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Cardiomyocyte death resulting from apoptosis has been implicated in the evolution of heart failure. In this review, we focus on the concept that the cardiotoxicity of excessive sympathetic nervous system activity observed in heart failure is in part due to myocytes death by apoptosis. In vitro, high doses of norepinephrine induce adult cardiomyocyte apoptosis via 3-adrenergic receptor-coupled signaling pathways (PKA and Ca2+ entry-dependent mechanisms). beta1-and beta2-AR co-exist in the cardiac cell. beta1-AR stimulation is pro-apoptotic, whereas beta2-AR stimulation is anti-apoptotic, mediating its protective effect via coupling to Gi. These in vitro observations have been confirmed in transgenic mice: cardiac beta1-AR overexpression increases apoptosis and leads to heart failure, whereas cardiac beta2-AR overexpression has no deleterious effects. beta-AR stimulation activates p38 kinases and JNK (via the small GTP protein Rac1); and exert anti- and pro-apoptotic effects, respectively. Other studies suggest that beta1-AR-stimulated apoptosis is dependent on Ca2+ -activated calmodulin kinase II and that the anti-apoptotic effect of beta2-AR is mediated via Akt-coupled pathways. beta-AR-stimulated apoptosis involves the mitochondrial pathway. Inhibition of mitochondrial permeability transition pore opening or caspase activation decreases beta-AR-stimulated apoptosis. Reactive oxygen species production is also involved in this process since superoxide dismutase/catalase-mimetics or catalase overexpression prevent beta-AR-stimulated apoptosis. In vivo, it has been shown that beta-AR blockers such as metoprolol and carvedilol have beneficial effects in animal models of chronic heart failure, associated with reduced apoptosis and improved cardiac systolic function. Understanding the mechanisms involved in the control of myocyte loss by the beta-adrenergic system will have direct clinical implications by improving the treatment of heart failure.

Carvedilol reduces disease progression in heart failure, but to our knowledge, its effects on hospitalizations and costs have not been evaluated.We examined the effects on hospitalization frequency and costs in the U.S. Carvedilol Heart Failure Trials Program. This program consisted of four concurrent, multicenter, double-blind, placebo-controlled studies involving 1,094 patients with New York Heart Association class II to IV heart failure, which treated patients with placebo or carvedilol for up to 15 months (median, 6.5 months).Detailed resource utilization data were collected for all hospitalizations occurring between randomization and the end of follow-up. In-patient care costs were estimated based on observed levels of resource use.Compared with placebo, carvedilol reduced the risk of hospitalization for any reason by 29% (p = 0.009), cardiovascular hospitalizations by 28% (p = 0.034) and heart failure hospitalizations by 38% (p = 0.041). Carvedilol also decreased the mean number of hospitalizations per patient (for cardiovascular reasons 30% [p = 0.02], for heart failure 53% [p = 0.03]). Among hospitalized patients, carvedilol reduced severity of illness during hospital admission, as reflected by shorter length of stay and less frequent use of intensive care. For heart failure hospital admissions, carvedilol decreased mean length of stay by 37% (p = 0.03) and mean number of intensive care unit/coronary care unit days by 83% (p = 0.001), with similar effects on cardiovascular admissions. As a result, estimated inpatient care costs with carvedilol were 57% lower for cardiovascular admissions (p = 0.016) and 81% lower for heart failure admissions (p = 0.022).Carvedilol added to angiotensin-converting enzyme inhibition reduces hospitalization risk as well as severity of illness and resource utilization during admission in patients with chronic heart failure.

We determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure.One hundred forty-six patients with New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) who had a pulmonary capillary wedge pressure/=15 mm Hg and a cardiac index/=2.5 L x min(-1) x m(-2) were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1 to intravenous infusion of levosimendan or placebo. Drug infusions were uptitrated over 4 hours from an initial infusion rate of 0.1 microg x kg(-1) x min(-1) to a maximum rate of 0.4 microg x kg(-1) x min(-1) and maintained at the maximal tolerated infusion rate for an additional 2 hours. Levosimendan caused dose-dependent increases in stroke volume and cardiac index beginning with the lowest infusion rate and achieving maximal increases in stroke volume and cardiac index of 28% and 39%, respectively. Heart rate increased modestly (8%) at the maximal infusion rate and was not increased at the 2 lowest infusion rates. Levosimendan caused dose-dependent decreases in pulmonary capillary wedge, right atrial, pulmonary arterial, and mean arterial pressures. Levosimendan appeared to improve dyspnea and fatigue, as assessed by the patient and physician, and was not associated with a significant increase in adverse events.Levosimendan caused rapid dose-dependent improvement in hemodynamic function in patients with decompensated heart failure. These hemodynamic effects appeared to be accompanied by symptom improvement and were not associated with a significant increase in the number of adverse events. Levosimendan may be of value in the short-term management of patients with decompensated heart failure.

Knowledge of left-sided cardiac filling pressures has an important role in the management of patients with chronic heart failure. However, the use of a pulmonary artery catheter to measure pulmonary capillary wedge pressure is generally reserved for hospitalized patients with decompensated heart failure, leaving only noninvasive means of estimating left heart pressures in the majority of patients. Unfortunately, the routine clinical evaluation of patients with chronic systolic heart failure lacks the sensitivity and specificity needed to accurately assess left atrial pressure. In this review, we focus on noninvasive methods that can reliably predict left-sided filling pressures and may have clinical application in the ambulatory setting.

Sympathetic nervous system activity to the myocardium is increased in patients with heart failure. It is now appreciated that norepinephrine (NE), the primary sympathetic neurotransmitter, can exert direct adverse effects on cardiac myocytes and might thereby contribute to pathological remodeling, a chronic process which leads to progressive left ventricular (LV) chamber dilation and loss of contractile function. The demonstration of apoptosis in failing human hearts has led to the thesis that continuing loss of viable myocytes is a mechanism for progressive myocardial failure. For many years it has been appreciated that chronic exposure to catecholamines can exert a toxic effect on the myocardium. In vitro studies in cultured cardiac myocytes show that tonic exposure to NE increases the number of apoptotic myocytes via stimulation of the beta-adrenergic receptor (beta-AR) pathway. Interestingly, a beta1-AR selective antagonist completely prevented NE-stimulated apoptosis, whereas a beta2-AR selective antagonist increased the amount of apoptosis, suggesting that beta1- versus beta2-AR may couple to different signaling pathways. In rats, isoproterenol infusion for as little as 12 hours increased the frequency of terminal deoxynucleotidyltransferase-mediated nick end-labeling (TUNEL)-positive myocytes. Likewise, mice that overexpress beta1-AR or G alpha s in the myocardium develop left ventricular dilation, contractile dysfunction and apoptosis. Although the link between apoptosis and myocardial failure remains to be proven, these in vitro and in vivo observations provide a rational mechanism by which beta-AR antagonists may help to prevent or slow LV remodeling and failure in patients.

