We have reported that a deficiency of tetrahydrobiopterin (BH(4)), an active cofactor of endothelial NO synthase (eNOS), contributes to the endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O(2)(-)) generation in the insulin-resistant state. To further confirm this hypothesis, we investigated the effects of dietary treatment with BH(4) on endothelium-dependent arterial relaxation and vascular oxidative stress in the aortas of insulin-resistant rats. Oral supplementation of BH(4) (10 mg. kg(-1). d(-1)) for 8 weeks significantly increased the BH(4) content in cardiovascular tissues of rats fed high levels of fructose (fructose-fed rats). Impairment of endothelium-dependent arterial relaxation in the aortic strips of the fructose-fed rats was reversed with BH(4) treatment. The BH(4) treatment was associated with a 2-fold increase in eNOS activity as well as a 70% reduction in endothelial O(2)(-) production compared with those in fructose-fed rats. The BH(4) treatment also partially improved the insulin sensitivity and blood pressure, as well as the serum triglyceride concentration, in the fructose-fed rats. Moreover, BH(4) treatment of the fructose-fed rats markedly reduced the lipid peroxide content of both aortic and cardiac tissues and inhibited the activation of 2 redox-sensitive transcription factors, nuclear factor-kappaB and activating protein-1, which were increased in fructose-fed rats. The BH(4) treatment of control rats did not have any significant effects on these parameters. These results indicate that BH(4) augmentation is essential for the restoration of eNOS function and the reduction of vascular oxidative stress in insulin-resistant rats.

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TOMIO OKAMURA, MIZUO MIYAZAKI, TADASHI INAGAMI, AND NOBORU TODA SUMMARY The possible role of the renin-angiotensin system in the maintenance of hypertension in two-kidney, one clip hypertensive rats was studied. Plasma renin activity rose rapidly and markedly in association with the elevation of blood pressure and then decreased gradually, although blood pressure remained high. Renin activity in the lung, aorta, and mesenteric artery also increased with the development of hypertension and then decreased in a way similar to that of plasma renin activity at the chronic stage of hypertension. Plasma angiotensin converting enzyme activity did not change significantly until 16 weeks after unilateral renal artery clipping, whereas vascular angiotensin converting enzyme activity significantly increased at the chronic, but not the acute, stage of hypertension. In chronically renal hypertensive rats, 1-sarcosine, 8-isoleucine angiotensin II or enalapril, an angiotensin converting enzyme inhibitor, lowered the blood pressure and enalapril also lowered the angiotensin converting enzyme activity of vascular tissues. The constrictor effect of angiotensin I was greater in isolated arteries from chronically hypertensive rats than in those from age-matched normotensive rats. These results suggest that the vascular renin-angiotensin system plays an important role in the maintenance of two-kidney, one clip hypertension. Elevated vascular angiotensin converting enzyme activity appears to increase local production of angiotensin II, which results in vasoconstriction by acting directly and indirectly through adrenergic nerves on vascular smooth muscle. (Hypertension 8: 560-565, 1986) KEY WORDS * angiotensin converting enzyme • renal hypertension * angiotensin T HE renin-angiotensin (RA) system plays an important role in the regulation of blood pressure and salt-water balance. Although overacceleration of this system was once considered a major cause of hypertension, this view is no longer prevalent because of the existence of hypertension with low levels of plasma renin activity (PRA), as observed in spontaneous hypertension in rats and low renin essential hypertension in humans. Furthermore, the intriguing findings that angiotensin converting enzyme (ACE) inhibitors can effectively relieve low renin hypertension has directed attention to the kallikrein-kinin system 1 and the prostaglandin system, 2 because ACE

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Mental stress is an important factor contributing to recognized mechanisms underlying cardiovascular events. Among these, stress-related endothelial dysfunction is an early risk factor that predicts future development of severe cardiovascular disorders. Acute mental stress by a variety of tests impairs endothelial function in humans, although the opposite results have been reported by some investigators. Chronic stress always deteriorates endothelial function in humans and experimental animals. Stress hormones, such as glucocorticoids and pro-inflammatory cytokines, and endothelin-1 liberated in response to mental stress participate in endothelial dysfunction possibly via downregulation of endothelial nitric oxide synthase (eNOS) expression, eNOS inactivation, decreased nitric oxide (NO) actions, and increased NO degradation, together with vasoconstriction counteracting against NO-induced vasodilatation. Catecholamines do not directly affect endothelial function but impair its function when blood pressure elevation by the amines is sustained. Endogenous opioids favorably affect endothelial function, which counteract deteriorating effects of other stress hormones and mediators. Inhibition of cortisol and endothelin-1 production, prevention of pro-inflammatory mediator accumulation, hypnotics, mirthful laughter, humor orientation, and lifestyle modification would contribute to the prevention and treatment for stress-related endothelial dysfunction and future serious cardiovascular disease.

