Preferential antagonism by diltiazem of alpha 2-adrenoceptor mediated vasoconstrictor responses in perfused tail arteries of spontaneous hypertensive rats

Abstract

Vasoconstrictor responses mediated by the alpha 2-adrenoceptor agonist TL99, were particularly sensitive to blockade by the calcium antagonist drug diltiazem in isolated perfused tail arteries of spontaneously hypertensive rats (SHR). In contrast, the vasoconstrictor responses induced by the alpha 1-adrenoceptor agonist methoxamine were significantly more resistant to antagonism by diltiazem. At higher concentrations (greater than 300 nmol/l) diltiazem became an effective antagonist of all alpha-adrenoceptor mediated responses. In normotensive Wistar Kyoto (WKY) or Sprague-Dawley (SD) rats diltiazem was significantly less potent against vasoconstrictor responses to TL99 than in SHR. The blockade of alpha 1-adrenoceptor mediated vasoconstriction by diltiazem was not significantly different when normotensive rats and SHR were compared. The vasoconstrictor responses evoked by 5HT in the perfused tail arteries were particularly resistant to blockade by diltiazem in SHR arteries. The responses to endogenously released noradrenaline, evoked by electrical field stimulation, were significantly antagonised by diltiazem (30 nmol/1-3 mumol/l) in SHR-tail arteries, while they were not modified in WKY-tail arteries. At the concentrations of diltiazem which blocked end organ responses to field stimulation, there was no modification of total tritium overflow from SHR-tail arteries after labelling the tissue with 3H-noradrenaline, indicating that diltiazem does not inhibit transmitter release at these concentrations. The tail artery preparation of SHR contains a population of postsynaptic alpha 2-adrenoceptors which mediate contraction in this blood vessel and the calcium entry blocker diltiazem is a potent antagonist of vasoconstrictor responses mediated by vascular alpha 2-adrenoceptors in hypertensive rats. These findings may be relevant to the antihypertensive action of diltiazem.