Clentiazem and diltiazem preserve endothelium-dependent relaxation following global rat heart ischemia.
OBJECTIVE
To evaluate the effects of the calcium channel blocker diltiazem and its chloride derivative clentiazem on coronary vasoregulation of isolated rat hearts exposed to ischemia-reperfusion. Diltiazem has been reported to prevent postreperfusion myocardial damage but its beneficial effects on coronary blood-flow regulation remain uncertain.


METHODS
Two groups of hearts were pretreated with a 10 min infusion of either diltiazem (10(-9) to 10(-6) mol/L) or clentiazem (10(-9) to 10(-7) mol/L) (n = 6 for each concentration) and exposed to 30 mins of no-flow ischemia. Another group (n = 6) received no pretreatment and was used as control. Endothelium-dependent and -independent relaxation were tested by assessing coronary flow increase to 5-hydroxytriptamine (10(-6) mol/L) and sodium nitroprusside (10(-5) mol/L) infusions, respectively, and were assessed before and after ischemia-reperfusion. Left ventricular pressure, dP/dt and coronary basal flow were also recorded. Postreperfusion results are expressed as a percentage of pre-ischemic value. Dunnet variance analysis was used to compare means of pretreated groups with the control group.


RESULTS
Endothelium-dependent relaxation was significantly improved with both drugs. Optimal preservation was obtained with diltiazem 10(-6) mol/L (66 +/- 4%) and clentiazem 10(-7) mol/L (83 +/- 4%), whereas endothelial response was almost abolished in control hearts (6 +/- 11%, P < 0.01). Clentiazem was found to be more potent than diltiazem at low concentration (10(-9) mol/L, clentiazem 89 +/- 13% versus diltiazem 3 +/- 16%, P < 0.05). Optimal endothelium-independent relaxation preservation was achieved at 10(-8) mol/L in both groups (diltiazem 86 +/- 4%, clentiazem 82 +/- 8%, control 47 +/- 10%, P < 0.05). Left ventricular pressure and dP/dt were not affected by any pretreatment. However, postreperfusion coronary basal flow was significantly increased in control hearts.


CONCLUSIONS
This study indicated that pre-ischemic infusion of diltiazem and clentiazem enhances endothelium-dependent and -independent coronary artery relaxation following reperfusion in the isolated rat heart model, without affective ventricular hemodynamics, and contributes to preservation of coronary artery autoregulation.
Dagenais
F
F
Department of Surgery, Montreal Heart Institute, Quebec.
Hollmann
C
C
Buluran
J
J
Cartier
R
R
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004110:Diltiazem / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004727:Endothelium / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015425:Myocardial Reperfusion; D009569:Nitric Oxide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D002121:Calcium Channel Blockers; D009569:Nitric Oxide; C056595:clentiazem; D004110:Diltiazem