Effect of nicardipine on rest and exercise hemodynamics in chronic congestive heart failure

The hemodynamic response to vasodilation induced by the new calcium channel antagonist nicardipine was studied in 10 patients with severe, chronic congestive heart failure. Rest and exercise hemodynamics were evaluated in the baseline state and after 1 week of oral nicardipine therapy (30 mg 3 times daily). In addition, respiratory gas exchange and arteriovenous oxygen difference were measured to assess changes in oxygen utilization. The responses of the sympathetic nervous system were evaluated by measuring plasma norepinephrine concentrations at rest and during maximal exercise. At rest, nicardipine administration was associated with significant reductions in mean systemic arterial pressure, systemic vascular resistance, pulmonary artery wedge pressure and pulmonary arterial pressure, and significant increases in cardiac index and stroke volume index. These effects were maintained during exercise. In contrast to findings with other calcium channel antagonists, no negative inotropic effect of nicardipine was identified. Nicardipine administration was associated with reduction of arteriovenous oxygen difference. Nicardipine had no effect on plasma norepinephrine concentrations, suggesting absence of reflex sympathetic nervous activation. Thus, nicardipine-mediated vasodilation leads to significant improvements in both rest and exercise cardiac performance.     

Role of calcium antagonists in the pharmacologic treatment of heart insufficiency

There has been increasing interest in the use of calcium antagonists as arterial vasodilator agents in the management of patients with congestive heart failure. Because congestive heart failure is mostly secondary to coronary artery disease, calcium antagonist drugs seem particularly appealing because of their anti-ischemic properties. The potent vasodilating action of calcium antagonists decreases impedance and improves ejection phase indexes of left ventricle function. However, these drugs interfere with calcium availability for myocardial contraction, and concern has been expressed about their potential depressant effect on myocardial performance. The net hemodynamic effect depends on the relative vascular versus myocardial potency of each calcium antagonist and on the indirect effects of reflex sympathetic activation. Balance between these factors is still influenced by the intrinsic status of left ventricle of the patient. Generally, the negative inotropic direct effect of the calcium antagonists is counteracted by the beneficial influence of the decrease of systemic vascular resistance. Because of its relatively more pronounced negative inotropic action, verapamil is not advisable in patients with left ventricular failure. Limited experience with diltiazem show no significant negative inotropic action. Nifedipine has been studied in its acute and long term effects. The use of sublingual nifedipine is established in the emergency management of acute pulmonary edema, specially in patients with arterial hypertension, or when acute ventricular dysfunction is associated with mitral or aortic insufficiency. Patients with chronic congestive heart failure have shown after nifedipine an increase in stroke volume and cardiac index at rest and during exercise, as well as decreases of pulmonary capillary wedge pressure during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Systemic and pulmonary hemodynamic responses to nicardipine during graded ergometric exercise in patients with moderate to severe essential hypertension

In 10 patients with moderate to severe hypertension, the hemodynamic effects of ergometric exercise and nicardipine, a dihydropyridine calcium channel antagonist, were characterized under basal conditions and after 1 week of therapy. The responses of plasma renin activity and catecholamines were also assessed. Nicardipine induced significant reductions of systolic, diastolic and mean blood pressure under conditions of rest and peak exercise (p less than 0.001), mediated by reversal of vasoconstriction (p less than 0.001). Overall, cardiac index and stroke volume index responses were not significantly altered by nicardipine. Although rest pulmonary wedge pressure was unchanged (6 +/- 3 to 5 +/- 4 mm Hg), peak exercise pulmonary wedge pressure decreased from 24 +/- 22 to 7 +/- 5 mm Hg (p less than 0.001) with nicardipine therapy. This effect of nicardipine on pulmonary wedge pressure was present across all work loads studied, and was accompanied by reduction of peak exercise pulmonary artery pressure from 43 +/- 10 to 25 +/- 7 mm Hg (p less than 0.001). Oxygen consumption was unchanged, associated with reduction of arteriovenous oxygen difference (p less than 0.02). Both plasma renin activity (p less than 0.05) and norepinephrine (p less than 0.005) were significantly increased with nicardipine therapy. Thus, nicardipine produced significant blood pressure reduction by reversal of vasoconstriction in patients with essential hypertension. The preservation of cardiac output, with markedly reduced pulmonary wedge pressure, indicated that nicardipine improved ventricular performance in response to reversal of vasoconstriction.     

