- Email: [email protected]
Alpha adrenoceptors and arrhythmias
J Mol Cell Cardiol 18 (Supplement 1) (1986) 7ALPHA-ADRENOCEPTORS IN HYPERTENSION ASSOCIATED WITH HEART FAILURE AND ANGINA PECTORIS. T. Giles, M. Thomas, G. Sander. Departments of Medicine, Tulane University School of Medicine and VA Medical Center, New Orleans, Louisiana. Alpha-adrenoceptors located in both the central nervous system and the periphery play an important role in the pathophysiology of hypertension associated with heart failure and angina pectoris. In both acute and chronic heart failure, central alpha-adrenoceptor agouists reduced cardiac work load by decreasing heart rate, systemic arterial pressure and reducing venous tone. Also, plasma cateeholamines were decreased. Exercise at comparable work loads was achieved at a lower pressure-rate product and effort capacity was sometimes increased. Central alphaadrenoceptor agonists increased effort capacity in patients with ischemic heart disease and angina pectoris. Again, the benefits are thought to be decreased heart rate, systemic arterial blood pressure and rate-pressure products during exercise; catecholamines are reduced in these patients as well. Peripherally, alpha-adrenoceptors are important in the development of hypertensive cardiomyopathy and heart failure; hypertrophy and diastolic dysfunction are major pathophysiologic factors. The role of alpha-adrenoceptors in hypertension with heart failure and angina pectoris should be considered when selecting therapy.
S A N e.-ADRENERGIC RECEPTOR REGULATES HYPERTROPHY AND GENE EXPRESSION OF CULTURED HEART MUSCLE CELLS. P. Simpson, N. Bishopric, S. Coughlin, J. Karliner, C. Ordahl, N. Starksen, N. White, and L. Williams, VAMC and Univ. of Calif., San Francisco, USA. Serum-free cultures of neonatal rat heart muscle cells have been used to study catecholaminergic regulation of growth and gene expression. ~1-adrenergic activation increased myocyte size by 1.5-to 2-fold over i-2 days with an EC50 20-200 rum for NE or EPI. Hypertrophied cells were quiescent as a result of =. stimulation alone and developed rhythmic contractility with concomitant 81 activation. These trophic effects on growth a n d beating required continuous surface receptor occupancy. 61 receptor K and number per cell, and el-stimulated phosphoinosltide hydrolysis, were unchanged ~n hypertrophied cells, although receptor number per unit cell area was reduced, el-stimulated hypertrophy was accompanied by a several-fold increase in cell content of contractile proteins (myosin heavy chain and actin) and contractile mRNA (e-actln). The c-myc proto-oncogene was increased by e I stimulation, but there was no increase in cell number or DNA synthesis. These studies demonstrate that the e -adrenergic receptor regulates hypertrophy and gene expression of cultured neonatal r~t heart muscle cells and raise the novel possibility that the surface receptor may influence the cell nucleus to increase the rate of mRNA transcription. Supported by the VA Research Service; the NIH; the AHA, California Affiliate; the Howard Hughes Medical Institute; and the ACC/Merck Fellowship (N.B.)
9
ALPHA ADRENOCEPTOHS AND ARRHYTIIMIAS. D.J. Sheridan and W. Culling. Departments of Cardiology, St. Mary's Hospital, Praed Street, London, and University Hospital of Wales, Cardiff U.K. While several studies have implicated alpha adrenoceptor activation in the arrhythmogenio effects of myocardial ischaemia and reperfusion, there is little direct evidence to support this. Accordingly, we studied the effect of alpha I adrenoeeptor stimulation with methoxamine on arrhythmias during isehaemia (fl6w reduced to 10% of control) and reperfusion in isolated guinea pig hearts. Catecholamine depletion significantly reduced ventrioular fibrillation during ischaemia, 0% Vs 37% and reperfusion, 14% Vs 79%. Ferfusion with methoxamine had no arrhythmogenic effect during normal perfusion, but reversed the antiarrhythmie effect of catecholamine depletion, during ischaemia (VF= 15%) and reperfusion (V= 54%) independent of beta-blockade, or H a receptor blockade9 This was associated with reduction in action potential duration and refractory period during ischaemia and reperfusion 9 These results indicate that direct alpha~} adrenoeeptor stimulation may induce ventrieular fibrillation during isehaemla and reperfusion, but not during normal perfusion.
S A N e.-ADRENERGIC RECEPTOR REGULATES HYPERTROPHY AND GENE EXPRESSION OF CULTURED HEART MUSCLE CELLS. P. Simpson, N. Bishopric, S. Coughlin, J. Karliner, C. Ordahl, N. Starksen, N. White, and L. Williams, VAMC and Univ. of Calif., San Francisco, USA. Serum-free cultures of neonatal rat heart muscle cells have been used to study catecholaminergic regulation of growth and gene expression. ~1-adrenergic activation increased myocyte size by 1.5-to 2-fold over i-2 days with an EC50 20-200 rum for NE or EPI. Hypertrophied cells were quiescent as a result of =. stimulation alone and developed rhythmic contractility with concomitant 81 activation. These trophic effects on growth a n d beating required continuous surface receptor occupancy. 61 receptor K and number per cell, and el-stimulated phosphoinosltide hydrolysis, were unchanged ~n hypertrophied cells, although receptor number per unit cell area was reduced, el-stimulated hypertrophy was accompanied by a several-fold increase in cell content of contractile proteins (myosin heavy chain and actin) and contractile mRNA (e-actln). The c-myc proto-oncogene was increased by e I stimulation, but there was no increase in cell number or DNA synthesis. These studies demonstrate that the e -adrenergic receptor regulates hypertrophy and gene expression of cultured neonatal r~t heart muscle cells and raise the novel possibility that the surface receptor may influence the cell nucleus to increase the rate of mRNA transcription. Supported by the VA Research Service; the NIH; the AHA, California Affiliate; the Howard Hughes Medical Institute; and the ACC/Merck Fellowship (N.B.)
9
ALPHA ADRENOCEPTOHS AND ARRHYTIIMIAS. D.J. Sheridan and W. Culling. Departments of Cardiology, St. Mary's Hospital, Praed Street, London, and University Hospital of Wales, Cardiff U.K. While several studies have implicated alpha adrenoceptor activation in the arrhythmogenio effects of myocardial ischaemia and reperfusion, there is little direct evidence to support this. Accordingly, we studied the effect of alpha I adrenoeeptor stimulation with methoxamine on arrhythmias during isehaemia (fl6w reduced to 10% of control) and reperfusion in isolated guinea pig hearts. Catecholamine depletion significantly reduced ventrioular fibrillation during ischaemia, 0% Vs 37% and reperfusion, 14% Vs 79%. Ferfusion with methoxamine had no arrhythmogenic effect during normal perfusion, but reversed the antiarrhythmie effect of catecholamine depletion, during ischaemia (VF= 15%) and reperfusion (V= 54%) independent of beta-blockade, or H a receptor blockade9 This was associated with reduction in action potential duration and refractory period during ischaemia and reperfusion 9 These results indicate that direct alpha~} adrenoeeptor stimulation may induce ventrieular fibrillation during isehaemla and reperfusion, but not during normal perfusion.