MDL 27,032 relaxes vascular smooth muscle and inhibits protein kinase C.
The smooth muscle relaxant effect of MDL 27,032, 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone, was studied in vitro using strips of femoral arteries and saphenous veins from dogs and trachea from guinea pigs. MDL 27,032 (10(-6)-10(-3) M) produced a concentration-dependent relaxation of arterial and venous strips contracted by carbachol. MDL 27,032 also antagonized contractions of arterial and venous strips produced by phorbol 12,13-dibutyrate (PDB), a protein kinase C activator, both in normal-Ca2+ and zero-Ca2+ medium. The compound inhibited protein kinase C in soluble extracts prepared from saphenous veins of dogs, with an IC50 value of 36.6 microM. MDL 27,032 was more effective against the contractions produced by phenylephrine and serotonin than by KCl in arteries, but no such selectivity was noted in veins. MDL 27,032 (10(-3) M) also inhibited accumulation of inositol phosphates in femoral artery but not in saphenous vein, and this effect may have contributed to the arterial-relaxant effect. Because the vascular smooth muscle relaxant effect of MDL 27,032 was endothelium independent, did not involve blockade of alpha-adrenoceptors or inhibition of cyclic nucleotide phosphodiesterases, stimulation of beta-adrenergic receptors, stimulation of adenosine A2-receptors, or activation of K+ channels, these data suggest that the relaxant effects of MDL 27,032 primarily involve inhibition of protein kinase C.
Cheng
H C
HC
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Robinson
P J
PJ
Dage
R C
RC
Jones
W D
WD
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010080:Oxazoles / Q000494:pharmacology*; D010081:Oxazolone / Q000031:analogs & derivatives*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D007295:Inositol Phosphates; D010080:Oxazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014665:Vasodilator Agents; C069455:4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone; D010081:Oxazolone; D015240:Phorbol 12,13-Dibutyrate; D011189:Potassium Chloride; D011493:Protein Kinase C; D015056:1-Methyl-3-isobutylxanthine