Calcium antagonists and left ventricular function: effects of nitrendipine in congestive heart failure

Calcium antagonists can affect the arterial vasculature, the venous capacitance vessels and the myocardium. The net effect of these agents on left ventricular (LV) performance depends on the interaction of effects on these 3 vascular components, and the state of LV function at the time that the drugs are administered. A calcium antagonist with profound arterial vasodilator effect might favorably influence LV performance even if it had negative inotropic properties. To demonstrate the direct effect of nitrendipine, a 1,4 dihydropyridine, on LV performance, the acute hemodynamic response to oral nitrendipine was studied in 8 patients with congestive heart failure. Administration of 10 to 20 mg of nitrendipine reduced preload, caused a decrease in both pulmonary wedge pressure and systemic vascular resistance, produced a modest decrease in blood pressure and an increase in stroke volume. In addition, plasma norepinephrine levels were significantly decreased. Plasma renin activity also tended to decrease. These data confirm that the drug can favorably alter performance of the failing left ventricle and further suggest that the vasodilator effect is not accompanied by reflex neurohumoral stimulation.     

Interrupting the adaptive changes in congestive heart failure.

Circulating plasma concentrations of norepinephrine, renin, angiotensin and vasopressin are increased in congestive heart failure. By increasing ventricular afterload, heart failure is further worsened, which in turn--in a vicious cycle--stimulates neurohumoral vasoconstrictor mechanisms. Furthermore, because of the compensatory but excessive stimulation of the sympathomimetic system, a down-regulation and desensitization particularly of the myocardial beta 1 receptors and depletion of myocardial catecholamine occurs in chronic heart failure. These defects may be restored toward normal by interventions that attenuate the activity of the sympathetic nervous system. A direct approach to modify the excessive vasoconstriction is to administer systemic vasodilator drugs, but despite favorable short-term effects, tolerance developed to most of these drugs during long-term treatment. One reason for the loss of effectiveness is the reflex activation of the sympathetic system, which increases vasoconstrictor hormone concentrations. Activation of the renin-angiotensin system can be modified effectively by angiotensin-converting enzyme inhibitors that have shown favorable responses in patients with chronic heart failure. Beta-blocking agents interfere with endogenous sympathetic activation and have produced beneficial effects in patients with congestive cardiomyopathy. Long-term treatment is associated with up-regulation of the number of beta receptors and an improved responsiveness to catecholamines. Owing to the negative inotropic effects of beta-blocking agents, some of the patients with severe heart failure deteriorated hemodynamically and clinically. Theoretically, it should be advantageous to have a substance that combines protection against excessive beta stimulation with a mild inotropic support to prevent cardiac decompensation. This may be achieved by a selective beta 1-partial agonist like xamoterol.     

Usefulness of calcium antagonists for congestive heart failure

In patients with congestive heart failure (CHF) due to dilated cardiomyopathy, nifedipine, diltiazem and several of the newer calcium antagonists including nicardipine, nitrendipine, felodipine and PN 200-110 (isradipine) improve left ventricular function. Because of its relatively more pronounced negative inotropic and chronotropic actions, verapamil is generally not tolerated by patients with left ventricular failure. In addition, even relatively vascular-selective agents such as nifedipine can occasionally cause significant left ventricular depression, particularly if combined with beta-adrenergic blocking agents. Comparative studies using nitroprusside to cause an equivalent decrease in arterial pressure indicate that nifedipine acts predominantly on the arterial vasculature, and that a small but significant decrease in contractility occurs, apparently due to a direct myocardial action. Although diltiazem causes a depression in myocardial contractility in dogs with volume overload heart failure, limited data show no significant negative inotropic action in patients with heart failure. The negative inotropic effects, if any, of newer and possibly more vascular-selective agents are not yet known. Calcium antagonists appear to act predominantly on the limb and coronary vasculature, with relatively less effect on renal and hepatic vessels. In patients with CHF, nifedipine causes an increase in coronary blood flow and a decrease in the aorto-coronary sinus oxygen difference indicating an improvement in myocardial energetics. Although nifedipine causes an increase in cardiac index and decreases in systemic vascular resistance and pulmonary capillary wedge pressure during exercise, the limited data available fail to show a short- or long-term increase in exercise capacity. Nifedipine causes an increase in plasma renin activity, possibly due to a direct action on the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rationale for the short term use of intravenous milrinone under hemodynamic guidance in patients with severe systolic heart failure

