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Background and aim Based on the reported cardioprotective effects of resveratrol, a polyphenolic antioxidant abundant in grapes that binds to estrogen receptors, and the well-characterized anti-inflammatory properties of 17β-estradiol, the effects of resveratrol on the functional expression of inflammatory enzymes were assessed in vascular smooth muscle cells (SMC) from normoglycaemic and streptozotocin-diabetic rats. Methods and results SMC were isolated from the aorta four weeks after treating rats with streptozotocin or its vehicle. In SMC exposed to a cytokine mixture for 24 h, unexpectedly, treatment with resveratrol (0.1–100 μM) as well as the structurally related isoflavone genistein (1 nM–1 μM) enhanced expression of inducible NO synthase (iNOS). Genistein failed to mimic the elevated iNOS activity induced by resveratrol. Inhibition of estrogen receptors by the pure antiestrogen ICI 182,780 reversed the action of resveratrol on iNOS. In addition, resveratrol failed to alter cyclooxygenase-2 protein levels but reduced the accumulation of prostaglandin E2 in the culture medium of SMC from normoglycaemic, but not diabetic rats. Conclusions These results indicate that resveratrol, at concentrations approaching putative peak plasma levels in vivo, exhibited no anti-inflammatory properties in vascular SMC from normal and diabetic rats. By contrast, resveratrol displayed a potential pro-inflammatory activity in settings of vascular inflammation.

ATP and 2-methyl-thio-ATP (2-Me-SATP) increase cytosolic calcium concentrations ([Ca 2+ ] i ) in rat striatal astrocytes (Centemeri et al. [1997] Br J Pharmacol 121:1700-1706). The aim of the present study was to: (1) characterize pyrimidine-induced [Ca 2+ ] i increases in the same experimental system, and (2) try to identify the multiple P2Y receptor subtypes mediating Ca 2+ mobilization. UDP and UTP triggered a concentration-dependent [Ca 2+ ] i elevation (EC 50 s = 0.58 μM ± 0.4 and 31 μM ± 6, respectively). Pyrimidine-evoked [Ca 2+ ] i elevation was solely due to mobilization from intracellular stores, because: (1) removing calcium from extracellular medium or (2) blocking its influx with Ni 2+ did not modify UTP responses; (3) the store-depleting agent thapsigargin completely abolished UTP-evoked [Ca 2+ ] i increments. Guanosine-5'-O-(2-thiodiphosphate) partially inhibited the UTP response, whereas pertussis toxin (PTx) had no effect. The phospholipase C inhibitor U-73122 significantly reduced the UTP-evoked [Ca 2+ ] i rise. Computer-assisted analysis indicated that the UTP and UDP responses are mediated by a single receptor, while ATP and 2-Me-SATP interact with two distinct receptors. The selective P2Y 1 receptor antagonist MRS2179 abolished the ATP higher potency component. Sequential challenges with the same nucleotides resulted in almost complete homologous desensitization. Pre-exposure to UTP lowered the subsequent responses to either ATP or 2-Me-SATP Maximally active concentrations of UTP and ATP were not additive. In conclusion, [Ca 2+ ] elevation in astrocytes by purines and pyrimidines is mediated by two distinct P2Y receptors, likely the P2Y 1 and P2Y 6 subtypes.

The understanding of the biological effects of estrogen on the vessel wall has improved dramatically since the discovery of estrogen receptors (ERs). Most, but not all estrogen-mediated effects in blood vessels are thought to be mediated by ERs. Two major ER subclasses have been characterized so far: the ERα and the more recently described ERβ. This review will primarily focus on a new perspective that highlights ERs as essential mediators of the vascular effects of estrogen. In view of the rising research interest in this area, it can be also expected that tissue- and ER subclass-selective agonists and antagonists will be developed over the next few years, thus providing invaluable tools for pharmacological and clinical applications. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 2, 171–184, 2001

Diabetes is associated with gender-specific macrovascular complications arising from increased oxidant stress in the vascular wall. In this study, male and female rats were treated with two structurally unrelated drugs sharing antioxidant properties, lercanidipine and Leucoselect (both 3 mg/kg/day), for 1 week starting 1 day after streptozotocin-diabetes induction. Concentration-response curves to L-nitroarginine methylester (L-NAME), superoxide dismutase and acetylcholine in aortic rings showed significantly greater nitric oxide-mediated relaxation in female compared with male non-diabetic rats. Diabetes increased contractility to noradrenaline and L-NAME in both genders, whereas relaxation to acetylcholine and iloprost were significantly attenuated in females only. Treatment with lercanidipine and Leucoselect restored, at least in part, responses to noradrenaline, acetylcholine and iloprost without affecting those to L-NAME and sodium nitroprusside. Unexpectedly, both drugs impaired superoxide dismutase response in female tissues. In conclusion, female rat aorta is markedly exposed to short-term diabetic vascular injury, which may be prevented by antioxidant treatment.

