Na + –K + –2Cl − cotransporter is implicated in gender differences in the response of the rat aorta to phenylephrine

1 Inhibition of the Na + –K + –2Cl − cotransporter (NKCC1) with bumetanide reduced contractile responses to phenylephrine (PE) in male rat aortas (129±4% of 60 m M KCl‐induced contraction control vs 108±7% bumetanide; PE 10 −5   M ; P <0.01) but did not change equivalent responses in female rat aortas. Removal of the endothelium blunted the effect of NKCC1 inhibition on the response to PE (10 −5   M ) in males, whereas in denuded aorta from female rats, bumetanide reduced this response (162±5% control vs 146±3% bumetanide; P <0.05). 2 NKCC1 basal activity did not show gender differences in intact aortic rings, but in the presence of PE, bumetanide‐sensitive 86 Rb + /K + uptake increased more in male than female aortas (179±8 in males vs 158±5 nmol 86 Rb + /K +  min −1  (g aorta) −1 in females; P <0.05). PE did not stimulate NKCC1 activity in denuded aorta from male rats. However, in female rats, PE increased NKCC1 activity similarly in both denuded (169±11 nmol 86 Rb + /K +  min −1  (g aorta) −1 ) and intact aortas. 3 Ovariectomy increased the bumetanide‐sensitive 86 Rb + /K + uptake increase elicited by PE (223±17 nmol 86 Rb + /K +  min −1  (g aorta) −1 ) and hormone replacement with 17 β ‐estradiol prevented this effect (159±29 nmol 86 Rb + /K +  min −1  (g aorta) −1 ). 4 Na + ,K + ‐ATPase basal activity, measured as ouabain‐sensitive 86 Rb + /K + uptake, was similar in male and female rats, but the effect of PE was significantly less in intact male aortas (232±16 in males vs 296±25 nmol 86 Rb + /K +  min −1  (g aorta) −1 in females; P <0.05). 5 Our results suggest that PE induced activation of NKCC1 and Na + ,K + ‐ATPase in the rat aorta in a gender‐dependent way.British Journal of Pharmacology (2006) 148 , 964–972. doi: 10.1038/sj.bjp.0706818