The effect of relaxants working through different transduction mechanisms on the tonic contraction produced in rat aorta by 4β‐phorbol dibutyrate

• Published in: British journal of pharmacology 1989-07, Vol.97 (3), p.647-656
• Main Authors: Obianime, A.W., Dale, M. Maureen
• Format: Article
• Language: English
• Subjects: 4 beta -phorbol dibutyrate; Animals; Aorta, Thoracic - drug effects; Benzopyrans - pharmacology; Biological and medical sciences; Cardiovascular system; Colforsin - pharmacology; Cromakalim; In Vitro Techniques; Isoproterenol - pharmacology; Male; Medical sciences; Methoxamine - pharmacology; Muscle Contraction - drug effects; Muscle Relaxation - drug effects; Muscle, Smooth, Vascular - drug effects; Nitroprusside - pharmacology; Parasympatholytics - pharmacology; Pharmacology. Drug treatments; Phorbol 12,13-Dibutyrate - pharmacology; protein kinase C; Pyrroles - pharmacology; Rats; Rats, Inbred Strains; smooth muscle; Vasodilator agents. Cerebral vasodilators; Xanthines - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1989.tb12000.x

1 We have examined the effects of a range of smooth muscle relaxants on the maintained contractions produced in rat aortic rings by the protein kinase C activator, 4β‐phorbol dibutyrate; these effects were compared with those on the contraction induced by the selective α1‐adrenoceptor agonist, methoxamine. The phorbol ester, at 0.3 μm, gave a sustained contraction which was, on average, of approximately the same magnitude as the maximum contraction produced by methoxamine, 10 μm. 2 The β‐adrenoceptor agonist, isoprenaline (0.01–1 μm) caused a dose‐related relaxation of the methoxamine‐induced contraction but had no effect on the contraction induced by the phorbol ester. 3 An activator of adenylate cyclase, forskolin (0.01–1 μm) produced a dose‐related relaxation of the methoxamine‐induced contraction and at 0.01–10 μm caused relaxation of the contraction induced by the phorbol ester. Similar results were obtained with the potassium channel activator, cromakalim (0.001–10 μm). 4 An activator of guanylate cyclase, sodium nitroprusside (0.001–100 μm) caused a dose‐related relaxation of both the methoxamine‐induced and the phorbol ester‐induced contraction, being more effective on the former than on the latter. Similar results were obtained with enprofylline (11000 μm). 5 Methoxamine (10 nM‐100 μm), given cumulatively, caused a dose‐related contractile response. Pretreatment with isoprenaline (1 μm), enprofylline (10 μm) and nicorandil (1 μm) resulted in partial decrease of the subsequent response to methoxamine, while nicorandil (10 μm), forskolin (1 μm), sodium nitroprusside (10 μm) and cromakalim (1 μm) totally abolished it. 6 The phorbol ester, given cumulatively, caused increasing contraction in the concentration range 30 nM‐10 μm. Pretreatment with forskolin (1 μm), sodium nitroprusside (10 μm), isoprenaline (1 μm), enprofylline (10 μm), nicorandil (1 μm or 10 μm), or cromakalim (1 μm or 10 μm), resulted in partial decrease of the subsequent response to 4β‐phorbol dibutyrate. 7 These results are discussed in the light of the suggestion that protein kinase C may have a role in the ‘latch‐bridge’ phase of smooth muscle contraction, and that inappropriate activation of protein kinase C may contribute to the pathogenesis of hypertension and other conditions involving vasospasm.