Patients with severe systolic heart failure have a decrease in both number and function of cardiac beta receptors, which may result in a poor inotropic response to I.V. beta-adrenergic agonists such as dobutamine. The I.V. use of the phosphodiesterase inhibitor milrinone, which is a combined positive inotrope/vasodilator in this patient population, is a more rational choice, especially if heart failure is chronic. Many of these patients may also be referred for consideration for cardiac transplantation, for which the use of invasive hemodynamic monitoring is typically necessary to determine whether severe hemodynamic compromise and pulmonary hypertension are reversible with therapy. The use of hemodynamically guided I.V. vasodilator therapy has also been extensively described as a tool to optimize oral vasodilator therapy and predict prognosis in patients evaluated for cardiac transplantation. This review summarizes the important studies supporting the rationale for and benefits of using I.V. milrinone under hemodynamic guidance in this patient population. (c)2000 by CHF, Inc.     

Sulfonylureas and platelet function

Intercellular vascular smooth muscle calcium results in vasoconstriction and is therefore a potentially adverse mechanism of increased aflerload in chronic congestive heart failure. Therefore, an evaluation was made of supine and tilt hemodynamic data, sympathetic reflexes, and the hormonal response to calcium channel antagonism after administration of nifedlpine in nine patients with severe chronic congestive heart failure. After a 10 mg oral dose, the peak hemodynamic response occurred at 30 minutes and was characterized primarily by afterload reduction, improvement of systemic flow, and reduction of pulmonary hypertension. Despite reduction of supine blood pressure, there was no orthostatic hypotension during head-up tilt at the same time of peak response. Reflex responses to sympathetic stimulation (cold presser test) were improved but still attenuated when compared with normal responses. Plasma renin activity increased significantly, but a dissociation of the aldosterone response was observed. Plasma catecholamine levels were not significantly altered. In summary, calcium antagonism resulted in significant afterload reduction and hemodynamic improvement in chronic congestive heart failure. This was associated with improved reflex responsiveness and, potentially, altered other vasoconstrictor hormones independently of the hemodynamic response. Calcium antagonism may provide a means to further understand vasoconstrictor mechanisms in heart failure and enhance therapy in appropriate patient subsets.     

Bolus nicardipine in the hemodynamic assessment for heart transplantation of patients with severe failure of ischemic origin and high pulmonary resistance]

Nicardipine i.v. bolus (5 mg/5 min) was administered in the pulmonary artery trunk in 13 patients (2 f, 11 m), mean age 48 +/- 8 yrs, affected by ischemia congestive heart failure, with pulmonary hypertension (pulmonary vascular resistances greater than 6 U.W. and/or systolic pulmonary artery blood pressure greater than or equal to 60 mmHg). The vasodilatation induced by nicardipine caused a rapid improvement of all hemodynamic parameters, with a significant reduction of systemic and pulmonary pressures and resistances; in addition, cardiac output increased significantly. Even if heart rate decreased and mean right atrial pressure fell, their variation did not reach statistical significance. These beneficial effects are attributable to the vasodilator action of nicardipine on the systemic and pulmonary vascular districts. Therefore, in the hemodynamic evaluation of patients with ischemic cardiomyopathy proposed for heart transplantation, we propose the employment of nicardipine in testing the vascular reactivity in cases with secondary pulmonary hypertension.     

Selection of vasodilator, inotropic or combined therapy for the management of heart failure

Vasodilator and inotropic drugs work through independent mechanisms in augmenting left ventricular pump function in patients with heart failure. The selection between these two classes of pharmacologic agents for an individual patient may be based on the control blood pressure as well as the underlying disease. Although vasodilator drugs are easiest and safest to employ in patients with normal or high arterial presure levels, even in relatively hypotensive subjects (systolic arterial pressure less than 105 mm Hg), a salutary hemodynamic effect can be achieved without an undue decrease in pressure. Inotropic drugs may be safest to administer to patients without coronary artery disease, but the oxygen-consuming effect of these drugs need not necessarily have an adverse effect on patients with ischemic heart disease. Combined vasodilator and inotropic drug therapy is the most potent pharmacologic means of restoring pump function in patients with severe heart failure. The long-term use of vasodilator and inotropic drugs in the treatment of heart failure is dependent on the availability of agents that will produce a sustained hemodynamic effect. Hydralazine, nitrates and prazosin have been employed alone or in combination and provide a promising approach to vasodilator treatment of heart failure. Better and more selective oral inotropic agents are needed to allow this therapeutic modality to be employed optimally.     

