EFFECTS OF THE CA2+ ANTAGONIST RO-40-5967 ON ENDOTHELIUM-DEPENDENT RESPONSES OF ISOLATED ARTERIES

Experiments were designed to determine whether the Ca channel inhibitor RO 40-5967 [(1S,2S)2-[2-[[3-(2-benzimidazolyl)propyl]methylamine]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride] causes endothelium-dependent relaxations or inhibits endothelium-dependent contractions of isolated blood vessels. Rings of dog femoral, carotid, and basilar arteries and of rat aorta, with and without endothelium, were suspended in conventional organ chambers for measurement of isometric force. During contractions evoked by phenylephrine (full alpha(1)-adrenergic agonist), St 587 (partial alpha(1)-adrenergic agonist) and endothelin-1 (ET), RO 40-5967 caused concentration-dependent relaxations of rings of dog femoral arteries; the relaxations to RO 40-5967 were greater in rings with endothelium than in those without endothelium. Nitro-L-arginine (NLA) and methylene blue (MB) inhibited the endothelium-dependent component of the response to RO 40-5967 during contractions to phenylephrine (PE) St 587 and ET. The endothelium-dependent relaxations evoked by RO 40-5967 during contractions to PE were not affected by diltiazem in the femoral artery, suggesting that this effect of the compound may not be related to its calcium channel inhibitor properties. Under bioassay conditions, RO 40-5967 stimulated release of relaxing factors from the endothelium of canine carotid arteries; the response of the detector tissues was inhibited by MB. In strips of canine femoral artery with endothelium, in which membrane potential of vascular smooth muscle cells (VSMC) was recorded with glass microelectrodes, RO 40-5967 did not cause endothelium-dependent hyperpolarizations. RO 40-5967 caused concentration-dependent inhibition of endothelium-dependent contractions of canine basilar arteries to acetylcholine (ACh), arachidonic acid (AA), and the Ca2+ ionophore A23187. Likewise, RO 40-5967 decreased the contractions evoked by ACh in rings with endothelium of the aorta of spontaneously hypertensive rats. These experiments suggest that in isolated arteries RO 40-5967 causes release of endothelium-derived relaxing factor (EDRF; nitric oxide, NO) and inhibits endothelium-dependent contractions. These effects of the compound may help explain its vasodilator properties in vivo.