Abstract 5: Intrarenal Responses to Angiotensin I and Angiotensin (1-7) in the Stroke-Prone Spontaneously Hypertensive Rat Are Y Chromosome Dependent

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The Y chromosome accounts for 15-20mmHg difference in arterial pressure; the gene(s) and mechanism(s) underlying this effect remain unknown. One candidate gene, the Sry3 gene, expressed exclusively on the hypertensive SHR Y chromosome has been shown in vitro to interact with the renin angiotensin system (RAS). Using a reciprocal Y consomic rat approach, we investigated the functional consequences of this interaction in vivo; examining the interaction of the Y chromosome with the renal vasculature. 16 week old normotensive rats (WKY), hypertensive rats (SHRSP) and two reciprocal Y consomic rat strains; one comprising the WKY autosomes and X chromosome with the hypertensive Y chromosome (WKY.SPGlaY) and vice versa (SP.WKYGlaY) were examined. We confirmed via radiotelemetry that systolic blood pressure (SBP) was Y chromosome dependent; SP.WKYGlaY had lower SBP than SHRSP (195±5mmHg vs 227±8mmHg, P<0.03) and was higher in WKY.SPGlaY compared to WKY (157±3mmHg vs 148±3mmHg, P<0.05). Compared to WKY rats, the vasodilator arm of the RAS was enhanced in SHRSP as evidenced by a higher plasma Ang(1-7):Ang II ratio (WKY:0.13±0.01 vs SHRSP:1.33±0.4, P<0.005) and a blunted renal blood flow (RBF) response to graded intrarenal Ang I and Ang(1-7) infusions. In response to 10ng/kg we observed a reduction in RBF of WKY:58±6% and 16±6% vs SHRSP: 17±6%, P<0.01 and 1±4%, P<0.05 respectively. Introgression of the normotensive Y chromosome into the SHRSP background (SP.WKYGlaY) resulted in a reduction in plasma Ang(1-7):AngII ratio (SP.WKYGlaY: 0.24±0.02, P<0.01) and an increased vasoconstrictor response to intrarenal Ang I and Ang(1-7) infusion. In response to 10ng/kg bolus RBF in SP.WKYGlaY reduced by 45±14%, P<0.01 and 41±18%, P<0.005, respectively compared to SHRSP, demonstrating the blunted responsiveness in the SHRSP is Y chromosome dependent. Investigation of the interlobular arteries via wire myography revealed increased sensitivity to Ang II in SHRSP compared to WKY which was reduced following introgression of the WKY Y chromosome (SP.WKYGlaY) confirming that the Y chromosome influences the RAS in the renal vasculature. This study provides novel evidence that the Y chromosome influences the vasodilatory arm of the RAS and intrarenal vascular function.

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