Hemodynamics of nicardipine in coronary artery disease

Calcium antagonists influence cardiovascular hemodynamics by 3 actions: peripheral arterial dilatation, coronary arterial dilatation and negative inotropic effect. The net hemodynamic effects vary depending on the relative strength of each action. Intravenous administration of the new compound nicardipine, a dihydropyridine derivative with calcium antagonist activity that is chemically related to nifedipine, induced a marked reduction of systemic vascular resistance in patients with and without β blockade. This was accompanied by an increase in cardiac output and left ventricular ejection fraction. In addition, end-diastolic pressure, peak (+) dP/dt and dP/dt measured at a developed pressure of 40 mm Hg and normalized for this pressure remained unchanged. The time constant of isovolumetric pressure drop during the first 40 ms also decreased. Intravenous administration of nicardipine prevented a marked increase in end-diastolic pressure during exercise, and augmented left ventricular ejection fraction in chronic heart failure. At doses producing similar increases in coronary sinus blood flow, intracoronary administration of nicardipine, unlike nifedipine, has little effect on left ventricular contractility and end-diastolic pressure. Nicardipine is a powerful systemic vasodilator with minimal effects on myocardial inotropic state, even in patients with compromised left ventricular function and patients receiving β blocker therapy.     

Hemodynamic effects of oral ephedrine given alone or combined with nitroprusside infusion in patients with severe left ventricular failure

Potent vasodilator or inotropic agents alone may be of limited value in some patients with severe congestive heart failure because of their exaggerated peripheral vascular effects. Nitroprusside and potent inotropic agents in combination are hemodynamically more effective than either alone. Although oral vasodilators can mimic nitroprusside, there is a need for potent oral inotropic agents. Ephedrine is an oral sympathomimetic inotropic drug. The hemodynamic effects of ephedrine alone (50 mg orally), nitroprusside alone and the two agents combined were studied in 11 patients with severe congestive heart failure. Heart rate increased from 89.9 ± 5.2 (standard error of the mean) to 98.2 ± 5.0 beats/min after ephedrine (P < 0.001) and to 96.4 ± 4.7 beats/min with ephedrine plus nitroprusside (P < 0.02); it was unchanged with nitroprusside alone. Mean systemic arterial pressure increased from 83.7 ± 2.1 to 89.2 ± 2.7 mm Hg after ephedrine (P < 0.02) and decreased to 73.4 ± 2.4 mm Hg with nitroprusside added (P < 0.01). Left ventricular filling pressure was unchanged after ephedrine but decreased from 30.9 ± 2.3 to 20.6 ± 2.1 mm Hg during nitroprusside infusion (P < 0.01). Control cardiac output averaged 3.94 ± 0.30 liters/min and increased by 1.25 ± 0.31 liters/min with nitroprusside, by 1.09 ± 0.30 liters/min after ephedrine and by 2.20 ± 0.34 liters/min with the two combined. Although the increases in cardiac output with each agent alone were significant and similar, the increase with the two combined was significantly greater than with either alone. The data suggest that ephedrine is an orally effective inotropic agent especially when combined with a vasodilator. Further evaluation of ephedrine in congestive heart failure is warranted.     

Levosimendan: a new era for inodilator therapy for heart failure?

