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Biomedical subjects

W S Colucci

Publications and source records attributed to W S Colucci.

At least 37 records · Page 2Linked to original sources
PubMed2000

Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators.

BACKGROUND: We determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Cardiotonic Agents↗
PubMed2000

Chronic alpha-adrenergic receptor stimulation modulates the contractile phenotype of cardiac myocytes in vitro.

BACKGROUND: Heart failure is characterized by contractile dysfunction of the myocardium and elevated sympathetic activity. We tested the hypothesis that chronic alpha-adrenergic (alpha-ADR) stimulation modifies the molecular and contractile phenotype of cardiac myocytes. METHODS AND RESULTS: Adult rat ventricular myocytes in culture were exposed to alpha-ADR stimulation (norepinephrine + propranolol) for 48 hours. alpha-ADR stimulation decreased the mRNAs for sarcoplasmic reticulum Ca(2+)-ATPase and Ca(2+) release channel by 56% and 52%, respectively, and increased mRNA and protein for the Na(+)-Ca(2+) exchanger by 70% and 39%, respectively. After washout of the alpha-ADR agonist, simultaneous measurement of [Ca(2+)](i) transients with fura 2 and myocyte shortening by video edge-detection showed that [Ca(2+)](i) amplitude and myocyte shortening were decreased in alpha-ADR-treated myocytes, and the time to peak and time from peak to 80% decline of both [Ca(2+)](i) and myocyte shortening were increased. The concentration-response curve for myocyte shortening by the Na(+) channel activator veratridine was shifted leftward in alpha-ADR-stimulated myocytes (EC(50), 21.6+/-4.6 versus 105.8+/-10.5 nmol/L, P:<0.001). CONCLUSIONS: Chronic alpha-ADR stimulation of cardiac myocytes causes decreases in the expression of sarcoplasmic reticulum Ca(2+)-ATPase and the Ca(2+) release channel that are associated with decreases in [Ca(2+)](i) and contractility. alpha-ADR stimulation simultaneously increases Na(+)-Ca(2+) exchanger expression, thereby increasing sensitivity to intracellular Na(+).

Adrenergic alpha-Agonists↗
PubMed2000

Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management.

Pulmonary vascular resistance is frequently elevated in patients with chronic left ventricular failure as a result of dysregulation of vascular smooth muscle tone and structural remodeling. The former is reversible over a period of minutes to days by pharmacological vasodilators, whereas the latter is relatively fixed and may resolve only slowly, over months to years. These abnormalities are due, at least in part, to pulmonary vascular endothelial dysfunction that results in impaired nitric oxide availability and increased endothelin expression. In patients with chronic heart failure, the resulting pulmonary hypertension directly affects right ventricular function and may affect exercise capacity, morbidity, and mortality. New treatment strategies, which include the use of agents that increase nitric oxide availability or oppose the actions of endothelin, may improve the structure and function of the pulmonary vasculature in patients with chronic heart failure.

Antihypertensive Agents↗
PubMed2000

Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group.

BACKGROUND: Intravenous infusion of nesiritide, a brain (B-type) natriuretic peptide, has beneficial hemodynamic effects in patients with decompensated congestive heart failure. We investigated the clinical use of nesiritide in such patients. METHODS: Patients hospitalized because of symptomatic congestive heart failure were enrolled in either an efficacy trial or a comparative trial. In the efficacy trial, which required the placement of a Swan-Ganz catheter, 127 patients with a pulmonary-capillary wedge pressure of 18 mm Hg or higher and a cardiac index of 2.7 liters per minute per square meter of body-surface area or less were randomly assigned to double-blind treatment with placebo or nesiritide (infused at a rate of 0.015 or 0.030 microg per kilogram of body weight per minute) for six hours. In the comparative trial, which did not require hemodynamic monitoring, 305 patients were randomly assigned to open-label therapy with standard agents or nesiritide for up to seven days. RESULTS: In the efficacy trial, at six hours, nesiritide infusion at rates of 0.015 and 0.030 microg per kilogram per minute decreased pulmonary-capillary wedge pressure by 6.0 and 9.6 mm Hg, respectively (as compared with an increase of 2.0 mm Hg with placebo, P<0.001), resulted in improvements in global clinical status in 60 percent and 67 percent of the patients (as compared with 14 percent of those receiving placebo, P<0.001), reduced dyspnea in 57 percent and 53 percent of the patients (as compared with 12 percent of those receiving placebo, P<0.001), and reduced fatigue in 32 percent and 38 percent of the patients (as compared with 5 percent of those receiving placebo, P<0.001). In the comparative trial, the improvements in global clinical status, dyspnea, and fatigue were sustained with nesiritide therapy for up to seven days and were similar to those observed with standard intravenous therapy for heart failure. The most common side effect was dose-related hypotension, which was usually asymptomatic. CONCLUSIONS: In patients hospitalized with decompensated congestive heart failure, nesiritide improves hemodynamic function and clinical status. Nesiritide is useful for the treatment of decompensated congestive heart failure.

