The primary goal of this study was to compare the effects of
isoproterenol which stimulates
beta-adrenergic receptors and
forskolin, and
NKH 477, a water soluble derivative of
forskolin, which stimulate
adenylyl cyclase in
stunned myocardium of conscious pigs, previously instrumented for measurements of left ventricular pressure and dP/dt, arterial pressure, and wall thickening. Ten min of coronary artery occlusion induced transmural reductions in blood flow (radioactive
microspheres) in subepicardium (-98 +/- 2%) and subendocardium (-99 +/- 1%). Wall thickening (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 time,
isoproterenol (0.2 microgram/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 micrograms/kg), which does not penetrate the blood-brain barrier, increased 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 diminished, P < 0.05, in the
stunned myocardium (+0.53 +/- 0.05 mm) compared with control (+0.95 +/- 0.07 mm).
beta-adrenergic receptor density, which was quantitated with 125I-cyanopindolol binding, was increased transmurally in
stunned myocardium compared with non-ischemic myocardium (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
adenylyl cyclase activity showed no differences. In summary, paradoxical responses to
beta-adrenergic receptor stimulation were observed in
stunned myocardium, with pharmacological stimulation with
isoproterenol evoking enhanced responses, and neural stimulation with inferior vena caval occlusion eliciting depressed responses. The diminished responses to
forskolin in vivo, in
stunned myocardium were out of proportion to the biochemical measurements, and may be attributed to neurally mediated cardiac effects of
forskolin, since the responses to direct stimulation of
adenylyl cyclase by
NKH 477 were preserved.