COMPARATIVE HYPOTENSIVE ACTIONS OF 3 NONPEPTIDE KAPPA-OPIOID AGONISTSON HIPPOCAMPUS OF SHRS AND NORMOTENSIVE WKY RATS

Comparative centrally mediated hypotensive effects of three nonpeptide kappa opioid agonist drugs (bremazocine, spiradoline, and U-50,488H) were evaluated in chloralose-anesthetized male spontaneously hypertens ive rats (SHRs) and in normotensive Wistar-Kyoto (WKY) and Sprague-Daw ley (SD) rats. The drugs were administered unilaterally into previousl y established active hypotensive sites in the dorsal hippocampus at do ses of 12, 24, and 48 nmol. Each drug produced dose-related decreases in mean arterial pressure, ranging from -5 to -40% of predrug control values, with bremazocine being somewhat more effective than spiradolin e, which was in turn slightly more active than U-50,488H. The effects were only marginally greater in SHRs than in normotensive controls. Ea ch drug caused a modest decrease in heart rate, but except for the hig hest dose of bremazocine, the effects were not statistically significa nt. The onset of hypotension after intrahippocampal injection of each agent was similar to 2 min and lasted similar to 30 min with U-50,488H and spiradoline and >60 min with bremazocine. The responses to all th ree drugs were completely blocked by prior injection of the active hip pocampal sites with nor-binaltorphimine (nor-BNI), a selective kappa-r eceptor antagonist. Because bremazocine is more selective for kappa-2 opioid receptors, whereas U-50,488H and spiradoline favor the kappa-l subtype, the results suggest that drugs active on each of these subtyp es should be investigated as potential antihypertensives.