Showing papers by "Arthur M. Feldman published in 1990"

Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium.

Abstract: beta-Adrenergic pathways in the human ventricular myocardium mediate the powerful positive inotropic effects of released neurotransmitters (norepinephrine) and circulating hormones (epinephrine) and the response to therapeutically administered beta-agonists. Two genetically and pharmacologically distinct receptors, beta 1 and beta 2, mediate the contractile effects of catecholamines in a similar manner. The biologic signal produced by the occupancy of beta-adrenergic receptors by catecholamine agonists is transduced, amplified, and regulated by a family of guanine nucleotide-binding proteins (G proteins), which serve both stimulatory and inhibitory functions. Although the major biochemical effector of beta-adrenergic receptors is the enzyme protein--coupled directly to ion channels that regulate inotropic and electrophysiological effects. In human ventricular myocardium, heart failure produces changes in the beta-adrenergic receptor pathways that have the collective effect of reducing the degree of inotropic stimulation that may be produced by a given amount of beta-agonist. These changes include downregulation of beta 1-adrenergic receptors, uncoupling of beta 2-adrenergic receptors, and an increase in the functional activity of the inhibitory G protein. These effects in turn are probably caused by exposure to increased amounts of neurotransmitter resulting from a complex series of changes in the cardiac sympathetic nervous system. Finally, the components of the beta-receptor-G protein system may be both acutely and chronically modulated by certain kinds of pharmacological therapy. These observations underscore the importance of the adrenergic nervous system in heart failure, and they create the potential for the development of new interventional strategies designed to alter the natural history of heart muscle disease and heart failure.

Peripartum myocarditis and cardiomyopathy.

Abstract: The clinical and pathologic features of 18 consecutive patients with peripartum cardiomyopathy at The Johns Hopkins Hospital were examined in an attempt to define the incidence of myocarditis and to determine its response to immunosuppressive agents. In addition to routine studies, patients were evaluated with echocardiography, nuclear ventriculography, right heart catheterization, and myocardial biopsy. Fourteen of the 18 patients (78%) showed evidence of myocarditis. Of these, 10 were treated with immunosuppressive therapy. Nine of the 10 treated patients with myocarditis had subjective and objective improvement. Follow-up endomyocardial biopsies in these patients showed resolution or substantial improvement in myocarditis. Four patients with myocarditis not treated with immunosuppressives also improved. All patients improving spontaneously presented with congestive heart failure within 1 month of delivery and improved dramatically within days of presentation. Four of the 18 patients showed no evidence of myocarditis. Of these, two improved, and two deteriorated (both requiring cardiac transplantation). None of these four patients were treated with immunosuppressive therapy. We conclude that in patients with peripartum cardiomyopathy, 1) the etiology remains unclear although myocarditis was present in 78% of those with this condition, 2) resolution of myocarditis is associated with significant improvement in left ventricular function, 3) myocarditis may resolve spontaneously without detectable loss of cardiac function, and 4) immunosuppressive therapy in patients with myocarditis and persistent left ventricular dysfunction may improve left ventricular function and prognosis.

Diminished beta-adrenergic receptor responsiveness and cardiac dilation in hearts of myopathic Syrian hamsters (BIO 53.58) are associated with a functional abnormality of the G stimulatory protein.

Abstract: Previous studies have demonstrated a diminution in the bioactivity of the guanine nucleotide-binding regulatory protein that stimulates adenylyl cyclase (Gs) in hearts of the hypertrophic BIO 146 Syrian hamster In this study, we measured functional activity and immunodetectable levels of Gs in a mutant strain of hamsters (BIO 5358) that develop a dilated cardiomyopathy Pathological studies demonstrated that 100-day-old BIO 5358 hamsters had substantial ventricular dilation when compared with age-matched F1B controls Additionally, these 100-day-old hamsters demonstrated diminished contractile response to beta-adrenergic receptor stimulation The pathological and hemodynamic changes were associated with defective coupling of Gs to adenylyl cyclase as adenylyl cyclase activation was distinctly decreased in the presence of isoproterenol, fluoride ion, guanine nucleotides, and forskolin Additionally, the ability of the alpha-subunit of Gs to reconstitute isoproterenol-stimulated adenylyl cyclase activity in S49 cyc- membranes was reduced approximately 65% By contrast, cyc- complementation assays did not reveal a difference between the functional activity of Gs in hearts from 30-day-old BIO 5358 hamsters and F1B controls Furthermore, beta-adrenergic receptor stimulation of adenylyl cyclase in the membranes of the young BIO 5358 hamsters was not significantly different from controls The substantial alterations in Gs bioactivity in hearts of the 100-day-old BIO 5358 hamsters was not associated with alterations in the immunodetectable levels of either alpha Gs or alpha Gi on Western Blots These results suggest that G protein changes are associated with ventricular dilation in BIO 5358 hamsters and that G protein levels are not always reflective of G protein bioactivity

Human cardiac sodium channels expressed in Xenopus oocytes.

Abstract: We report the expression of voltage-dependent Na+ channels in Xenopus oocytes injected with total RNA isolated from explanted human hearts. The expressed channels demonstrate characteristic voltage-dependent gating, inhibition by tetrodotoxin, and selectivity for Na+. Oocytes injected with sterile water or intentionally degraded RNA had no similar channel activity. The antiarrhythmic agent lidocaine (20 microM) inhibits current flow through the channel in a voltage-dependent fashion. Na+ channels expressed by injection of human cardiac RNA into Xenopus oocytes qualitatively resemble channels in the native tissue.