Use this URL to cite or link to this record in EThOS:
Title: The effect of anti-hypertensive agents on platelets, prostacyclin and thromboxane, and observations on prostacyclin and thromboxane in normal and hypertensive pregnancy
Author: Greer, Ian Andrew
ISNI:       0000 0001 0902 885X
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1985
Availability of Full Text:
Access from EThOS:
Access from Institution:
Prostacyclin (PGI2) is a potent vasodilator and anti-platelet prostaglandin which is the major product of arachidonic acid metabolism in vascular tissue. It is thought to function as a local vasoprotective agent, protecting blood vessels from platelet deposition and subsequent damage. Thromboxane A2(TxA2) is the major product of arachidonic acid metabolism in platelets, and has actions directly opposed to those of prostacyclin as it is a potent vasodilator and platelet aggregating agent, which is synthesised and released when platelet aggregation occurs. It has been proposed that a balance exists between these two substances to maintain vascular integrity. Disturbance of this balance may be important in diseases associated with platelet consumption and vasoconstriction such as pregnancy induced hypertension (PIH) and prostacyclin deficiency and excess TXA2 production have both been implicated in the pathophysiology of this condition. Recently, adrenoceptor antagonists and calcium channel blocking agents have been used in the treatment of PIH. The aims of this thesis were firstly to study the effects of these drugs on platelet function and PGI2 and TxA2 production in vitro, and secondly, to study plasma levels of PGI2 and TXA2 metabolites in normal pregnancy and PIH, and assess the effect of treatment with an adrenoceptor antagonist (labetalol) on levels of these substances and platelet consumption in PIH. The effects of seven adrenoceptor antagonists on platelet aggregation and TxA2 production in platelet rich plasma were studied in vitro. Labetalol, pindolol and propranolol inhibited platelet aggregation and TxA2 generation in a dose dependent manner, probably by preventing release of arachidonic acid from membrane phospholipids. This effect was independent of any adrenoceptor blocking property, as several other adrenoceptor antagonists - atenolol, metoprolol, timolol and prazosin were without effect. This platelet inhibitory effect may be related to membrane stabilising activity or lipid solubility as these properties were common to all three effective agents. The effects of labetalol, pindolol and propranolol on vascular PGI2 production was studied using umbilical artery, however, these agents had little effect, causing only slight inhibition of PGI2 production at high drug concentrations. These 3 agents acted synergistically with PGI2 - either exogenous or derived from vessel wall - to inhibit platelet aggregation in platelet rich plasma. It has recently become possible to measure platelet aggregation in whole blood. This may be more physiological than traditional turbidometric techniques using platelet rich plasma as it leaves platelet in their natural milieu surrounded by red and white cells which can themselves influence platelet aggregation. The effects of labetalol, pindolol, propranolol and atenolol on platelet aggregation in whole blood was studied. Labetalol, pindolol and propranolol inhibited aggregation in a dose dependent manner and acted synergistically with exogenous PGI2 to inhibit platelet aggregation. They also inhibited PGI2 and TXA2 production from whole blood. Atenolol had no effect on either aggregation or TxA2 or PGI2 production. The calcium channel blocking agent nicardipine was similarly assessed and found to inhibit aggregation but it had no effect on TxA2 or PGI2 production. Labetalol and nicardipine were also found to act synergistically with low concentrations of aspirin to inhibit platelet aggregation in whole blood. Cross-sectional and longitudinal studies of plasma levels of PGI2 and TxA2 metabolites throughout normal pregnancy were performed. Prostacyclin metabolites were found to be increased in the first trimester compared to the non-pregnant state, while TxA2 metabolite levels were slightly reduced in the second and third trimesters. Cross-sectional and longitudinal studies of these substances in PIH were also performed and plasma PGI2 metabolites were found to be reduced, providing further evidence that PIH is associated with PGI2 deficiency. No change in TxA2 metabolites was noted in PIH. The effects of treatment with labetalol on plasma levels of PGI2 and TxA2 metabolites, and on platelet consumption were studied in PIH. Labetalol therapy did not affect levels of TXA2 metabolites but seemed to increase PGI2 metabolite levels if these were initially low, although no consistent effect on plasma PGI2 metabolite levels was noted if these were initially within the normal range. Following therapy with labetalol platelet consumption was significantly reduced especially in severe PIH. This reduction in platelet consumption suggests that the anti-platelet properties of labetalol studied in vitro may well exist in vivo, and such platelet protective therapy may be of value in the treatment of this disease. The anti-platelet properties of adrenoceptor antagonists, used either alone or in combination with prostacyclin or aspirin, which have been described in this thesis, require further clinical evaluation, but offer new therapeutic possibilities not only in PIH but also in other vascular disorders associated with platelet activation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Drug treatment of hypertension