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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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Summary

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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References

  • Cambridge D, Davey MJ, Massingham R (1977) Prazosin: A selective antagonist of postsynaptic α-adrenoceptors. Br J Pharmacol 59:pp 514–515

    Google Scholar 

  • Cavero I, Shepperson NB, Lefèvre-Borg F, Langer SZ (1983) Differential inhibition of vascular smooth muscle responses to α-1 and α2-adrenocepter agonists by diltiazem and verapamil. Circ Res 52:I-69–I-76

    Google Scholar 

  • De Jonge A, Van Meel JCA, Timmermans PBMWM, Van Zwieten PA (1981) A lipophilic, selective α1-adrenocepter agonist: 2-(2-choloro-5-trifluoromethylphenylimino)imidazoolidine (St 587). Life Sci 28:200902016

    Google Scholar 

  • Docherty JR, McGrath JC (1980) A comparison of pre- and post-junctional potencies of several alpha-adrenoceptor agonists in the cardiovascular system and anococcygeus muscle of the rat. Evidence for two types of postjunctional alpha-adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 312: 107–116

    Google Scholar 

  • Doxey JC, Smith CFC, Walker JM (1977) Selectivity of blocking agents for pre- and postsynaptic α-adrenoceptors. Br J Pharmacol 60:91–96

    Google Scholar 

  • Flavahan NA, McGrath JC (1981) Demonstration of simultaneous α1-adrenocepter mediated effects of phenylephrine in the cardiovascular system of the pithed rat. Br J Pharmacol 72:585P

    Google Scholar 

  • Fleckenstein A (1977) Specific pharmacology of calcium in myocardium, cardiac pacemakers and vascular smooth muscle. Ann Rev Pharmacol Toxicol 17:149–166

    Google Scholar 

  • Gerhold M, Haeusler G (1983) α2-Adrenoceptors in rat resistance vessels. Naunyn-Schmiedeberg's Arch Pharmacol 322:29–33

    Google Scholar 

  • Hicks PE, Cannon JG (1980) Cardiovascular effects of 2-(N,N-dimethyl)-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene in pithed rats: differential antagonism by yohimbine and prazosin. J Pharm Pharmacol 32:786–788

    Google Scholar 

  • Kobinger W, Pichler L (1981) α1- and α1-adrenoceptor subtypes: selectivity of various agonists and relative distribution of receptors as determined in rats. Eur J Pharmacol 73:313–321

    Google Scholar 

  • Korstanje C, Wilffert B, De Jonge A, Thoolen MJMC, Timmermans PBMWM, Van Zwieten PA (1984) Calcium-influxdependent and-independent α2-adrenocepter processes of vasoconstriction in vivo do not operate via different α2-adrenocepter subtypes. J Cardiovasc Pharmacol in press

  • Lefèvre-Borg F (1983) Effect of TL-99 on cardiovascular α- and β-adrenoceptors in pithed rats. Br J Pharmacol 78: 140 P

  • Llenas J, Massingham R (1983) A comparison of the effects of verapamil and cinnarizine upon responses elicited by selective α2-adrenocepter agonists in the autoperfused canine hindlimb. Eur J Pharmacol 87:53–59

    Google Scholar 

  • Mathy MJ, Thoolen MJMC, Timmermans PBMWM, Van Zwieten PA (1983a) Sgd 101/75: Cardiovascular effects in various animal preparations: Interactions with vascular postjunctional α1 and α2-adrenoceptorsr. Br J Pharmacol 81:255–262

    Google Scholar 

  • Mathy MJ, Doods H, Thoolen MJMC, Wilffert B, De Jonge A, Timmermans PBMWM, Van Zwieten PA (1983b) Selective stimulations of vascular postjunctional α1-adrenoceptorsr by (−)-amidephrine in rats and cats. J Auton Pharmacol 3: 249–255

    Google Scholar 

  • Pichler L, Hörtnagl H, Kobinger W (1982) B-HT 958, a new α-adrenoceptor agonist with a high pre/postsynaptic activity ratio. Naunyn-Schmiedeberg's Arch Pharmacol 320:110–114

    Google Scholar 

  • Ruffolo RR Jr, Nelson WL, Yaden EL (1983) Blockade of post-junctional vascular alpha1- and alpha2-adrenoceptors in the pithed rat by the enantiomers of WB-4101. Naunyn-Schmiedeberg's Arch Pharmacol 322:93–97

    Google Scholar 

  • Schramm M, Thomas G, Towart R, Franckowiak G (1983a) Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels. Nature 303:535–537

    Google Scholar 

  • Schramm M, Thomas G, Towart R, Franckowiak (1983b) Activation of calcium channels by novel 1,4-dihydropyridines. A new mechanism for positive inotropics or smooth muscle stimulants. Arzneim-Forsch 33:1268–1272

