Superoxide dismutase decreases mortality, blood pressure, and cerebral blood flow responses induced by acute hypertension in rats.

Abstract

Oxygen radicals are known to be produced by the cerebral vasculature during acute, pressor-induced hypertension and are also known to inactivate endothelium-derived relaxing factor. The objective of our present study was to determine if the oxygen radical scavenger superoxide dismutase (24,000 units/kg plus 1,600 units/kg/min) alters the pressor, cerebral blood flow, and mortality responses to systemic norepinephrine in rats. Increasing doses (0.01-30 /tg/kg i.v.) of norepinephrine were given by bolus injection to eight rats, and changes in the cortical microcirculatory blood flow were measured by laser-Doppler flowmetry. Superoxide dismutase shifted the norepinephrine-blood pressure and -cerebral blood flow dose-response curves moderately, but significantly, to the right such that it took more norepinephrine to reach a given blood pressure. However, superoxide dismutase had no effect on the autoregulation of cerebral blood flow. Additionally, whereas five (63%) of the eight control rats died after the 10 /tg/kg norepinephrine dose, all eight rats treated with superoxide dismutase survived this dose. The mechanism by which superoxide dismutase reduced mortality is uncertain. The blood pressure and cerebral blood flow results suggest that superoxide dismutase prevents oxygen radicals from destroying endothelium-derived relaxing factors, which reduce the pressor effects of norepinephrine. (Stroke 1991^2:489-494) A cute, drag-induced hypertension is known to cause abnormalities in the cerebral circulation. These abnormalities include increased cerebral vascular permeability to dye and proteins, 1 ' 2 a loss or "breakthrough" of autoregulation, and forced dilation of the arterial vasculature, which imparts a "sausage-string" appearance. 3 -4 Additionally, we and our colleagues have shown that following acute hypertension induced by pressor agents or experimental traumatic brain injury, abnormalities of the cerebral arterioles are caused by oxygen radicals formed during increased arachidonic acid metabolism. 5- 7 The abnormalities include sustained dilation, decreased reactivity to hypocapnia, endothelial le-

High Pressure Induces Superoxide Production in Isolated Arteries Via Protein Kinase C–Dependent Activation of NAD(P)H Oxidase

“…12 Thus, it is logical to hypothesize that high intraluminal pressure (P i ) itself can also promote vascular O 2 ·Ϫ generation in hypertension. This idea is congruent with previous observations that even short-term increases in P i , both in vivo and in vitro, impair endothelial function, [13][14][15][16] an effect that can be prevented by superoxide dismutase (SOD). 17 However, the possible role of high P i alone in the upregulation of arterial O 2 ·Ϫ production and the underlying signaling mechanisms has not yet been elucidated.…”

“…17 Other studies also showed that in the coronary and cerebral circulation, short-term increases in P i in vivo also impair endothelial function. [13][14][15][16] Mechanosensitive production of reactive oxygen species has also been linked to pressure-induced constriction of arterioles. 24,25 To provide further evidence for high P iinduced oxidative stress, we demonstrated with real-time lucigenin chemiluminescence measurements that high P i itself induced significant increases in arterial O 2 ·Ϫ generation (Figures 2A and 2B), whereas normal levels of P i had minimal effect.…”

Reactive Oxygen Species, Nitric Oxide and Hypertensive Endothelial Dysfunction

“…Similar observations have also been reported in ex vivo studies in that treatments of SHR aortic rings with ROS-scavengers such as Tiron or mercaptopropionylglycine (MPG) reverse oxidative stress-mediated endothelial dysfunction and decrease p22-phox expression, O 2 -generation and overall NAD(P)H oxidase activity [40]. CuZn-SOD prevents vascular damage and increases survival in rats made hypertensive by ang II or norepinephrine infusion [208]. Similarly, overexpression of Mn-SOD using gene transfer techniques has been shown to reduce ROS levels and improve endothelial function in a number of disease states associated with endothelial dysfunction such as diabetes and low-renin model of hypertension [209,210].…”

Heme Oxygenase-1 Gene Promoter Polymorphism Is Associated With Coronary Artery Disease in Japanese Patients With Coronary Risk Factors

“…44 Additional data in other models of hypertension support the notion that oxygenderived free radicals contribute to either the causes or consequences of hypertension. 45 As mentioned above, these 4 risk factors (hypercholesterolemia, diabetes mellitus, hypertension, and smoking) are related to oxidative stress, which plays a major role in atherogenesis. At present, we do not know precisely why the development of CAD is associated with the genotype of (GT) n repeats in the human HO-1 gene promoter only in patients with hypercholesterolemia or diabetes mellitus or in smokers.…”