Sex-Specific Effect of Endothelin in the Blood Pressure Response to Acute Angiotensin II in Growth-Restricted Rats

Abstract

The renal endothelin system contributes to sex differences in blood pressure with males demonstrating greater endothelin type-A receptor-mediated responses relative to females. Intrauterine growth restriction programs hypertension and enhance renal sensitivity to acute angiotensin II in male growth-restricted rats. Endothelin is reported to work synergistically with angiotensin II. Thus, this study tested the hypothesis that endothelin augments the blood pressure response to acute angiotensin II in male growth-restricted rats. Systemic and renal hemodynamics were determined in response to acute angiotensin II (100 mg/kg per minute for 30 minutes) with and without the endothelin type-A receptor antagonist, Atrasentan (ABT-627; 10 ng/kg per minute for 30 minutes), in rats pretreated with enalapril (250 mg/L for 1 week) to normalize the endogenous renin-angiotensin system. Endothelin type-A receptor blockade reduced angiotensin II-mediated increases in blood pressure in male control and male growth-restricted rats. Endothelin type-A receptor blockade also abolished hyper-responsiveness to acute angiotensin II in male growth-restricted rats. Yet, blood pressure remained significantly elevated above baseline after endothelin type-A receptor blockade, suggesting that factors in addition to endothelin contribute to the basic angiotensin II-induced pressor response in male rats. We also determined sex-specific effects of endothelin on acute angiotensin II-mediated hemodynamic responses. Endothelin type-A receptor blockade did not reduce acute angiotensin II-mediated increases in blood pressure in female control or growth-restricted rats, intact or ovariectomized. Thus, these data suggest that endothelin type-A receptor blockade contributes to hypersensitivity to acute angiotensin II in male growth-restricted rats and further supports the sex-specific effect of endothelin on blood pressure.

Keywords: angiotensin II; blood pressure; endothelins; renin–angiotensin system; sex characteristics.

Figure 1. Mean arterial Pressure (MAP)

a) Male control and growth-restricted (IUGR) rats. b) Female control and growth-restricted rats. MAP was measured at 16 weeks of age in chronically instrumented, conscious animals pretreated with the angiotensin convertor enzyme inhibitor, enalapril (250mg/L for 1 week). MAP was measured at baseline during an acute infusion of ANG II (100 ng/kg/min) for 30 min, and during a 30 minute infusion of ANG II plus the ET_A receptor antagonist, ABT-627 (10 ng/kg/min for 30min). Values were allowed to return to baseline between acute treatments. *P<0.05 versus baseline control. †P<0.05 versus baseline IUGR. ‡ P< 0.05 vs. ANG II control. # P<0.05 vs. Ang II IUGR.. Data values represent mean±SEM

Figure 2. Glomerular Filtration Rate (GFR)

a) Male control and growth-restricted (IUGR) rats. b) Female control and growth-restricted rats. GFR was measured at 16 weeks of age in chronically instrumented, conscious animals pretreated with the angiotensin convertor enzyme inhibitor, enalapril (250mg/L for 1 week). Renal function was measured at baseline during an acute infusion of ANG II (100 ng/kg/min) for 30 min, and during a 30 minute infusion of ANG II plus the ET_A receptor antagonist, ABT-627 (10 ng/kg/min for 30 min). Values were allowed to return to baseline between acute treatments. *P<0.05 versus baseline control. †P<0.05 versus baseline IUGR. ‡ P< 0.05 vs. ANG II control. # P<0.05 vs. Ang II IUGR. Data values represent mean±SEM.

Figure 3. Effective Renal Plasma Flow (eRPF)

a) Male control and growth-restricted (IUGR) rats. b) Female control and growth-restricted rats. eRPF was measured at 16 weeks of age in chronically instrumented, conscious animals pretreated with the angiotensin convertor enzyme inhibitor, enalapril (250mg/L for 1 week). Renal function was measured at baseline during an acute infusion of ANG II (100 ng/kg/min) for 30 min, and during a 30 minute infusion of ANG II plus the ET_A receptor antagonist, ABT-627 (10 ng/kg/min for 30min). Values were allowed to return to baseline between acute treatments. *P<0.05 versus baseline control. †P<0.05 versus baseline IUGR. ‡ P< 0.05 vs. ANG II control. # P<0.05 vs. Ang II IUGR. § P< 0.05 vs. ANG+ABT II control. Data values represent mean±SEM.

Figure 4. Renal Vascular Resistance (RVR)

a) Male control and growth-restricted (IUGR) rats. b) Female intact control and growth-restricted rats. RVR was measured at 16 weeks of age in chronically instrumented, conscious animals pretreated with the angiotensin convertor enzyme inhibitor, enalapril (250mg/L for 1 week). Renal function was measured at baseline during an acute infusion of ANG II (100 ng/kg/min) for 30 min, and during a 30 minute infusion of ANG II plus the ET_A receptor antagonist, ABT-627 (10 ng/kg/min for 30min). Values were allowed to return to baseline between acute treatments. *P<0.05 versus baseline control. †P<0.05 versus baseline IUGR. ‡ P< 0.05 vs. ANG II control. # P<0.05 vs. Ang II IUGR. Data values represent mean±SEM.