TISSUE AND SPECIES VARIATION IN THE VASCULAR RECEPTOR-BINDING OF H-3 P1075, A POTENT K-ATP OPENER VASODILATOR

A high-affinity receptor site for H-3-P1075 previously observed in rat aorta has been proposed to mediate the vasorelaxation effects of P107 5 and other ATP-sensitive K+ channel (K-ATP) openers. We tested this h ypothesis by correlating the receptor binding of H-3-P1075 with its va sorelaxation effects in several isolated vascular preparations from th ree species: rat, rabbit and dog. In rat aorta and mesenteric artery, H-3-P1075 (1-5 nM) showed high amounts of specific binding (5-10 fmol/ mg tissue), which was 48 to 79% of total binding. In contrast, little (less than or equal to 17%) to no specific binding of H-3-P1075 (1-5 n M) was observed in dog coronary artery, dog mesenteric artery or rabbi t mesenteric artery. However, all vascular preparations studied relaxe d with P1075 (1-100 nM), showing maximal relaxations at 30 to 100 nM. The P1075 relaxation EC(50) values in rat aorta, rabbit mesenteric art ery and dog coronary artery ranged from 7.5 to 24.1 nM depending on th e level of contractile activation. Thus, the pharmacological effect of P1075 could be correlated with the presence of specific receptor bind ing sites only in rat vascular preparations. These data show that ther e are significant differences in the characteristics of the proposed s pecific receptor site for H-3-P1075 in different vascular preparations from different species, and they raise questions regarding the pharma cological significance of this K-ATP opener binding site. Until such q uestions are resolved, it appears that the study of functional signifi cance of this receptor site as well as further biochemical characteriz ation of this receptor site may necessitate the use of only the rat va scular preparations.