Biomedical subjects

W S Colucci

Publications and source records attributed to W S Colucci.

At least 109 records · Page 6Linked to original sources

PubMed1990

Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy.

Dilator reserve of the coronary microvasculature is diminished in patients with dilated cardiomyopathy. Although increased extravascular compressive forces, tachycardia, and increased myocardial mass can explain some impairment, recent evidence suggests the possibility of intrinsic microvascular disease. We tested the hypothesis that impairment of endothelium-dependent dilation of the microvasculature could be a contributing mechanism. We infused the endothelium-dependent dilator acetylcholine (Ach) (10(-8) to 10(-6) M) and the smooth muscle vasodilator adenosine (AD) (10(-6) to 10(-4) M) into the left anterior descending coronary artery in eight patients with dilated cardiomyopathy (mean ejection fraction, 28%) and seven controls (atypical chest pain). Small vessel resistance was assessed by measuring coronary blood flow (CBF) at constant arterial pressure with a Doppler velocity catheter (corrected for cross-sectional area by angiography). With Ach, control patients increased CBF 232 +/- 40% (mean +/- SEM), whereas CBF did not significantly change in cardiomyopathy patients (41 +/- 24%) (p less than 0.0001, control vs. cardiomyopathy). With AD, control patients increased CBF 422 +/- 56% and cardiomyopathy patients increased CBF 268 +/- 43% (p = 0.13). An index of the proportion of coronary flow reserve attributable to endothelium-dependent vasodilation was obtained by standardizing each patient's Ach dose response to his maximal AD flow response. In seven control patients receiving both Ach and AD, 56 +/- 9% of the maximal AD flow response was attained with the endothelium-dependent vasodilator Ach, whereas in seven cardiomyopathy patients receiving both Ach and AD, only 23 +/- 14% of the maximal AD response was attained (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1990

Muscle blood flow during forearm exercise in patients with severe heart failure.

Muscle fatigue is a prominent symptom in patients with chronic heart failure (CHF). To determine whether it results from an intrinsic abnormality of vasodilating capacity of the vasculature in exercising muscle, we studied local forearm blood flow (FBF) during exercise in 13 patients with severe CHF and in eight normal untrained subjects of similar age. Intermittent forearm static exercise was performed by squeezing a hand dynamometer for 5 seconds, three times per minute, for 5 minutes at 15%, 30%, and 45% of maximum voluntary contraction. FBF was measured by mercury-in-rubber strain gauge venous plethysmography at baseline before exercise and during the last 3 minutes of each exercise state. Exercise was repeated after 24 hours of intravenous administration of milrinone in the patients with CHF. FBF increased with forearm exercise in a reproducible manner during 24 hours in the normal subjects: rest, 2.54 +/- 0.23 (0 hours), 2.90 +/- 0.23, (24 hours); 15%, 7.25 +/- 0.92, 5.85 +/- 0.56; 30%, 9.20 +/- 1.08, 10.05 +/- 0.85; 45%, 14.62 +/- 1.64, 13.85 +/- 1.09 ml/100 ml/min; p = NS, 0 versus 24 hours. In patients with CHF, FBF was reduced at baseline compared with normal subjects (1.70 +/- 0.15 ml/100 ml/min, p less than 0.05), but no significant differences from normal subjects were observed during exercise (15%, 5.04 +/- 0.65; 30%, 7.64 +/- 0.99; 45%, 12.56 +/- 1.20 ml/100 ml/min). Peak exercise blood flow was correlated negatively with central venous pressure (r = -0.65, p less than 0.05) and positively with right ventricular ejection fraction (r = 0.59, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Enhanced alpha 1-adrenergic responsiveness in cardiomyopathic hamster cardiac myocytes. Relation to the expression of pertussis toxin-sensitive G protein and alpha 1-adrenergic receptors.

The pathogenesis of the myopathy occurring in the heart of the cardiomyopathic strain of the Syrian hamster is not well understood but is believed to be associated with abnormal calcium handling by myopathic cells. The purpose of this study was to determine whether the cardiomyopathy occurring in strain BIO 14.6 animals is associated with an enhanced alpha 1-adrenergic receptor-mediated rise in cytosolic calcium, whether a pertussis toxin-sensitive G protein is involved in coupling the alpha 1-adrenergic receptor to changes in intracellular calcium and whether enhanced alpha 1 responsiveness is associated with an increase in the level of expression of the alpha 1-adrenergic receptor or in the pertussis toxin-sensitive G protein or proteins. To test the hypothesis that the cardiomyopathic state is associated with a greater alpha 1-receptor-mediated rise in cytosolic calcium, we studied the effect of phenylephrine (in the presence of propranolol) on time-averaged cytosolic calcium concentration ([Ca2+]i) in isolated cardiac myocytes from cardiomyopathic and age-matched control hamsters. Phenylephrine caused a greater increase both in time-averaged [Ca2+]i (an increase of 48 +/- 8% versus 12 +/- 3%, p less than 0.01) and in contractility (+181 +/- 22% versus +35 +/- 9%, p less than 0.01) in cardiomyopathic than in normal cardiac myocytes. Exposure to pertussis toxin (200 ng/ml for 3 hours) attenuated the alpha 1-adrenergic receptor-mediated increase in contractility and time-averaged [Ca2+]i in both cardiomyopathic and normal cells. The level of pertussis toxin-sensitive G protein, as determined by pertussis toxin-mediated [32P]ADP-ribosylation, was 1.6-fold higher in cardiomyopathic versus normal hamster hearts. The density of alpha 1-adrenergic receptors, as measured by the antagonist radioligand [3H]prazosin and the affinity of the receptor for agonist and antagonist were similar in myopathic and normal heart membranes. Thus, in cardiac myocytes from hamsters, the alpha 1-adrenergic receptor-mediated effects on [Ca2+]i and contractility appear to be mediated by a pertussis toxin-sensitive G protein or proteins. In myocytes from cardiomyopathic hamsters, these alpha 1-adrenergic effects were increased in magnitude, as was the level of pertussis toxin-sensitive G protein, but there was no measurable alteration in the density or ligand binding properties of alpha 1-adrenergic receptors.

Animals↗

PubMed1990

Acute increase in exercise capacity with milrinone: lack of correlation with resting hemodynamic responses.

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.

Anaerobic Threshold↗

PubMed1990

In vivo studies of myocardial beta-adrenergic receptor pharmacology in patients with congestive heart failure.

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)

Diastole↗

PubMed1989

Endothelin-1 increases intracellular calcium mobilization but not calcium uptake in rabbit vascular smooth muscle cells.

Conflicting evidence has been reported regarding the role of endothelin-1, a potent vasconstrictor peptide, in stimulating extracellular calcium influx in rabbit vascular smooth muscle. The objective of this study was to elucidate the effects of endothelin-1 on transmembrane 45Ca2+ influx and intracellular calcium mobilization in cultured rabbit aortic smooth muscle cells. In calcium containing buffer, endothelin-1 induced a concentration-dependent 45Ca2+ efflux response over the range of 10 pM to 100 nM with an EC50 of approximately 60 pM. Maximum endothelin-stimulated 45Ca2+ efflux was not affected by the absence of extracellular calcium or the presence of 1 microM verapamil. Endothelin-1 did not induce transplasmalemmal 45Ca2+ uptake at times up to 30 min. These findings suggest that an alteration in intracellular calcium handling, rather than extracellular calcium influx, is responsible for the endothelin-stimulated increase in intracellular calcium concentration in rabbit aortic smooth muscle cells.

Animals↗

PubMed1989

Observations on the intracoronary administration of milrinone and dobutamine to patients with congestive heart failure.

