Background-Heart rate reduction (HRR) improves left ventricular (LV) filling, increases myocardial O 2 supply, and reduces myocardial O 2 consumption, which are all beneficial in congestive heart failure (CHF). However, the long-term effects of HRR on cardiac function and remodeling are unknown. Methods and Results-We assessed, in rats with CHF, the effects of long-term HRR induced by the selective I f current inhibitor ivabradine (as food admix for 90 days starting 7 days after coronary artery ligation). To assess intrinsic modifications of LV tissue induced by long-term HRR, all parameters were reassessed 3 days after interruption of treatment. Ivabradine decreased heart rate over the 90-day treatment period (Ϫ18% versus untreated at 10 mg · kg Ϫ1 · d

Endothelin-1 is an endothelium-derived vasoconstrictor peptide. Its circulating levels are below those known to evoke direct vascular effects. To study whether low concentrations of endothelin-1 potentiate the effects of other vasoconstrictor hormones, we suspended isolated human internal mammary and left anterior descending coronary artery rings in organ chambers for isometric tension recording. In mammary artery rings, the contractions to norepinephrine (3 x 10-8 M) were potentiated by threshold (3 X 10-10 M) and low concentrations (10`M) of endothelin-1 (96±35% and 149±58% increase from control; p<0.01 and 0.001; n=6). The inhibitor of endothelial nitric oxide formation L-NG-monomethyl arginine did not affect the potentiating effects of the peptide. The calcium antagonist darodipine (10`M) prevented the potentiation of the response to norepinephrine evoked by endothelin-1. Similarly, contractions to serotonin (10`or 3 x 10-8 M) were amplified by endothelin-1 (3 x 10-10 M) in the mammary (30±9%o) and in the coronary arteries (59±25%). Endothelin-1 (10-9 M) further potentiated the response (57±23% in mammary and 87±26% in coronary arteries;p <0.05; n=7 and 3). The sensitivity of mammary arteries to calcium chloride was markedly enhanced in the presence of endothelini1 (3 x 1010 M; concentration shift, eightfold; pc

Microparticles (MPs) are small fragments generated from the plasma membrane after cell stimulation. Among the candidate proteins harbored by MPs, we recently showed that sonic hedgehog (Shh) is present in MPs generated from activated/apoptotic human T lymphocytes [Martínez et al., Blood (2006) vol. 108, 3012-3020]. We show here that Shh carried by MPs induces nitric oxide (NO) release from endothelial cells, triggers changes in the expression and phosphorylation of enzymes related to the NO pathway, and decreases production of reactive oxygen species. When PI3-kinase and ERK signaling were specifically inhibited, the effects of MPs were reversed. In vivo injection of MPs in mice was also able to improve endothelial function by increasing NO release, and it reversed endothelial dysfunction after ischemia/reperfusion. Silencing the effects of Shh with cyclopamine, a specific inhibitor of Shh, or siRNA, an inhibitor of the Shh receptor Patched, strongly reduced production of NO elicited by MPs. Taken together, we propose that the biological message carried by MPs harboring Shh may represent a new therapeutic approach against endothelial dysfunction during acute severe endothelial injury.

In genetic models of human and rat hypertension, increased sodium intake is associated with specific alterations of the structure and function of conduit arteries involving extracellular matrix, but independent of BP and atherosclerosis.