The effect of alpha 2-adrenoceptor antagonists in isolated globally ischemic rat hearts.
The alpha 2-adrenoceptor antagonist, yohimbine, has been reported to protect hypoxic myocardium. Yohimbine has several other activities, including 5-HT receptor antagonism, at the concentrations at which protection was found. Therefore we designed a study to determine if yohimbine was protecting ischemic myocardium via antagonism of alpha 2-adrenoceptors. In isolated globally ischemic rat hearts, the effects of two structurally distinct classes of alpha 2-adrenoceptor antagonists, the indole alkaloids (yohimbine and rauwolscine) and the imidazolines (idozoxan and tolazoline) were investigated. Pretreatment with yohimbine (1-10 microM) caused a concentration-dependent increase in reperfusion left ventricular developed pressure and a reduction in end diastolic pressure and lactate dehydrogenase release. The structurally similar compound rauwolscine (10 microM) also protected the ischemic myocardium. In contrast, idozoxan (0.3-10 microM) or tolazoline (10 microM) had no protective effects. The cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results indicate that the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor antagonistic activity.
Sargent
C A
CA
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Pharmacology, Princeton, NJ 08543.
Dzwonczyk
S
S
Grover
G J
GJ
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D004146:Dioxanes / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D019329:Idazoxan; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D014043:Tolazoline / Q000494:pharmacology; D017725:Ventricular Pressure / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology*
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D012702:Serotonin Antagonists; D015016:Yohimbine; D012701:Serotonin; D014043:Tolazoline; D007770:L-Lactate Dehydrogenase; D003000:Clonidine; D019329:Idazoxan