A direct intracoronary infusion technique was used to characterize the mechanisms of action of milrinone, a new phosphodiesterase inhibitor. Because of the small quantity of drug infused, it is possible to achieve a therapeutic concentration of drug in the heart with little or no systemic accumulation. Because loading conditions are largely unaffected during intracoronary drug infusion, it is possible to use left ventricular +dP/dt as a convenient measure of changes in contractility. Intracoronary milrinone infusion caused a dose-related increase in +dP/dt associated with a substantial improvement in left ventricular pump function. In addition, there is a small decrease in heart rate, which appeared to be secondary to reflex withdrawal of sympathetic tone, since it was associated with a decrease in plasma norepinephrine. Measurement of forearm vascular resistance and forearm venous capacitance by plethysmography indicated that although there was no significant decrease in forearm vascular resistance during intracoronary drug infusion, there was a small increase in venous capacitance. Subsequent intravenous administration of milrinone caused a substantial further improvement in left ventricular pump function, associated with a substantial decrease in left- and right-sided cardiac filling pressures and forearm vascular resistance, and an increase in forearm venous capacitance. These findings suggest that reflex sympathetic withdrawal may contribute to the venous dilation that occurs with milrinone, but that the major effects of milrinone on vascular tone are due to a direct vascular action of the drug. Intracoronary infusion of dobutamine has also demonstrated a substantial decrease in the inotropic response to beta-adrenergic stimulation in patients with congestive heart failure, presumably because of down-regulation of beta-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Circulation↗

PubMed1989

Use of a conductance catheter to detect increased left ventricular inotropic state by end-systolic pressure-volume analysis.

The slope of the left ventricular end-systolic pressure-volume relationship is thought to be a load-independent index of contractile state. However, clinical application requires a practical technique to simultaneously measure pressure and volume in man. We used a left ventricular conductance catheter to derive the left ventricular end-systolic pressure-volume relationship over a range of arterial pressures during nitroprusside infusion and washout in 14 patients, and to characterize the effect of dobutamine, a positive inotropic drug. End-systole was defined as the maximum pressure-to-volume ratio. Dobutamine (5 micrograms/kg/min) increased the slope of the end-systolic pressure-volume relationship in 11 of 14 patients, the mean slope increasing by 43% from 1.4 +/- 0.1 to 2.1 +/- 0.2 mm Hg/% end-diastolic volume (p less than 0.01). In 12 of 14 patients there was a leftward and upward shift of the end-systolic pressure-volume relationship with dobutamine. T quantitate this shift, we derived left ventricular pressure at control end-systolic volume before and after dobutamine. Dobutamine increased the mean end-systolic pressure at control end-systolic volume in 12 of 14 patients, the average increased by 37% from 134 +/- 10 to 189 +/- 23 mm Hg (p less than 0.01). We conclude that the conductance catheter can be used in man to detect a drug-induced change in left ventricular contractile state. This technique may be useful in the evaluation of drugs with positive inotropic actions, and in assessing the response of individual patients to positive inotropic agents.

Cardiac Catheterization↗

PubMed1989

Distribution and function of human ventricular beta adrenergic receptors in congestive heart failure.