Spirally cut strips of cerebral and peripheral arteries from dogs were used for comparing the vasoconstricting effect of serotonin, norepinephrine, K + , and transmural electrical stimulation. Sensitivity of cerebral (basilar, posterior cerebral, and middle cerebral) arterial strips to serotonin was markedly greater than that to norepinephrine with respect to the median effective concentration (ED 30 ) and the maximum response. Contractile responses of isolated human cerebral arteries to serotonin and norepinephrine were similar to those observed in the dog arteries. In contrast, proximal and distal strips from superior mesenteric arteries and strips from renal arteries were more sensitive to norepinephrine than they were to serotonin. Mean values of contractions caused by 5 X 10~CM serotonin relative to those caused by 30 mM K + in cerebral, internal carotid, external carotid, common carotid, and superior mesenteric arteries were in a descending order, whereas those for norepinephrine were in an ascending order. These studies demonstrate that a gradual transition occurs from characteristic responses seen in mesenteric arteries (high sensitivity to norepinephrine, low sensitivity to serotonin) to those seen in cerebral arteries (high sensitivity to serotonin, low sensitivity to norepinephrine). Transmural stimulation did not produce contractions of cerebral and internal carotid arteries, but contractions were produced in external carotid, common carotid, and superior mesenteric arteries. It appears that sympathetic nerves cannot play an important role in the regulation of vascular tone in large cerebral arteries. KEY WORDSneurogenic control spirally cut arterial strips carotid arteries human different sensitivity to drugs mesenteric arteries dog Methods Mongrel dogs of both sexes, weighing 8-15 kg, were used. The dogs were anesthetized with sodium pentobarbital (30 mg/kg, iv) and killed by bleeding from the common carotid arteries. The brain and the internal carotid (0.5-1 mm, o.d.), external carotid (1.5- 98

Helical strips of human coronary arteries contracted in response to histamine concentration dependently, they relaxed with low concentrations and contracted with high concentrations. Treatment with cimetidine potentiated contraction in the strips with intact and damaged endothelium to a similar extent and attenuated relaxation. Removal of endothelium abolished relaxation and potentiated contraction in the cimetidine-treated strips. Methylene blue increased the contractile response to histamine in the strips with endothelium but did not alter the response in the damaged-endothelium strips. Histamine-induced relaxations in the intact strips were suppressed or abolished by treatment with ETYA, AA861, a lipoxygenase inhibitor, and by chlorpheniramine but were unaffected by indomethacin. Chlorpheniramine also abolished amine-induced contraction. It may be concluded that histamine-induced contraction in human coronary arteries is mediated by H, receptors in smooth muscle, and relaxation is mediated by H 2 receptors in smooth muscle and H, receptors in endothelium. while human coronary arteries respond with contractions. 4 Histamine constricts proximal middle cerebral arteries from dogs but dilates the distal arteries.6 These differing actions may be derived from the ability of histamine to activate histaminergic H, and H 2 receptors in vascular smooth muscle and to also activate H, receptors in endothelium, which possibly mediate the release of prostaglandin (PG) I 2 7 " or endothelium-derived relaxing factor. 3910Intravenous injections of histamine provokes coronary vasospasm in patients with variant angina," and endogenous histamine is regarded as one candidate for the genesis of the vasospasm.12 Large amount of histamine may be released by antigen-antibody reactions 13 as well as by many clinical drugs commonly used, such as morphine and d-tubocurarine.14 Similar coronary vasospasm is also produced by the amine in miniature swine in which the coronary artery is denuded and the high cholesterol diet is fed." However, the mechanism of histamine action in human coronary arteries has not yet been determined.From the Department of Pharmacology. Shiga University of Medical Sciences, Seta, Ohtsu, Japan.This paper was presented in part at the Symposium on Vasodilatation, July 1986, in Rochester, Minnesota.Address for correspondence: Dr. Noboru Toda, Department of Pharmacology, Shiga University of Medical Sciences, Seta, Ohtsu 520-21, Japan.Received June 13, 1986; accepted March 18, 1987. Therefore, the present study was undertaken to further clarify the response to histamine of coronary arteries isolated from human cadavers and to pharmacologically analyze the mechanism of its action in relation to vascular endothelium and H, and H 2 receptors. Materials and MethodsVentral, interventricular, and circumflex branches of the left coronary artery were isolated from human hearts (17 males, aged 54 to 84, and 9 females, aged 26 to 68) during autopsy up to 6 hours after death. Causes of death were stomach, rectum, lung, pharyn...