Gender differences in response to endothelin-1 in coronary arteries: transcription, receptors and calcium regulation.

1. Experiments were designed to determine how sex hormonal status may influence production and response to endothelins. 2. Circulating concentrations of endothelin-1 were not different between sexually mature male and female pigs and did not differ between females of low- and high-oestrogen status. 3. Expression of messenger RNA for preproendothelin was not different in aortic endothelial cells derived from sexually mature male and female pigs. 4. Endothelin-1, endothelin-3 and sarafotoxin S6c caused concentration-dependent contractions of rings of coronary arteries suspended for the measurement of isometric force. Only in response to endothelin-1 were contractions greater in arteries from female than in male pigs. This difference was not related to oestrogen levels in females. 5. The intrinsic force-calcium relationship defined in smooth muscle cells permeabilized with either triton-X or beta-escine was not different in coronary arteries from male and female pigs. The calcium sensitivity was increased to the same extent by endothelin-1 in smooth muscle from male and female pigs. 6. Competitive inhibition of radiolabelled endothelin-1 by unlabelled endothelin-1 was not different in membranes prepared from coronary arteries from male and female pigs. However, competitive inhibition of radiolabelled endothelin-1 by unlabelled endothelin-3 showed two binding sites. The affinity of the high affinity binding site was increased only in females with high oestrogen levels. 7. These results suggest that there are gender differences in contractions of porcine coronary arteries to endothelin-1. These differences may not relate to transcriptional regulation for the production of the peptide in endothelial cells, to the regulation of the number or affinity of endothelin receptors or to intrinsic calcium-sensitivity of the contractile proteins. Rather they are probably due to differences in the regulation of intracellular calcium.