Comparative hypotensive actions of three nonpeptide kappa opioid agonists on 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 hypertensive rats (SHRs) and in normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats. The drugs were administered unilaterally into previously established active hypotensive sites in the dorsal hippocampus at doses 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 spiradoline, which was in turn slightly more active than U-50,488H. The effects were only marginally greater in SHRs than in normotensive controls. Each drug caused a modest decrease in heart rate, but except for the highest dose of bremazocine, the effects were not statistically significant. The onset of hypotension after intrahippocampal injection of each agent was approximately 2 min and lasted approximately 30 min with U-50,488H and spiradoline and >60 min with bremazocine. The responses to all three drugs were completely blocked by prior injection of the active hippocampal sites with nor-binaltorphimine (nor-BNI), a selective kappa-receptor antagonist. Because bremazocine is more selective for kappa-2 opioid receptors, whereas U-50,488H and spiradoline favor the kappa-1 subtype, the results suggest that drugs active on each of these subtypes should be investigated as potential antihypertensives.