Beneficial effects of alpha 1-adrenoceptor activity on myocardial stunning in dogs.
This study was undertaken to elucidate whether alpha-1 adrenoceptor activity is beneficial to contractile dysfunction during reperfusion after a brief period of ischemia (stunned myocardium) in 54 open-chest dogs. Contractile dysfunction assessed by fractional shortening (FS) was observed 3 hours after the onset of reperfusion following 15 minutes of complete occlusion of the left anterior descending coronary artery. Pretreatment with prazosin (4 micrograms/kg/min i.c.) further deteriorated contractile dysfunction compared with the untreated condition (12.7 +/- 0.6% versus 6.9 +/- 0.4% with prazosin treatment, p less than 0.001). Conversely, alpha 1-adrenoceptor agonists, methoxamine (1.0 microgram/kg/min i.c.) and norepinephrine (0.24 microgram/kg/min i.c.) with rauwolscine and propranolol, significantly attenuated contractile dysfunction (FS in the methoxamine-treated group, 17.3 +/- 0.3%, p less than 0.001 versus the untreated group; FS in the norepinephrine-treated group, 18.0 +/- 0.9%, p less than 0.05 versus 13.6 +/- 1.1% in the propranolol group). Both adenosine release and hyperemic coronary flow response during the early reperfusion period were significantly attenuated in the prazosin-treated group, and both were enhanced in the alpha 1-adrenoceptor stimulation groups. These results suggest that beneficial effects of alpha 1-adrenoceptor activity may be due to the enhanced release of adenosine. To test the cause-effect relation between the extent of adenosine release and contractile dysfunction during reperfusion, 8-phenyltheophylline was infused to block adenosine receptors in the methoxamine-treated group. The treatment with 8-phenyltheophylline completely abolished (FS, 7.4 +/- 0.3%) the beneficial effect of the enhanced adenosine release by alpha 1-adrenoceptor stimulation. Furthermore, in the prazosin-treated group, adenosine (9 micrograms/kg/min) was additionally infused into the left anterior descending coronary artery 5 minutes before and 2 hours after the onset of reperfusion. Both hyperemic coronary flow and contractile dysfunction (FS, 17.3 +/- 0.3%) recovered to the levels of the alpha 1-adrenoceptor stimulation groups. However, treatment with papaverine could not prevent deleterious effects of prazosin despite the fact that comparable hyperemic flow was obtained. Instead, lactate production up to 10 minutes after the onset of reperfusion was significantly larger (p less than 0.01) despite augmented contractile function in the prazosin-treated and the 8-phenyltheophylline with methoxamine-treated groups compared with the untreated group. The electron microscopic examination revealed no irreversible myocardial injury with and without pharmacological interventions. Thus, we conclude that alpha 1-adrenoceptor activity can reduce the magnitude of myocardial stunning and that its cellular mechanism is due to enhanced adenosine release by alpha 1-adrenoceptor activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Kitakaze
M
M
First Department of Medicine, Osaka University School of Medicine, Japan.
Hori
M
M
Sato
H
H
Iwakura
K
K
Gotoh
K
K
Inoue
M
M
Kitabatake
A
A
Kamada
T
T
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation; D004285:Dogs; D006940:Hyperemia / Q000503:physiopathology; D008729:Methoxamine / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009638:Norepinephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology
D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D011433:Propranolol; D008729:Methoxamine; D000241:Adenosine; D009638:Norepinephrine; D011224:Prazosin