1. Activation of particulate guanylyl cyclase by endothelins in cultured SV-40 transformed cat iris sphincter smooth muscle cells.
- Author
-
Ding KH, Latimer AJ, and Abdel-Latif AA
- Subjects
- Animals, Calcium metabolism, Carbachol antagonists & inhibitors, Carbachol pharmacology, Cats, Cell Line, Transformed, Dose-Response Relationship, Drug, Down-Regulation drug effects, Endothelin Receptor Antagonists, Endothelin-3 antagonists & inhibitors, Enzyme Activation, Guanylate Cyclase antagonists & inhibitors, Iris cytology, Iris enzymology, Muscle, Smooth cytology, Muscle, Smooth enzymology, Nitric Oxide physiology, Phorbol 12,13-Dibutyrate pharmacology, Protein Kinase C antagonists & inhibitors, Protein Kinase C physiology, Receptors, Endothelin agonists, Receptors, Endothelin physiology, Simian virus 40, Vasodilator Agents pharmacology, Cyclic GMP metabolism, Endothelin-1 pharmacology, Endothelin-3 pharmacology, Guanylate Cyclase metabolism, Iris drug effects, Muscle, Smooth drug effects
- Abstract
We investigated the effects of endothelins (ETs) on cGMP production in cultured SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells. ET-3 increased cGMP formation in a concentration-dependent manner (EC50 = 98nM), which was 2.5 times higher than that of ET-1. The ET(B)receptor agonists sarafotoxin-S6c and IRL 1620 also increased cGMP production, mimicking the effects of the ETs. The ET(B) receptor antagonist BQ 788, but not the ET(A) receptor antagonist BQ610, dose-dependently blocked ET-3-stimulated cGMP formation (IC50=10nM). The phorbol ester, Phorbol 12, 13-dibutyrate (PDBu), which inhibits particulate guanylyl cyclase in smooth muscle, dose-dependently inhibited ET-3-stimulated cGMP accumulation (IC50=66nM). LY83583 and ODQ, inhibitors of soluble guanylyl cyclases, as well as inhibitors of the nitric oxide cascade and of intracellular Ca2+ elevation had no appreciable effect on ET-3-induced cGMP production. ET-3 markedly inhibited carbachol-induced intracellular Ca2+ mobilization. We conclude that ET-3 increases intracellular cGMP levels in SV-CISM-2 cells through activation of the ET(B) receptor subtype and subsequent stimulation of the membrane-bound guanylyl cyclase. Elevation of cGMP by ET and the subsequent inhibition of muscarinic stimulation of intracellular Ca2+ mobilization by the cyclic nucleotide could serve to modulate the contractile effects of Ca2+-mobilizing agonists in the iris sphincter smooth muscle.
- Published
- 1999
- Full Text
- View/download PDF