BASAL MUSCARINIC ACTIVITY DOES NOT IMPEDE BETA-ADRENERGIC ACTIVATION IN RABBIT HEARTS IN CONTROLS OR THYROXINE-INDUCED CARDIAC-HYPERTROPHY

We tested the hypothesis that basal myocardial muscarinic receptor act ivity acts as a ''brake'' on beta-adrenergic activation and that this effect would be greater in hearts subjected to thyroxine (T-4)-induced (0.5 mg/kg for 16 days) hypertrophy due to an increase in muscarinic receptor density. Twenty control and 20 T-4-treated open-chest anesthe tized New Zealand white rabbits were given isoproterenol (0.5 mu g/kg/ min, 10 min i.v.) and/or atropine (3 mg/kg bolus). Coronary blood flow (radioactive microspheres), aortic and left ventricular (LV) pressure , and wall thickening of the LV free wall were recorded. Hearts were q uickly excised and stored in liquid nitrogen. Cyclic guanosine monopho sphate (GMP) and cyclic adenosine monophosphate (AMP) were determined by radioimmunoassay. T-4 increased heart weight/body weight ratio, blo od pressures, and the first derivative of the maximal rate of increase of LV systolic pressure (dP/dt(max)). Isoproterenol increased heart r ate in both groups. Atropine had no effects on hemodynamic parameters either alone or after stimulation with isoproterenol. At this dose, at ropine completely blocked the depressant effects of acetylcholine (10 mu g/kg). Isoproterenol increased the maximal time derivative of wall thickening (dWT/dt(max)) in control (from 11.0 +/- 1.0 to 16.4 +/- 1.5 mm/s) but not in T-4 animals. T-4 increased subepicardial (EPI) and s ubendocardial (ENDO) coronary blood flow. Isoproterenol increased coro nary flow (control: EPI, from 173 +/- 11 to 346 +/- 28 ml/min/100 g; E NDO, from 197 +/- 15 to 364 +/- 30 ml/min/100 g; T-4: EPI, from 314 +/ - 45 to 459 +/- 43 ml/min/100 g; ENDO, from 339 +/- 48 to 458 +/- 43 m l/min/100 g). Cyclic AMP levels were higher in T-4 animals. Isoprotere nol increased cyclic AMP (control: EPI, from 540 +/- 82 pmol/g to 1,09 6 +/- 110; ENDO, 596 +/- 58 to 1,050 +/- 145 pmol/g; T-4: EPI, from 88 2 +/- 107 pmol/g to 1,319 +/- 222; ENDO, from 954 +/- 134 to 1,409 +/- 261 pmol/g). Atropine, alone or after stimulation with isoproterenol, had no effect on coronary flow or cyclic AMP in either group. Cyclic GMP levels were unaffected by T-4-induced hypertrophy or by any of the treatments in either group. Thus it appears that basal muscarinic act ivity does not significantly influence function or signal transduction either at baseline or during beta-adrenergic stimulation in controls or in T-4-induced hypertrophy.