Beta-adrenergic receptor signalling in stunned myocardium of conscious pigs.
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.
Sato
S
S
Department of Medicine, Harvard Medical School, Brigham & Women's Hospital, Boston, MA 02115, USA.
Sato
N
N
Kudej
R K
RK
Uechi
M
M
Asai
K
K
Shen
Y T
YT
Ishikawa
Y
Y
Vatner
S F
SF
Vatner
D E
DE
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000818:Animals; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology; D003331:Coronary Vessels / Q000601:surgery; D004837:Epinephrine / Q000097:blood; D015151:Immunoblotting; D007545:Isoproterenol / Q000494:pharmacology; D017682:Myocardial Stunning / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015424:Reperfusion; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013552:Swine; D013564:Sympathetic Nervous System / Q000502:physiology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D000262:Adenylyl Cyclases; D000254:Sodium-Potassium-Exchanging ATPase; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine