ucn-1028-c and zaprinast

The role of 3',5'-cyclic guanosine monophosphate (cGMP) in the activation of mitogen-activated protein kinases (MAPKs) was investigated in rat pinealocytes. Treatment with dibutyryl cGMP (DBcGMP) dose-dependently increased the phosphorylation of both p44 and p42 isoforms of MAPK. This effect of DBcGMP was abolished by PD98059 (a MAPK kinase inhibitor), H7 (a nonspecific protein kinase inhibitor), and KT5823 [a selective cGMP-dependent protein kinase (PKG) inhibitor]. Elevation of cellular cGMP content by treatment with norepinephrine, zaprinast (a cGMP phosphodiesterase inhibitor), or nitroprusside was effective in activating MAPK. Natriuretic peptides that were effective in elevating cGMP levels in this tissue were also effective in activating MAPK. Our results indicate that, in this neuroendocrine tissue, the cGMP/PKG signaling pathway is an important mechanism used by hormones and neurotransmitters in activating MAPK.

Topics: Alkaloids; Animals; Atrial Natriuretic Factor; Calcium-Calmodulin-Dependent Protein Kinases; Carbazoles; Cells, Cultured; Cyclic GMP; Dibutyryl Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flavonoids; Indoles; Isoquinolines; Male; Naphthalenes; Natriuretic Peptide, C-Type; Neurosecretory Systems; Nitroprusside; Phosphodiesterase Inhibitors; Phosphorylation; Pineal Gland; Protein Kinase C; Purinones; Rats; Rats, Sprague-Dawley; Sulfhydryl Reagents; Sulfonamides; Thionucleotides

1. In rat aortic rings precontracted by phenylephrine, H7 (10(-5)M) and staurosporine (10(-7)M), which inhibit PKA, PKG and PKC, and H-89 (10(-6)M), which inhibits PKA and PKG, potentiated relaxations induced by nitroglycerin. Forskolin-induced relaxations were not affected by H7 (10(-5)M). 2. Nitroglycerin-induced relaxations were not affected by calphostin-C (10(-7)M), which inhibits PKC, H-89 (10(-7)M), which inhibits PKA, and staurosporine (2 x 10(-9)M), which inhibits PKC. 3. Iberiotoxin (3 x 10(-8)M), an inhibitor of large conductance Kca channels, partly inhibited the relaxation induced by nitroglycerin and completely inhibited the potentiating effect of H7 on nitroglycerin-induced relaxations. 4. The potentiating effect of zaprinast (10(-5)M), an inhibitor of cGMP-phosphodiesterase, on nitroglycerin-induced relaxation was not affected by iberiotoxin. In the presence of methylene blue (10(-5)M), an inhibitor of guanylate cyclase, the residual relaxing response to nitroglycerin was not affected by H7, but it was inhibited by iberiotoxin. 5. These results suggest that the potentiation of nitroglycerin-induced relaxation by H7, staurosporine and H-89 may be due to inhibition of PKG.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Aorta; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Drug Synergism; Enzyme Inhibitors; In Vitro Techniques; Isoquinolines; Male; Muscle, Smooth, Vascular; Naphthalenes; Nitroglycerin; Potassium Channels; Protein Kinase C; Purinones; Rats; Rats, Wistar; Staurosporine; Sulfonamides; Vasodilator Agents