Abstract-The peptide hormone relaxin (RLX) has been shown to elicit a powerful vasodilatory response in several target organs. This response is mediated by the stimulation of intrinsic nitric oxide (NO) generation. The present study was designed to clarify whether RLX directly promotes the relaxation of vascular smooth muscle cells through stimulation of NO generation. Vascular smooth muscle cells from bovine aortas were incubated with RLX at concentrations ranging from 1 nmol/L to 1 mol/L. The expression and activity of NO synthase, production of NO, and the intracellular levels of cGMP and Ca 2ϩ were determined. The cell morphology and signal transduction mechanisms of these bovine aortic smooth muscle cells in response to RLX were also studied. RLX stimulated the expression of immunoreactive inducible NO synthase and increased significantly and in a concentration-related fashion inducible NO synthase activity, NO generation, and intracellular cGMP levels. Concurrently, RLX significantly decreased cytosolic Ca 2ϩ concentrations and caused changes in cell shape and the actin cytoskeleton that were consistent with cell relaxation. The signal transduction mechanisms leading to the enhanced expression of inducible NO synthase protein and activity caused by RLX involve the activation of tyrosine kinase, phosphatidylcholine-phospholipase C, and the transcription factor nuclear factor-B, similar to bacterial endotoxins and proinflammatory cytokines. This study suggests that RLX is an endogenous agent capable of regulating vascular tone by activation of the L-arginine-NO pathway in vascular smooth muscle cells. Key Words: muscle, smooth, vascular Ⅲ relaxin Ⅲ nitric oxide R elaxin is a peptide hormone of Ϸ6 kDa that is predominantly produced by the ovaries and is best known for its actions on the female reproductive system.1 Recently, evidence has been accumulating that RLX has additional multiple effects on organs other than the reproductive ones. In particular, previous research in our laboratory has shown that RLX exerts a powerful effect on blood vessels, causing vasodilation in the uterus, mammary gland, pigeon crop sac, mesocecum, and coronary system. 2-8 Our findings fit well with those of other authors that RLX also decreases blood pressure in spontaneously hypertensive rats.9,10 All of the above findings support the idea that RLX is effective in reducing vascular tone. Concerning the mechanism of action of RLX on its target organs, our studies of coronary vessels in the isolated, perfused rat and guinea pig heart 7,8 have shown that the vasodilatory action of RLX is mediated by stimulation of endogenous production of NO, which is a powerful vasorelaxant. 11,12 It is worth noting that stimulation of intrinsic NO production is also involved in the response to RLX in different cells, such as rat and guinea pig serosal mast cells, 13 human and rabbit platelets, 14 and mammary adenocarcinoma MCF-7 cells. 15There is general agreement that the vasodilatory action of NO is primarily an endothelium-dependent process. I...

Despite the fact that the relationship between platelets and the inflammatory and immune responses has been reviewed previously, the allocation of platelets among the inflammatory cells is still at issue. Recent developments in our understanding of platelet-associated signalling events have offered new potential insights into platelet functions in inflammatory and immune-related diseases. In recent years, it has been established that a range of molecules, mainly associated with the platelet surface and/or the platelet granules, regulate the capacity of platelets to cross-talk with other inflammatory cells during the process of inflammation, and of vascular inflammation in particular. This is the case with platelet-derived growth factor (PDGF), secreted from platelet alpha-granules, with P-selectin, expressed on the platelet surface, and with platelet histamine, which is secreted from platelets in response to aggregatory and inflammatory stimuli. The nature and mechanism of action of these regulatory molecules, physiologically present in platelets and mobilised upon platelet activation and aggregation, is the subject of this review. The participation of platelets, through PDGF, P-selectin and histamine, is also discussed in overtly inflammatory disorders, such as acute respiratory distress syndrome, mesangial glomerulonephritis, chronic inflammatory bowel disease, disseminated intravascular inflammation, and allergic vasculitis, focusing on possible pharmacological interventions specifically active against growth factors, adhesion molecules and platelet histamine.

Relaxin was previously shown to cause coronary vasodilation and to inhibit mast cell activation through a stimulation of endogenous nitric oxide production. This suggests that relaxin may have beneficial effects on ischemia-reperfusion-induced myocardial injury, which is triggered by endothelial damage and impaired nitric oxide generation. In this study, we tested the effect of relaxin on isolated and perfused guinea pig hearts subjected to ischemia and reperfusion. Ischemia was induced by ligature of the left anterior descending coronary artery; removal of the ligature induced reperfusion. Relaxin, at the concentration of 30 ng/ml of perfusion fluid, causes: a significant increase in coronary flow and in nitric oxide generation; a significant decrease in malonyldialdehyde production and in calcium overload, both markers of myocardial injury; an inhibition of mast cell granule exocytosis and histamine release, which are known to contribute to myocardial damage; a reduction of ultrastructural abnormalities of myocardial cells; an improvement of heart contractility. The beneficial effects of relaxin were blunted by the NO synthase inhibitor L-NMMA. The current study provides first experimental evidence that relaxin has a powerful protective effect on the heart undergoing ischemia and reperfusion acting through a nitric oxide-driven mechanism.

The synergistic effect between histamine and other monoamines on platelet aggregation may explain some aspects of allergic vasculitis in which platelet aggregation is present.

These results suggest that morphine, cocaine and methadone are activated into free radicals which produce membrane lipid perturbation and histamine release, suggesting that a massive release of mast cell histamine could be an additional risk factor in heroin and cocaine overdoses.