We have shown that stimulation of beta-adrenergic receptors (beta-AR) by norepinephrine (NE) increases apoptosis in adult rat ventricular myocytes (ARVMs) via a cAMP-dependent mechanism that is antagonized by activation of G(i) protein. The family of mitogen-activated protein kinases (MAPKs) is involved in the regulation of cardiac myocyte growth and apoptosis. Here we show that beta-AR stimulation activates p38 kinase, c-jun N-terminal kinases (JNKs), and extracellular signal-regulated kinase (ERK1/2) in ARVMs. Inhibition of p38 kinase with SB-202190 (10 micrometer) potentiated beta-AR-stimulated apoptosis as measured by flow cytometry and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining. SB-202190 at this concentration specifically blocked beta-AR-stimulated activation of p38 kinase and its downstream substrate MAPK-activated protein kinase-2 (MAPKAPK2). Pertussis toxin, an inhibitor of G(i)/G(o) proteins, blocked the activation of p38 kinase and potentiated beta-AR-stimulated apoptosis. Activation of G(i) protein with the muscarinic receptor agonist carbachol protected against beta-AR-stimulated apoptosis. Carbachol also activated p38 kinase, and the protective effect of carbachol was abolished by SB-202190. PD-98059 (10 micrometer), an inhibitor of ERK1/2 pathway, blocked beta-AR-stimulated activation of ERK1/2 but had no effect on apoptosis. These data suggest that 1) beta-AR stimulation activates p38 kinase, JNKs, and ERK1/2; 2) activation of p38 kinase plays a protective role in beta-AR-stimulated apoptosis in cardiac myocytes; and 3) the protective effects of G(i) are mediated via the activation of p38 kinase.

Many patients remain markedly symptomatic despite optimal current therapy for heart failure. Beta-blockers have often been viewed as contraindicated in this group because of their potential adverse short-term effects on cardiac function.One hundred thirty-one patients with severe congestive heart failure were enrolled into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had symptomatic, advanced heart failure while on standard triple therapy, as evidenced by a mean ejection fraction of 0.22, marked reduction in distance traveled in a 6-minute corridor walk test, and severe impairment in quality of life measured by the Minnesota Living With Heart Failure Questionnaire. After a 2-week, open-label test of 6.25 mg twice daily carvedilol, 105 patients were randomized (2:1) to receive either carvedilol (up to 25 mg twice daily, n = 70) or matching placebo (n = 35) for 6 months while background therapy with digoxin, diuretics, and an angiotensin-converting enzyme inhibitor remained constant. Ten patients (8%) did not complete the open-label period because of adverse events and 11.4% in both the carvedilol and placebo groups dropped out in the double-blind phase. The study was terminated early by the Data Safety and Monitoring Board and follow-up evaluation was therefore aborted before the projected number of patients and follow-up time was achieved. Quality of life, which was the primary endpoint, improved similarly in the carvedilol and placebo groups, whereas the global assessment by the physicians and the patient exhibited a better response to carvedilol (P.05). Hospitalization and mortality rate were too low to evaluate a difference, and exercise time and New York Heart Association classification did not change significantly in response to the drug. Left ventricular ejection fraction rose significantly (+0.09) in the carvedilol group compared with the placebo group (+0.02, P = .004).The beta-blocker carvedilol can be safely employed in patients with severe heart failure. Improved left ventricular function with a trend for some improvement in symptoms combined with the experience with the drug in the larger population of less severe patients in this multicenter trial suggests that carvedilol may have a favorable long-term effect in heart failure of diverse severity.

We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction.Patients (n = 366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF)or = 0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n = 232) or placebo (n = 134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (P = .008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated.Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials.We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fractionor = 0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n = 145) or carvedilol (n = 133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P = .014) or by a global assessment of progress judged either by the patient (P = .002) or by the physician (P.001). In addition, treatment with carvedilol was associated with a significant increase in ejection fraction (P.001) and a significant decrease in the combined risk of morbidity and mortality (P = .029). In contrast, carvedilol therapy had little effect on indirect measures of patient benefit, including changes in exercise tolerance or quality-of-life scores. The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure.These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor.

Controlled clinical trials have shown that beta-blockers can produce hemodynamic and symptomatic improvement in chronic heart failure, but the effect of these drugs on survival has not been determined.We enrolled 1094 patients with chronic heart failure in a double-blind, placebo-controlled, stratified program, in which patients were assigned to one of the four treatment protocols on the basis of their exercise capacity. Within each of the four protocols patients with mild, moderate, or severe heart failure with left ventricular ejection fractionsor = 0.35 were randomly assigned to receive either placebo (n = 398) or the beta-blocker carvedilol (n = 696); background therapy with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor remained constant. Patient were observed for the occurrence death or hospitalization for cardiovascular reasons during the following 6 months, after the beginning (12 months for the group with mild heart failure).The overall mortality rate was 7.8 percent in the placebo group and 3.2 percent in the carvedilol group; the reduction in risk attributable to carvedilol was 65 percent (95 percent confidence interval, 39 to 80 percent; P0.001). This finding led the Data and Safety Monitoring Board to recommend termination of the study before its scheduled completion. In addition, as compared with placebo, carvedilol therapy was accompanied by a 27 percent reduction in the risk of hospitalization for cardiovascular causes (19.6 percent vs. 14.1 percent, P = 0.036), as well as a 38 percent reduction in the combined risk of hospitalization or death (24.6 percent vs, 15.8 percent, P0.001). Worsening heart failure as an adverse reaction during treatment was less frequent in the carvedilol than in the placebo group.Carvedilol reduces the risk or death as well as the risk of hospitalization for cardiovascular causes in patients with heart failure who are receiving treatment with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor.

We describe the results of two placebo-controlled trials (MIL-1077 and MIL-1078) designed to evaluate the clinical efficacy of oral milrinone administered together with converting enzyme inhibitors to patients with congestive heart failure. Although these trials were terminated prematurely, they provide the only controlled data regarding the effect of oral milrinone on exercise capacity in patients receiving converting enzyme inhibitors. Of the 254 patients randomized, 140 completed one of the trials or reached an end point and are the basis of this report. In both trials, there was a clear trend for an increase in exercise capacity in the milrinone-treated patients (+26 +/- 8% vs. +5 +/- 7% in MIL-1077 and +11 +/- 5% vs. +2 +/- 4% in MIL-1078). Symptoms of congestive heart failure were decreased in one trial but not the other. Quality of life, as assessed by a questionnaire, was not effected in either trial. There was an increased incidence of adverse events in milrinone-treated patients. Adverse events related primarily to hypotension and vasodilation led to discontinuation of drug in 18 milrinone-treated patients vs. 1 placebo-treated patient. Milrinone had little or no proarrhythmic effect and cardiovascular deaths were distributed equally between the milrinone and placebo groups. These data suggest that when used in combination with a converting enzyme inhibitor, oral milrinone improves exercise capacity but is associated with a high incidence of adverse events that appear to be related to excessive vasodilation.

The functional importance of abnormalities in the myocardial beta-adrenergic receptor (BAR) pathway of patients with congestive heart failure (CHF) is not known. To address this issue, the inotropic, chronotropic, and lusitropic responses to BAR stimulation were studied in patients with CHF and in patients without cardiac disease. To evaluate inotropic responsiveness, dobutamine was infused directly into the left main coronary artery. The maximum inotropic response, as assessed by measurement of left ventricular +dP/dt, was markedly reduced in patients with CHF; however, the concentration-response curve for the effect of dobutamine was not shifted relative to that of normal subjects. The magnitude of the impairment in the inotropic response to intracoronary dobutamine was inversely related to resting plasma norepinephrine. Although there was no relation between resting plasma norepinephrine and any measure of hemodynamic function, the improvement in pump function that occurred with intracoronary dobutamine resulted in a rapid decrease in plasma norepinephrine. Preinfusion of the phosphodiesterase inhibitor, milrinone, into the coronary artery resulted in a significant increase in the response to intracoronary dobutamine. To evaluate chronotropic responsiveness, the heart rate responses to a graded infusion of isoproterenol and during maximal exercise on a cycle ergometer were determined. The isoproterenol dose causing a 25 beat/min increase in heart rate (ISO25) was significantly higher in patients with CHF than in normal subjects. Likewise, the heart rate at peak exercise was significantly reduced in patients with CHF, despite similar levels of plasma norepinephrine at peak exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The acute administration of milrinone, a positive inotropic vasodilator agent, improves resting hemodynamic function and maximal and submaximal metabolic responses to exercise in patients with severe congestive heart failure. 2. To determine whether the improvement in exercise capacity induced by milrinone administration can be predicted by its acute positive inotropic and/or vasodilator effects at rest, milrinone was administered intravenously (progressive doses of 12.5 to 75 microns/kg) to 15 patients with heart failure (functional classes III and IV, New York Heart Association) at rest, and during maximal upright exercise testing on a cycle ergometer. Serum drug levels were matched for the resting and exercise tests. Drug administration for exercise tests was placebo-controlled and double-blind. 3. At rest, milrinone administration caused substantial decreases in right atrial pressure (-53%), left ventricular end-diastolic pressure (-30%), and systemic vascular resistance (-35%); and increases in cardiac index (+59%), peak positive dP/dt (+20%) and stroke work index (+51%). Administration of milrinone during exercise resulted in a 15% increase in peak oxygen uptake and a 16% increase in anaerobic threshold. However, none of the changes in resting hemodynamic function correlated significantly in magnitude with the changes in peak oxygen uptake and anaerobic threshold. 4. Thus, the acute improvement in exercise capacity that occurs with milrinone is not predicted by the positive inotropic or vasodilator effects of the drug at rest.

