BETA-ADRENERGIC-RECEPTOR SIGNALING IN STUNNED MYOCARDIUM OF CONSCIOUSPIGS

The primary goal of this study was to compare the effects of isoproter enol which stimulates beta-adrenergic receptors and forskolin, and NKH 477, a water soluble derivative of forskolin, which stimulate adenyly l cyclase in stunned myocardium of conscious pigs, previously instrume nted for measurements of left ventricular pressure and dP/dt, arterial pressure, and wall thickening, Ten min of coronary artery occlusion i nduced transmural reductions in blood now (radioactive microspheres) i n subepicardium (-98 +/- 2%) and subendocardium (-99 +/- 1%). Wall thi ckening (piezoelectric crystals) fell from 2.50 +/- 0.26 mm to -0.26 /- 0.26 mm and remained depressed at 1.37 +/- 0.19 mm after 20-30 min coronary artery reperfusion, reflecting myocardial stunning. At that t ime, isoproterenol (0.2 mu g/kg) increased wall thickening in stunned myocardium (+1.40 +/- 0.16 mm, P < 0.05) more than in control (+ 0.71 +/- 0.22 mm), while forskolin elicited the opposite effects. NKH 477 ( 30 mu g/kg), which does not penetrate the blood-brain barrier, increas ed systolic wall thickening similarly before (+ 0.95 +/- 0.25 mm) and during (+ 1.01 +/- 0.24 mm) myocardial stunning, The reflex inotropic responses to inferior vena caval occlusion on wall thickening were dim inished, P < 0.05, in the stunned myocardium (+ 0.53 +/- 0.05 mm) comp ared with control (+ 0.95 +/- 0.07 mm). beta-adrenergic receptor densi ty, which was quantitated with I-125-cyanopindolol binding, was increa sed transmurally in stunned myocardium compared with non-ischemic myoc ardium (subepicardium: + 23 +/- 5%, subendocardium: + 34 +/- 13%, P < 0.05). Basal and forskolin-stimulated adenylyl cyclase activities were decreased slightly, but significantly, in the stunned subendocardium but not in the subepicardium, while isoproterenol stimulation of adeny lyl cyclase activity showed no differences. In summary, paradoxical re sponses to beta-adrenergic receptor stimulation were observed in stunn ed myocardium, with pharmacological stimulation with isoproterenol evo king enhanced responses, and neural stimulation with inferior vena cav al occlusion eliciting depressed responses, The diminished responses t o forskolin in vivo, in stunned myocardium were out of proportion to t he biochemical measurements, and may be attributed to neurally mediate d cardiac effects of forskolin, since the responses to direct stimulat ion of adenylyl cyclase by NKH 477 were preserved. (C) 1997 Academic P ress Limited.