Venous contraction to endothelin-1 in congestive heart failure.

Abstract

Endothelin-1 (ET-1) is produced by endothelial cells and can stimulate either the ET A or the ET 8 receptors. The role of ET-1 and the identity of the endothelin receptors involved in mediating tone in the mesenteric small veins of the -Golden Syrian hamster are not known. ET-1. induces venoconstriction, thereby increasing the preload to the heart in congestive heart failure. However, mechanisms mediating contraction to ET-1 in the mesenteric small veins of the cardiomyopathic hamsters in the early and late stages of CHF are not known. Therefore, mechanisms mediating ET-1 induced contraction were determined in the mesenteric small veins of the Golden Syrian and cardiomyopathic hamsters in the early and late sta~es of CHF. Baseline intraluminal diameter of small veins was measured before anci after treatment with either ET A or ET 8 receptor antagonists. .ET-1 induced contraction was higher in the · early stage of CHF, while it was· decreased in the late stage of CHF. Blockade of the ET A receptor decreased ET-1 induced contraction in the mesenteric small veins from the control and cardiomyopathic hamsters in both the early and late stage of CHF. ET 8 receptor blockade decreased the ET-1 induced contraction in the control and cardiomyopathic hamsters in the early, but not late, stage of CHF. Therefore, ET-1 induced contraction in the mesenteric small veins is mediated by the ET A receptors alone in the late stage of CHF, while both the ET A and ET 8 receptors mediate vasoconstriction in the controls and in the early stage of CHF. Stimulation of ET-1 receptors is associated with an increase in calcium levels within the vascular smooth muscle cells. It is not known whether the increase in reactivity to ET-1 in the early stage of CHF or the decrease in reactivity to ET-1 in the late stage of CHF is due to problems with mobilization of the intracellular calcium levels within the vascular smooth muscle cell. Following ET-1, calcium levels within the vascular smooth muscle cell were increased to a larger extent in the early stage of CHF, than in the late stage _of CHF, in agreement with the vascular reactivity data. Calcium levels were also measured before and after treatment with either ET A or ET B receptor antagonists. Blockade of the ETA receptor inhibited the ET-1. ·induced increase in calcium levels in the mesenteric small veins from the control and cardiomyopathic hamsters in both the early and late stage of CHF. However, ETa_ receptor blockade inhibited the ET-1 induced increase in calcium levels in only the control and cardiomyopathic hamsters in the early stage of CHF. These results indicate the absence of a functional responses mediated by the ET a receptor in the late stage of CHF. Studies have shown that NO can modulate the contraction to ET-1 in the vasculature. Baseline intraluminal diameter of small veins were measured before and after treatment with N-nitro-L-arginine (LNA), a specific inhibitor of nitric oxide · synthase. LNA decreased the contraction to ET-1 in the early stage of CHF, but increased contraction to ET-1 in the late stage of CHF. This indicates thatNOS mediates a vasodilatory effect that counteracts contraction to ET-1 in the late stage, but contributes to the vasoconstrictor effect of ET-1 in the late stage of CHF. NOS activity was. measured to identify the NOS isoforms contributing to the modulation of ET-1 induced vascular reactivity. Total NOS activity was significantly increased in the cytosolic fraction of small veins from hamsters in the late stage of CHF and in the particulate fraction in hamsters in the early stage of CHF. In the late stage, the increase in NOS activity was inhibitable by 1400W, an iNOS selective inhibitor, suggesting that an increase in iNOS decreases the contraction to ET-1. In summary, in the early stage of CHF, there is an increase in the vascular reactivity to ET-1 associated with an increase in intracellular calcium levels and partially mediated by NOS. This may-increase preload and impair myocardial function in CHF. There is an absence of ET 8 receptor-mediated responses in the late stage of CHF, associated with very high plasma ET -1 levels and imp•aired intracellular calcium · signaling. NOS activity is significantly enhance4 in the mesenteric small veins from the cardiomyopathic hamsters in the late phase of CHF, and this increase in NOS activity is at least partially dependent on iNOS and may contribute to impaired venous contraction to ET-1 in cardiomyopathic hamsters. This may serve as a compensatory mechanism to decrease the preload to the failing heart.