The cellular basis for the blunted response to beta-adrenergic stimulation in supraventricular tachycardia-induced cardiomyopathy.
Chronic tachycardia-induced dilated cardiomyopathy causes increased plasma catecholamines and alterations in beta-adrenergic responsiveness in vivo. However, whether isolated myocyte contractile response to beta-stimulation is directly affected by the development of cardiomyopathy and how these changes are related to alterations in the beta-adrenergic receptor system remain unclear. Accordingly, isolated myocyte function and beta-adrenergic responsiveness were examined in two groups of 12 pigs each: sham controls, and with supraventricular tachycardia induced cardiomyopathy (SVT; pace: 240 beats/min, 3 weeks). Isolated LV myocyte percent and velocity of shortening were examined at baseline, with isoproterenol (2-100 nM), and forskolin (0.1-4 microM). Baseline percent and velocity of shortening were significantly reduced with SVT compared to controls (1.6 +/- 0.1 vs 5.4 +/- 0.2%, 56 +/- 3 vs 25 +/- 1 micron/s, respectively, P < 0.05). The maximal increase in the percent and velocity of shortening with isoproterenol was significantly blunted in the SVT myocytes compared with controls (3.2 +/- 0.4 vs 9.7 +/- 1.0%, 48.0 +/- 5.3 vs 122.6 +/- 15.5 micron/s, respectively, P < 0.05). Similarly, maximal increase in the percent and velocity of shortening with forskolin were reduced with SVT compared to controls (3.3 +/- 0.4 vs 10.5 +/- 0.6%, 50.7 +/- 6.4 vs 120.1 +/- 9.7 micron/s, respectively, P < 0.05). In order to determine the cellular basis for these changes in beta-adrenergic response, myocyte structure, sarcolemmal beta-receptor density and affinity, and adenylate cyclase activity were examined. There was a 25% reduction in beta-receptor number with SVT (P < 0.05) but no change in affinity. Basal adenylate cyclase activity was lower with SVT compared to control (46 +/- 3 vs 77 +/- 10 pmol cyclic AMP/mg/min, P < 0.05), and exhibited a blunted response with both isoproterenol (1 mM; 106 +/- 19 vs 203 +/- 26 pmol cyclic AMP/mg/min, P < 0.05) and forskolin (100 microns: 209 +/- 35 vs 378 +/- 58 pmol cyclic AMP/mg/min, P < 0.05). Finally, myofibrillar content within SVT myocytes was significantly reduced from controls (43 +/- 7 vs 63 +/- 4%, P < 0.05). In summary, the cellular basis for the depressed myocyte contractile response to beta-stimulation with tachycardia induced SVT are probably due to several factors which include: decreased expression of beta-receptors, alterations in beta-receptor transduction, reduced adenylate cyclase activity, and decreased myocyte contractile protein content.
Tanaka
R
R
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425.
Fulbright
B M
BM
Mukherjee
R
R
Burchell
S A
SA
Crawford
F A
FA
Zile
M R
MR
Spinale
F G
FG
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000378:metabolism*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011897:Random Allocation; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012508:Sarcolemma / Q000378:metabolism; D013552:Swine; D013617:Tachycardia, Supraventricular / Q000150:complications / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000502:physiology
D011943:Receptors, Adrenergic, beta; D000262:Adenylyl Cyclases; D009638:Norepinephrine