Abstract

A high-affinity receptor site for ³H-P1075 previously observed in rat aorta has been proposed to mediate the vasorelaxation effects of P1075 and other ATP-sensitive K⁺ channel (K_ATP) openers. We tested this hypothesis by correlating the receptor binding of ³H-P1075 with its vasorelaxation effects in several isolated vascular preparations from three species: rat, rabbit and dog. In rat aorta and mesenteric artery,³H-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 (≤17%) to no specific binding of³H-P1075 (1–5 nM) was observed in dog coronary artery, dog mesenteric artery or rabbit mesenteric artery. However, all vascular preparations studied relaxed with P1075 (1–100 nM), showing maximal relaxations at 30 to 100 nM. The P1075 relaxation EC₅₀values in rat aorta, rabbit mesenteric artery and dog coronary artery ranged from 7.5 to 24.1 nM depending on the level of contractile activation. Thus, the pharmacological effect of P1075 could be correlated with the presence of specific receptor binding sites only in rat vascular preparations. These data show that there are significant differences in the characteristics of the proposed specific receptor site for ³H-P1075 in different vascular preparations from different species, and they raise questions regarding the pharmacological significance of this K_ATP opener binding site. Until such questions are resolved, it appears that the study of functional significance of this receptor site as well as further biochemical characterization of this receptor site may necessitate the use of only the rat vascular preparations.