In vitro effects of antihypertensive drugs on thromboxane agonist (U46619)-induced vasoconstriction in human internal mammary artery

Abstract

Hypertension is a major problem in the perioperative period of cardiac and non-cardiac surgery. The vascular endothelium plays a crucial role in modulating vascular tone by producing vasodilators as well as vasoconstrictors. Thromboxane A2 (TxA2), a prototypical vasoconstrictor produced by endothelium and platelets, may play an important role in the pathogenesis of hypertension and subsequent ischaemic events. Although multiple drugs are currently available to treat perioperative hypertension, there is a paucity of data comparing these agents. Therefore, we examined the in vitro vascular effects of commonly used antihypertensive drugs on human internal mammary artery (IMA) segments. Relaxation responses to adenosine (a nucleoside), enalaprilat (a competitive inhibitor of angiotensin-converting enzyme), fenoldopam (a D1-dopamine receptor agonist), hydralazine, labetalol (an alpha- and beta-adrenergic blocker), nicardipine (a calcium channel blocker), nicorandil (K(+)-ATP channel opener), nitroglycerin (GTN, a nitrosovasodilator), and sodium nitroprusside (SNP, a nitrosovasodilator) were studied in IMA segments pre-contracted with the TxA2 analogue (U46619, 1.0 x 10(-8) M). Effects of labetalol were also studied in IMA segments pre-contracted with norepinephrine (1.0 x 10(-6) M). All drugs were added in a cumulative fashion (range 10(-10) to 10(-3) M). All agents in the current study, with the exception of enalaprilat, dilated the IMA segments pre-contracted with U46619. Only GTN and SNP induced a complete (90-100%) relaxation. The order of efficacy of the in vitro relaxation was as follows: SNP, GTN, nicardipine, nicorandil, fenoldopam, hydralazine, adenosine, and labetalol. The potency was in the order of GTN, SNP, fenoldopam, nicorandil, hydralazine, adenosine, and nicardipine. Various antihypertensive agents are effective in attenuating U46619-induced IMA vasoconstriction, but the efficacy and potency differ. The in vitro vasodilation may not be simply extrapolated to the clinical efficacy or outcome of each antihypertensive therapy; however, our data provide additional grounds for the choice of antihypertensive medication. Further clinical studies are needed to help to fully elucidate the use of different antihypertensive agents and clinical outcomes.