Sex differences in the pressor and tubuloglomerular feedback response to angiotensin II. Hypertension 59:129–135

Abstract—Awareness of sex differences in the pathology of cardiovascular disease is increasing. Previously, we have shown a role for the angiotensin type 2 receptor (AT2R) in the sex differences in the arterial pressure response to Ang II. Tubuloglomerular feedback (TGF) contributes in setting pressure-natriuresis properties, and its responsiveness is closely coupled to renal Ang II levels. We hypothesize that, in females, the attenuated pressor response to Ang II is mediated via an enhanced AT2R mechanism that, in part, offsets Ang II–induced sensitization of the TGF mechanism. Mean arterial pressure was measured via telemetry in male and female wild-type (WT) and AT2R knockout (AT2R-KO) mice receiving Ang II (600 ng/kg per minute SC). Basal 24-hour mean arterial pressure did not differ among the 4 groups. After 10 days of Ang II infusion, mean arterial pressure increased in the male WT (286 mm Hg), male AT2R-KO (262 mm Hg), and female AT2R-KO (264 mm Hg) mice, however, the response was attenuated in female WT mice (124 mm Hg; P between sex and genotype0.016). TGF characteristics were determined before and during acute subpressor Ang II infusion (100 ng/kg per minute IV). Basal TGF responses did not differ between groups. The expected increase in maximal change in stop-flow pressure and enhancement of TGF sensitivity in response to Ang II was observed in the male WT, male AT2R-KO, and female AT2R-KO but not in the female WT mice (P between sex and genotype 0.05; both). In conclusion, these data indicate that an enhanced AT2R-mediated pathway counterbal-ances the hypertensive effects of Ang II and attenuates the Ang II–dependent resetting of TGF activity in females. Thus