Contraction of vascular smooth muscle induced by phorbol 12, 13 dibutyrate in human and rat pulmonary arteries

• Published in: British journal of pharmacology Vol. 104; no. 3; pp. 639 - 644
• Main Authors: Savineau, Jean‐Pierre, Marthan, Roger, Crevel, Huguette
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.1991; Nature Publishing
• Subjects: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester - pharmacology; Animals; Atropine - pharmacology; Biological and medical sciences; Blood vessels and receptors; Calcium - metabolism; contraction; Fundamental and applied biological sciences. Psychology; human tissue; Humans; In Vitro Techniques; Isometric Contraction - drug effects; Muscle Contraction - drug effects; Muscle Tonus - drug effects; Muscle, Smooth, Vascular - drug effects; Phentolamine - pharmacology; Phorbol 12,13-Dibutyrate - pharmacology; phorbol ester; Potassium - pharmacology; Propranolol - pharmacology; protein kinase C; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; pulmonary arteries; Pulmonary Artery - drug effects; Rats; Smooth muscle; Tetrodotoxin - pharmacology; Trifluoperazine - pharmacology; Verapamil - pharmacology; Vertebrates: cardiovascular system; Human; Protein kinase C; Enzyme; Animal; Smooth muscle; Circulatory system; Muscle contraction; In vitro; Pulmonary artery; Dose activity relation
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1991.tb12482.x

1 The effect of phorbol 12,13 dibutyrate (PDB) on vascular tone was studied in both human and rat isolated pulmonary arterial strips (HPA and RPA, respectively). 2 PDB (1 nm to 2 μm) produced slowly developing, sustained and concentration‐dependent contractions in HPA (mean EC50 = 3.5 nm, n = 5) and RPA (mean EC50 = 120 nm, n = 5). The maximal response was 185.6 ± 25% and 207 ± 27.5% (n = 5) of that induced by K+‐rich (80 mm) solution, and 223 ± 34.5% and 176.5 ± 38.6% of the noradrenaline (10 μm)‐induced contraction in HPA and RPA, respectively. 3 PDB‐induced contractions were not altered either by the presence of atropine (10 μm), propranolol (5 μm), phentolamine (5 μm) or tetrodotoxin (10 μm) in the bathing solution, or by the removal of endothelium from pulmonary arteries. 4 In HPA, the amplitude of PDB‐induced contractions was significantly reduced by removal of external calcium ions, addition of verapamil (10 μm) or trifluoperazine (TFP, 5 μm) and significantly increased by Bay K 8644 (0.5 μm). In contrast, in RPA, calcium‐free solution and verapamil had only a moderate effect on the maximal PDB‐induced contraction (approximately 20% reduction), whereas Bay K 8644 and TFP had no significant effect. In both HPA and RPA, PDB‐contractions in calcium‐free solutions were not modified by ryanodine (25 μm) or by 8‐(N,N diethylamino)octyl‐3,4,5, trimethoxybenzoate hydrochloride (TMB‐8, 50 μm). 5 PDB‐induced contractions were inhibited by protein kinase C (PKC) antagonists. The maximal response was decreased by 60 ± 10.5% and 35 ± 11.5% (n = 5) by 1‐(5‐isoquinolinesulphonyl)‐2‐methyl‐piperazine (H7, 50 μm), 70.5 ± 12.2% and 56 ± 18% (n = 5) by phloretin (100 μm) and 80.7 ± 8.4% and 71 ± 14% (n = 5) by staurosporine (25 nm) in HPA and RPA, respectively. 6 Long term treatment (15–20 h) of arterial strips with phorbol esters (phorbol 12,13 didecanoate, or PDB) abolished the contractile response to subsequent addition of PDB. 7 These results show that PDB is a potent vasoconstrictor agent in human and rat pulmonary arteries. Unlike the rat, part of the PDB response depends on calcium influx in human preparations. PDB action appears mainly mediated by the activation of protein kinase C. PKC could thus play a major role in the control of vascular pulmonary reactivity.