This study examined the characteristics and distribution of sarcolemmal and light vesicular beta-adrenergic receptors (BAR) in left ventricular myocardium from 15 adults (aged 17 to 58 years) without left ventricular dysfunction or coronary artery disease and 29 patients (aged 14 to 53 years) with end-stage congestive heart failure (CHF). Sarcolemmal and intracellular fractions were prepared by 40,000 x g and 108,000 x g centrifugation, respectively. Agonist and antagonist binding properties were assessed by nonlinear computer modelling of isoproterenol-125I-pindolol (IPIN) displacement curves. Adenylate cyclase activity was also examined. Distribution of intracellular and sarcolemmal BAR was similar in normal and failing left ventricular myocardium, with intracellular BAR comprising 4.5 +/- 2.2% of total BAR in normal human heart and 5.7 +/- 5.1% of total BAR in CHF patients. For sarcolemmal BAR, antagonist affinity was similar for normal and CHF patients (KD IPIN in normals, 21.7 +/- 2.6 pM; KD IPIN in CHF, 20 +/- 2.3 pM). Agonist affinity was somewhat higher in CHF patients (KD isoproterenol in normals, 33 +/- 4.9 nM; KD isoproterenol in CHF, 6.2 +/- 1.5 nM). Sarcolemmal BAR number was reduced in CHF from 21.4 +/- 2.9 to 16.4 +/- 1.3 fmol/mg protein (P less than 0.04). Cyclic AMP production (pmol/mg protein/min above basal) was less in CHF after Gpp(NH)p stimulation (normals, 82 +/- 20; CHF, 27 +/- 9; P less than 0.01) and after stimulation with Gpp(NH)p + isoproterenol (normals, 129 +/- 25; CHF, 56 +/- 13; P less than 0.02). Stimulation with manganese + forskolin resulted in similar levels of cyclic AMP production in normals and in CHF patients. We conclude that: (a) sarcolemmal BAR number is reduced in CHF, but BAR are not redistributed intracellularly and (b) beta-adrenergic transmembrane signalling in CHF is also impaired at the level of the guanine nucleotide regulatory proteins.

Adenylyl Cyclases↗

PubMed1989

Mechanism of the attenuated peak heart rate response to exercise after orthotopic cardiac transplantation.

The mechanism responsible for attenuation of the peak heart rate response to exercise in patients after cardiac transplantation was studied. Because the donor heart is believed to be surgically denervated, the peak heart rate response to exercise is dependent primarily on 1) an increase in the circulating levels of the catecholamines norepinephrine and epinephrine at peak exercise, and 2) the end-organ responsiveness of the sinoatrial (SA) node to beta-adrenergic stimulation. To assess the former mechanism, the levels of plasma nonepinephrine and epinephrine were measured at rest and at peak exercise on a cycle ergometer in 23 transplant recipients an average of 7 +/- 1 months after transplantation and in 23 normal subjects matched for age. To assess the latter mechanism, the heart rate response to a graded infusion of isoproterenol was determined in six normal subjects with and without atropine pretreatment and in eight transplant recipients. In transplant recipients, both the absolute plasma levels of nonepinephrine and epinephrine at peak exercise and the increments from baseline to peak exercise were comparable with or greater than those in normal subjects. In transplant recipients, the isoproterenol dose that increased heart rate by 25 beats/min over baseline was not different from that in atropine-treated normal subjects (normal subjects 9 +/- 2 ng/kg per min; transplant recipients 11 +/- 1 ng/kg per min; p = NS). These data show that after cardiac transplantation, there is a normal or slight elevation of circulating catecholamines at peak exercise, and that the responsiveness of the SA node to beta-adrenergic stimulation is normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Myocardial and vascular actions of milrinone.

Milrinone exerts potent positive inotropic and direct vasodilator properties in vitro. Several studies have been undertaken to elucidate the relative contributions of each of these actions to the overall haemodynamic effect of milrinone in patients with congestive heart failure. Intracoronary infusion of milrinone to patients with congestive heart failure results in a dose-related increase in left ventricular filling pressure, +dP/dt, indicating a positive inotropic effect due to direct myocardial stimulation. Infusion of milrinone into the brachial artery increases forearm blood flow and decreases forearm vascular resistance, indicating a direct vasodilator action in patients with congestive heart failure. The relative contribution of milrinone's positive inotropic and vasodilator actions has been assessed by two approaches. First, the haemodynamic effects of nitroprusside and milrinone were compared at doses that caused equal reductions in arterial pressure. Under this condition, the improvement in left ventricular pump function caused by milrinone exceeded that caused by nitroprusside, suggesting that a significant portion of milrinone's overall effect could not be attributed merely to vasodilatation. Second, the haemodynamic effects of intracoronary and intravenous milrinone administration were compared in the same subjects. Under these conditions, the haemodynamic effect of intracoronary drug infusion accounted for a substantial portion of the improvement in left ventricular pump function. The conclusion from these studies, taken together, is that the overall haemodynamic effect of milrinone is due to significant contributions from both its positive inotropic and its vasodilator actions. Consequently, milrinone differs significantly from pure vasodilators, such as nitroprusside, and relatively pure positive inotropic agents, such as dobutamine.

