Serelaxin

Serelaxin (RLX030) is an investigational drug for the treatment of acute heart failure (AHF), targeting the relaxin receptor. Serelaxin is a recombinant form of human relaxin-2, a hormone that (among other functions) is produced during pregnancy and mediates the haemodynamic changes that occur during this time, such as increased blood output of the heart and blood flow in the kidney. Human-relaxin-2 mediates vasodilation (widening of blood vessels) by increasing the production of nitric oxide (NO), a potent vasodilator. Activation of the relaxin receptor RXFP1 activates several enzymes in a phosphorylation cascade that eventually results in the activation of NO synthase in endothelial cells and the subsequent production of NO. Relaxin can also bind to a secondary receptor, endothelial B receptor, which is upregulated as a result of the previous pathway. Relaxin binding to endothelial B receptor on endothelial cells also induces vasodilation.

Relaxin causes vasodilation by an indirect mechanism, where it inhibits the potent vasoconstrictors angiotensin II and endothelin. In addition to vasodilation, the effects of relaxin are also seen in the kidneys, by significantly increasing creatinine clearance, which is a measure of kidney function, as well as increased renal blood flow. Relaxin also functions as a cardiac stimulant. Studies have demonstrated that relaxin increases calcium sensitivity of cardiac myofilaments as well as increasing phosphorylation of the myofilaments by protein kinase C (PKC). These modifications both function to increase the force generated by the myofilaments without increasing the energy consumption of the cardiac myocytes. Thus relaxin and serelaxin can increase stroke volume, the amount of blood pumped per heart beat, without increasing the energy demand on the already strained heart of acute heart failure patients.