nitroarginine and rutecarpine

Rutaecarpine (Rut) has been shown to induce hypotension and vasorelaxation. In vitro studies indicated that the vasorelaxant effect of Rut was largely endothelium-dependent. We previously reported that Rut increased intracellular Ca2+ concentrations ([Ca2+]i) in cultured rat endothelial cells (ECs) and decreased [Ca2+]i in cultured rat vascular smooth muscle (VSMCs) cells. The present results showed that the hypotensive effect of Rut (10-100 microgram/kg i.v.) was significantly blocked by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine. In aortic rings, Rut (0. 1-3.0 microM)-induced vasorelaxation was inhibited by Nomega-nitro-L-arginine and hydroquinone but not by antagonists of the various K+ channels, 4-aminopyridine, apamin, charybdotoxin, or glibenclamide. Rut (0.1 and 1.0 microM) inhibited the norepinephrine-induced contraction generated by Ca2+ influx and at 1.0 microM increased cyclic GMP (cGMP) production in endothelium-intact rings and to a lesser extent in endothelium-denuded rings. In whole-cell patch-clamp recording, nonvoltage-dependent Ca2+ channels were recorded in ECs and Rut (0.1, 1.0 microM) elicited an opening of such channels. However, in VSMCs, Rut (10.0 microM) inhibited significantly the L-type voltage-dependent Ca2+ channels. In ECs cells, Rut (1.0, 10.0 microM) increased nitric oxide release in a Ca2+-dependent manner. Taken together, the results suggested that Rut lowered blood pressure by mainly activating the endothelial Ca2+-nitric oxide-cGMP pathway to reduce smooth muscle tone. Although the contribution seemed to be minor in nature, inhibition of contractile response in VSMCs, as evidenced by inhibition of Ca2+ currents, was also involved. Potassium channels, on the other hand, had no apparent roles.

Topics: 4-Aminopyridine; Alkaloids; Animals; Aorta, Thoracic; Calcium; Calcium Channels; Calcium Channels, L-Type; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Hydroquinones; In Vitro Techniques; Indole Alkaloids; Isometric Contraction; Male; Membrane Potentials; Models, Cardiovascular; Muscle, Smooth, Vascular; Nitroarginine; Norepinephrine; Patch-Clamp Techniques; Potassium Channel Blockers; Quinazolines; Rats; Rats, Sprague-Dawley; Vasodilation; Vasodilator Agents

The mechanisms underlying the rutaecarpine-induced vasodilatation were studied using isolated rat mesenteric arterial ring segments. The results showed that rutaecarpine (0.1 microM to 0.1 mM) produced a dose-dependent vasorelaxing response in our preparations, which were precontracted with phenylephrine. This vasodilator effect was significantly attenuated by removal of the endothelium, treatment with L-NG-nitro-arginine, a nitric oxide synthase inhibitor, and methylene blue, a guanylyl cyclase inhibitor, but not by treatment with atropine, triprolidine and yohimbine. Rutaecarpine pretreatment (1 microM to 0.1 mM) reduced both the phasic (fast) and tonic (slow) phases of phenylephrine-induced contractions, suggesting that a reduction in intracellular calcium might be involved. It is thus concluded that while the vasorelaxing effect of rutaecarpine appeared to be endothelium-dependent and to involve nitric oxide and guanylyl cyclase, neither muscarinic receptors, histamine H1 receptors nor alpha 2-adrenoceptors are involved. Moreover, a direct effect on the vascular smooth muscle cell, possibly through a reduction in intracellular Ca2+, can not be excluded.

Topics: Acetylcholine; Alkaloids; Animals; Arginine; Atropine; Calcium; Dose-Response Relationship, Drug; Endothelium, Vascular; In Vitro Techniques; Indole Alkaloids; Male; Mesenteric Arteries; Methylene Blue; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroarginine; Phenylephrine; Quinazolines; Rats; Rats, Sprague-Dawley; Triprolidine; Vasodilation; Yohimbine