Vol. 170, No. 2, 1990 BIOCHEMICALANDBIOPHYSICALRESEARCH COMMUNICATIONS July 31, 1990 Pages 843-850 NITRIC OXIDE AND CYCLIC GNP FORMATION UPON ELECTRICAL FIELD STIMULATION CAUSE RELAXATION OF CORPUS CAVERNOSUM SMOOTH MUSCLE Louis J. Ignarro, Peggy A. Bush, Georgette M. Buga, Keith S. Wood Jon M. Fukuto and Jacob Rajfer* Department of Pharmacology and Division of Urology, *Department of Surgery University of California, Los Angeles, California 90024 Received June 18, 1990 SUMMARY: In the presence of functional adrenergic and cholinergic blockade, electrical field stimulation relaxes corpus cavernosum smooth muscle by unknown mechanisms. We report here that electrical field stimulation of isolated strips of rabbit corpus cavernosum promotes the endogenous formation and release of nitric oxide (NO), nitrite, and cyclic GMP. Corporal smooth muscle relaxation in response to electrical field stimulation, in the presence of guanethidine and atropine, was abolished by tetrodotoxin and potassium-induced depolarization, and was markedly inhibited by NG-nitro-L-arginine, NG-amino-L-arginine, oxyhemoglobin, and methylene blue, but was unaffected by indomethacin. The inhibitory effects of NG-substituted analogs of L-arginine were nearly completely reversed by addition of excess L-arginine but not D-arginine. Corporal smooth muscle relaxation elicited by electrical field stimulation was accompanied by rapid and marked increases in tissue levels of nitrite and cyclic GMP, and all responses were nearly abolished by NG-nitro-L-arginine. These observations indicate that penile erection may be mediated by NO generated in response to nonadrenergic-noncholinergic neurotransmission. 01990 Academic Press, Inc. In the human and rabbit, the trabecular corpus cavernosum is innervated by at least three neuroeffector pathways that control smooth muscle tone: adrenergic, cholinergic, and nonadrenergic-noncholinergic or NANC (1,2). Adrenergic neurotransmission mediates contraction of corporal smooth muscle, which causes detumescence or diminished penile erection, whereas cholinergic neurotransmission promotes smooth muscle relaxation and penile erection. Adrenergic function is attenuated by activation of both prejunctional alpha,- adrenoceptors and prejunctional muscarinic receptors innervated by interneuronal cholinergic fibers (l-3). In the presence of both guanethidine (an adrenergic neuronal blocker) and atropine (a muscarinic receptor blocker), electrical field stimulation (EFS) results in excitation of only the NANC neurons and the response is rapid and marked corporal smooth muscle relaxation that is abolished by the sodium channel blocker tetrodotoxin (1,2). Many classes of pharmacological agents have been tested and found to be without effect on this relaxation response (3). Thus, neither the mechanism of corporal smooth muscle relaxation nor the 0006-291X/90 $1.50 843 Copyright 0 1990 by Academic Press. Inc. All rights of reproduction in any form reserved.