ANALYSIS OF THE VASORELAXANT ACTION OF JATROPHONE IN THE ISOLATED AORTA OF THE RAT - INFLUENCE OF POTASSIUM CHANNEL BLOCKERS

The mechanism underlying the relaxant response of rat aortic rings to the diterpene jatrophone was investigated. Jatrophone (3 and 10-mu-M) did not affect acetylcholine-induced endothelium-dependent relaxations, but caused concentration-dependent inhibition of noradrenaline (NA)-induced concentrations in unrubbed, and to a lesser extent, in denuded rings. Jatrophone (30-mu-M) fully prevented responses to angiotensin II and NA, while responses to KCl (up to 220 mM) were unaffected. In depolarizing medium (KCl 40 mM), jatrophone (3-30-mu-M) antagonized Ca2+-induced contractions in a concentration-dependent and noncompetitive manner, while verapamil (10-100 nM) caused a concentration-dependent, rightward displacement and depression of the Ca2+ concentration-response curve. Jatrophone (1 to 300-mu-M) concentration dependently relaxed rat aortic rings precontraction with either NA (1-mu-M) or KCl (80 mM), yielding EC50 s of 11 and 24-mu-M, respectively. These relaxant responses to jatrophone were unaffected by glibenclamide (1-mu-M), but the concentration-response curve was displaced to the right (2- to 8-fold) by other K+ channel blockers such as tetraethylammonium (10 and 30 mM), 4-aminopyridine (3 and 10 mM) or procaine (1 and 3 mM). These results indicate that jatrophone relaxes the rat aorta, at least in part, by activating K+ channels distinct from the ATP-sensitive subtype. Since jatrophone, like verapamil, relaxed preparations contracted with KCl and inhibited Ca2+-induced contractions in depolarized preparations, this diterpene may also block Ca2+ influx through voltage-sensitive channels. However, additional actions of jatrophone on receptor-operated Ca2+ channels causing Ca2+ efflux and/or release cannot be fully ruled out.