Showing papers by "Arthur M. Feldman published in 1991"

Selective gene expression in failing human heart. Quantification of steady-state levels of messenger RNA in endomyocardial biopsies using the polymerase chain reaction.

Abstract: BACKGROUNDEvaluation of gene expression in failing human heart has been limited by the availability of cardiac tissue.METHODS AND RESULTSWe used the polymerase chain reaction (PCR) to assess gene expression in small quantities of failing and nonfailing human heart. PCR is a powerful new molecular biological tool that allows a small quantity of DNA to be amplified as much as 1 million-fold. Total RNA was extracted from 3-5 mg samples of human heart and reverse-transcribed to complementary DNA (cDNA). With selected oligonucleotide primers, we used PCR to amplify cDNAs encoding atrial natriuretic peptide, beta-myosin heavy chain, phospholamban, and cytoskeletal beta-actin. To quantify the relative levels of messenger RNA (mRNA) in human heart, a known amount of a control RNA was present in the reverse transcription and PCR reactions. The amount of mRNA in the sample could therefore be assessed in relation to the amount of control product. The control RNA was transcribed from a synthetic DNA template containi...

Usefulness of OPC-8212, a quinolinone derivative, for chronic congestive heart failure in patients with ischemic heart disease or idiopathic dilated cardiomyopathy.

Abstract: To evaluate the safety and efficacy of the inotropic agent OPC-8212 in patients with chronic congestive heart failure, 76 patients with impaired cardiac function and diminished exercise tolerance were studied. They were randomized to 12 weeks of double-blind therapy with either 60 mg/day of OPC-8212 or placebo. The study drug was added to their baseline medical regimen. The primary study outcome was the combined outcome of the time to either mortality (of all cause) or substantial worsening of heart failure (major morbidity), whichever occurred first. Treatment with OPC-8212 significantly (p

Experimental issues in assessment of G protein function in cardiac disease.

Abstract: In 1971, Rodbell and coworkers1 found that the ability of an effector to promote synthesis of the second-messenger cyclic AMP (cAMP) by the enzyme adenylyl cyclase was dependent on the presence of guanyl nucleotides. This landmark finding led to the discovery of guanine nucleotide-binding proteins, or G proteins, in the late 1970s.2-4 We now know that the G proteins are ubiquitous in eukaryotes and compose a large family of highly homologous proteins that couple nearly 100 different receptors with effector enzymes (see reviews in References 5-8). Two G proteins that have undergone extensive investigations are the stimulatory G protein (G5) and the inhibitory G protein (G1) that couple receptors with stimulation or inhibition of adenylyl cyclase, respectively. Effector-stimulated activation of G proteins can also mediate modification of ion channel activity independent of cAMP synthesis.7 There is direct evidence that organ-specific alterations in G protein function contribute to the pathophysiology of human disease. The florid diarrhea associated with Vibrio cholerae bacteria is the result of irreversible activation of GQ; an inherited mutation in the G, gene is responsible for at least some cases of Albright's hereditary osteodystrophy,9 and some human endocrine tumors harbor oncogenic mutations in the a-subunits of various G proteins.'0 Because the beat-to-beat control of cardiac contractility is mediated by the receptor-G protein-adenylyl cyclase complex,11,12 recent interest has focused on the role of G proteins in heart disease in both humans and animal models. However, the exact role of the different G proteins in cardiac disease remains a contentious issue. Recent reviews1314 have discussed the biochemistry and molecular biology of cardiac G proteins. This communication will clarify some of the experimental issues relating to G proteins and cardiovascular research by discussing the strengths and

Effects of chronic ethanol exposure on cardiac receptor-adenylyl cyclase coupling: studies in cultured embryonic chick myocytes and ethanol fed rats.

Abstract: Ethanol effects in the brain appear to be mediated at least in part by an alteration in receptor-effector coupling via guanine nucleotide-binding regulatory proteins (G proteins). To test the hypothesis that a similar pathway participates in the cardiotoxic effects of ethanol, we assessed the effects of chronic ethanol on two commonly used experimental models: embryonic chick myocytes in culture and ventricular myocardium from chronically fed rats. Ethanol had no effect on either the function or quantity of G proteins as assessed by effector-stimulated adenylyl cyclase activity and the levels of ADP-ribosylation substrates. In contrast, effector-stimulated adenylyl cyclase activity was significantly altered in the liver of ethanol-fed rats. These results suggest that receptor-effector coupling via G proteins in our two cardiac models is insensitive to ethanol and that ethanol effects may be species or organ specific.

Inotropic agents and adrenergic agonists as therapy for congestive heart failure

Abstract: The primary cardiac abnormality in patients with congestive heart failure due to a dilated cardiomyopathy is pump failure. Therefore, we intuitively expect that inotropic agents, drugs that increase the contractility of the heart, would be beneficial in patients with heart failure. Because the most potent mechanism for increasing cardiac contractility is the adrenergic pathway, agents have been developed that augment cardiac contractility via stimulation of adrenergic receptors. Alternately, other pharmaceuticals have been developed that interact with more distal sites in the excitation contraction-coupling pathway. However, with the exception of digoxin, no inotropic agents have proven to be of long-term benefit in patients with congestive failure. This review briefly outlines recent observations on the use of new inotropic agents and adrenergic agonists in the treatment of patients with congestive heart failure.