EFFECT OF VASCULAR SMOOTH-MUSCLE RELAXANTS ON THE PROTEIN-KINASE C-MEDIATED CONTRACTION IN THE RAT PULMONARY-ARTERY

In the rat pulmonary artery, phorbol 12,13-dibutyrate induces a contra ction due to the activation of the protein kinase C. We investigated t he sensitivity of this protein kinase C-mediated contraction to a vari ety of vascular smooth muscle relaxants. Pretreatment of rat pulmonary artery with relaxant compounds altered the subsequent concentration-r esponse curve to phorbol 12,13-dibutyrate (0.05-2 mu M) in a variable manner. Isoprenaline (0.1-10 mu M), nifedipine (0.01-1 mu M) and croma kalim (0.1-10 mu M) had no effect, whereas vasoactive intestinal pepti de (VIP, 1-10 nM), forskolin (0.1-2 mu M), theophylline (0.1-2.5 mM), 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO 20-1724, 2-20 mu M) , dipyridamole (10-100 mu M), 8 bromo-cyclic GMP (8-br-cGMP, 5-500 mu M) and dibutyryl cyclic AMP (db-cAMP, 100-500 mu M) shifted the concen tration-response curve to phorbol 12,13-dibutyrate to the right and de creased the maximal response. When cumulative concentrations of relaxa nts were applied on the plateau of the contraction induced by 0.2 or 2 mu M phorbol 12,13-dibutyrate, again, isoprenaline, nifedipine and cr omakalim failed to decrease the protein kinase C-mediated contraction, whereas the other agents produced concentration-dependent relaxation. From their inhibitory effect on the 0.2 mu M phorbol 12,13-dibutyrate -induced contraction, the rank order of potency of these relaxants was : VIP >> forskolin > RO 20-1724 > 8-br-cGMP > theophylline > dipyridam ole > db-cAMP. In chemically (beta escin) skinned preparations, cGMP ( 5-500 mu M) and cAMP (50-1000 mu M) antagonized in a concentration dep endent manner the contraction induced by phorbol 12,13-dibutyrate at c onstant Ca2+ concentration. These results show that protein kinase C-m ediated contraction in pulmonary vascular smooth muscle is not altered by ion channel modulators or by stimulation of the beta-adrenoceptor with isoprenaline. On the other hand, protein kinase C-mediated contra ction is reduced by other compounds which increase the intracellular c yclic nucleotide content. The interaction between protein kinase C and cyclic nucleotide-dependent protein kinases may be important in the p hysiological and pathophysiological control of tone in the pulmonary c irculation.