Atrial Natriuretic Factor↗
PubMed2000

Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure.

BACKGROUND: Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET(A) receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET(A) receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy. METHODS AND RESULTS: This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index </=2.5 L. min(-1). m(-2) were randomized to 1 of 3 doses (1.5, 3.0, or 6.0 mg/kg) of sitaxsentan or placebo as an intravenous infusion over 15 minutes. Hemodynamic responses were assessed by catheterization of the right side of the heart for 6 hours. Sitaxsentan decreased pulmonary artery systolic pressure, pulmonary vascular resistance, mean pulmonary artery pressure, and right atrial pressure (P</=0.001, 0.003, 0.017, and 0.031, respectively) but had no effect on heart rate, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, or systemic vascular resistance. Plasma ET-1 levels were elevated at baseline and decreased with sitaxsentan. CONCLUSIONS: In patients with moderate to severe heart failure receiving conventional therapy, acute ET(A) receptor blockade caused selective pulmonary vasodilation associated with a reduction in plasma ET-1. Sitaxsentan may be of value in the treatment of patients with pulmonary hypertension secondary to chronic heart failure.

Cardiac Output, Low↗
PubMed2000

p38 mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against beta -adrenergic receptor-stimulated apoptosis. Evidence for Gi-dependent activation.

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.

Animals↗
PubMed2000

Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro.

We tested the hypothesis that the inflammatory cytokines can regulate fibroblast extracellular matrix metabolism. Neonatal and adult rat cardiac fibroblasts cultures in vitro were exposed to interleukin (IL)-1beta (4 ng/mL), tumor necrosis factor-alpha (TNF-alpha; 100 ng/mL), IL-6 (10 ng/mL), or interferon-gamma (IFN-gamma; 500 U/mL) for 24 hours. IL-1beta, and to a lesser extent TNF-alpha, decreased collagen synthesis, which was measured as collagenase-sensitive [(3)H]proline incorporation, but had no effect on cell number or total protein synthesis. IL-1beta decreased the expression of procollagen alpha(1)(I), alpha(2)(I), and alpha1(III) mRNA, but increased the expression of procollagen alpha(1)(IV), alpha(2)(IV), and fibronectin mRNA, indicating a selective transcriptional downregulation of fibrillar collagen synthesis. IL-1beta and TNF-alpha each increased total matrix metalloproteinase (MMP) activity as measured by in-gel zymography, causing specific increases in the bands corresponding to MMP-13, MMP-2, and MMP-9. IL-1beta increased the expression of proMMP-2 and proMMP-3 mRNA, suggesting that increased metalloproteinase activity is due, at least in part, to increased transcription. The effects of IL-1beta were not dependent on NO production. Thus, IL-1beta and TNF-alpha decrease collagen synthesis and activate MMPs that degrade collagen. These observations suggest that IL-1beta and TNF-alpha may contribute to ventricular dilation and myocardial failure by promoting the remodeling of interstitial collagen.

Animals↗
PubMed2000

Impaired cell shortening and relengthening with increased pacing frequency are intrinsic to the senescent mouse cardiomyocyte.

