Sex differences in endothelial function in porcine coronary arteries: a role for H2O2 and gap junctions?
OBJECTIVE
Cardiovascular risk is higher in men and postmenopausal women compared with premenopausal women. This may be due to sex differences in endothelial function. Here, sex differences in endothelial function of porcine coronary arteries (PCAs) were investigated.


METHODS
Distal PCAs were studied under myographic conditions and after precontraction with U46619. Concentration-response curves to bradykinin were constructed in the presence of a range of inhibitors.


RESULTS
In male and female PCAs, bradykinin produced comparable vasorelaxant responses. Inhibition of NO and prostanoid synthesis produced greater inhibition in males compared with females. Removing H2 O2 with PEG-catalase reduced the maximum relaxation in the absence, but not the presence of L-NAME and indomethacin in females, and had no effect in males. Blocking gap junctions with 100 µM carbenoxolone or 18α-glycyrrhetinic acid further inhibited the endothelium-derived hyperpolarization (EDH)-mediated response in females but not in males. In female PCAs, the maximum EDH-mediated response was reduced by inhibiting SKCa with apamin and by inhibiting IKCa with TRAM-34, or with both. In male PCAs, at maximum bradykinin concentration, the EDH-mediated response was reduced in the presence of apamin but not TRAM-34. Western blot did not detect any differences in connexins 40 or 43 or in IKCa expression between male and female PCAs.


CONCLUSIONS
H2 O2 mediated some part of endothelium-dependent vasorelaxation in female PCAs and EDH was more important in females, with differences in the contribution of gap junctions and IKCa channels. These findings may contribute to understanding vascular protection in premenopausal women.
Pharmacology Research Group, Queen's Medical Centre, School of Life Sciences, University of Nottingham Medical School, Nottingham, UK.
P S
PS
Wong
R E
RE
Roberts
M D
MD
Randall
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D002229:Carbenoxolone / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D017630:Connexins / Q000378:metabolism; D003331:Coronary Vessels / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D017629:Gap Junctions / Q000502:physiology*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012727:Sex Characteristics; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D017630:Connexins; D011720:Pyrazoles; C411671:TRAM 34; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C070295:catalase-polyethylene glycol; C119129:18alpha-glycyrrhetinic acid; D001030:Apamin; D011092:Polyethylene Glycols; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006861:Hydrogen Peroxide; D002374:Catalase; D002229:Carbenoxolone; D006034:Glycyrrhetinic Acid; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin
bradykinin; connexin (Cx); endothelium-derived hyperpolarization (EDH); gap junctions; hydrogen peroxide (H2O2); intermediate-conductance calcium-activated K+ channel (IKca); nitric oxide (NO); porcine coronary artery (PCA); sex differences; small-conductance calcium-activated K+ channel (SKca)