Interaction of Selective Α‐adrenoceptor Agonists and Antagonists With Human and Rabbit Blood Platelets

1 Mammalian platelets vary widely in their responses to catecholamines in part because these agonists can act via excitatory a-and inhibitory P-adrenoceptors. In the absence of antagonists, adrenaline enhances the response of rabbit platelets to an excitatory agonist, e.g. adenosine-5'-O-(1-thiodiphosphate) (ADP-a-s) acting at another receptor, but has no effect on the response of rat or guinea pig platelets to such an agonist. In the presence of a P-adrenoceptor antagonist, adrenaline enhances the response of rat, but not guinea-pig platelets to ADP-a-S and the extent of the enhanced effect on rabbit platelets is increased. In the presence of an a-adrenoceptor antagonist, adrenaline inhibits the response of rabbit and rat platelets to ADP-a-S but has no such effect on the response of guinea-pig platelets.

Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 89%

Mammalian platelet adrenoceptors

Kerry

Scrutton

Wallis

1984

“…However, the enhancement of responses to noradrenaline was greater with UK14304 than with rilmenidine. The difference may be due to the fact that UK14304 is a full agonist (Grant & Scrutton, 1980;Cambridge, 1981), whereas rilmenidine is a partial agonist (Li & Rand, 1988). Therefore we used UK14304 to determine whether or not a2-adrenoceptor agonists enhanced vasoconstrictor responses of the rat tail artery produced by agents other than those activating a1-adrenoceptors.…”

Section: Discussionmentioning

confidence: 99%

α₂‐Adrenoceptor agonists enhance responses to certain other vasoconstrictor agonists in the rat tail artery

Xiao¹,

Rand²

1989

1 The effects of the a2-adrenoceptor agonists clonidine, rilmenidine, TL99 and UK14304 on the vasoconstrictor response to sympathetic nerve stimulation and on the concentration-response curves to noradrenaline and phenylephrine were compared in two isolated, perfused vascular tissues: the rat tail artery (which has both postjunctional al-and a2-adrenoceptors), and the rabbit ear artery (in which only cx-adrenoceptors are present postjunctionally). 2 In the rabbit ear artery, the first observable effect of a2-adrenoceptor agonists was inhibition of vasoconstrictor responses to sympathetic nerve stimulation. This occurred with concentrations of the M2-adrenoceptor agonists which were far below those producing vasoconstriction. Responses to noradrenaline were not affected. 3 In contrast, in the rat isolated perfused tail artery, a2-adrenoceptor agonists, in concentrations that produced no other observable effects, enhanced the vasoconstrictor responses to sympathetic nerve stimulation and to noradrenaline. Much higher concentrations of a2-adrenoceptor agonists produced vasoconstriction in most preparations and only then reduced the response to sympathetic nerve stimulation. The enhancing effect of CX2-adrenoceptor agonists was blocked by idazoxan, but not by prazosin.4 Vasoconstrictor responses in the rat tail artery to the relatively selective xl-adrenoceptor agonist phenylephrine were enhanced by X2-adrenoceptor agonists. The enhancement of the response to phenylephrine was greater than that to the mixed a1-and a2-adrenoceptor agonist noradrenaline. 5 Vasoconstrictor responses in the rat tail artery to vasopressin, ATP and KCl, like those to a1-adrenoceptor agonists, were enhanced by a2-adrenoceptor agonists. However, vasoconstrictor responses to 5-hydroxytryptamine and angiotensin II were not enhanced.

“…Furthermore, since aspirin also failed to block the effects of Paf-acether alone or associated with adrenaline on exhausted platelets, it is clear that cyclo-oxygenase products did not account for the aggregating effects of Paf-acether alone or associated with adrenaline, when secretion was prevented. Adrenaline thus exerts at least two distinct effects on platelets, both initiated by its interaction with CX2-adrenoceptors (yohimbinesensitive) (Grant & Scrutton, 1980;Hsu etal., 1979). A classical effect, amplified by cyclo-oxygenase metabolites is observed in heparinized and in citrated PRP, since adrenaline-induced aggregation and secretion are suppressed by aspirin (Cazenave et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

Triggering by Paf‐acether and adrenaline of cyclo‐oxygenase‐independent platelet aggregation

Fouque

Vargäftig

1984

Platelet‐activating factor (Paf‐acether, 1‐alkyl‐2‐acetyl‐sn‐glycero‐3‐phosphorylcholine) induced full aggregation and a limited release reaction of human platelets in plasma or in blood. Cyclo‐oxygenase inhibition with aspirin only reduced aggregation when induced by threshold amounts of Paf‐acether, whereas higher concentrations surmounted inhibition whether tested in citrated or in heparinized platelet‐rich plasma or blood. Aspirin‐induced inhibition of platelet secretion by Paf‐acether was insurmountable and independent of the anti‐coagulant used. Paf‐acether and adrenaline acted synergistically in inducing aggregation in citrate and in heparin. Aspirin in vitro or after oral ingestion at doses that suppressed aggregation induced by arachidonic acid alone, failed to reduce significantly the synergized aggregation induced by Paf‐acether alone or combined with adrenaline. Twenty‐four hours after the oral ingestion of aspirin, when aggregation by arachidonic acid remained blocked, a slight inhibitory activity on the effect of Paf‐acether noted 4 h after aspirin, had ceased. This was probably accounted for by the synthesis of thromboxane A2 by newly formed platelets, since the in vitro addition of aspirin, or of the thromboxane/endoperoxide receptor inhibitor 13‐azaprostanoic acid caused the 24 h platelets to behave in a manner similar to platelets collected 4 h after aspirin. The α2‐adrenoceptor inhibitor, yohimbine, blocked the direct effect of adrenaline as well as its synergism with Paf‐acether. Since the synergistic effect of Paf‐acether and adrenaline was maintained when thrombin‐degranulated platelets were used, and aspirin remained ineffective against it, it is clear that the augmented platelet responsiveness is not accounted for by the platelet release reaction. Paf‐acether and adrenaline act synergistically and stimulate platelets by cyclo‐oxygenase‐independent mechanisms, which may be relevant in human physiopathological conditions.