Increased heart rate enhances cardiac contractility and accelerates relaxation. Both the force- and relaxation-frequency relationships are critical to myocardial function, especially during stress, and have been shown to be impaired in senescent myocardium. While senescent myocardium is characterized by decreased sarcoplasmic reticulum calcium ATPase activity, it is unclear if altered calcium regulation is directly responsible for the attenuated contractility and relaxation observed with increasing pacing frequency in aged myocardium. We examined this issue using freshly dissociated left ventricular myocytes, isolated from young adult and senescent mouse hearts. Myocytes were paced from 2 to 9 Hz at 37 degrees C, and cell shortening and [Ca(2+)](i)were simultaneously measured using video edge-detection and fura-2 fluorescence, respectively. In adult myocytes, increasing the pacing rate resulted in a progressive increase in percent cell shortening (CS) (P<0.01). This positive CS-frequency relationship was paralleled by an increase in [Ca(2+)](i)transient amplitude (P<0.05). In contrast, the CS-frequency relationship was blunted in senescent myocytes with no increase in percent CS or [Ca(2+)](i)transient amplitude with increasing pacing rate. With increased pacing, the decreases in time constants (tau) of cell relengthening and Ca(2+)transient decay were much steeper in adult compared to senescent myocytes (P<0.05). This study demonstrates that adult mouse myocytes exhibit augmented intracellular Ca(2+)transient amplitude and enhanced intracellular Ca(2+)removal with increasing pacing frequency, resulting in increased cell shortening and enhanced relengthening with frequency. In contrast, senescent mouse myocytes exhibit impaired calcium handling with increasing pacing frequency, which correlated with impairment of both cell shortening and relengthening.

Aging↗
PubMed2000

Inhibition of protein phosphatase 1 induces apoptosis in neonatal rat cardiac myocytes: role of adrenergic receptor stimulation.

The mechanisms that regulate cardiac myocyte apoptosis are not well understood. To study the role of protein phosphatase 1 (PP1) and 2A (PP2A) in apoptosis, we exposed cultured neonatal rat cardiac myocytes to the phosphatase inhibitor okadaic acid (OA). Exposure (18 h) to 100 nM OA (a concentration which inhibits both PP1 and PP2A) decreased the number of adherent cells, caused genomic DNA fragmentation, and increased the percentage of apoptotic cells. These effects did not occur at a lower concentration of OA (1 nM) which is relatively specific for PP2A. Stimulation of alpha1- or beta-adrenergic receptors with norepinephrine (NE) in the presence of propranolol or prazosin partially blocked OA-induced apoptosis as measured by flow cytometry. Likewise, stimulation of adenylyl cyclase with forskolin reduced OA-induced apoptosis. Conversely, inhibition of protein kinase A with H89 or protein kinase C with chelerethrine potentiated OA-induced apoptosis. OA increased caspase-3 activity, and this effect was reduced by NE. Thus, inhibition of PP1 stimulates apoptosis in NRVM and stimulation of adrenergic receptors protects against OA-induced apoptosis.

Animals↗
PubMed2000

Adrenergic regulation of myocardial apoptosis.

Increased sympathetic nerve activity to the myocardium is a central feature in patients with heart failure. Norepinephrine, the primary transmitter of the sympathetic nervous system, signals via binding to alpha- and beta-adrenergic receptors (AR) that are coupled to G-proteins. Pharmacologic studies of cardiac myocytes in vitro demonstrate that beta-AR can stimulate apoptosis. Likewise, in transgenic mice overexpression of beta 1-AR or G alpha s is associated with myocyte apoptosis and the development of dilated cardiomyopathy. Whereas beta 1-AR stimulate apoptosis in vitro and in vivo, beta 2-AR may either stimulate or inhibit apoptosis and myocardial failure depending on the level of expression. Receptors coupling to Gi and Gq may also be able to mediate or modulate apoptosis and the development of myocardial failure, suggesting the potential for interactions between the beta-AR system and numerous remodeling stimuli that act through Gi or Gq signaling pathways. It appears likely that the mitogen-activated protein kinase superfamily plays a key role in mediating the actions of adrenergic pathways on myocyte apoptosis. These observations suggest that the adrenergic nervous system plays an important role in the regulation of myocyte apoptosis, and may thus contribute to the development of myocardial failure.

Adrenergic beta-Agonists↗
PubMed2000

Survival and prognosis: investigation of Crataegus extract WS 1442 in congestive heart failure (SPICE)--rationale, study design and study protocol.

