 538 +/- 278 to 752 +/- 262 pg/ml (p less than 0.01) in patients with CHF and from 193 +/- 63 to 401 +/- 147 pg/ml (p less than 0.01) in controls. The increase in peripheral or coronary sinus plasma ANF concentrations did not differ between patients with CHF and controls. At the three lowest ANF infusion rates, cardiac index (CI), systemic vascular resistance (SVR), and LV contractility assessed by peak positive dP/dt remained unchanged both in patients with CHF and in controls. At the highest ANF infusion rate, CI increased from 2.18 +/- 0.53 to 2.54 +/- 0.49 L/min/m2 (p less than 0.01) and SVR decreased from 14.6 +/- 3.6 to 12.8 +/- 4.5 mm Hg.min/L (p less than 0.01) in patients with CHF. There was no associated change in heart rate (HR), mean arterial blood pressure (MAP), cardiac filling pressures, or peak positive dP/dt.(ABSTRACT TRUNCATED AT 250 WORDS)