Endothelin receptor sub type distribution predisposes coronary arteries todamage

Several vasoactive drugs that lower blood pressure and increase heart rate induce regional cardiotoxicity in the dog, most frequently of right coronar y arteries and right atrium, The basis for this selective damage is thought to result from local changes in vascular tone and blood flow.. Administrat ion of an endothelin receptor antagonist (ETRA, SE 209670) to dogs induced damage most frequent and severe in the right coronary artery and right atri um. Because site predisposition may correlate with distribution of vasoacti ve receptors, the objectives of this study were to map endothelin (ET) rece ptor distribution and density within regions of dog heart using both gene ( mRNA) and protein expression endpoints for dog ETA and ETB receptors, and, additionally, correlate ET receptor subtype density with regional cardiac b lood flow. A 10- to 15-mmHg reduction in mean arterial pressure with a conc omitant increase in heart rate (10-20%), a six- and twofold increase in reg ional blood flow to the right and left atrium, respectively, and acute hemo rrhage, medial necrosis, and inflammation were observed in the right corona ry arteries and arteries of the right atrium after ETRA infusion for 5 days . Radioligand protein binding to quantify both ET receptors in normal dog h eart indicated a twofold greater density of ET receptors in atrial regions versus ventricular regions. Importantly, ET receptor density in coronary ar teries was markedly (about five- to sixfold) increased above that in atrial or ventricular tissues. ET receptor subtype characterization indicated ETB receptors were three times more prevalent in right coronary arteries compa red to left coronary arteries and in situ hybridization confirmed localizat ion of ETB in vascular smooth musle. ETA receptor density was comparable in rigid and left coronary arteries. Quantitative real-time polymerase chain reaction for ETA and ETB receptor mRNA transcripts supported the site preva lence for message distribution. Consequently, the composite of protein and message expression profiles for ETA and ETB receptors indicated a dispropor tionate distribution of ET, receptors within right coronary artery of dog a nd this, along with functional measures of blood flow after ETRA infusion i ndicated a predisposition for exaggerated pharmacological responses and sub sequent damage to right coronary arteries by ET and/or ETRAs.