Regulation of cyclic GMP levels in the ductus deferens of the rat.

The cyclic GMP level in the ductus deferens is elevated by acetylcholine, norepinephrine, KCl, and the phosphodiesterase inhibitor SC-2964. The presence of extracellular Ca++ is required for the effects of all of these agents on cyclic GMP levels. In addition, Ca++ appears to be an important factor for the basal turnover of cyclic GMP in this tissue, but it may be less important in other tissues. These observations have led us to the following working hypothesis (Fig. 5): The interactions of some hormones or neurotransmitters with membrane receptors secondarily increase cyclic GMP formation after primarily increasing the influx of extracellular Ca++ or changing the distribution of Ca++ among intracellular pools or compartments. However, in addition to this possibility, other hormonal effects on particulate and/or soluble guanylate cyclase that do not involve Ca++ mediation must also be considered. Some agents that are known to increase cyclic GMP in tissues have been reported in preliminary communications to activate cell-free preparations of guanylate cyclase (Amer and McKINNEY, 1973; White, Ignarro, and George, 1973), but these reports have not yet been confirmed by other laboratories. Secretin has been reported to stimulate guanylate cyclase activity from several tissues (Thompson, Johnson, Lavis, and Williams, 1974), but the significance of this report is unclear since secretin has not yet been shown to increase cyclic GMP levels in any tissue. Thus, although not convincingly established, some hormones may increase particulate guanylate cyclase activity in a manner similar to that by which hormones increase adenylate cyclase activity. Alternatively, some hormones may increase soluble guanylate cyclase activity with mediating factors other than Ca++ being involved, or hormone-receptor interaction at the plasma membrane could conceivably induce a dislocation and change in effective activity of a reversibly bound, membrane-associated guanylate cyclase. Elucidating which or how many of these possibilities are operative will require thorough study and understanding of the fundamental behavior and properties of soluble and particulate guanylate cyclase activities.