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Differential effect of calcium entry blockers on α 1-adrenoceptor-mediated vasoconstriction in vivo

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Summary

The effects of the calcium entry blockers nifedipine, (−)-verapamil and the dihydropyridine derivative PY 108-068 were evaluated on the increase in diastolic pressure of pithed normotensive rats caused by the selective α1-adrenoceptor agonists cirazoline, (−)-phenylephrine, (±)-erythro-methoxamine, (−)-amidephrine and St 587 [(2-chloro-5-trifluoromethylphenylimino)-2-imidazolidine] as well as by the mixed α1/α2-adrenoceptor agonists clonidine and DPI [(3,4-dihydroxyphenylimino)-2-imidazolidine]. The calcium entry inhibitors (up to 3 mg/kg) caused 3- to 5-fold, parallel rightward shifts of the log dose-pressor effect curves to cirazoline, (−)-phenylephrine, (±)-erythro-methoxamine and (−)-amidephrine accompanied by only a slight depression of the maximal pressor response. In contrast, the calcium entry inhibitors produced a dose-dependent profound depression of both maximum and slope of the log dose-pressor response curves to St 587 and clonidine. For DPI about 10-and 100-fold parallel displacements to the right without reduction of the maximum were found following treatment with 1 and 3 mg/kg of nifedipine, respectively. Infusion of vasopressin to counteract the vasodilatory action produced by the calcium entry inhibitors did not significantly change the pattern of interference observed under the conditions of decreased baseline diastolic pressure. The results indicate that α1-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat, which is characterized by its sensitivity to blockade by prazosin and its relative insensitivity to antagonism by yohimbine or rauwolscine, can be subdivided into two distinct processes which are differentially influenced by blockade of calcium entry. It is suggested that cirazoline, (−)-phenylephrine, (±)-erythro-methoxamine and (−)-amidephrine initiate vasoconstriction predominantly by a mechanism independent of extracellular calcium influx. On the other hand, St 587 and clonidine increase arterial pressure via a mechanism which seems to be mainly governed by an entry of extracellular calcium ions. DPI probably triggers both processes of vasoconstriction in the intact circulatory system of the pithed normotensive rat.

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Author notes

  1. J. C. A. van Meel

    Present address: Dr. Karl Thomae GmbH, D-7950, Biberach an der Riss, Germany

Authors and Affiliations

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

    P. B. M. W. Timmermans, M. J. Mathy, B. Wilffert, H. O. Kalkman, M. J. M. C. Thoolen, A. de Jonge, J. C. A. van Meel & P. A. van Zwieten

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  1. P. B. M. W. Timmermans
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  2. M. J. Mathy
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  3. B. Wilffert
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  4. H. O. Kalkman
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  5. M. J. M. C. Thoolen
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  6. A. de Jonge
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  7. J. C. A. van Meel
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  8. P. A. van Zwieten
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Timmermans, P.B.M.W., Mathy, M.J., Wilffert, B. et al. Differential effect of calcium entry blockers on α 1-adrenoceptor-mediated vasoconstriction in vivo. Naunyn-Schmiedeberg's Arch. Pharmacol. 324, 239–245 (1983). https://doi.org/10.1007/BF00502618

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  • DOI: https://doi.org/10.1007/BF00502618

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