Infarct size-limiting properties of Ro 40-5967, a novel nondihydropyridine calcium channel, in anesthetized rats: comparison with verapamil.
We assessed the hemodynamic and infarct size (IS)-limiting effects of the new calcium antagonist Ro 40-5967 in a rat model of ischemia/reperfusion and compared the effects of Ro 40-5967 with those of verapamil. Open-chest rats underwent 20-min coronary occlusion followed by 2-h reperfusion. We determined area at risk (AAR) and IS at the end of reperfusion by India ink injection and triphenyltetrazolium chloride (TTC) staining, using computerized analysis of enlarged sections after color video acquisition. Ro 40-5967 [0.3 mg/kg intravenous (i.v.) bolus 15 min before ischemia + 0.3 mg/kg/h i.v. infusion] and verapamil (0.3 mg/kg followed by 0.3 mg/kg/h) induced significant and similar limitations of IS (percentage of AAR: controls, 61.2 +/- 3.5%; Ro 40-5967, 41.0 +/- 4.0%; verapamil, 43 +/- 4.8%; both p < 0.01 versus controls). The IS-limiting effect of Ro 40-5967 was not accompanied by any changes in heart rate (HR) or rate-pressure product (RPP), whereas verapamil decreased both HR and RPP throughout ischemia/reperfusion. In contrast, verapamil administered at a lower dose (0.03 mg/kg followed by 0.03 mg/kg/h), which induced hemodynamic effects similar to those of Ro 40-5967, had no effect on IS (57.1 +/- 5.2, p = NS). Furthermore, additional hemodynamic studies performed in noninfarcted rats showed that Ro 40-5967 exerted negative inotropic effects that were less marked than those induced by verapamil. Therefore, Ro 40-5967 exerts myocardial protective effects that appear to be independent of changes in systemic hemodynamics or myocardial contractility.
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Department of Pharmacology, VACOMED, IFRMP, Rouen University Medical School, France.
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Blanc
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Thuillez
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D000758:Anesthesia; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D020748:Mibefradil; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D014700:Verapamil / Q000494:pharmacology*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D020748:Mibefradil; D014700:Verapamil