H2O2 and endothelium-dependent cerebral arteriolar dilation. Implications for the identity of endothelium-derived relaxing factor generated by acetylcholine.

Abstract

We studied the mechanism of the vasodilator effect of H2O2 on cerebral arterioles and its effect on endothelium-dependent responses to acetylcholine. Topical application of H2O2 (0.1-1 microM) on the brain surface of anesthetized cats equipped with cranial windows induced dose-dependent arteriolar dilation, which was markedly inhibited by topical deferoxamine, showing that it was probably mediated by generation of hydroxyl radical. Higher concentrations of H2O2 (3 microM) also induced dilation, which was unaffected by deferoxamine, indicating the participation of other mechanisms. After topical application of H2O2, endothelium-dependent responses to acetylcholine were eliminated or converted to vasoconstriction, and in bioassay experiments, acetylcholine-mediated endothelium-derived relaxing factor (EDRF) was absent. Superoxide dismutase plus catalase restored the appearance of transferable EDRF after 1 microM H2O2 but not after 3 microM H2O2. Application of H2O2 in the assay window eliminated the responses to nitroprusside and nitric oxide but did not affect responses to adenosine, to EDRF from the donor window, or responses to S-nitroso-L-cysteine. The inhibiting effect of H2O2 on the response to nitroprusside was partially eliminated after topical application of N-acetyl-L-cysteine. The results show that H2O2 inhibits the vasodilator action of nitroprusside and nitric oxide probably because it oxidizes thiols in vascular smooth muscle and prevents the formation of a nitrosothiol. EDRF from acetylcholine and S-nitroso-L-cysteine still produce dilation in the presence of the blockade induced by H2O2. The findings suggest strongly that the EDRF from acetylcholine in cerebral vessels is a nitrosothiol like S-nitroso-L-cysteine.

Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen.

“…We (34,35) and, more recently, others (64) have reported that biological thiols potentiate the bioactivity of EDRF. There is ample evidence in this regard that thiols react with NOx to form S-nitrosothiols (28,29,46,53). In support of biological relevance for SNOHO, we have now demonstrated HCYSH-dependent Snitrosothiol formation from endogenously derived NOx.…”

“…At the same time, however, our understanding of the role played by the endothelium in modulating platelet-vessel wall interaction has changed substantially. It is now widely appreciated that the endothelium plays a dynamic role in counteracting platelet activation by secreting products such as prostacyclin and endothelium-derived relaxing factor (EDRF), the latter having been identified as nitric oxide (NO [ 26,27 ] or a closely related S-nitrosothiol [ RS-NO ] [ 28,29 ]). …”

Constriction/Dilatation of the Cerebral Microvessels by Intravascular Endothelin-1 in Cats

“…L-NMMA competitively blocks the production of nitric oxide from L-arginine (Palmer et al, 1988) that may occur in the cerebrovascular endothelium, vascular smooth muscle, and perivascular nerve terminals (Bredt et al, 1990). Nitric oxide has been proposed to be the EDRF in the cerebral vessels (Faraci, 1990;Prado et al, 1992), although some authors support nitrosothiol as a candidate at least for ace tylcholine (Wei and Kontos, 1990;Rosenblum, 1992). It seems likely, therefore, that nitric oxide, or EDRF, participated in the cerebral vasodilative effect of high doses of ET -1 observed in the present study.…”

Potential Benefits of Peroxynitrite

“…NO reacts with superoxide, which is also produced during reperfusion, to form PN, and also the powerful and cytotoxic oxidants, hydroxyl radical and nitrogen dioxide [29]. Superoxide, hydrogen peroxide, and hydroxyl radicals are reported to be strongly vasoactive [21,23,[78][79][80]. Brain metabolism regulates cerebral blood flow, and studies suggest that changes in extracellular potassium concentration link brain metabolic activity with blood flow [81].…”

“…PN and hydrogen peroxide can generate hydroxyl radicals [5,165,175], that produce tissue injury [93,115,[176][177][178], and produce pronounced cerebral arteriolar dilation in low concentrations [80,82], as both radicals dilate cerebral arterioles by opening ATP-sensitive potassium channels [82]. Wei, Kontos et al examined the roles of these radicals on vascular responses and how these radicals are modified by radical scavengers in a feline cranial window model [179].…”