Rosuvastatin, a new HMG-CoA reductase inhibitor, protects ischemic reperfused myocardium in normocholesterolemic rats.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to upregulate endothelial nitric oxide synthase in isolated endothelial cells in a manner that is independent of their lipid-lowering effects. Nitric oxide inhibits polymorphonuclear leukocyte (PMN) adherence and attenuates cardiac dysfunction caused by PMNs after ischemia/reperfusion. Therefore, the authors hypothesized that a new statin, rosuvastatin, could attenuate PMN-induced cardiac dysfunction, and examined the effects of rosuvastatin in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. Rosuvastatin (0.25 or 1.25 mg/kg) given 18 h before ischemia/reperfusion significantly improved left ventricular developed pressure (P < 0.01) and the maximal rate of development of left ventricular developed pressure (+dP/dt(max), P < 0.01) compared with ischemia/reperfused hearts obtained from rats given 0.9% NaCl. The time point for the improved cardiac performance caused by rosuvastatin (1.25 mg/kg) was 20 min after reperfusion. In addition, rosuvastatin significantly reduced PMN adherence to the vascular endothelium and subsequent infiltration into the postischemic myocardium (P < 0.01). The nitric oxide synthase inhibitor N omega-nitro-l-arginine methyl ester (50 micromol/l) blocked these cardioprotective effects. These results provide evidence that rosuvastatin significantly attenuates PMN-induced cardiac contractile dysfunction in the isolated perfused rat heart.

Mechanisms of amelioration of glucose-induced endothelial dysfunction following inhibition of protein kinase C in vivo.

Inhibition of protein kinase C (PKC) activity has been shown to improve the endothelial dysfunction associated with hyperglycemia and diabetes. The mechanisms by which inhibition of PKC activity ameliorates endothelial dysfunction in diabetes are not well understood. We investigated the relationship between PKC inhibition and leukocyte-endothelium interaction in the microcirculation of the rat mesentery exposed to 25 mmol/l D-glucose for 12 h. D-Glucose significantly increased leukocyte rolling and adherence in mesenteric postcapillary venules. This proinflammatory action of D-glucose was inhibited by superfusion of the mesentery with 30 nmol/l bisindolylmaleimide-I, a potent, selective PKC inhibitor (P < 0.01 vs. glucose alone after 90 min of superfusion). Immunohistochemical localization of the cell adhesion molecules P-selectin and intercellular adhesion molecule (ICAM)-1 on the endothelial cell surface was increased by 25 mmol/l D-glucose (P < 0.001 vs. control tissue from rats injected with saline), which was significantly reduced by bisindolylmaleimide-I (P < 0.001 vs. glucose alone). In addition, we studied adhesion of isolated neutrophils to rat superior mesenteric artery (SMA) vascular segments stimulated with 25 mmol/l D-glucose for 4 h in vitro. Pretreatment of the SMA vascular segments with either superoxide dismutase enzyme (100 units/ml) or bisindolylmaleimide-I (30 nmol/l) equally inhibited the increased neutrophil adherence to SMA endothelium in response to glucose. These data demonstrate that inhibition of PKC activity reduces leukocyte-endothelium interactions by suppressing surface expression of endothelial cell adhesion molecules in response to increased oxidative stress. These results provide a novel mechanism by which inhibition of PKC activity improves endothelial cell function in hyperglycemia and diabetes.

Attenuation of neutrophil-mediated myocardial ischemia-reperfusion injury by a calpain inhibitor.

Calpains are ubiquitous neutral cysteine proteases. Although their physiological role has yet to be clarified, calpains seem to be involved in the expression of cell adhesion molecules. Therefore, we hypothesized that a selective calpain inhibitor could attenuate polymorphonuclear (PMN) leukocyte-induced myocardial ischemia-reperfusion (I/R) injury. We examined the effects of the calpain inhibitor Z-Leu-Leu-CHO in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. Z-Leu-Leu-CHO (10 and 20 microM, respectively) significantly improved left ventricular developed pressure (LVDP) (P < 0.01) and the maximal rate of development of LVDP (P < 0.01) compared with I/R hearts perfused without Z-Leu-Leu-CHO. In addition, Z-Leu-Leu-CHO significantly reduced PMN adherence to the vascular endothelium and subsequent infiltration into the postischemic myocardium (P < 0.01). Moreover, Z-Leu-Leu-CHO significantly inhibited expression of P-selectin on the rat coronary microvascular endothelium (P < 0.01). These results provide evidence that Z-Leu-Leu-CHO significantly attenuates PMN-mediated I/R injury in the isolated perfused rat heart to a significant extent via downregulation of P-selectin expression.

Vascular effects of poly-N-acetylglucosamine in isolated rat aortic rings.

BACKGROUND: [corrected] Poly-N-acetylglucosamine (p-GlcNAc) is a secretion of marine diatoms that is known to be useful in controlling bleeding. As a component of promoting hemostasis, p-GlcNAc is thought to exert vasoconstrictor effects in arteries. The present study was undertaken to determine whether p-GlcNAc induced a significant vasoconstrictor effect and, if so, what the mechanism of this effect might be. MATERIALS AND METHODS: We examined vascular effects of p-GlcNAc on isolated aortic rings obtained from Sprague-Dawley rats. The rings were suspended in organ baths and precontracted with U46619, a thromboxane A2 mimetic. RESULTS: p-GlcNAc produced a concentration-dependent vasoconstriction over the range of 14 to 100 microg/ml. At a concentration of 100 microg/ml, p-GlcNAc significantly contracted aortic rings by 133 +/- 20 mg of developed force (P < 0.01). Neither a deacetylated derivative of p-GlcNAc nor a structurally related macromolecule, chitin, contracted rat aortic rings, indicating a specificity for p-GlcNAc. The vasoconstriction to p-GlcNAc was totally abolished in deendothelialized rat aortic rings, suggesting that an endothelial component is essential to the vasoconstriction. Pretreatment with the endothelin ET(A) receptor antagonist, JKC-301 (0.5 and 1 microM), significantly diminished p-GlcNAc-induced vasoconstriction by 57 to 61% (P < 0.01). However, p-GlcNAc did not significantly diminish nitric oxide release from rat aortic endothelium. CONCLUSION: These results provide evidence that p-GlcNAc significantly contracts isolated rat aortic rings via an endothelium-dependent mechanism, partly via enhancement of endothelin-1 release from endothelial cells.