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 contraction due to the activation of the protein kinase C. We investigated the sensitivity of this protein kinase C-mediated contraction to a variety of vascular smooth muscle relaxants. Pretreatment of rat pulmonary artery with relaxant compounds altered the subsequent concentration-response curve to phorbol 12,13-dibutyrate (0.05-2 microM) in a variable manner. Isoprenaline (0.1-10 microM), nifedipine (0.01-1 microM) and cromakalim (0.1-10 microM) had no effect, whereas vasoactive intestinal peptide (VIP, 1-10 nM), forskolin (0.1-2 microM), theophylline (0.1-2.5 mM), 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO 20-1724, 2-20 microM), dipyridamole (10-100 microM), 8 bromo-cyclic GMP (8-br-cGMP, 5-500 microM) and dibutyryl cyclic AMP (db-cAMP, 100-500 microM) shifted the concentration-response curve to phorbol 12,13-dibutyrate to the right and decreased the maximal response. When cumulative concentrations of relaxants were applied on the plateau of the contraction induced by 0.2 or 2 microM phorbol 12,13-dibutyrate, again, isoprenaline, nifedipine and cromakalim 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 microM phorbol 12,13-dibutyrate-induced contraction, the rank order of potency of these relaxants was: VIP >> forskolin > RO 20-1724 > 8-br-cGMP > theophylline > dipyridamole > db-cAMP. In chemically (beta escin) skinned preparations, cGMP (5-500 microM) and cAMP (50-1000 microM) antagonized in a concentration dependent manner the contraction induced by phorbol 12,13-dibutyrate at constant Ca2+ concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Savineau
J P
JP
Laboratoire de Physiologie, Université de Bordeaux II, France.
Gonzalez De La Fuente
P
P
Marthan
R
R
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004928:Escin / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D011651:Pulmonary Artery / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D015240:Phorbol 12,13-Dibutyrate; D004928:Escin; D011493:Protein Kinase C