Basal Muscarinic Activity Does Not Impede β-Adrenergic Activation in Rabbit Hearts in Controls or Thyroxine-Induced Cardiac Hypertrophy

We tested the hypothesis that basal myocardial muscarinic receptor activity acts as a "brake" on beta-adrenergic activation and that this effect would be greater in hearts subjected to thyroxine (T4)-induced (0.5 mg/kg for 16 days) hypertrophy due to an increase in muscarinic receptor density. Twenty control and 20 T4-treated open-chest anesthetized New Zealand white rabbits were given isoproterenol (0.5 microg/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 quickly excised and stored in liquid nitrogen. Cyclic guanosine monophosphate (GMP) and cyclic adenosine monophosphate (AMP) were determined by radioimmunoassay. T4 increased heart weight/body weight ratio, blood pressures, and the first derivative of the maximal rate of increase of LV systolic pressure (dP/dt[max]). Isoproterenol increased heart rate in both groups. Atropine had no effects on hemodynamic parameters either alone or after stimulation with isoproterenol. At this dose, atropine completely blocked the depressant effects of acetylcholine (10 microg/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 T4 animals. T4 increased subepicardial (EPI) and subendocardial (ENDO) coronary blood flow. Isoproterenol increased coronary flow (control: EPI, from 173 +/- 11 to 346 +/- 28 ml/min/100 g; ENDO, from 197 +/- 15 to 364 +/- 30 ml/min/100 g; T4: EPI, from 314 +/- 45 to 459 +/- 43 ml/min/100 g; ENDO, from 339 +/- 48 to 458 +/- 43 ml/min/100 g). Cyclic AMP levels were higher in T4 animals. Isoproterenol increased cyclic AMP (control: EPI, from 540 +/- 82 pmol/g to 1,096 +/- 110; ENDO, 596 +/- 58 to 1,050 +/- 145 pmol/g; T4: EPI, from 882 +/- 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 T4-induced hypertrophy or by any of the treatments in either group. Thus it appears that basal muscarinic activity does not significantly influence function or signal transduction either at baseline or during beta-adrenergic stimulation in controls or in T4-induced hypertrophy.