Summary
Changes with age in the coronary vascular response to endothelin-1 were investigated in perfused hearts isolated from 2-, 6- and 24-month-old (mo) male Fisher-344 rats. Endothelin-1 injected as a single bolus (0.3, 3 and 30 nmol) into the coronary artery supply caused dose-dependent vasoconstriction in all three age groups. While there was no age-related change in the vasoconstriction induced by the lower doses (0.3 and 3 nmol), the higher dose (30 nmol) elicited a more pronounced vasoconstriction in 6- and 24-mo rats than that in 2-mo rats. NG-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide formation, markedly enhanced the vasoconstriction induced by 30 nmol endothelin-1 in 2-and 6-mo rats but only slightly and non-significantly enhanced that vasoconstriction in 24-mo rats. Haemoglobin, which inhibits activation of guanylate cyclase by nitric oxide, enhanced the endothelin-1-induced vasoconstriction in 2-mo rats, but not in 6- and 24-mo rats. The acetylcholine-induced coronary vasodilation was more pronounced in 2- and 6-mo rats than in 24-mo rats and was attenuated by L-NNA in 2- and 6-mo rats. The coronary vasodilation induced by nitroprusside (0.1 mmol), a pharmacological precursor of nitric oxide, did not change with age. Endothelin-1 (30 nmol) markedly increased the release of 6-keto-prostaglandin F1α, (6-keto-PGF1α) in all three age groups. The prostaglandin synthesis inhibitor indomethacin enhanced the endothelin-1-induced vasoconstriction in 2- and 6-mo rats to a similar extent. These results indicate that endothelium-derived vasodilators such as endothelium-derived relaxing factor (EDRF) and prostacyclin may be released by endothelin-1 to modulate the endothelin-1-induced coronary vasoconstriction. The endothelial cell function to release EDRF in response to endothelin-1 decreases with aging. This decrease in EDRF release may be the main factor in the increase with age of the endothelin-1-induced coronary vasoconstriction.
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Katano, Y., Ishihata, A., Morinobu, S. et al. Modulation by aging of the coronary vascular response to endothelin-1 in the rat isolated perfused heart. Naunyn-Schmiedeberg's Arch Pharmacol 348, 82–87 (1993). https://doi.org/10.1007/BF00168541
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DOI: https://doi.org/10.1007/BF00168541