EVALUATION OF THE ALPHA-1 AND ALPHA-2 ADRENOCEPTOR-MEDIATED EFFECTS OF A SERIES OF DIMETHOXY-SUBSTITUTED TOLAZOLINE DERIVATIVES IN THE CARDIOVASCULAR-SYSTEM OF THE PITHED RAT

  • 1 January 1985
    • journal article
    • research article
    • Vol. 232  (1) , 94-99
Abstract
The .alpha.-1 and .alpha.-2 adrenoceptor-mediated effects of a series of dimethoxy-substituted tolazoline derivatives were investigated in the cardiovascular system of the pithed rat. The 2,5- and 3,5-dimethoxy-substituted tolazoline derivatives produced vasopressor responses that were inhibited by the .alpha.-1 adrenoreceptor antagonist, prazosin (0.1 mg/kg i.v.), and were not affected by the .alpha.-2 adrenoceptor antagonist, yohimibine (1 mg/kg i.v.), suggesting that these derivatives selectively activate postsynaptic vascular .alpha.-1 adrenoceptors. The 2,5- and 3,5-dimethoxy-substituted derivatives of tolazoline did not produce an .alpha.-2 adrenoceptor-mediated inhibition of neurogenic tachycardia in cord-stimulated pithed rats and were therefore presumed to be devoid of .alpha.-2 adrenoceptor agonist activity. 2,3-Dimethoxytolazoline produced a vasopressor effect that was inhibited by yohimbine but not by prazosin, suggesting selective activation of postsynaptic vascular .alpha.-2 adrenoceptors. 2,3-Dimethoxytolazoline elicited a dose-dependent, .alpha.-2 adrenoceptors-mediated inhibition of neurogenic tachycardia in cord-stimulated pithed rat. 3,4-Dimethoxytolazoline was a weak .alpha.-1 adrenoceptor agonist in the vasculature of the pithed rat and was devoid of agonist activity at .alpha.-2 adrenoceptors. 3,4-Dimethoxytolazoline was an .alpha.-2 adrenoceptors agonist of similar potency as yohimbine. Evidently dimethoxy-substituted derivatives of tolazoline possess different activities and selectivities at .alpha.-1 and .alpha.-2 adrenoceptors depending on the positions of substitution. Whereas 2,5- and 3,5-dimethoxytolazoline are potent and selective .alpha.-1 adrenoceptor agonists, the 2,3-dimethoxy-substituted derivative is a selective .alpha.-2 adrenoceptor agonist. 3,4-Dimethoxytolazoline is a elatively potent and selective .alpha.-2 adrenoceptor antagonist. These compounds, which differ only in the positions of their respective dimethoxy substitutions, may be useful tools with which to probe and subclassify .alpha. adrenoceptors.

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