Cardiotonic Agents↗

PubMed1989

Modulation of cardiac autonomic activity during and immediately after exercise.

Fluctuations in heart rate above 0.03 Hz reflect autonomic modulation of sinoatrial node activity. To assess the dynamics of autonomic nervous activity during and immediately after exercise, we determined the power spectrum of heart rate and respiratory fluctuations in 43 normal subjects without known cardiac disease, 8 patients with severe congestive heart failure, and 6 patients status-post cardiac transplantation before, during, and after graded-work load exercise on a cycle ergometer. Before exercise, heart rate fluctuations (spectral power) at both high (0.15-0.80 Hz) and low (0.03-0.15 Hz) frequencies were significantly higher in normal subjects than in either heart failure or transplant patients but were not different between the two groups with heart disease. During exercise, heart rate power at all frequencies rapidly and progressively decreased in normal subjects, until at peak exercise it was not different from the other two groups. During recovery, heart rate power increased in normal subjects but remained significantly below base line. The findings demonstrate a marked reduction of autonomic modulation of heart rate in patients with heart failure and after cardiac transplant and support a progressive withdrawal of vagal activity during exercise with a gradual increase during recovery in normal subjects.

Adolescent↗

PubMed1989

Beta-adrenergic receptor number and adenylate cyclase function in denervated transplanted and cardiomyopathic human hearts.

To test the hypothesis that there is up-regulation of beta-adrenergic receptor density or supersensitivity of beta-adrenergic receptor-stimulated adenylate cyclase in the denervated transplanted human heart, we studied myocardium from transplanted, normal, and failing hearts. Myocardium was obtained from 10 patients 9 +/- 3 months after cardiac transplantation, from 10 patients without cardiac disease, and from eight patients with symptomatic congestive heart failure due to idiopathic cardiomyopathy. beta-Adrenergic receptor density in transplanted myocardium (15 +/- 3 fmol/mg protein, 1.20 +/- 0.14 fmol/mg DNA) was not different from that in normal myocardium (22 +/- 3 fmol/mg protein, 1.46 +/- 0.13 fmol/mg DNA; p = NS for both). In myocardium from cardiomyopathic hearts, beta-adrenergic receptor density was markedly reduced (8 +/- 2 fmol/mg protein, 0.84 +/- 0.13 fmol/mg DNA; p less than 0.05 and p less than 0.01 vs. normal myocardium, respectively). Likewise, the response of adenylate cyclase to isoproterenol in transplanted myocardium was not significantly different from that in normal myocardium, but the response was markedly depressed in cardiomyopathic myocardium. Although forskolin-stimulated adenylate cyclase activity was similar in all three groups, guanine nucleotide-stimulated adenylate cyclase activity was markedly reduced in transplanted myocardium (20 +/- 17 vs. 78 +/- 13 pmol/mg/min for normal myocardium, p less than 0.01) and to a lesser degree in cardiomyopathic myocardium (39 +/- 14 pmol/mg/min, p less than 0.03 vs. normal myocardium). Thus, there is no evidence of beta-adrenergic receptor up-regulation or supersensitivity in denervated transplanted human myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗

PubMed1989

Impaired chronotropic response to exercise in patients with congestive heart failure. Role of postsynaptic beta-adrenergic desensitization.

