Effects of alpha 1-adrenoreceptor subtype blockade on ischemia-reperfusion injury.
To clarify the roles of subclasses of alpha 1-adrenoreceptors in ischemic-reperfused myocardium, we compared the effect of the nonselective alpha 1-blocker bunazosin with that of the alpha 1A-blocker WB4101 and the alpha 1B-blocker chlorethylclonidine (CEC) in isolated rat hearts. After 30 min of preperfusion, Langendorff-perfused hearts were subjected to 25 min of global ischemia followed by 30 min of reperfusion. Hearts were randomly divided into 4 groups, with one of the following substances being added to the perfusate: buffer alone (control), 10(-6) mol/L bunazosin, 10(-7) mol/L WB4101, or 10(-7) mol/L CEC. Bunazosin had a negative inotropic effect and preserved the postischemic ATP content, reduced the postischemic increase in intracellular Na+ content and then enhanced postreperfusion recovery of creatine phosphate. Bunazosin also reduced myocardial 45Ca2+ uptake during reperfusion (control 5.2 vs bunazosin 2.5 mumol/g dry weight of tissue (dwt), p < 0.01). However, the recovery of left ventricular developed pressure (DP) was not improved when bunazosin was added to the perfusate during reperfusion. WB4101 had neither a negative inotropic nor an energy-sparing effect, but it improved the recovery of DP (control 43% vs WB4101 56% of preischemic value, p < 0.05) with no reduction in myocardial 45Ca2+ uptake. CEC had a negative inotropic and energy-sparing effect and then reduced myocardial 45Ca2+ uptake (CEC 3.1 mumol/g dwt, p < 0.05), but it did not improve the recovery of DP. These results suggest that the preischemic administration of an alpha 1B-adrenoreceptor subtype blocker protected ischemic-reperfused myocardium via reduction of Ca2+ overload, whereas the selective blockade of the alpha 1A-adrenoreceptor subtype reduced myocardial damage via mechanism(s) other than Ca2+ metabolism.
Shinmura
K
K
Department of Geriatric Medicine, Keio University School of Medicine, Tokyo, Japan.
Tani
M
M
Suganuma
Y
Y
Hasegawa
H
H
Ebihara
Y
Y
Nakamura
Y
Y
Asakura
Y
Y
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D011799:Quinazolines; C051731:chlorethylclonidine; C018176:bunazosin; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D003000:Clonidine