To determine the relationship between vascular alpha 1-adrenergic receptor occupancy and receptor-coupled calcium flux, we have studied [3H]prazosin binding and l-norepinephrine-induced 45Ca efflux in cultured vascular smooth muscle cells isolated from the rabbit aorta. In a crude cellular homogenate, [3H]prazosin bound to a single high affinity site (Kd = 0.096 nM; Bmax = 105 +/- 15 fmol/mg of protein), whereas l-norepinephrine (NE) binding was best described by a two-site model with 43 +/- 8% of sites of high affinity (KH = 92 +/- 3 nM) and 57 +/- 7% of sites of low affinity (KL = 7460 +/- 4330 nM). NE-stimulated 45Ca efflux was concentration-dependent (EC50 = 108 nM) and potently inhibited by prazosin (IC50 = 0.15 nM), but not yohimbine (no inhibition at 10 microM). For the total receptor pool identified by [3H]prazosin binding, the relationship between receptor occupancy by NE and NE-stimulated 45Ca efflux was markedly nonlinear, such that 50% of maximum NE-stimulated efflux occurred with occupancy of only approximately 7% of receptors. Likewise, following irreversible inactivation of 69 +/- 5% of receptors by phenoxybenzamine, maximal NE-stimulated 45Ca efflux was decreased by only 8 +/- 2%. These two experimental approaches provide direct evidence for the presence in cultured rabbit aortic smooth muscle cells of a sizable pool of alpha 1-adrenergic receptors in excess of those needed for maximum NE-stimulated 45Ca efflux. This evidence of "spare" receptors, together with the finding of two affinity states of agonist binding, raises the possibility of functional heterogeneity of alpha 1-adrenergic receptors in this system.

Two patients with cirrhosis and ascites complicated by extensive unilateral pleural transudates refractory to therapy with dietary sodium restriction, diuretics, and repeated thoracentesis were successfully managed by tetracycline-induced pleural symphysis. The intrapleural instillation of this antibiotic prevented the recurrence of the effusion and substantially relieved the patients' symptoms with minimal undesirable side effects.

