Serelaxin (brand name Reasanz; developmental code name RLX-030) is a medication which is marketed in

Russia Russia (, , ), or the Russian Federation, is a List of transcontinental countries, transcontinental country spanning Eastern Europe and North Asia, Northern Asia. It is the List of countries and dependencies by area, largest country in the ...

for the treatment of acute heart failure (AHF), targeting the

relaxin receptor The relaxin receptors are a subclass of four closely related G protein-coupled receptors (GPCR) that bind relaxin peptide hormones. Below is list of human relaxin receptors, their endogenous peptide hormones, and what downstream enzymes are ac ...

. It was also under development in other places in the world, including in the

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, and

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, but ultimately was not marketed in these areas. Serelaxin is a recombinant form of human

relaxin Relaxin is a protein hormone of about 6000 Da first described in 1926 by Frederick Hisaw. The relaxin family peptide hormones belong to the insulin superfamily and consists of seven peptides of high structural but low sequence similarity; rela ...

-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 Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...

(NO), a potent

vasodilator Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...

. Activation of the relaxin receptor RXFP1 activates several enzymes in a

phosphorylation cascade A phosphorylation cascade is a sequence of signaling pathway events where one enzyme phosphorylates another, causing a chain reaction leading to the phosphorylation of thousands of proteins. This can be seen in signal transduction of hormone messag ...

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 In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

(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 In cardiovascular physiology, stroke volume (SV) is the volume of blood pumped from the left ventricle per beat. Stroke volume is calculated using measurements of ventricle volumes from an echocardiogram and subtracting the volume of the blood i ...

, the amount of blood pumped per heart beat, without increasing the energy demand on the already strained heart of acute heart failure patients.

Acute heart failure

Serelaxin has undergone clinical trials in patients with acute heart failure, conducted by

Novartis Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...

. Serelaxin has completed several clinical trials as a therapy for AHF. Phase I trials examined safety and tolerability, while phase II trials evaluated its haemodynamic effects and symptom relief. The Pre-RELAX-AHF phase II trial administered a dose of 30 μg/kg/day and showed a decrease in blood pressure, improved dyspnoea, and increased renal blood flow. In phase III the RELAX-AHF trial gave a 48hr intravenous infusion of the same dose. It significantly improved patients' dyspnoea, resulted in a 30% reduction in worsening of heart failure symptoms, a decreased hospital stay and a reduction in signs and symptoms of congestion. The FDA granted serelaxin "breakthrough therapy" designation, meant to expedite the development and review of drugs for life-threatening conditions. On 22 March 2017, Novartis announced that the global Phase III study of serelaxin in patients with acute heart failure did not meet its primary endpoints.

References

{{Vasodilators used in cardiac diseases Drugs developed by Novartis Drugs acting on the cardiovascular system