CL-065

The pharmacological activity of CL-065 (trans-3-acetamido-2, 2-dimethyl-4-hydroxy-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 (KATP) 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 KATP-channel openers cromakalim (1.0 nM–1.0 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 KATP channels.