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Vasodilation following the infusion of acetylcholine is due to the release of endothelium-derived relaxing factor (EDRF). However, the role of EDRF in neurogenic coronary vasodilation, when acetylcholine is released outside the vessel at the adventitial-medial junction, has not been established. The action of EDRF in parasympathetic coronary vasodilation was tested in the present study using a specific inhibitor of EDRF synthesis, nitro-L-arginine methyl ester (L-NAME). Experiments were conducted on closed-chest, alpha-chloralose-anesthetized dogs with the heart paced at a constant rate. Phentolamine and propranolol were administered to block alpha- and beta-adrenergic receptors, and ibuprofen was given to inhibit prostaglandin synthesis. Intracoronary infusion of L-NAME decreased the coronary vasodilation in response to intracoronary acetylcholine or vagal stimulation. The coronary response to the endothelium-independent vasodilator nitroglycerin was unaffected by L-NAME. These data demonstrate that L-NAME specifically inhibits coronary vasodilation caused by acetylcholine and vagal stimulation, indicating that parasympathetic coronary vasodilation is dependent on EDRF.

311C90 (zolmitriptan zomig: (S)-4[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone)is a novel 5-HT 1B/1D receptor agonist with proven e cacy in the acute treatment of migraine. Here, we describe the receptor speci®city of the drug and its actions on trigeminal-evoked plasma protein extravasation into the dura mater of the anaesthetized guinea-pig. 2 At the`5-HT 1B -like' receptor mediating vascular contraction (rabbit saphenous vein), the compound was a potent (p[A 50 ]=6.79+0.06) partial agonist achieving 77+4% of the maximum e ect to 5-hydroxytryptamine (5-HT). In the same experiments, sumatriptan (p[A 50 ]=6.48+0.04) was half as potent as 311C90 and produced 97+2% of the 5-HT maximum e ect. Studies in which receptor inactivation methods were used to estimate the a nity (pK A ) and e cacy relative to 5-HT (t rel. ) for each agonist con®rmed that 311C90 exhibits higher a nity than sumatriptan (pK A =6.63+0.04 and 6.16+0.03, respectively) and that both drugs are partial agonists relative to 5-HT (t rel =0.61+0.03 and 0.63+0.10, respectively, compared to 5-HT=1.0). 3 Consistent with its e ects in rabbit saphenous vein, 311C90 also produced concentration-dependent contractions of primate basilar artery and human epicardial coronary artery rings. In basilar artery, agonist potency (p[A 50 ]=6.92+0.07) was similar to that demonstrated in rabbit saphenous vein, again being 2 ± 3 fold higher than for sumatriptan (p[A 50 ]=6.46+0.03). Both agonists produced about 50% of the maximum response obtained with 5-HT in the same preparations. In rings of human coronary artery, the absolute potency of 311C90 and sumatriptan was higher than in primate basilar artery (p[A 50 ]=7.3+0.1 and 6.7+0.1, respectively), but maximum e ects relative to 5-HT were lower (37+8% and 35+7%, respectively). In both types of vessel, the inability of 5-HT 1B/1D agonists to achieve the same maximum as the endogenous agonist 5-HT is explained by the additional presence of 5-HT 2A receptors. 4 311C90 displayed high a nity at human recombinant 5-HT 1D (formerly 5-HT 1Da ) and 5-HT 1B (formerly 5-HT 1Db ) receptors in transfected CHO-K1 cell membranes (pIC 50 values=9.16+0.12 and 8.32+0.09, respectively). In intact cells, the drug produced concentration-dependent inhibition of forskolin-stimulated adenylyl cyclase (p[A 50 ]=9.9 and 9.5, respectively) achieving the same maximum e ect as 5-HT. Excepting human recombinant 5-HT 1A and 5-ht 1F receptors at which the drug behaved as an agonist with modest a nity (pIC 50 =6.45+0.11 and 7.22+0.12, respectively), 311C90 exhibited low, or no detectable a nity (pK i or pK B 4 5.5) at numerous other monoamine receptors, including other 5-HT receptor subtypes. 5 When administered to anaesthetized guinea-pigs ten minutes before unilateral electrical stimulation of the trigeminal ganglion (1.2 mA, 5 Hz, 5 ms, 5 min), 311C90 (3 ± 30 mg kg 71 , i.v.) caused a dosedependent inhibition of [ 125 I]-albumin extravasation within the ipsilateral dura mater. At the same doses, the drug also produced dose-depen...

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