Milrinone and dobutamine were compared in 15 patients with New York Heart Association functional class III and IV congestive heart failure. Dobutamine and milrinone were administered intravenously according a graded titration schedule up to maximum doses (14 micrograms/kg/min and 75 micrograms/kg, respectively) or until increased ventricular ectopy or a reduction in left ventricular end-diastolic pressure to 10 mm Hg or less occurred. Although both agents markedly increased cardiac index, milrinone caused a significantly greater reduction in left and right heart filling pressures and mean arterial pressure than did dobutamine, and for any given increase in dP/dt, milrinone caused a greater reduction in systemic vascular resistance than did dobutamine. Thus, the hemodynamic effects of milrinone are best represented by a combination of the actions of dobutamine, a positive inotropic agent, and a vasodilator such as nitroprusside, which causes both arterial and venous dilation. The positive inotropic responses of individual patients to dobutamine (5 micrograms/kg/min) and milrinone (25 micrograms/kg) were compared. The increases in dP/dt with both agents were variable, and correlated poorly (r = .50; p = .059). Patients were divided into two groups: Group I consisted of eight patients in whom the ratio of the increase in dP/dt with dobutamine vs milrinone was greater than 1.0 (good dobutamine responders); group II consisted of seven patients in whom this ratio was less than 1.0 (poor dobutamine responders).(ABSTRACT TRUNCATED AT 250 WORDS)

Cultured vascular smooth muscle cells derived by enzymatic dissociation of rabbit aortic media were used for study of alpha 1-adrenergic receptors (AAR) and receptor-coupled calcium flux. AAR were characterized by binding of the alpha 1-selective radioligand [3H]prazosin, and norepinephrine-stimulated 45calcium efflux was measured as an index of AAR-mediated calcium flux. The binding of [3H]prazosin to a crude cellular homogenate was to a single, saturable site of high affinity (Kd = 0.15 nM, Bmax = 75-125 fmol/mg protein), which was stereo-specific and exhibited the appropriate potency order for competition by agonists. Prazosin (Kd = 0.07 nM) was approximately 3000-fold more potent than the alpha 2-selective antagonist yohimbine (Kd = 222 nM), both of which exhibited Hill coefficients of one, indicative of binding to a single receptor type. In intact cells, norepinephrine caused a concentration-related (EC50 = 100 nM) increase in 45calcium efflux which was blocked by low concentrations of prazosin (IC50 approximately equal to 0.1 nM), but not yohimbine (IC50 greater than 100 nM). An alpha 1-selective concentration of prazosin (100 nM) fully blocked norepinephrine-stimulated 45calcium efflux, and therefore, it appears that this effect does not involve alpha 2-adrenergic receptors. Treatment of cultured cells with 1-norepinephrine for 48 h caused a concentration-related decrease in both AAR density and maximum norepinephrine-stimulated 45calcium efflux. This cultured vascular smooth muscle cell system provides several advantages for the study of alpha-adrenergic receptor coupling and regulation.

Beta-adrenergic sympathomimetic agents such as dobutamine and dopamine, and phosphodiesterase inhibitors such as amrinone, milrinone, and enoxamone, exert a direct positive inotropic effect upon the myocardium by causing an increase in cyclic AMP levels. The phosphodiesterase inhibitors also exert a substantial direct vasodilator effect. Both the sympathomimetic agents and the phosphodiesterase inhibitors can be of value in the acute, short-term management of myocardial failure. At present, the use of these agents for long-term therapy of congestive heart failure is unproven, and remains investigational.

Although there is theoretical and indirect evidence to suggest that patients with severe congestive heart failure may have desensitization of myocardial beta-adrenergic responsiveness, there is little direct evidence in patients. The purpose of this study was to determine whether myocardial beta-adrenergic inotropic responsiveness is reduced in patients with severe congestive heart failure and markedly elevated plasma norepinephrine levels. To assess myocardial beta-adrenergic inotropic responsiveness, the beta-adrenergic agonist dobutamine was infused directly into the left main coronary artery, and the change in +dP/dt was measured as an index of change in inotropic state. Eight patients with severe New York Heart Association functional Class III and IV congestive heart failure were compared with 4 patients without significant congestive heart failure. The increase in +dP/dt at an intracoronary dobutamine infusion rate of 25 micrograms/min in patients with severe congestive heart failure was significantly less than in the patients without heart failure (heart failure, 33 +/- 8%; no heart failure, 69 +/- 12%; p less than 0.05). Although the maximum intracoronary dobutamine infusion rate was substantially higher in patients with heart failure (94 +/- 25 micrograms/min) compared with patients without heart failure (38 +/- 7 micrograms/min), the increase in +dP/dt at maximum infusion rates was also significantly less in patients with heart failure (heart failure, 52 +/- 8%; no heart failure, 93 +/- 24%; p less than 0.05). Plasma norepinephrine concentration was normal in the 4 patients without heart failure and was markedly elevated (range, 307-3,967 ng/l) in the patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

