Key result
Chronic hyperhomocysteinemia severely impairs EDHF-mediated renal vasodilation compared with a standard diet.
Why the study?
The influence of hyperhomocysteinemia on endothelium-derived hyperpolarizing factor (EDHF)–mediated vasodilation in the renal microcirculation was unknown.
Chronic hyperhomocysteinemia severely impairs EDHF-dependent vasodilatory responses in the rat kidney, which may contribute to the development of microangiopathy.
Hyperhomocysteinemia may impair renal endothelial function; hypothesis-generating for human microvascular disease.
BACKGROUND: Endothelial dysfunction is an early event in the development of vascular complications in hyperhomocysteinemia. Endothelial cells release a number of vasodilators, including NO and prostacyclin. Several lines of evidence have indicated the existence of a third vasodilator pathway, mediated by endothelium-derived hyperpolarizing factor (EDHF). EDHF is a major determinant of vascular tone in small resistance vessels. The influence of hyperhomocysteinemia on EDHF is unknown. The present in vivo study evaluates the integrity of the EDHF pathway in the renal microcirculation of rats with acute and chronic hyperhomocysteinemia. METHODS AND RESULTS: EDHF-mediated vasodilation was evaluated as the renal blood flow (RBF) response to intrarenal acetylcholine during systemic NO synthase and cyclooxygenase inhibition. Acute hyperhomocysteinemia induced by intravenous homocysteine did not affect EDHF-mediated vasodilation. In contrast, intravenous methionine with subsequent hyperhomocysteinemia impaired the EDHF-mediated RBF response. When the methionine infusion was preceded by adenosine periodate oxidized to prevent the cleavage of S-adenosylhomocysteine to homocysteine and adenosine, a similar impairment of EDHF was observed, but with normal homocysteine levels. Animals with chronic hyperhomocysteinemia induced by a high-methionine, low-B vitamin diet during 8 weeks had a severely depressed EDHF-mediated vasodilation compared with those on a standard diet. Endothelium-independent vasodilation to deta-NONOate and pinacidil was not affected in acute and chronic hyperhomocysteinemia, demonstrating intact vascular smooth muscle reactivity. CONCLUSIONS: EDHF-dependent responses are impaired in the kidney of hyperhomocysteinemic rats. Because EDHF is a major regulator of vascular function in small vessels, these findings have important implications for the development of microangiopathy in hyperhomocysteinemia.
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Vriese et al. (2004) studied Hyperhomocysteinemia. Experimentally induced hyperhomocysteinemia vs. Standard diet / Baseline was evaluated on EDHF-mediated vasodilation (renal blood flow response to intrarenal acetylcholine). Chronic hyperhomocysteinemia induced by an 8-week high-methionine, low-B vitamin diet severely depressed EDHF-mediated vasodilation in the rat kidney compared with a standard diet.
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