Premium
The effect of forskolin on 5‐HT 1 ‐like and angiotensin II‐induced vasoconstriction and cyclic AMP content of the rabbit isolated femoral artery
Author(s) -
Randall V.A.,
MacLennan S.J.,
Martin G.R.,
Wilson V.G.
Publication year - 1996
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.1476-5381.1996.tb15447.x
Subject(s) - forskolin , angiotensin ii , medicine , endocrinology , ketanserin , chemistry , vasoconstriction , angiotensin ii receptor type 1 , prazosin , adenylyl cyclase , receptor , renin–angiotensin system , serotonin , 5 ht receptor , biology , antagonist , blood pressure
1 A characteristic feature of vasoconstrictor 5‐HT 1 ‐like receptors in vitro is that responses mediated by these receptors are enhanced by other vasoconstrictor agents. In the present study, we have examined the influence of cellular cyclic AMP on vasoconstrictor responses to activation of 5‐HT 1 ‐like receptors in isolated ring segments of the rabbit femoral artery (RbFA), and determined whether modulation of this second messenger underlies the ability of angiotensin II, an endogenous vasoconstrictor, to enhance 5‐HT 1 ‐like responses. 2 In the presence of 0.1 μ m ketanserin (to antagonize 5‐HT 2 ‐receptors) and 0.3 μ m prazosin (to antagonize α 1 ‐adrenoceptors), 5‐HT produced a concentration‐related contraction, which was significantly augmented by pre‐contraction of the vessel with 0.1‐0.45 nM ([A 30 ]) angiotensin II. Responses to 5‐HT in the presence of angiotensin II were inhibited by the 5‐HT 1 ‐like/5‐HT 2 antagonist, metergoline (1 μ m ). 3 The directly‐acting adenylyl cyclase activator, forskolin (1 μ m ), abolished responses to angiotensin II and caused a rightward shift and concomitant depression of the 5‐HT concentration‐effect (E/[A]) curve. Higher concentrations of forskolin (> 10 μ m ) abolished responses to 5‐HT and 1 μ m sodium nitroprusside abolished responses to 5‐HT and angiotensin II ( n = 7). 4 In the presence of angiotensin II (0.1‐0.45 nM), however, 1 μ m forskolin failed to inhibit 5‐HT‐induced contractions; the E/A curve for 5‐HT (in the presence of forskolin and angiotensin II) was not significantly different from that produced in the presence of angiotensin II alone. Similarly, the presence of angiotensin II (0.1‐0.45 nM) was also able to overcome partially the inhibitory effect of 1 μ m sodium nitroprusside against 5‐HT‐induced contractions ( n = 7). In marked contrast, 5‐HT failed to elicit a contraction in the presence of angiotensin II and 10 μ m forskolin ( n = 5). 5 5‐HT (1 μ m ) significantly reduced basal cyclic AMP accumulation by 35%, whereas angiotensin II (0.45 nM) was without effect. The combination of angiotensin II and 5‐HT failed to alter significantly the reduction in cyclic AMP produced by 5‐HT alone. Forskolin (1 μ m ) increased cyclic AMP levels 7 fold above basal, but neither 1 μ m 5‐HT nor a combination of 1 μ m 5‐HT and 0.45 nM angiotensin II produced a significant decrease in cyclic AMP content. 6 Whilst moderate concentrations of forskolin can inhibit the reponses to either agent, simultaneous activation of angiotensin II and 5‐HT 1 ‐like receptors can overcome the inhibitory effect of elevated levels of cyclic AMP. Since the potentiating effect of angiotensin II, in either the presence or absence of forskolin, occurs without significant alteration of cellular cyclic AMP, it seems likely that a cyclic AMP‐independent pathway is implicated in the synergistic interaction between angiotensin II and vasoconstrictor 5‐HT 1 ‐like receptors.