This investigation sought to determine how different components of the hemostatic system affect the development of venous thrombosis in rats displaying hyperlipidemia, either on a genetic basis or secondary to metabolic disorders. On employing an experimental model of collagen-triggered venous thrombosis, both spontaneously hyperlipidemic (Yoshida strain) and streptozotocin-induced diabetic rats generated about 2.3-fold greater thrombi than normolipidemic controls. This was associated with significant platelet activation, as revealed by increased levels of serum thromboxane B2 in diabetics (1.5-fold) as well as in Yoshida (8-fold) rats, in comparison with controls. In contrast, ex vivo total fibrinolytic activity, as measured by euglobulin lysis time, did not differ between normo- and hyperlipidemic or diabetic animals. Plasminogen activator inhibitor activity was lower in both Yoshida and diabetic rats than in controls. However, tissue-type plasminogen activator activity was differently affected by the genetic or the diabetes-related hyperlipidemia, showing significantly lower values in Yoshida (-26%), but significantly higher values in diabetic rats (+29%) than in normolipidemic controls. We conclude that platelet activation, rather than consistent modifications of the fibrinolytic system, is likely to influence the enhanced thrombus development associated with primary or secondary forms of hyperlipidemia.

Calcium metabolism appears to be altered in human and experimental hypertension, which represents an important risk factor for thrombotic events. We investigated the possible effect of the calcium antagonist nicardipine on a model of experimental venous thrombosis in spontaneously hypertensive rats (SHR). Thrombus formation was highly enhanced in SHR with respect to normotensive Wistar Kyoto rats (WKY). Nicardipine, when administered orally (10 mg kg −1 ) at a single dose or once a day for three days, completely counteracted the increase in thrombus size caused by hypertension. Furthermore, a significant rise in prostacyclin production from aortic tissue [19.2±1.5 vs 13.2±2.4 ng (mg dry tissue) −1 ], associated with a fall in thromboxane A2 release from activated platelets (328.3±74.6 vs 705.0±88.1 ng ml −1 ), was observed in nicardipine-treated SHR. Plasma triglyceride and free fatty acid levels were also lowered by drug administration. Our results suggest that the actions of nicardipine on calcium metabolism result in antithrombotic effect through an increased availability of vasodilating eicosanoids in vessel walls and through a reduced amount of prothrombotic agents (thromboxane, free fatty acids).

Myocardial ischemia was induced in perfused paced isovolumic left heart preparation of the rabbit by reducing, for a period of 40 min, the flow rate from 20 ml/min to 0.2 ml/min (severe model) and to 1 ml/min (moderate model). The relationship between prostaglandin biosynthesis and cardiac ischemic damage was evaluated in the two experimental models. The results obtained indicate that the total amount of 6-keto-PGF1 alpha generated increases with the severity of the ischemia, particularly during the 20 min of reperfusion (moderate model 81.8 +/- 13.7 ng: severe model 375 +/- 102 ng). The inhibition of the prostaglandin synthesis, prostaglandin-E2, and 6-keto-prostaglandin-F1 alpha (PGE2 and 6-keto-PGF1 alpha levels below the detection limits) by Aspirin (20 micrograms/ml) and Indomethacin (1 microgram/ml) in moderate myocardial ischemia was correlated with greater increments in resting diastolic tension (nearly 100% and 40%, respectively). This phenomenon was also associated to a further decrease on cardiac contractility and increase on coronary perfusion pressure upon reperfusion. On the contrary drugs which stimulated prostaglandin generation in myocardial tissue, such as Defibrotide (400 micrograms/ml), completely protected the organ from ischemia. U-60257 (3 micrograms/ml) and FPL-55712 (2 micrograms/ml), compounds, which respectively inhibits biosynthesis and the effects of leukotrienes, displayed a beneficial activity on this moderate model of ischemia. The present data suggests that the deleterious effect of nonsteroidal antiinflammatory drugs in low flow myocardial ischemia and reperfusion damage may be associated with removal of PGI2 and PGE2 from ischemic myocardium.