Gender differences in mesenteric relaxations to anandamide and carbachol in Spontaneously Hypertensive Rats

W.-S. Vanessa Ho. St George’s, University of London, London, United Kingdom.

Gender is thought to influence vascular function, particularly in relation to endothelial dysfunction in hypertension. Using isolated small mesenteric arteries from male Spontaneously Hypertensive Rats (SHR), we have recently demonstrated that relaxation to the endocannabinoid, anandamide is partly endothelium (ec)-dependent and is limited by degradation via fatty acid amide hydrolase (FAAH; Ho, 2008). Here, we have examined the mesenteric relaxation to anandamide and carbachol, a mucarinic receptor agonist that requires ec to elicit relaxations, in female and male SHR (Charles River; 200-350g). Data are expressed as mean±s.e.m (n≥4 rats) and analysed by two-way analysis of variance of the whole data set. P<0.05 was considered statistically significant. In female SHR, relaxation to anandamide was slightly attenuated by endothelial removal (+ec: pEC50 = 6.1±0.1; Emax = 97±1%; -ec: pEC50 = 5.9±0.1; Emax = 90±2%; P<0.01) and displayed greater (P<0.05) maximal responses than in male SHR (+ec: pEC50 = 6.8±0.2; Emax = 72±8%; -ec: pEC50 = 6.1±0.3; Emax = 57±7%; vs +ec, P<0.01). However, anandamide responses in females were not affected by treatment with the FAAH inhibitor, URB597 (3’-carbamoyl biphenyl-3-yl-cyclohexylcarbamate), 17β-estradiol or testosterone (all at 1μM) (+ec, +URB597: pEC50 = 6.4±0.4; Emax = 94±1%; +17β-estradiol: pEC50 = 6.1±0.2; Emax = 100±4%; +testosterone: pEC50 = 6.4±0.3; Emax = 96±1%). On the other hand, the endothelium-dependent responses to carbachol were biphasic; initial relaxations (male: pEC50 = 7.5±0.1; Emax = 97±1%; female: pEC50 = 7.0±0.1; Emax = 88±5%; P<0.01) followed by contractions at concentrations ≥1μM. Carbachol-induced contractions were inhibited by the cyclooxygenase inhibitor, indomethacin (10μM) and were attenuated in female SHR (data not shown). These data suggest that, despite endothelium impairments in SHR, anandamide induces greater mesenteric relaxations in females, which are accompanied by subtle, gender differences in the activities of FAAH and cyclooxygenases.

Ho WS (2008). Fundam Clin Pharmacol, 22: 12.