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1. The putative role of vasoactive intestinal polypeptide (VIP) as the relaxant neurotransmitter in human cavernosal smooth muscle has been studied in isolated tissue preparations. 2. Consistent neurogenic relaxations were evoked by electrical field stimulation (EFS; 2-64 pulses/train, 0.8 ms pulse duration, 10 Hz). VIP (0.1-3 microM) relaxed cavernosal smooth muscle in a dose-dependent fashion. Relaxant responses to both EFS and VIP were reduced in tissue from impotent men. 3. Neurogenic relaxant responses were not diminished in the presence of the VIP-inactivating peptidase, alpha-chymotrypsin (alpha-CT, 2 units ml-1). In contrast VIP-induced relaxations were completely abolished. 4. Inhibition of nitric oxide synthase by NG-nitro-L-arginine (30 microM), and of guanylate cyclase by methylene blue (50 microM) caused highly significant reductions of neurogenic relaxant responses whereas VIP-evoked relaxations were unaffected. 5. It is concluded that VIP-evoked relaxations are not mediated by the NO-guanosine 3':5'-cyclic monophosphate (cyclic GMP) pathway and that VIP release is not essential for neurogenic relaxation of human cavernosal smooth muscle. VIP does not therefore act as the major relaxant neurotransmitter in this tissue.

1. The inhibitory transmission in isolated preparations of cavernosal smooth muscle from human penis has been studied. 2. Electrical field stimulation (EFS; 2-64 pulses/train, 0.8 ms pulse duration, 10 Hz) evoked relaxation of preparations treated with guanethidine (50 microM). The EFS-evoked relaxations were atropine-resistant and tetrodotoxin-sensitive indicating their origin to be non-adrenergic, non-cholinergic (NANC) nerve stimulation. 3. EFS-evoked relaxation was attenuated dose-dependently by the nitric oxide (NO)-synthase inhibitor, L-NG-nitro arginine (L-NOARG; 0.3-100 microM) but not by D-NG-nitro arginine. The inhibitory effect of L-NOARG on transmission was antagonized by L-arginine (100 microM), a NO precursor, but not by D-arginine. 4. Incubation with methylene blue (10-50 microM), a known inhibitor of guanylate cyclase activation by NO, caused a concentration-related inhibition of EFS-evoked relaxation. 5. It is concluded that NANC nerve-evoked relaxation of human cavernosal smooth muscle is mediated by NO or a NO-like substance.