UNLABELLED: SPICE is the first, international, randomized, placebo-controlled, double-blind study to investigate the influence of the herbal drug Crataegus Special Extract WS 1442 (hawthorn leaves with flowers) on mortality of patients suffering from congestive heart failure. BACKGROUND: In vitro and experimental animal studies have suggested the following pharmacological modes of action of standardized Crataegus extracts: (1) cAMP-independent positive inotropy; (2) peripheral and coronary vasodilation; (3) protection against ischemia-induced ventricular arrhythmias; (4) antioxidative properties; and (5) anti-inflammatory effects. STUDY DESIGN: In this randomized, placebo-controlled, double-blind, international trial (approximately 120 investigational centers in seven European countries), up to 2300 patients with congestive heart failure, New York Heart Association class II and III and markedly impaired left ventricular function, will be enrolled and treated over a period of 24 months. During this time patients receive either two film-coated tablets of 450 mg of the Special Extract WS 1442 standardized to 84.3 mg of oligomeric procyanidines or matched placebo per day in addition to standard therapy for congestive heart failure, such as diuretics, digoxin or digitoxin, beta-adrenoceptor blockers and angiotensin-converting-enzyme inhibitors. The primary outcome variable is the combined endpoint of cardiac death, non-lethal myocardial infarction, and hospitalization due to progression of heart failure. Secondary outcome variables are total mortality, exercise duration, echocardiographic parameters, quality of life as well as pharmacoeconomic parameters. The first patient was included in October 1998. The trial is expected to be completed at the end of 2002.

Adult↗
PubMed2000

Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart.

We tested the hypothesis that left ventricular (LV) remodeling late after myocardial infarction (MI) is associated with myocyte apoptosis in myocardium remote from the infarcted area and is related temporally to LV dilation and contractile dysfunction. One, four, and six months after MI caused by coronary artery ligation, LV volume and contractile function were determined using an isovolumic balloon-in-LV Langendorff technique. Apoptosis and nuclear morphology were determined by terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) and Hoechst 33258 staining. Progressive LV dilation 1-6 mo post-MI was associated with reduced peak LV developed pressure (LVDP). In myocardium remote from the infarct, there was increased wall thickness and expression of atrial natriuretic peptide mRNA consistent with reactive hypertrophy. There was a progressive increase in the number of TUNEL-positive myocytes from 1 to 6 mo post-MI (2.9-fold increase at 6 mo; P < 0. 001 vs. sham). Thus LV remodeling late post-MI is associated with increased apoptosis in myocardium remote from the area of ischemic injury. The frequency of apoptosis is related to the severity of LV dysfunction.

Animals↗
PubMed2000

Altered beta-adrenergic signal transduction in nonfailing hypertrophied myocytes from Dahl salt-sensitive rats.

Desensitization of the beta-adrenergic receptor (beta-AR) response is well documented in hypertrophied hearts. We investigated whether beta-AR desensitization is also present at the cellular level in hypertrophied myocardium, as well as the physiological role of inhibitory G (G(i)) proteins and the L-type Ca(2+) channel in mediating beta-AR desensitization. Left ventricular (LV) myocytes were isolated from hypertrophied hearts of hypertensive Dahl salt-sensitive (DS) rats and nonhypertrophied hearts of normotensive salt-resistant (DR) rats. Cells were paced at a rate of 300 beats/min at 37 degrees C, and myocyte contractility and intracellular Ca(2+) concentration ([Ca(2+)](i)) were simultaneously measured. In response to increasing concentrations of isoproterenol, DR myocytes displayed a dose-dependent augmentation of cell shortening and the [Ca(2+)](i) transient amplitude, whereas hypertrophied DS myocytes had a blunted response of both cell shortening and the [Ca(2+)](i) transient amplitude. Interestingly, inhibition of G(i) proteins did not restore beta-AR desensitization in DS myocytes. The responses to increases in extracellular Ca(2+) and an L-type Ca(2+) channel agonist were also similar in both DS and DR myocytes. Isoproterenol-stimulated adenylyl cyclase activity, however, was blunted in hypertrophied myocytes. We concluded that compensated ventricular hypertrophy results in a blunted contractile response to beta-AR stimulation, which is present at the cellular level and independent of alterations in inhibitory G proteins and the L-type Ca(2+) channel.

