Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have a key role in the control of heart rate and neuronal excitability. Ivabradine is the first compound acting on HCN channels to be clinically approved for the treatment of angina pectoris. HCN channels may offer excellent opportunities for the development of novel anticonvulsant, anaesthetic and analgesic drugs. In support of this idea, some well-established drugs that act on the central nervous system - including lamotrigine, gabapentin and propofol - have been found to modulate HCN channel function. This Review gives an up-to-date summary of compounds acting on HCN channels, and discusses strategies to further explore the potential of these channels for therapeutic intervention.

Despite considerable progress over the last decades, acute myocardial infarction continues to remain the major cause of morbidity and mortality worldwide. The present therapies include only cause-dependent interventions, which are not able to reduce myocardial necrosis and optimize cardiac repair following infarction. This review highlights the cellular and molecular processes after myocardial injury and focuses on chemokines, the main modulators of the inflammatory and reparatory events, as the most valuable drug targets.

Objective-The chemokine receptor CX 3 CR1 is an inflammatory mediator in vascular diseases. On platelets, its ligation with fractalkine (CX 3 CL1) induces platelet activation followed by leukocyte recruitment to activated endothelium. Here, we evaluated the expression and role of platelet-CX 3 CR1 during hyperlipidemia and vascular injury. Methods and Results-The existence of CX 3 CR1 on platelets at mRNA and protein level was analyzed by RT-PCR, quantitative (q)PCR, FACS analysis, and Western blot. Elevated CX 3 CR1 expression was detected on human platelets after activation and, along with increased binding of CX 3 CL1, platelet CX 3 CR1 was also involved in the formation of platelet-monocyte complexes. Interestingly, the expression of CX 3 CR1 was elevated on platelets from hyperlipidemic mice. Accordingly, CX 3 CL1-binding and the number of circulating platelet-monocyte complexes were increased. In addition, CX 3 CR1 supported monocyte arrest on inflamed smooth muscle cells in vitro, whereas CX 3 CR1-deficient platelets showed decreased adhesion to the denuded vessel wall in vivo. Conclusion-Platelets

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. An increasing body of evidence has implicated oxidative stress as being contributory to homocysteine's deleterious effects on the vasculature. Elevated levels of homocysteine may lead to increased generation of superoxide by a biochemical mechanism involving nitric oxide synthase, and, to a lesser extent, by an increase in the chemical oxidation of homocysteine and other aminothiols in the circulation. The resultant increase in superoxide levels is further amplified by homocysteinedependent alterations in the function of cellular antioxidant enzymes such as cellular glutathione peroxidase or extracellular superoxide dismutase. One direct clinical consequence of elevated vascular superoxide levels is the inactivation of the vasorelaxant messenger nitric oxide, leading to endothelial dysfunction. Scavenging of superoxide anion by either superoxide dismutase or 4,5-dihydroxybenzene 1,3-disulfonate (Tiron) reverses endothelial dysfunction in hyperhomocysteinemic animal models and in isolated aortic rings incubated with homocysteine. Similarly, homocysteine-induced endothelial dysfunction is also reversed by increasing the concentration of the endogenous antioxidant glutathione or overexpressing cellular glutathione peroxidase in animal models of mild hyperhomocysteinemia. Taken together, these findings strongly suggest that the adverse vascular effects of homocysteine are at least partly mediated by oxidative inactivation of nitric oxide.