Sex differences in myogenic tone: a novel physiological role for EDHF

1Melissa V. Chan, 2Adrian J. Hobbs, 1Ramona S. Scotland & 1Amrita Ahluwalia 1Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, 2WIBR, UCL, Gower St, London WC1E 6AE.

A major mechanism involved in regulating vascular tone, and therefore organ blood flow and blood pressure, is myogenic constriction; described as the constriction produced in response to increases in intraluminal pressure in resistance arteries. Myogenic constriction is moderated by the release of endothelium-derived dilators that tonically oppose the constriction response. Recently we have demonstrated that endothelium-dependent relaxation is predominantly mediated by nitric oxide (NO) and, to a lesser extent, prostacyclin (PGI2) in male arteries but by endothelium-derived hyperpolarising factor (EDHF) in female arteries, a difference that appears to be associated with a protection of female mice from experimentally-induced hypertension (Scotland et al., 2005). In the current study we have investigated whether there are differences in the magnitude of the myogenic response in arteries of male and female mice and whether the sex-specific release of endothelium-derived dilators might underlie any differences seen.

Male and female (8-10 weeks old) C57BL/6 mice were killed by cervical dislocation, the mesenteric bed rapidly removed and placed in cold Krebs solution. Third order arteries (80-120 μm) were cleaned of extraneous tissue, mounted in a perfusion myograph chamber (Living Systems) and superfused with Krebs at 10ml/min (37°C, gassed with 21%O2/ 5% CO2 in N2). Pressure-diameter curves (20-100mmHg) were constructed, in the absence of flow, in 20mmHg steps. Responses were measured in the absence and presence of inhibitors of the synthesis or release of NO (L-NAME, 300μM, 30min), PG2 (indomethacin, 5 μM, 30 min), or EDHF (TRAM-34 (10μM) with apamin (50nM), 30 min). Passive diameter (Dpassive) at each pressure was measured in the presence of Ca2+-free Krebs containing 2mM EGTA. Myogenic constriction at each pressure was calculated as (Dpassive- Dactive)/Dpassive x 100%.

All vessels developed constriction at pressures above 60mmHg. However, myogenic constriction was significantly (P<0.01) greater in male arteries than female arteries (tone at 100mmHg was 25.9±2.3%, n=15 and 20.9±2.4%, n=12 respectively). L-NAME significantly enhanced myogenic constriction in both male (from 23.9±3.5% to 32.5±3.3%, n=5, P<0.001) and female (from 18.6±3.7% to 33.6±3.1%, n=5, P<0.001) arteries whilst indomethacin had no significant effect on myogenic tone in arteries from either sex (n=5 for each). Inhibition of EDHF release had no affect on myogenic tone in males (n=5), but caused a profound increase in myogenic constriction in female arteries (from 20.2±3.9% to 30.4±2.8%, n=5, P<0.001).

Our results show that the magnitude of myogenic constriction is greater in male mesenteric resistance arteries than female. Whilst NO opposes myogenic tone in arteries from both sexes, EDHF moderates pressure-induced constriction in arteries of female mice only. This sex-specific release of EDHF may underlie the decreased constriction of female resistance arteries to pressure elevation and is likely to contribute to the relative protection of females from hypertension and endothelial dysfunction, when NO bioavailability is reduced.

Scotland, R.S. et al. (2005) Circulation, 111: 796-803