Abstract
BackgroundThe 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 (ETA) and endothelin B (ETB) 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.MethodsMale 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 (ETA and ETB agonist, 10−12 to 10−8 M) and sarafotoxin 6c (S6c, ETB agonist, 10−12 to 10−8 M) using the blood-perfused juxtamedullary nephron preparation.ResultsControl 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 ETB 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 ETB receptor activation.ConclusionThese data demonstrate that sex does not significantly influence afferent arteriole reactivity to ET receptor activation. Gonadectomy potentiated the responsiveness of the afferent arteriole to ETB-induced vasoconstriction in females, but not males, suggesting that female sex hormones influence ETB-mediated vasoconstriction in the renal microcirculation.
Highlights
The pathogenesis of hypertension is distinct between men and women
Effect of gonadectomy on Afferent arterioles (AA) responsiveness to ET-1 To assess the role of male and female sex hormones on ET-1-induced vasoconstriction of AA, we determined the effect of OVX and ORX on AA responsiveness to ET-1 compared to vessels from sham-operated male and female rats, respectively
AA reactivity to ET-1 in arterioles from OVX rats was similar to responses from sham-operated females (Fig. 2b)
Summary
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. The literature contains multiple studies showing that premenopausal women have lower blood pressure than age-matched men [1,2,3] This male-female difference in blood pressure can be further exaggerated in different experimental models of hypertension [3], highlighting that mechanisms regulating blood pressure are sex-specific. Vascular tone is under strict control relying on a balance between vasoconstrictor and vasodilator signaling mechanisms [4] Alterations in these vasodilator and/or vasoconstrictor signals are implicated as central contributors to the pathogenesis of hypertension and even end organ injury. The overall impact of ET-1 on vascular tone results from a balance between direct vasoconstrictor effects via ETA and ETB receptors on smooth muscle cells and vasodilator effects mediated by ETB receptors on endothelial cells [12]
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