    Google Scholar 

  • Tanaka T, Weitzell R, Starke K (1978) High selectivity of rauwolscine for presynaptic α-adrenoceptors. Eur J Pharmacol 52:239–240

    Google Scholar 

  • Timmermans PBMWM, Van Meel JCA, Van Zwieten PA (1980) Evaluation of the selectivity of α-adrenoceptor blocking drugs for postsynaptic α1 in a simple animal model. J Auton Pharmacol 1:53–60

    Google Scholar 

  • Timmermans PBMWM, Van Meel JCA, De Jonge A, Mathy MJ, Van Zwieten PA (1983a) Influence of nifedipine on functional responses in vivo initiated at α2-andreneceptor. J Cardiovasc Pharmacol 5:1–6

    Google Scholar 

  • Timmermans PBMWM, Thoolen MJMC, Mathy MJ, Wilffert B, De Jonge A, Van Zwieten PA (1983b) Sgd 101/75 is distinguished from other selective α1-andreneceptors agonist by the inhibition of its pressor responses by calcium entry blockade and vasodilatation in pithed rats and cats. Eur J Pharmacol 96:187–192

    Google Scholar 

  • Timmermans PBMWM, Mathy MJ, Wilffert B, Kalkman HO, Thoolen MJMC, De Jonge A, Van Meel JCA, Van Zwieten PA (1983c) Differential effect of calcium-entry blockers on α1-andreneceptors meditiate vasoconstriction in vivo. Naunyn-Schmiedeberg's Arch Phrmacol 324:239–245

    Google Scholar 

  • Timmermans PBMWM, Mathy MJ, Thoolen MJMC, De Jonge A, Wilffert B, Van Zwieten PA (1984a) Invariable susceptibility to blockade by nifedipine of vasoconstriction to various α1-andreneceptors agonists in pithed rats. J Pharm Pharmacol in press

  • Timmermans PBMWM, Wilffert B, Mathy MJ, Dijkstra D, Horn AS, Van Zwieten PA (1984b) 82-16 agonist selectivities of mono- and dihydroxy-2-N,N-di-n-propyl-aminotetralins. Eur J Pharmacol 97:55–65

    Google Scholar 

  • Van Meel JCA, De Jonge A, Kalkman HO, Wilffert B, Timmermans PBMWM, Van Zwieten PA (1981a) Organic and inorganic calcium antagonists reduced vasoconstriction in vivo mediated by postsynaptic α2-andrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 316:288–293

    Google Scholar 

  • Van Meel JCA, De Jonge A, Timmermans PBMWM, Van Zwieten PA (1981b) Selectivity of some alpha adrenoceptor agonists for peripheral alpha-1 and alpha-2 adrenoceptors in the normotensive rat. J Pharmacol Exp Ther 219:760–767

    Google Scholar 

  • Van Meel JCA, Wilffert B, De Zoeten K, Timmermans PBMW, Van Zwieten PA (1982) The inhibitory effect of newer calcium antagonists (nimodipine and PY-108-068) on vasoconstriction in vivo mediated by postsynaptic α1-andrenoceptors. Arch Int Pharmacodyn Ther 260:206–217

    Google Scholar 

  • Wallenstein S, Zucker SL, Fleiss JL (1980) Some statistical methods useful in circulation research. Circ Res 47:1–9

    Google Scholar 

  • Weitzell R, Tanaka T, Starke K (1979) Pre- and postsynaptic effects of yohimbine stereoisomers on noradrenergic transmission in the pulmonary artery of the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 308:127–136

    Google Scholar 

  • Wilffert B, Timmermans PBMWM, Van Zwieten PA (1982) Extrasynaptic location of alpha-2 and noninnervated beta-2 adrenoceptors in the vascular system of the pithed normotensive rat. J Pharmacol Exp Ther 221:762–768

    Google Scholar 

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Author notes

  1. B. Wilffert

    Present address: Dr. Karl Thomae GmbH, D-7950, Biberach/Riß, FRG

  2. P. B. M. W. M. Timmermans

    Present address: E. I. Dupont de Nemours & Comany (Inc.), Experimental Station Building 400-4257, 19898, Wilmington, Delaware, USA

Authors and Affiliations

  1. Department of Pharmacy, Division of Pharmacotherapy, University of Amsterdam, Plantage Muidergracht 24, 1018 TV, Amsterdam, The Netherlands

    B. Wilffert, P. N. M. van Heiningen, M. J. Mathy, A. de Jonge, M. J. M. c. Thoolen, P. B. M. W. M. Timmermans & P. A. van Zwieten

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  3. M. J. Mathy
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Wilffert, B., van Heiningen, P.N.M., Mathy, M.J. et al. 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. Naunyn-Schmiedeberg's Arch. Pharmacol. 328, 76–82 (1984). https://doi.org/10.1007/BF00496110

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