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Contraction of vascular smooth muscle induced by phorbol 12, 13 dibutyrate in human and rat pulmonary arteries
Author(s) -
Savineau JeanPierre,
Marthan Roger,
Crevel Huguette
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12482.x
Subject(s) - verapamil , contraction (grammar) , medicine , endocrinology , calcium , phorbol , phentolamine , chemistry , vascular smooth muscle , muscle contraction , protein kinase c , protein data bank (rcsb pdb) , propranolol , biology , biochemistry , enzyme , smooth muscle
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 n m to 2 μ m ) produced slowly developing, sustained and concentration‐dependent contractions in HPA (mean EC 50 = 3.5 n m , n = 5) and RPA (mean EC 50 = 120 n m , n = 5). The maximal response was 185.6 ± 25% and 207 ± 27.5% ( n = 5) of that induced by K + ‐rich (80 m m ) solution, and 223 ± 34.5% and 176.5 ± 38.6% of the noradrenaline (10 μ m )‐induced contraction in HPA and RPA, respectively. 3 PDB‐induced contractions were not altered either by the presence of atropine (10 μ m ), propranolol (5 μ m ), phentolamine (5 μ m ) or tetrodotoxin (10 μ m ) 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 μ m ) or trifluoperazine (TFP, 5 μ m ) and significantly increased by Bay K 8644 (0.5 μ m ). 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 μ m ) or by 8‐(N,N diethylamino)octyl‐3,4,5, trimethoxybenzoate hydrochloride (TMB‐8, 50 μ m ). 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 (H 7 , 50 μ m ), 70.5 ± 12.2% and 56 ± 18% ( n = 5) by phloretin (100 μ m ) and 80.7 ± 8.4% and 71 ± 14% ( n = 5) by staurosporine (25 n m ) 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.