Levosimendan is a new inotropic and vasodilator agent. The inotropic effect is mediated by calcium concentration-dependent conformational changes in troponin C during systole leading to sensitization of the contractile apparatus to calcium ions. The vasodilator effect is mediated by opening potassium channels on vascular smooth muscle. It has a complex pharmacokinetic profile, with a long-acting metabolite that has hemodynamic effects persisting for approximately 1 week. Although it is absorbed orally, it has been developed only for intravenous use thus far. The hemodynamic effects are not reduced and may be enhanced in the presence of beta-blockers, possibly an important attribute when dealing with exacerbation of heart failure caused by or in the presence of beta-blockers. More patients with heart failure have participated in randomized controlled trials of levosimendan than of any other intravenous inotropic agent. Experience with its use after cardiac surgery is limited. Preliminary observations suggest that hemodynamic changes are associated with symptomatic benefit and a reduction in morbidity and mortality in patients with severe heart failure caused by left ventricular systolic dysfunction, compared with placebo in one study and dobutamine in another. Levosimendan may be the first inotropic agent that it is both safe and effective in altering clinical outcomes relevant for patients. Part of this benefit may be achieved because levosimendan allows other inotropic agents that may have adverse effects on patient outcome to be avoided. Further research is required to confirm whether levosimendan reduces mortality and morbidity compared with a placebo and when administered repetitively. If it does, it may become routine therapy for the treatment of severe heart failure.     

The potential role of endothelin as a vasoconstrictor substance in congestive heart failure.

A rapidly growing body of data supports the concept of in situ regulation of vascular tone: the ability of vasoactive substances to regulate vascular tone at their site of production within the wall of the vasculature. Sufficient data exist to suggest that ineffective production or response to endothelium-dependent vasodilator substances, or excessive production or responsiveness to endothelium-dependent vasoconstrictor substances may play an important role in cardiovascular disorders such as hypertension, coronary artery spasm, restenosis following coronary angioplasty, and congestive heart failure. The present review summarizes data which support the concept that endothelin, a potent vasoconstrictor produced by the endothelium, may play a role in the excessive vasoconstriction of heart failure. Increased circulating plasma endothelin may be particularly relevant to the range of pulmonary vasoconstriction encountered in congestive heart failure, with a correlation revealing that the greatest increase of plasma endothelin occurs in patients with marked pulmonary hypertension within the congestive heart failure patients studied.     

The effects of sublingually administered nitroglycerin on forearm vascular resistance in patients with heart failure and in normal subjects

This study examined the effects of sublingually administered nitroglycerin on forearm resistance vessels in normal subjects (n = 9) and in patients with congestive heart failure (n = 8). Forearm blood flow was measured with a strain-gauge plethysmograph and forearm vascular resistance was calculated. To assess the magnitude of reflex forearm vasoconstriction triggered by decreased central venous pressure after sublingual nitroglycerin, lower body negative pressure (LBNP) was applied to produce a comparable decrease in central venous pressure to that after nitroglycerin. The change in forearm vascular resistance during LBNP was compared with that after nitroglycerin. In normal subjects, LBNP increased but nitroglycerin did not change forearm vascular resistance. In patients with congestive heart failure neither nitroglycerin nor LBNP changed forearm vascular resistance. The direct vasodilator effect of nitroglycerin on forearm resistance vessels assessed by the difference between the change in forearm vascular resistance produced by nitroglycerin and that during LBNP tended to be less in patients with congestive heart failure than in normal subjects, which might have resulted from decreased vasodilator capacity of resistance vessels in patients with congestive heart failure. Changes in forearm vascular resistance with a cold pressor test were not different between normal subjects and patients with congestive heart failure. These data suggest that in normal subjects, nitroglycerin does not alter forearm vascular resistance because its dilator effect is offset by reflex vasoconstriction. In patients with congestive heart failure, reflex vasoconstriction is impaired but the direct vasodilator effect of nitroglycerin also tends to be reduced, so that as a net effect forearm vascular resistance is not altered.     

Experience with calcium antagonist drugs in congestive heart failure

Several clinical studies have demonstrated beneficial hemodynamic effects of calcium antagonist drugs when used as arterial vasodilators in the treatment of certain patients with moderate to severe congestive heart failure. These drugs usually decrease systemic vascular resistance and improve ejection phase indexes of left ventricular function in such patients. However, calcium antagonists have intrinsic negative inotropic effects and other vasodilators such as nitroprusside, hydralazine and captopril appear to be more beneficial when used in the treatment of severe congestive heart failure.     

Pharmacologic therapy for patients with congestive cardiomyopathy

Treatment in congestive heart failure is directed at improving cardiac output and decreasing preload and afterload without significantly increasing the oxygen requirements of the heart. This paper reviews the current approach to heart failure with inotropic and vasodilator drugs in patients with heart failure.     

