Ca2+ channel ligand sensitive responses to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate in vascular smooth muscle

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Abstract
The action of a tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), on isolated rat aortic and tail artery strips has been characterized. TPA (10-9 - 10-7 M) produced a graded contraction developing maximum tension over 30-40 min. The contraction was irreversible and was not relaxed by prolonged washing with physiologic saline. Relaxation occurred upon washing with Ca+ -free saline but readdition of Ca2+ restored response. TPA was without significant effect in rat tail arteries in physiologic saline but produced responses in saline containing elevated K+ (15 mM). The protein kinase C inhibitor, CP-46,665-1 (4-aminomethyl-1-[2,3-(di-n-decyloxy)n-propyl]-4-phenylpiperidine dihydrochloride) (5 .times. 10-5 M), blocked the responses to TPA but was without effect on response to Bay K 8644 (2,6-dimethyl-3-carbomethoxy-5-nitro-4-(2-trifluoromethylphenyl) 1,4-dihydropyridine), KC1, phenylephrine, and B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin dihydrochloride). The calcium channel antagonist nifedipine and its analogue, 2,6-dimethyl-3,5-dicarbomethoxy-4-(3-cyanophenyl)-1,4-dihydropyridine, inhibited TPA responses with IC50 values of 9.28 .times. 10-9 and 1.96 .times. 10-7 M, respectively. Responses to Bay K 8644 in rat aorta were maximum in the presence of elevated KC1 (10 mM), but TPA at concentrations of 10-9and 3 .times. 10-9 M potentiated responses to Bay K 8644 in physiologic saline to levels approximating those in elevated K+ saline. TPA similarly potentiated responses to Ca2+ in Ca2+ -free solution. In the presence of TPA, 10-8 and 3 .times. 10-8 M, responses to Ca2+ in nondepolarizing saline were potentiated to levels seen under depolarizing conditons. The present results suggest a relationship between protein kinase C and Ca2+ sensitivity of the contractile apparatus, may also contribute to the observed effects.