Adenylate Cyclase Toxin↗
PubMed2000

Altered inotropic responsiveness and gene expression of hypertrophied myocardium with captopril.

Inotropic responsiveness to beta-adrenergic stimulation is generally found to be impaired in left ventricular (LV) hypertrophy and failure. To investigate the mechanisms by which angiotensin-converting enzyme inhibitor therapy may modulate inotropic responsiveness with long-term pressure overload, we studied the effects of captopril treatment on cardiac gene expression, LV muscle mechanical contraction, and intracellular calcium (Ca(2+)) transients from spontaneously hypertensive rats (SHR). LV papillary muscles from untreated SHR, age-matched normotensive Wistar-Kyoto rats (WKY), and SHR treated with captopril (CAP(Rx) started at 12, 18, and 21 months of age) were studied. All animals were studied at 24 months of age or when heart failure developed. In untreated SHR, alpha-myosin heavy chain (MHC) gene expression and protein were decreased, the Ca(2+) transient (with the bioluminescent indicator aequorin) was prolonged, and abundance of Na(+)/Ca(2+) exchanger mRNA levels increased in comparison to WKY. Active stress development at L(max) and the maximum rate of stress development were depressed and contractile duration prolonged in SHR relative to WKY. Isoproterenol administration further decreased active stress in untreated SHR despite an increase in intracellular Ca(2+) levels. In CAP(Rx) SHR, alpha-MHC gene expression and protein levels were increased, the Ca(2+) transient was not prolonged, Na(+)/Ca(2+) exchanger expression was downregulated, and papillary muscle function demonstrated increased active stress and maximum rate of stress development in response to isoproterenol. The increased abundance of alpha-MHC mRNA in conjunction with an increase in V(1) myosin isozyme suggests that captopril affects transcriptional regulation of cardiac gene expression. Restored LV inotropic responsiveness to beta-adrenergic stimulation in CAP(Rx) SHR appears to be coupled to normalization of Na(+)/Ca(2+) exchanger mRNA expression, upregulation of V(1) myosin isozyme levels, and increased speed of contraction.

Adrenergic beta-Agonists↗
PubMed2000

Noninvasive methods for detecting elevated left-sided cardiac filling pressure.

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.

Blood Pressure↗
PubMed2000

Adrenergic overload and apoptosis in heart failure: implications for therapy.

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.

Adrenergic beta-Agonists↗
PubMed1999

Opposing effects of beta(1)- and beta(2)-adrenergic receptors on cardiac myocyte apoptosis : role of a pertussis toxin-sensitive G protein.

BACKGROUND: beta-Adrenergic receptor (beta-AR) stimulation increases apoptosis in adult rat cardiac (ventricular) myocytes (ARVMs) via activation of adenylyl cyclase. beta(2)-ARs may couple to a G(i)-mediated signaling pathway that can oppose the actions of adenylyl cyclase. METHODS AND RESULTS: In ARVMs, beta-AR stimulation for 24 hours increased the number of apoptotic cells as measured by flow cytometry. beta-AR-stimulated apoptosis was abolished by the beta(1)-AR-selective antagonist CGP 20712A (P<0.05 versus beta-AR stimulation alone) but was potentiated by the beta(2)-AR-selective antagonist ICI 118,551 (P<0.05 versus beta-AR stimulation alone). The muscarinic agonist carbachol also prevented beta-AR-stimulated apoptosis (P<0.05 versus beta-AR stimulation alone), whereas pertussis toxin potentiated the apoptotic action of beta-AR stimulation (P<0.05 versus beta-AR stimulation alone) and prevented the antiapoptotic action of carbachol. CONCLUSIONS: In ARVMs, stimulation of beta(1)-ARs increases apoptosis via a cAMP-dependent mechanism, whereas stimulation of beta(2)-ARs inhibits apoptosis via a G(i)-coupled pathway. These findings have implications for the pathophysiology and treatment of myocardial failure.

Adenylate Cyclase Toxin↗