Effect of early and advanced atherosclerosis on vascular responses to serotonin, thromboxane A2, and ADP.

In monkeys with early and advanced atherosclerosis, we examined responses to the three major vasoactive agonists that are released when platelets aggregate. Measurements were obtained in normal cynomolgus monkeys and in monkeys fed an atherogenic diet for 4 +/- 1, 9 +/- 1, and 19 +/- 1 months (mean +/- SEM). Morphometry of femoral and iliac arteries indicated that 4 months of atherogenic diet produced only slight intimal thickening, 9 months produced early lesions, and 19 months produced approximately 5-10 fold greater intimal proliferation than did 9 months of atherogenic diet. Serotonin and adenosine 5'-diphosphate (ADP), which are endothelium-dependent agonists, and adenosine and phenylephrine, which are endothelium-independent agonists, were injected intra-arterially into the perfused hind limb. Thromboxane A2 analogue U46619 also was studied. Vasoconstrictor responses to serotonin were potentiated, and vasodilator responses to ADP were impaired by early and advanced atherosclerosis. In contrast, vasoconstrictor responses to phenylephrine and vasodilator responses to adenosine were similar in all groups. Vasoconstrictor responses to U46619 were potentiated by advanced atherosclerosis. Thus, vascular responses to serotonin, ADP, and thromboxane A2 are altered by atherosclerosis in a direction that would favor vasoconstriction when platelets aggregate. Furthermore, because responses to endothelium-dependent agonists are altered, these data suggest that endothelium is dysfunctional in early atherosclerosis. These findings may explain, in part, the propensity for exaggerated vasoconstriction even in arteries with minimal atherosclerotic lesions.