The effects of synthetic rat adrenomedullin (rAM), a novel vasorelaxant peptide originally isolated from human pheochromocytoma. on receptor binding and CAMP generation were studied in cultured rat vascular smooth muscle cells (VSMC). A binding study using ["51]rAM revealed the presence of a single class of high-affinity (& 1.3 x lo-* M) binding sites for rAM m VSMC. The apparent K, of rat calcitonin gene-related peptide (rCGRP) was 3 x lo-' M. Affinity labeling of VSMC membranes with ["'I]rAM revealed two distinct labeled bands with apparent molecular weights of 120 and 70 kDa, both of which were abolished by excess unlabeled rAM or rCGRP. rAM stimulated CAMP formation with an approximate EC,, of lo-* M, the effect of which was additive with isoproterenol, but not with rCGRP. The rAM-induced CAMP response was unaffected by propranalol. indomethacin, or quinacrine, but inhibited by a CGRP receptor antagonist, human CGRP[8-371. These data suggest that VSMC possesses specific AM receptors functionally coupled to adenylate cyclase with which CGRP interacts.

We designed the present study to assess any changes in plasma concentrations of the novel vasorelaxant peptide adrenomedullin in patients with essential hypertension. Plasma adrenomedullin concentrations were measured in 45 patients with untreated essential hypertension, 15 patients with borderline hypertension, and 30 normotensive control subjects. After 4 weeks of effective calcium channel blocker-based antihypertensive therapy, adrenomedullin concentrations were measured again. The concentrations were higher in hypertensive patients with increased serum creatinine levels or decreased glomerular filtration rates compared with borderline hypertensive patients and normotensive subjects, although values in normotensive and hypertensive individuals overlapped. Plasma adrenomedullin concentrations were positively correlated with serum creatinine levels and inversely correlated with glomerular filtration rates in the hypertensive patients, whereas adrenomedullin values were not correlated with blood pressure level, left ventricular mass index, or left ventricular ejection fraction. Despite blood pressure control with antihypertensive therapy, plasma adrenomedullin concentrations were not changed. Reversed-phase high-performance liquid chromatographic analysis showed that a major component of immunoreactive adrenomedullin in the plasma of normotensive subjects and hypertensive patients is human adrenomedullin-(1-52). These results indicate that plasma adrenomedullin concentrations are elevated in many hypertensive patients with renal dysfunction and its major component is human adrenomedullin-(1-52).

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Background-To explore the role of intracellular oxidative stress in high glucose-induced atherogenesis, we examined the effect of probucol and/or ␣-tocopherol on the migration and growth characteristics of cultured rabbit coronary vascular smooth muscle cells (VSMCs). Methods and Results-Chronic high-glucose-medium (22.2 mmol/L) treatment increased platelet-derived growth factor (PDGF)-BB-mediated VSMC migration, [ 3 H]thymidine incorporation, and cell number compared with VSMCs treated with normal-glucose medium (5.6 mmol/Lϩ16.6 mmol/L mannose). Probucol and ␣-tocopherol significantly suppressed high glucose-induced increase in VSMC migration, cell number, and [3 H]thymidine incorporation. Probucol and ␣-tocopherol suppressed high glucose-induced elevation of the cytosolic ratio of NADH/NAD ϩ , phospholipase D, and membrane-bound protein kinase C activation. Probucol, ␣-tocopherol, and calphostin C improved the high glucose-induced suppression of insulin-mediated [ 3 H]deoxyglucose uptake. Chronic high-glucose treatment increased the oxidative stress, which was significantly suppressed by probucol, ␣-tocopherol, suramin, and calphostin C. Conclusions-These findings suggest that probucol and ␣-tocopherol may suppress high glucose-induced VSMC migration and proliferation via suppression of increases in the cytosolic ratio of free NADH/NAD ϩ , phospholipase D, and protein kinase C activation induced by high glucose, which result in reduction in intracellular oxidative stress.

These results indicate that (1) lyso-PC induces human coronary artery SMC migration at least in part through release of endogenous bFGF and (2) this lyso-PC-induced migration can be further induced by PDGF-BB and ET-1 and can be inhibited by human AM and vitamin E. Lyso-PC may recruit medial SMCs during the process of coronary atherosclerosis in part by releasing bFGF in concert with PDGF-BB or ET-1 in vascular tissues. This lyso-PC-induced SMC migration may be suppressed by AM and vitamin E under certain pathological conditions.