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| Sex hormone regulation of systemic endothelial and renal microvascular reactivityin type-2 diabetes: studies in gonadectomized and sham-operated Zucker diabetic rats. A A Ajayi, G O Ogungbade, A O Okorodudu Eur J Clin Invest 2004; 34(5):349-357 ICID: 440114 |
| Article type: Original article |
| IC™ Value: 34.83 |
| BACKGROUND: Male Zucker diabetic rats exhibit a more severe endotheliopathyin comparison with their female diabetic litter mates. The plasma concentrations of both thromboxanesand endothelins are elevated in diabetes, and the receptor cross-talk between TXA(2) and ET-1 receptorsmay be enhanced in type-2 diabetic Zucker rats. AIMS: To determine the role of the endogenous sex steroidhormones, testosterone and estradiol on the systemic and renal microvascular reactivity to ET-1, thromboxane-mimeticU46619, ET-TXA(2) receptor interaction, and the nitric oxide vasodilator system in Zucker hypertensive-diabeticrats. METHODS: Male and female Zucker rats aged 8-10 weeks were each divided into two groups. The malerats were castrated or underwent a sham operation. The female rats were spayed (bilateral ovariectomyand hysterectomy) or had a sham operation. All rats were studied 4-6 weeks after the gonadectomy or shamoperations. Blood glucose and insulin as well as plasma concentrations of testosterone and estradiolwere determined. Haemodynamic studies were undertaken with determination of the dose-response curve formean arterial pressure (MAP), renal cortical flow (RCF) and renal medullary blood flow (MBF) in responseto ET-1 and U46619, and the effect of interdiction of the ET-TXA(2) interaction with ET-antagonists BQ610and BQ788. The role of endogenous NO was assessed by its response to graded acetylcholine doses and toa L-NG-nitro-arginine methyl ester (L-NAME) infusion. RESULTS: Castrated male rats had a significantlylower blood glucose concentration (295 +/- 33 mg dL(-1)) compared with their sham-controls (481 +/- 40mg dL(-1)), P = 0.008. Mean arterial pressure tended to be lower in the castrated rats. Gonadectomy reducedthe plasma testosterone and estradiol concentrations. Castration abolished the hypotensive action ofU46619 compared with sham-operated male rats (P < 0.0001, anova). Conversely, the pressor action of U46619seen in the sham-operated female rats was reversed to a profound hypotensive action in the spayed rats(P < 0.001, anova). The change in MAP after U46619 was inversely correlated to the plasma testosteroneconcentration (r = -0.73, P = 0.027). The paradoxical hypotensive response elicited by ET-1 in the Zuckerdiabetic rats of both sexes was abolished by castration only (P < 0.005, anova). Castration caused asignificant (P = 0.011) augmentation of the vasodilator response to acetylcholine, while spaying causeda slight attenuation. Castration, but not spaying, resulted in significant increases in MBF after U46619(P = 0.003, anova), ET-1 (P = 0.005, anova) and acetylcholine (P = 0.053, anova). The ET-(B) antagonistBQ788 augmented the U46619-induced rise in MAP in castrated male rats, and also abolished the U46619-inducedincrease in MBF (P < 0.01 anova). L-NAME (25 mg kg(-1)) increased MAP and decreased MBF in the gonadectomizedand sham-operated rats, except for the castrated male Zucker rats, where it significantly increased MBF(+90 +/- 31 PU) (P = 0.0004, anova) despite the increase in MAP. CONCLUSIONS: Testosterone and estradiolregulate systemic and microvascular reactivity to TXA(2) receptor stimulation in type-2 diabetic Zuckerrats. The impact of testosterone on blood glucose concentration, blood pressure, and the systemic andrenal microcirculatory response to ET-1 and NO, as well as the endothelin-thromboxane receptor crosstalk, is greater, and opposite to that of estradiol. The effects of testosterone withdrawal may at leastin part be mediated by the ET-B receptor subtype and NO generation. Androgen blockade should be investigatedfurther for the reversal or delay of hypertensive-diabetic endotheliopathy. |
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ICID 440114 PMID 15147332 - click here to show this article in PubMed database |
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