1 Relaxin (RLX) is a multifunctional hormone which, besides its role in pregnancy and parturition, has also been shown to influence the cardiovascular system. In this study, we investigated the effect of RLX on coronary flow of rat and guinea-pig hearts, isolated and perfused in a Langendorff apparatus. RLX was either added to the perfusion fluid at a concentration of 5 x 109 M for a 20-min perfusion, or given as a bolus into the aortic cannula at concentrations of 10-9 M, 5 x io-9 M and 10-8 M dissolved in 1 ml of perfusion fluid. 2 RLX, given either for a 20-min perfusion or as a bolus in the aortic cannula to guinea-pig and rat isolated hearts, increased the coronary flow and the amount of nitrite, a stable end-product of nitric oxide (NO) metabolism, that appeared in the perfusates in a concentration-dependent fashion. 3 The increase in coronary flow and in nitrite in the perfusates induced by RLX was significantly reduced by pretreatment with the nitric oxide synthase (NOS) 4 The effects of RLX on coronary flow and nitrite amounts in the perfusates were compared with those induced by the endothelium-dependent vasodilator agent, acetylcholine (ACh, I0--I0-M), and by the endothelium-independent vasodilator agent, sodium nitroprusside (SNP, I0--10-6 M). The results obtained show that RLX is more effective than ACh and SNP in increasing coronary flow. 5 The results of this study show that RLX increases coronary flow through stimulation of NO production; hence this hormone should be regarded as a novel agent capable of improving myocardial perfusion.

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.

We investigated the effects of agents acting at histamine receptors on both, spontaneous release of ACh from the basolateral amygdala (BLA) of freely moving rats, and fear conditioning. Extensive evidence suggests that the effects of histamine on cognition might be explained by the modulation of cholinergic systems. Using the microdialysis technique in freely moving rats, we demonstrated that perfusion of the BLA with histaminergic compounds modulates the spontaneous release of ACh. The addition of 100 mm KCl to the perfusion medium strongly stimulated ACh release, whereas, 0.5 microm tetrodotoxin (TTX) inhibited spontaneous ACh release by more than 50%. Histaminergic H3 antagonists (ciproxifan, clobenpropit and thioperamide), directly administered to the BLA, decreased ACh spontaneous release, an effect fully antagonized by the simultaneous perfusion of the BLA with cimetidine, an H2 antagonist. Local administration of cimetidine alone increased ACh spontaneous release slightly, but significantly. Conversely, the administration of H1 antagonists failed to alter ACh spontaneous release. Rats receiving intra-BLA, bilateral injections of the H3 antagonists at doses similar to those inhibiting ACh spontaneous release, immediately after contextual fear conditioning, showed memory consolidation impairment of contextual fear conditioning. Post-training, bilateral injections of 50 microg scopolamine also had an adverse effect on memory retention. These observations provide the first evidence that histamine receptors are involved in the modulation of cholinergic tone in the amygdala and in the consolidation of fear conditioning.

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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.