Experimental evidence that rejection, but not transplantation, modulates coronary reactivity to direct and indirect vasodilation.
OBJECTIVE
To investigate the coronary response to direct and indirect vasodilation in a canine model of orthotopic heart transplantation because of the potential benefits of preserved vascular function during rejection. In cardiac transplants, reversal of vascular abnormalities is considered to be of prime importance for recovery from graft failure and rejection.


METHODS
Cardiac function and coronary bloodflow were monitored with electromagnetic flow probes. Hemodynamic data were collected either postoperatively, at the height of the recovery period, or during the severe rejection phase. Nitroglycerin (n = 7) as a 5 micrograms/kg intravenous bolus and diltiazem (n = 5) as a 150 micrograms/kg intravenous bolus were administered as direct stimulants of the coronary vasculature. Ouabain (n = 7), a digitalis derivative, at 20 micrograms/kg/min and calcium gluconate (n = 9) at 0.05 mEq/kg were given as indirect coronary vasodilators. Amrinone (n = 6), having both vasodilator and inotropic properties, was also studied (0.75 mg/kg intravenous bolus followed by a 200 micrograms/kg infusion).


RESULTS
Under control conditions, all drugs significantly increased coronary bloodflow: nitroglycerin +47%, diltiazem +33%, ouabain +25%, calcium gluconate +36% and amrinone +65%. Coronary vascular resistance was reduced by a similar magnitude in all cases. In the rejection phase, ouabain and calcium gluconate, despite increasing stroke work, failed to induce significant changes in coronary bloodflow. Among the direct vasodilators used, only nitroglycerin augmented coronary perfusion (+38%) during rejection; the magnitude of its action on coronary vascular resistance was similar to that observed under control conditions.


CONCLUSIONS
These results suggest that transplantation per se does not interfere with the response to either direct or indirect coronary dilation. Severe rejection blunted indirect coronary dilation. In these conditions, inotropic challenges appear to be detrimental. The observation that the coronary vasculature remained sensitive to nitroglycerin despite severe rejection suggested that a drug-specific coronary vasodilator reserve is still present. This study provides valuable arguments for the use of vasodilator therapy during graft rejection since rejection and ischemia are intimately related.
Dumont
L
L
Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Québec.
D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D004110:Diltiazem / Q000494:pharmacology; D004285:Dogs; D006084:Graft Rejection / Q000503:physiopathology*; D016027:Heart Transplantation; D005996:Nitroglycerin / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D010042:Ouabain; D004110:Diltiazem; D005996:Nitroglycerin; D000676:Amrinone; D002118:Calcium