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Function of myocardial α1-receptors
j Mol Cell Cardiol 17 (Supplement 3) (1985)
94IS
GLYCOLYSlS GOOD OR BAD FOR THE ISCHEMIC HEART IT'S GOOD LH Opie, MRC Heart Unit, University of Cape Town Medical School, Observatory 7925, South Africa. In simple organisms, totally reliant on glycolysis for energy needs, deprivation of energy accelerates glycolysis by the Pasteur effect which is regarded as beneficial because it synthesizes ATP. In myocardial ischemia glycolysis can either be enhanced or reduced according to the severity and the proposal is that enhanced rates of glycolysis help to conserve the ischemic myocardium. This proposition is based on the following experimental systems: (i) infusions of GIK to animals with coronary artery ligation give benefit (but there is also reduced myocardial fatty acid extraction); (ii) decreased release of enzyme from isolated rat hearts perfused with fatty acid, and here the benefit appears to be related to the glycolytic rate; (iii) development of ischemic contracture - here glycolysis prevents and lack of glycolysis accelerates ischemic contracture in an isolated rat heart preparation; and (iv) action potential duration - a variety of procedures designed to inhibit glycolysis shortens the action potential. These strong arguments for the "benefit" of glycolysis may not apply to all ischemic hearts; the critical point appears to be the severity of the ischemia. -
9 5 M Y O C A R D I A L BETA-ADRENOCEPTORS AND CARDIAC CONTRACTILE FUNCTION. D B Barnett. Department of Pharmacology & Therapeutics, University of Leicester, Leicester, UK. Beta-adrenergic receptors (ADR) have been identified and eharacterised in the human heart as well as many animal species. The different proportions of both beta-I and beta-2 subtype present in atria and ventricles exhibits marked species variation which may relate to the relative dependence on noradrenergic innervation and stimulation by circulating hormonal adrenaline. InotropIc action of catecholamines is probably mediated via the beta-i subtype whereas both beta-2 and beta-I ADR's appear to subserve chronotroplsm. Alteration of cardiac adrenergic function or responsiveness has been described in a number of physiological and pathological Situations including thyroid disorder, heart failure and myocardial Ischaemia and hypertrophy. Changes of functional and biochemical activity of cardiac beta-ADR's linked to contractility in these circumstances has been reported. Variability of results may reflect the animal model used and factors including degree of the receptor effector coupling and the presence of 'spare' receptoPs in myocardium from different species. Both homologous and heterologous regulation of cardiac beta-ADR concentration and coupling to second messenger systems has been demonstrated. The effect Of these modulatory influences may determine the acute and long term efficacy of inotropic drugs acting via the betaADR which may themselves produce down regulation. The relationship of these factors to the use of beta-i selective partial agonlst8 in heart failure will be discussed.
9 6 F U N C T I O N OF MYOCARDIAL ~I-RECEPTORS. J.-B. Osnes, H. Aass, T. Skomedal. Department of Pharmacology, University of Oslo, P.O.Box 1057 Blindern, 0316 Oslo 3, Norway. In addition to the well known ~-adrenergic heart effects, stimulation of myocardial Q-receptors also increases heart function. The myocardium contains about the same number of d-receptors and ~-receptors. Stimulation of cardiac Q-receptors evokes moderately increased rate and force of contraction, unchanged or slightly prolonged duration of each contraction, increased relaxation (proportionally to or slightly less than contraction), usually unchanged heart rate, usually unchanged or reduced automaticity, moderately increased slow inward current, prolonged refractory period, usually unchanged conduction velocity. The antiarrhythmic effects may be turned into arrhythmogenic action by ischemia. Q-Stimulation moderately activates glycogen phosphorylase, inhibits glycogen synthase and activates phosphofructokinase. The primary mediator for myocardial dl-adrenergic stimulation has not been settled but increased formation of inositol trisphosphate and diacylglycerol may be the initial step. The inotropic effect is assumed to be related to increased systolic Ca ++ and possibly increased sensitivity of the myofilaments to Ca ++. Both adrenaline and noradrenaline are able to stimulate both ~- and d-receptors in the myocardium. Although the ~-effects obviously are the dominating ones, the d-effects contribute to the inotropic response. Concomitant ~-stimulation seems, however, to attenuate the d-adrenergic effect. In some situations the d-effects may have an augmented importance, as in hypothyroidism, during cardiac ~-blockade and during muscarinic cholinergic stimulation of the heart.