Comparative hemodynamic effects of converting enzyme inhibitor and sodium nitroprusside in severe heart failure

In nine patients with severe congestive heart failure, the acute response to the infusion of a nonspecific vasodilator, sodium nitroprusside, was compared with the infusion of the converting enzyme inhibitor, teprotide (SQ 20, 881). The hemodynamic effects were similar. Nitroprusside and teprotide increased cardiac index 24 and 20 percent, respectively, reduced mean arterial pressure 11 and 14 percent and pulmonary wedge pressure 21 and 24 percent, and produced no significant change in heart rate (?0.5 and ?0.7 percent). Arterial partial pressure of oxygen decreased in response to nitroprusside infusion from 75.8 ± 4.1 to 65.4 ± 3.2 mm Hg (p < 0.05) but did not change in response to teprotide infusion (77.0 ± 4.5 before and 76.3 ± 3.0 mm Hg after). Circulating norepinephrine levels were lowered in response to both agents in spite of the decrease in mean arterial pressure (nitroprusside 754 ± 126 to 580 ± 82 pg/ml, p < 0.05; teprotide 807 ± 136 to 518 ± 92 pg/ml, p < 0.05). Although the control plasma renin activity did not correlate closely with the hemodynamic response to either agent in this small series, this level did correlate directly with the dose of nitroprusside required to produce the desired hemodynamic response.Therefore, converting enzyme inhibition produces an acute hemodynamic response in severe congestive heart failure comparable with that of sodium nitroprusside with less detrimental acute effect on pulmonary oxygen transport. Long-term oral therapy with converting enzyme inhibitor deserves evaluation in congestive heart failure.     

Calcium sensitizer agents: a new class of inotropic agents in the treatment of decompensated heart failure

The clinician's primary objective in treating a patient with decompensated heart failure is rapid and effective stabilization. This goal often is achieved through the use of inotropic support. Classic inotropic agents (beta-adrenergic agonists and phosphodiesterase III inhibitors) can provide short-term hemodynamic benefits, but their long-term use has been correlated with poor survival rates. Calcium sensitizers comprise a new drug class that offers hemodynamic and symptomatic improvements without increasing cAMP and intracellular calcium concentrations. These agents enhance contractility without a concurrent increase in the risk of cardiac events and thus represent a significant improvement over classic positive inotropic agents. Levosimendan is the most potent calcium sensitizer to date, exhibiting a unique dual mechanism of action that combines a positive inotropic action mediated via calcium sensitization and a vasodilator property via ATP-dependent potassium channels. Available clinical data suggest that calcium sensitizer agents represent a promising class of inotropic agents in a field that has seen few advances in recent decades.     

Hemodynamic and neurohormonal effects of quinidine in patients with severe left ventricular dysfunction secondary to coronary artery disease or idiopathic dilated cardiomyopathy.

Quinidine causes vasodilation directly and by inhibition of adrenergic vasoconstriction, but it also exerts negative inotropic activity. Although this drug is often administered to patients with severe congestive heart failure, the net consequences of these opposing actions have not been evaluated in such patients. The hemodynamic and neurohormonal response to oral quinidine (600 mg) in 19 patients with severe chronic heart failure was therefore determined. Vasodilation was the predominant effect of quinidine, with reductions in mean arterial, left ventricular filling and right atrial pressures of -9% (confidence interval [CI] -5 to -13), -8% (CI -19 to 3), -15% (CI -26 to -4), respectively. The quinidine-induced vasodilation increased plasma norepinephrine and epinephrine concentrations by 44% (CI +17 to +72) and 47% (CI +2 to +91), respectively. No change in cardiac performance was noted, with the cardiac index slightly increased (+10%, CI +2 to +17) and stroke work index unchanged (0%, CI -11 to +11) after quinidine. Although the mean serum quinidine concentration was within the therapeutic range or lower in all patients, the serum quinidine concentration and the change in mean arterial pressure did correlate (r2 = 0.64). In conclusion, vasodilation is the predominant hemodynamic effect of oral quinidine in patients with congestive heart failure. However, potential adverse effects may be caused by consequent neurohormonal activation.