Effects of Endothelin in Integrated Venous Function in Health and Disease

Al-Najeer, Afrah
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University of Guelph

The endothelin system and integrated venous function are both under the influence of sex steroids. However, there is limited understanding of the influence of gender and acute deprivation of steroid hormones on venoconstrictor responses to ET-1. Unpressurized mesenteric vessels of gonadally intact, or neutered male and female rats were used to assess vascular responses to (Endothelin) ET-1 or the selective endothelin B receptor (ETBR) agonist, sarafotoxin 6c (S6c) in presence and absence of the selective endothelin A receptor (ETAR) antagonist (BQ-610) and/or and the selective ETBR antagonist (BQ-788). There were no differences in ET-1 contractile responses between intact male and female rats. However, S6c produced significantly greater responses in the veins of intact male compared to intact female. In intact rats, blockade of ETARs revealed gender related differences in ETAR mediated venoconstriction, whereas blockade of both ETARs and ETBRs eliminated these differences. Ovariectomy enhanced the contractile responses to S6c in veins. Blockade of ETARs by BQ-610 was reduced in veins following ovariectomy and castration. These results suggest that intact male veins produce greater ETBR mediated contractions, estrogen can modulate ETBR mediated contractions, and ETARs are under the influence of both sex steroid hormones. HF is associated with elevated plasma ET-1 levels and an increase in cardiac preload due to venoconstriction. The role of elevated plasma ET-1 levels in altered venous functions in HF has not been evaluated yet. Therefore we aimed to identify the changes in ET-1 vascular contractile responses and concomitant alterations in the ET-1 receptors mediated vascular contractile responses together with changes in receptors mRNA and protein expression levels in mesenteric veins. At 4, 8 and 16 weeks post sham operation or Myocardial infarction (MI), venoconstrictor responses were recorded using a pressure myograph. RT-qPCR and Western blotting were used to quantify mRNA and protein expression of receptors. In Mesenteric veins, vasoconstrictor responses to ET-1 and S6c were progressively reduced in the period following MI. BQ-788 significantly reduced ET-1 responses in 4 and 16wk sham but not HF mice. BQ-610 abolished ET-1 responses in 4wk HF and sham mice, whereas in 16 wk mice, BQ-610 caused greater inhibition in ET-1 responses in HF than sham mice and co-application of BQ-788/BQ-610 completely inhibited ET-1 responses in sham and HF mice. ETBR but not ETAR mRNA and protein expression was decreased in HF mesenteric veins compared to those of sham mice. In conclusion, a reduced venoconstrictor response to ET-1 in HF is associated with the functional and molecular down regulation of venous ETBR post-MI

Endothelin-1, Heart failure, veins, gender