94IS
GLYCOLYSlS GOOD OR BAD FOR THE ISCHEMIC HEART IT'S GOOD LH Opie, MRC Heart Unit, University of Cape Town Medical School, Observatory 7925, South Africa. In simple organisms, totally reliant on glycolysis for energy needs, deprivation of energy accelerates glycolysis by the Pasteur effect which is regarded as beneficial because it synthesizes ATP. In myocardial ischemia glycolysis can either be enhanced or reduced according to the severity and the proposal is that enhanced rates of glycolysis help to conserve the ischemic myocardium. This proposition is based on the following experimental systems: (i) infusions of GIK to animals with coronary artery ligation give benefit (but there is also reduced myocardial fatty acid extraction); (ii) decreased release of enzyme from isolated rat hearts perfused with fatty acid, and here the benefit appears to be related to the glycolytic rate; (iii) development of ischemic contracture - here glycolysis prevents and lack of glycolysis accelerates ischemic contracture in an isolated rat heart preparation; and (iv) action potential duration - a variety of procedures designed to inhibit glycolysis shortens the action potential. These strong arguments for the "benefit" of glycolysis may not apply to all ischemic hearts; the critical point appears to be the severity of the ischemia. -
9 5 M Y O C A R D I A L BETA-ADRENOCEPTORS AND CARDIAC CONTRACTILE FUNCTION. D B Barnett. Department of Pharmacology & Therapeutics, University of Leicester, Leicester, UK. Beta-adrenergic receptors (ADR) have been identified and eharacterised in the human heart as well as many animal species. The different proportions of both beta-I and beta-2 subtype present in atria and ventricles exhibits marked species variation which may relate to the relative dependence on noradrenergic innervation and stimulation by circulating hormonal adrenaline. InotropIc action of catecholamines is probably mediated via the beta-i subtype whereas both beta-2 and beta-I ADR's appear to subserve chronotroplsm. Alteration of cardiac adrenergic function or responsiveness has been described in a number of physiological and pathological Situations including thyroid disorder, heart failure and myocardial Ischaemia and hypertrophy. Changes of functional and biochemical activity of cardiac beta-ADR's linked to contractility in these circumstances has been reported. Variability of results may reflect the animal model used and factors including degree of the receptor effector coupling and the presence of 'spare' receptoPs in myocardium from different species. Both homologous and heterologous regulation of cardiac beta-ADR concentration and coupling to second messenger systems has been demonstrated. The effect Of these modulatory influences may determine the acute and long term efficacy of inotropic drugs acting via the betaADR which may themselves produce down regulation. The relationship of these factors to the use of beta-i selective partial agonlst8 in heart failure will be discussed.
9 6 F U N C T I O N OF MYOCARDIAL ~I-RECEPTORS. J.-B. Osnes, H. Aass, T. Skomedal. Department of Pharmacology, University of Oslo, P.O.Box 1057 Blindern, 0316 Oslo 3, Norway. In addition to the well known ~-adrenergic heart effects, stimulation of myocardial Q-receptors also increases heart function. The myocardium contains about the same number of d-receptors and ~-receptors. Stimulation of cardiac Q-receptors evokes moderately increased rate and force of contraction, unchanged or slightly prolonged duration of each contraction, increased relaxation (proportionally to or slightly less than contraction), usually unchanged heart rate, usually unchanged or reduced automaticity, moderately increased slow inward current, prolonged refractory period, usually unchanged conduction velocity. The antiarrhythmic effects may be turned into arrhythmogenic action by ischemia. Q-Stimulation moderately activates glycogen phosphorylase, inhibits glycogen synthase and activates phosphofructokinase. The primary mediator for myocardial dl-adrenergic stimulation has not been settled but increased formation of inositol trisphosphate and diacylglycerol may be the initial step. The inotropic effect is assumed to be related to increased systolic Ca ++ and possibly increased sensitivity of the myofilaments to Ca ++. Both adrenaline and noradrenaline are able to stimulate both ~- and d-receptors in the myocardium. Although the ~-effects obviously are the dominating ones, the d-effects contribute to the inotropic response. Concomitant ~-stimulation seems, however, to attenuate the d-adrenergic effect. In some situations the d-effects may have an augmented importance, as in hypothyroidism, during cardiac ~-blockade and during muscarinic cholinergic stimulation of the heart.