Afferent arteriole responsiveness to endothelin receptor activation: does sex matter?

BACKGROUND: The pathogenesis of hypertension is distinct between men and women. Endothelin-1 (ET-1) is a potential contributor to sex differences in the pathophysiology of hypertension. ET-1 participates in blood pressure regulation through activation of endothelin A (ET(A)) and endothelin B (ET(B)) receptors including those in the vasculature. Previous studies demonstrated that sex and sex hormones evoke discrepancies in ET-1-mediated control of vascular tone in different vascular beds. However, little is known about sex- and sex hormone-related differences in ET-1-dependent renal microvascular reactivity. Accordingly, we hypothesized that loss of sex hormones impairs afferent arteriole reactivity to ET-1. METHODS: Male and female Sprague Dawley rats were subjected to gonadectomy or sham surgery (n = 6/group). After 3 weeks, kidneys from those rats were prepared for assessment of renal microvascular responses to ET-1 (ET(A) and ET(B) agonist, 10(−12) to 10(−8) M) and sarafotoxin 6c (S6c, ET(B) agonist, 10(−12) to 10(−8) M) using the blood-perfused juxtamedullary nephron preparation. RESULTS: Control afferent arteriole diameters at 100 mmHg were similar between sham male and female rats averaging 14.6 ± 0.3 and 15.3 ± 0.3 μm, respectively. Gonadectomy had no significant effect on control arteriole diameter. In sham males, ET-1 produced significant concentration-dependent decreases in afferent arteriole diameter, with 10(−8) M ET-1 decreasing diameter by 84 ± 1%. ET-1 induced similar concentration-dependent vasoconstrictor responses in sham female rats, with 10(−8) M ET-1 decreasing the diameter by 82 ± 1%. The afferent arteriolar vasoconstrictor responses to ET-1 were unchanged by ovariectomy or orchiectomy. Selective ET(B) receptor activation by S6c induced a concentration-dependent decline in afferent arteriole diameter, with 10(−8) M S6c decreasing diameter by 77 ± 3 and 76 ± 3% in sham male and female rats, respectively. Notably, ovariectomy augmented the vasoconstrictor response to S6c (10(−12) to 10(−9) M), whereas orchiectomy had no significant impact on the responsiveness to ET(B) receptor activation. CONCLUSION: These data demonstrate that sex does not significantly influence afferent arteriole reactivity to ET receptor activation. Gonadectomy potentiated the responsiveness of the afferent arteriole to ET(B)-induced vasoconstriction in females, but not males, suggesting that female sex hormones influence ET(B)-mediated vasoconstriction in the renal microcirculation.