The mechanism responsible for the attenuated heart rate (HR) response to exercise in patients with congestive heart failure (CHF) was investigated in 46 normal subjects and 59 patients with CHF stratified by peak exercise oxygen consumption (VO2). The peak exercise HR and the increment in HR from rest to peak exercise were decreased in CHF patients, and both correlated strongly with peak VO2 (r = 0.810, p less than 0.0001; r = 0.863, p less than 0.0001, respectively). Peak exercise norepinephrine level (NE) and the increment in NE from rest to peak exercise were not attenuated in CHF patients. Resting NE was elevated in CHF patients and correlated inversely with peak VO2 (r = -0.595, p less than 0.001). However, no significant correlation occurred between peak VO2 and either peak exercise NE or the exercise increment in NE. The ratio of the exercise increments in HR and NE, and indirect index of sinoatrial node sympathetic responsiveness, was markedly reduced in CHF patients and was inversely related to the severity of exercise impairment. Likewise, the HR response to a graded isoproterenol infusion was markedly reduced in CHF patients. Age-matching of normal subjects and CHF patients did not affect the foregoing observations. Infusion of CHF patients with the phosphodiesterase inhibitor milrinone caused a significant increase in the ratio of the exercise increments in HR and NE. These data strongly suggest that the attenuated HR response to exercise in CHF patients is due, at least in part, to postsynaptic desensitization of the beta-adrenergic receptor pathway.

Adult↗

PubMed1989

Effects of beta-adrenergic agents on systolic and diastolic myocardial function in patients with and without heart failure.

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.

Adrenergic beta-Agonists↗

PubMed1989

Positive inotropic/vasodilator agents.

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.

Adrenergic beta-Agonists↗

PubMed1988

Differential effects of norepinephrine and phorbol ester on alpha-1 adrenergic receptor number and surface-accessibility in DDT1 MF-2 cells.

The short (5-60 min) and long (24 hrs) term effects of norepinephrine (10 uM) and the phorbol ester, 12-0-tetradecanoyl phorbol-13-acetate (10 nM), on total cellular and surface-accessible alpha-1 adrenergic receptor number were determined in DDT1 MF-2 smooth muscle cells. The density of alpha-1 adrenergic receptors was determined with [3H]-prazosin in a crude cellular homogenate (total cellular receptors) and in intact cells at 4 degrees C (surface-accessible receptors). Under basal conditions, all receptors were accessible to the cell surface at 4 degrees C. Short term norepinephrine exposure caused an approximately 40% decrease in surface-accessible binding without a change in total receptor number. Long term norepinephrine exposure caused a further decrease in surface-accessible binding, and an approximately 30% decrease in total receptor number. In contrast, phorbol ester had no effect on surface-accessible or total receptor number with either short or long term exposure. These data suggest that sequestration of cell surface alpha-1 adrenergic receptors is an early step in the process of agonist-mediated down-regulation. In DDT1 MF-2 cells, phorbol ester, alone, does not mimmick the effect of agonist on receptor sequestration or number.

Cell Line↗

PubMed1988

Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis.

Neurohumoral modulation of cardiovascular function is an important component of the hemodynamic alterations in patients with chronic congestive heart failure (CHF). Analysis of heart rate (HR) variability is a noninvasive means of investigating the autonomic control of the heart. The variability of HR and respiratory signals, both derived from ambulatory electrocardiographic recordings, were analyzed with power spectral analysis to evaluate autonomic control in 25 patients with chronic stable CHF (class III or IV) and 21 normal control subjects. In the patients with CHF, HR spectral power was markedly reduced (p less than 0.0001) at all frequencies examined (0.01 to 1.0 Hz, period 1 to 100 seconds) and virtually absent at frequencies greater than 0.04 Hz. Heart rate fluctuations at very low frequencies (0.01 to 0.04 Hz) less effectively differentiated CHF patients from control subjects, due to discrete (about 65 seconds, 0.015 Hz) oscillation in HR, which was associated with a similar pattern in respiratory activity in many of the patients with CHF. These findings demonstrate a marked derangement of HR modulation in patients with severe CHF. The frequency characteristics of HR fluctuations in these patients are consistent with abnormal baroreflex responsiveness to physiologic stimuli, and suggest that there is diminished vagal, but relatively preserved sympathetic, modulation of HR.

Adult↗