Drugs online research references
Basic Res Cardiol. 1994 Jan-Feb;89(1):80-93.
Adenylate cyclase activation promotes the recruitment of coronary vasodilator reserve and improves subendocardial contractility during coronary hypoperfusion.
Ikeda Y, Miura T, Tanaka N, Mikami S, Oda T, Takaki A, Fujii T, Kohno M, Katayama K, Matsuzaki M.
Second Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Japan.
This study was designed to examine the effects of an adenylate cyclase activator, NKH477, on epicardial and endocardial contraction and coronary blood flow (CoF) in the presence or absence of ischemia and to compare it to those of adenosine. We measured coronary pressures (CoP), coronary blood flow, epicardial and endocardial wall thickening (i.e., %EPWT and %ENWT, respectively, by sonomicrometry) in 18 anesthetized dogs. The left circumflex coronary artery was perfused with arterial blood using a pressure controlled servo pump. Propranolol (0.5 mg/kg) and atropine (0.25 mg) were used to minimize the neurogenic effects. CoP decreased from 100 mm Hg to 40 mm Hg with and without drugs. At CoP of 100 mm Hg, intracoronary infusion of NKH477 (10(-8) M/kg/min) produced a two-fold increase in CoF, but there were no changes in either the %EPWT or the %ENWT. During coronary hypofusion at coronary pressures equal to 40 mm Hg, NKH477 increased CoF from 16 +/- 2 to 28 +/- 4 mL/min (p < 0.05) and improved %ENWT significantly from 6 +/- 7 to 23 +/- 7% (p < 0.05). However %EPWT was not improved by NKH477. On the other hand, the intracoronary infusion of adenosine (10 micrograms/kg/min) increased CoF from 16 +/- 5 to 21 +/- 6 mL/min (p < 0.05) at CoP of 40 mm Hg. However, this dose of adenosine failed to improve %ENWT (16 +/- 10% vs. 14 +/- 10%, n.s.). Thus, the improvement of subendocardial function by NKH477 might be related to the improvement of subendocardial perfusion which could be induced by the potentiation of endogenously released adenosine as well as the direct vasodilator effect. This contrasts with the effects of exogenously administered adenosine, which failed to improve subendocardial contractility.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8010938&dopt=Abstract
Cardiovasc Drugs Ther. 1993 Dec;7(6):851-61.
Effects of beta-blockers and Ca(2+)-antagonists on the response of the isolated working rat heart to adrenergic stimulants after cardioplegic arrest.
Hattingh P, Coetzee A, Harper I, Genade S, Lochner A.
Department of Anesthesiology, University of Stellenbosch Medical School, Tygerberg, South Africa.
During coronary artery bypass graft (CABG) surgery, patients pretreated with the combination of beta-blocking drugs and Ca2+ antagonists for control of myocardial ischemia often respond inadequately to adrenergic stimulants administered after cardioplegic arrest. In this study, the effects of the combination of a beta-blocker (propranolol) and a Ca2+ antagonist (nifedipine) on the spontaneous recovery, as well as the adrenergic response of the isolated, perfused, working rat heart after a period of cardioplegic arrest were evaluated. After pretreatment of the animals with propranolol and/or nifedipine, hearts were removed, perfused in the presence of pretreatment drugs, subjected to 45 minutes of normothermic cardioplegic arrest, reperfused, and finally stimulated with exponentially increasing concentrations of a sympathomimetic drug. Propranolol, and to a lesser extent nifedipine, protected the hearts during cardioplegic arrest, as indicated by the improved recovery and maximum response to adrenergic stimulation after cardioplegia. Isoprenaline, a beta-stimulant, (at a 100 x higher than conventional concentration), elicited an adequate inotropic and chronotropic response. Stimulation by the alpha, beta-stimulant adrenaline or dobutamine improved only the inotropic response of propranolol and combination treated hearts. Cautious extrapolation of the results to human may suggest continuation of drug therapy of patients before CABG surgery.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8011559&dopt=Abstract
Circ Res. 1994 Jul;75(1):133-43.
Protein kinase-dependent Cl- currents in feline ventricular myocytes.
Zhang K, Barrington PL, Martin RL, Ten Eick RE.
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Ill. 60611.
A Cl- current (ICl) induced by isoproterenol (ISO) has been identified in isolated guinea pig ventricular myocytes. This ISO-induced ICl can be inhibited by propranolol and mimicked by forskolin (FSK), suggesting that beta-receptors, cAMP, and protein kinase A (PKA) are involved in regulating the involved Cl- channel. Because activation of protein kinase C (PKC) mediated via alpha-adrenergic receptor stimulation is also known to regulate several ion channels, the idea that activation of PKC also can induce ICl was investigated by using isolated feline ventricular myocytes and the whole-cell patch-clamp technique. We found that extracellularly applied phorbol 12-myristate 13-acetate (PMA) could activate ICl in feline ventricular cells. Control experiments indicated that in the absence of PMA or other interventions, the steady-state current-voltage relation of patches maintained for more than 40 minutes was unchanged over a voltage range from -100 to +80 mV. This suggests that the present findings are not complicated by the development over time after patching of a steady-state ICl, similar to the findings reported for canine atrial myocytes. When induced by PMA, ICl was noninactivating and outwardly rectifying; it reversed polarity at approximately the equilibrium potential for Cl- and was sensitive to the Cl- channel blocker 9-anthracene carboxylic acid. In contrast, PMA failed to induce ICl when either staurosporine or calphostin C was added to the patch pipette solution used to internally dialyze the myocytes. The kinetic properties of PMA- and FSK-induced ICl were similar. When supramaximal concentrations of both ISO (1 mumol/L) and PMA (6 mumol/L) were applied simultaneously, the size of the induced ICl was the same as that induced by the same concentrations of either agonist applied alone. In addition, maximal induction of ICl with PMA (6 mumol/L) prevented the effects of FSK (1 mumol/L, the concentration causing approximately 40% of the maximal response [approximately EC40]), yet the effects of simultaneously applied submaximal concentrations (eg, approximately EC25 to approximately EC40) of both 0.5 mumol/L PMA and 1 mumol/L FSK were roughly additive. The results suggest that (1) both PMA and ISO or FSK can induce ICl with approximately equal efficacy, (2) the PMA- and ISO- or FSK-induced ICls are similar, and (3) they all flow through the same set of Cl- channels, implying that channel phosphorylation via either PKA or PKC can activate this feline cardiac ICl.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8013071&dopt=Abstract
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