title: Clentiazem and diltiazem preserve endothelium-dependent relaxation following global rat heart ischemia.
abstract: 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.
authors.affiliation: Department of Surgery, Montreal Heart Institute, Quebec.
authors.forename: F
authors.initials: F
authors.lastname: Dagenais
authors.forename: C
authors.initials: C
authors.lastname: Hollmann
authors.forename: J
authors.initials: J
authors.lastname: Buluran
authors.forename: R
authors.initials: R
authors.lastname: Cartier
mesh_terms: 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
chemical_list: D002121:Calcium Channel Blockers; D009569:Nitric Oxide; C056595:clentiazem; D004110:Diltiazem