The Lack of Involvement of Cyclic Nucleotides in the Smooth Muscle Relaxant Action of BRL 34915

1. The relaxant effect of BRL 34915 has been examined on four isolated preparations, the bovine retractor penis (BRP), guinea-pig taenia coli, guinea-pig trachea and rabbit aortic strip contracted by either histamine, carbachol, noradrenaline or 10 mM KCl. Even though the probability of the involvement of external calcium entering through voltage-operated channels in these tissues varied, there was little corresponding variation in sensitivity to BRL 34915. 2. The relaxant effect of BRL 34915 on the BRP and guinea-pig taenia coli was unaffected by haemoglobin 3.3 microM or Apamin 0.5 microM, concentrations which blocked completely the relaxant effect of non-adrenergic, non-cholinergic (NANC) nerve stimulation in these tissues. 3. BRL 34915 in doses causing maximum relaxation did not increase the levels of either cyclic AMP or cyclic GMP in the BRP, although the appropriate enzymes were present and could be stimulated by forskolin or sodium nitroprusside. 4. In the BRP isoprenaline 30 microM acting through beta-receptors caused maximum relaxation but did not raise the levels of cyclic AMP, even though lower doses of 2 microM did raise the levels of this nucleotide in the rabbit uterus. 5. These results provide some indirect evidence that membrane hyperpolarization may not be the only cause of the smooth muscle relaxation induced by BRL 34915. However, neither a rise in cyclic AMP nor cyclic GMP are satisfactory alternative mechanisms.