In A7r5 vascular smooth muscle cells, the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) caused a marked increase in the rate of unidirectional Ca2+ influx and a 63 +/- 9% increase in net 30-min 45Ca2+ uptake. Maximal TPA-stimulated 45Ca2+ uptake occurred at concentrations less than or equal to 3 nM and was equivalent to the maximal uptake stimulated by 55 mM KCl or 1 microM Bay k 8644. TPA-stimulated Ca2+ uptake was not additive to KCl- or Bay k 8644-stimulated uptake, and was inhibited by verapamil (100 microM), nitrendipine (1 microM), or high concentrations of Bay k 8644 (greater than or equal to 10 microM). The biologically inactive phorbol ester 12-O-tetradecanoyl phorbol-13-acetate methyl ether (10 nM) had no effect on 45Ca2+ uptake. TPA caused a 43 +/- 12% increase in Ca2+ efflux in 30 min, and exposure to TPA (10 nM) for 5 and 30 min caused no significant change in net cellular Ca2+ content as determined by radioisotopic equilibration or atomic absorption spectroscopy. TPA caused no apparent change in intracellular free Ca2+ concentration as determined with quin 2. Thus, in A7r5 cells, TPA causes a marked increase in Ca2+ influx through channels with the pharmacological characteristics of dihydropyridine-sensitive, voltage-dependent channels. This TPA-stimulated Ca2+ uptake is associated with increased Ca2+ efflux and no significant change in net cellular Ca2+ content or intracellular free Ca2+ concentration.

Cyclic AMP plays a central role in modulating systolic and diastolic myocardial function. Consequently, the adrenergic nervous system, acting through myocardial beta-adrenergic receptors, very likely plays a significant role in regulating left ventricular systolic and diastolic function. Theoretically, beta-adrenergic agonists and antagonists may further modify myocardial systolic and diastolic function. Although the effects of beta-adrenergic agents are clearly demonstrable in vitro, it has been more difficult to evaluate the direct myocardial effects of beta-adrenergic agents in patients. These difficulties are related both to technical aspects of the measurement of systolic and diastolic parameters and to the potentially confounding effects of secondary nonmyocardial drug actions and reflex-mediated changes in myocardial and/or vascular adrenergic activity. A number of strategies for evaluating the direct myocardial actions of beta-adrenergic agents are discussed. Two promising approaches are the use of direct intracoronary drug infusion and the analysis of left ventricular pressure-volume relationships. The positive inotropic action of beta-adrenergic agonists is substantially attenuated in many patients with left ventricular failure due to end-organ desensitization of the beta-adrenergic pathway. Nevertheless, a beta-adrenergic agonist may still cause a substantial improvement in left ventricular pump function in such patients. There is less information available regarding the effect of beta-adrenergic agonists on myocardial relaxation. Preliminary data from the intracoronary infusion of dobutamine suggest that isovolumic relaxation is accelerated. Conversely, preliminary data suggest that a beta-adrenergic antagonist, esmolol, causes a slowing of isovolumic myocardial relaxation. Further studies will be needed to determine whether these drug effects result in a significant alteration in hemodynamic performance during diastole, and to evaluate the possibility that beta-adrenergic-mediated myocardial relaxation is attenuated in patients with heart failure.