Time-Dependent Effects of Extraluminally-Applied Oxyhemoglobin and Endothelial Removal on Vasodilator Responses in Isolated, Perfused Canine Basilar Arteries

Abstract

The effects of oxyhemoglobin (oxyHb) and removal of the endothelium have been measured in isolated, perfused canine basilar arteries treated with intraluminal vasodilator drugs. In preparations with an intact endothelium, acetylcholine (ACh) produces a biphasic response, where a small vasodilation precedes a vasoconstriction. Calcium ionophore A23187 and thimerosal induce a vasodilation at low doses and a biphasic response at high doses. Sodium nitroprusside (SNP) evokes only a vasodilation. Extraluminally applied oxyHb itself produces a transient vasoconstriction and then a gradual increase in perfusion pressure. After this treatment, the vasoconstriction to ACh was enhanced as was the vasodilation to SNP. Significant attenuation of the vasodilator action of A23187 and thimerosal was also observed. Subsequent removal of endothelium produced no further change in response. This implies that the action of extraluminal oxyHb is to eliminate any endothelium-dependent responses. If cerebral vasospasm after subarachnoid hemorrhage is initiated by hemoglobin released from the clot surrounding the artery, at least one component of its action appears to involve interference with endothelial function.

The Pharmacology of Nitric Oxide in the Peripheral Nervous System of Blood Vessels

“…Methemoglobin was much less potent in scavenging NO (Martin et al, 1985b). In isolated, perfused rabbit basilar and dog femoral arteries, it was noted that extraluminal application of oxyHb interfered with the relaxation mediated by NO liberated from the endothelium, although the extent was less than that induced by intraluminal application (Hongo et al, 1988;Toda et al, 1988;Tsuji et al, 1989). The difference in vasoconstrictions in response to oxyHb and L-NA in vivo would be due to non-NO compounds such as vasoconstrictor prostanoids (Toda et al, 1980(Toda et al, , 1991aOkamoto et al, 1984;Fujiwara et al, 1984), free radicals, such as superoxide anions (Katusic and Vanhoutte, 1989) and hydroxyl radicals (Steele et al, 1991), endothelin-1 (Cooks et al, 1991Matsumura et al, 1991;Itoh et al, 1994), etc.…”

Temporal changes in perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin after subarachnoid hemorrhage

“…Recent studies have excluded or supported the following mechanisms: formation of oxygen radicals, 24,28 release of free radicals and initiation of lipid peroxidation, 3,47 release of eicosanoids, 33 development of proliferative arteriopathy, 43 and release of endothelin-1. 40,45 Other mechanisms, such as scavenging of endotheliumderived relaxing factor (EDRF)-nitric oxide (NO) 11,50 or damage to adventitial nerves, 16,20,42 remain under investigation.…”

“…However, deoxyhemoglobin, as oxyhemoglobin, also scavenges NO 19,22 in a reaction that produces a stable nitrosylhemoglobin. 19,53 Thus, both hemoglobins eliminate the action of this vasodilatory agent, 11,19,22,50 and vasospasm could be produced by the unopposed action of constricting agents 39,51 like endothelin-1. 40,45 The existence of such a mechanism is further supported by the loss of vasodilatory properties of the vessel wall 15,35 with preservation of its vasoconstrictive abilities.…”

Amelioration of Vasospasm After Subarachnoid Hemorrhage in Transgenic Mice Overexpressing CuZn–Superoxide Dismutase

“…In addition, it was reported that hemoglobin binding of NO inhibited endotheliumdependent relaxation in the cerebral artery. 43,44 In smooth muscle cells, soluble guanylate cyclase or guanosine monophosphate, which is necessary for the relaxation response, was reduced in the canine basilar artery after SAH. 45,46 Thus, scavenging of NO or decreased response of smooth muscle to NO may also result in impaired endothelium-dependent relaxation.…”