Gender difference in vascular and platelet reactivity to thromboxane A2-mimetic U46619 and to endothelial dependent vasodilation in Zucker fatty (hypertensive, hyperinsulinemic) diabetic rats

We examined the hypothesis that gender differences exist in platelet and vascular reactivity in type-2 diabetes mellitus, using Zucker fatty diabetic rats of both sexes and their lean littermates. Type-2 diabetes is characterized by excessive platelet production of TXA(2), which is thrombogenic. Testosterone up-regulates platelet TXA(2) receptors and the aggregation response to thromboxane mimetics. Conversely, estrogen increases vascular nitric oxide (NO) production and inhibits platelet aggregation. Hemodynamic studies were undertaken with the determination of dose-response curve for MAP and renal cortical blood flow (RCF) in response to U46619, angiotensin-II, phenylephrine and endothelin-1, as well as the systemic hemodynamic response to acetylcholine and L-NG nitro-arginine methylester (L-NAME). Platelet aggregation response was evaluated using whole blood impedance aggregometry. There were significant gender differences in the systemic blood pressure and RCF response to TXA(2)-mimetic U46619 and angiotensin-II (P <0.02, ANOVA) but not to phenylephrine or endothelin-1. Male rats exhibited a paradoxical hypotensive response to U46619 (-18 +/- 11 mmHg) compared with a peak pressor response of +6 +/- 1 mmHg in female rats (P < 0.01, ANOVA). The male rats exhibited an attenuated systemic vasodilator response (P < 0.001, ANOVA) to acetylcholine (fall in MAP in male diabetic rats being -24 +/- 8 mmHg, compared with a fall of -50 +/- 8 mmHg in females), but a greater rise in the renal cortical resistance in response to NO inhibition by L-NAME (P < 0.03) compared with the female rats. Both the slope (46 +/- 2) and the peak magnitude of the U46619-induced whole blood platelet aggregation (13 +/- 1) ohms were significantly higher (P <0.01, ANOVA) in male (n = 10)compared with female diabetic rats (n = 8) (29 +/- 0.8 slope, 10.0 +/- 0.8 ohms, respectively). Thus, the male diabetic Zucker rats exhibited an impaired response to vasoconstrictors (U46619 and angiotensin-II) and to endothelial (NO)-mediated vasodilation. The male gender may therefore be associated with the greater prothrombotic activity and a worse impairment of endothelial reactivity in the type-2 diabetic state. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.