Interactions between the putative calcium entry promotor Bay k 8644 and pressor responses produced by α-1 and α2-adrenocepter agonists in the pithed normotensive rat

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Abstract
Interactions between the putative calcium entry promotor Bay k 8644 and both α-1 and α1-adrenocepter mediated increases in diastolic pressure were studied in the pithed normotensive rat. The α1-adrenocepter mediated pressor responses elicited by B-HT920, TL-99, DP-6,7-ADTN and B-HT958 were potentiated by Bay k 8644, reflected by a leftward shift and an increase in the maximum of the log dose-pressor respinse curves. The α-1-adrenocepter effects elicited by cirazoline, methoxamine, (−)-amidephrine, St 587, (−)-phenylephrine and Sgd 101/75 were less enhanced by Bay k 8644. Only a leftward shift of the dose-response curves was observed, which was most pronounced for (−)-phenylephrine and Sgd 101/75. The α-1 and α2-adrenocepter pressor components of (−)-noradrenaline were similarly distinguished by Bay k 8644 as observed for the selective α-1 or α2-adrenocepter agonists. Effects of Bay k 8644 on the increase in diastolic pressure mediated by B-HT 920, St 587 and cirazoline were also studied after pretreatment with the calcium entry blocker nifedipine. After additional pretreatment with nifedipine the potentiation by Bay k 8644 observed for B-HT 920 and St 587 was more pronounced. The presence of nifedipine had no effect on the interaction between Bay k 8644 and cirazoline. It is concluded that Bay k 8644 behaves as a mirror image of nifedipine. The observation that Bay k 8644 enhances α2-adrenocepter mediated pressor effects more effectively than α1-adrenocepter increases in diastolic pressure is in accordance with the hypothesis of the more pronounced calcium dependency of α2-adrenocepter mediated pressor responses. The data obtained for ceptor mediated pressor responses. The data obtained for St 587 and (−)-phenylephrine are in apparent contradiction to the finding that the pressor responses to the former drug are more markedly inhibited by calcium entry blockade than those of the latter. It is suggested that St 587 employs calcium channels which are already maximally modulated and that (−)-phenylephrine makes use of calcium channels which are in a rather inactive state. The hypothesis is put forward that the intrinsic activity of α2-adrenocepter agonists reflects their ability to bring calcium channels in an active state.

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