ATP-sensitive potassium-channel-opening activity of CL-065, a 3-[(substituted-carbonyl)amino]-2H-1-benzopyran, in the rat

The pharmacological activity of CL-065 (trans-3-acetamido-2,2-dimethyl-4-hydrox-3,4-dihydro-2H-1-benzopyran- 6-carbonitrite) was investigated in anaesthetized spontaneously hypertensive rats (SHR) and isolated thoracic aorta of Sprague-Dawley rats. The intravenous administration of CL-065 (0.1-2.0 mg kg^-1) to anaesthetized SHR induced a dose-dependent reduction of mean arterial pressure (MAP) with maximum effect approximately 5 min after injection and which persisted for over 3 h. CL-065 also induced a reflex tachycardia which seemed to parallel the time course of the hypotensive effect. The hypotensive effect of CL-065 was blocked by pretreatment with glibenclamide (5 mg kg^-1, i.v.), a specific ATP-sensitive potassium (K(ATP)) channel blocker. Moreover, CL-065 (0.01-10 μM) resulted in dose-dependent vasodilatory effects on phenylephrine (0.3 μM)-induced vasoconstriction in isolated thoracic aorta. The vasorelaxation elicited by CL-065 was antagonized competitively by pretreatment with glibenclamide (0.1-1.0 μM; pA₂ = 6.90 ± 0.09; slope = 1.03 ± 0.18). Similarly, the other two K(ATP)-channel openers cromakalim (1.0 nM-1.O μM) and nicorandil (0.1-30 μM) also induced vasorelaxation in thoracic aorta. The EC50 of cromakalim, CL-065 and nicorandil (i.e. the doses having half the maximum effect) were approximately 0.083, 0.17, and 4.5 μM, respectively, for phenylephrine (0.3 μM)-induced vasoconstriction in isolated thoracic aorta. Moreover, increased extracellular potassium levels (20-60 mM) resulted in concentration-dependent attenuation of the vasodilator effect of CL-065. In conclusion, CL-065 induces a depressor effect via activation of K(ATP) channels.