THE NEGATIVE FUNCTIONAL AND METABOLIC EFFECTS OF MUSCARINIC STIMULATION ARE ENHANCED BY BETA-ADRENERGIC ACTIVATION IN CONTROL AND HYPERTROPHIC DOG HEARTS IN-VIVO

The aim of the current study was to determine if the effects of muscar inic stimulation on left ventricular function and metabolism are great er during beta-adrenergic activation, whether a cyclic GMP-mediated me chanism is responsible, and if this is altered by left ventricular hyp ertrophy (LVH) induced by aortic valve stenosis. Acetylcholine (Ach) ( 5 mu g/kg/min) and/or isoproterenol (Iso) (0.1 mu g/kg/min) was infuse d into a branch of the left anterior descending (LAD) artery in 8 cont rol and 8 LVH open-chest anesthetized dogs. LVH increased heart weight , heart-to-body weight ratio and systolic left ventricular pressure. L VH reduced muscarinic receptor density (fmol/mg protein) (control: 149 .2 +/- 18.6; WH: 77.8 +/- 8.6), but not affinity. Alone, Ach had no ef fect on regional force, work or metabolism. Iso increased peak force ( g) (control: baseline-7.4 +/- 0.4; Iso-12.4 +/- 2.2; LVH: baseline-6.7 +/- 0.8; Iso-16.3 +/- 2.7, regional work (g mm/min)) (control: baseli ne-1250 +/- 186; Iso-1813 +/- 409; LVH: baseline-927 +/- 235; Iso-1244 +/- 222), and O-2 consumption (ml O-2/min/100 g) (control: baseline-3 .3 +/- 0.2; Iso-8.1 +/- 2.0; LVH: baseline-4.8 +/- 1.0; Iso-8.3 +/- 1. 1). During Iso, Ach reduced segment shortening (control: Iso-14.5 +/- 1.2; Iso+Ach-10.5 +/- 1.8; LVH: Iso-10.4 +/- 1.5; Iso+Ach-7.6 +/- 1.3) and peak force (control: Iso+Ach-7.7 +/- 1.0; LVH: Iso+Ach-10.5 +/- 1 .4). Ach also reduced work (control: Iso+Ach-875 +/- 217; LVH: Iso+Ach -776 +/- 180) and O-2 consumption (control: Iso+Ach-3.4 +/- 0.7; LVH: Iso+Ach-3.6 +/- 0.6) in the presence of Iso. Cyclic GMP was higher in the LVH animals during all treatments and was elevated from baseline b y Ach in both groups. Neither Iso nor Iso+Ach had a significant effect on cyclic GMP. Thus, the negative functional and metabolic effects of muscarinic stimulation are enhanced during beta-adrenergic activation . This does not, however, appear to be dependent on a cyclic GMP-media ted mechanism. Despite reduced number of muscarinic receptors, this re sponse was not altered by pressure-induced cardiac hypertrophy.