Rotigaptide (ZP-123) is a drug under clinical investigation for the treatment of

cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the Cardiac cycle, heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per mi ...

s – specifically atrial fibrillation. It is a

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

analog that has been shown to increase

gap junction Gap junctions are specialized intercellular connections between a multitude of animal cell-types. They directly connect the cytoplasm of two cells, which allows various molecules, ions and electrical impulses to directly pass through a regula ...

intercellular conductance in

cardiac muscle cell Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...

s.Shiroshita-Takeshita A, Sakabe M, Haugan K, Hennan J, Nattel S (2007). Model- Dependent Effects of the Gap Junction Conduction–Enhancing Antiarrhythmic Peptide Rotigaptide (ZP123) on Experimental Atrial Fibrillation in Dogs. ''Circulation''. 115: 310- 318. Gap junctions are protein channels that are responsible for conducting electrical impulses between cells in the heart to maintain normal rhythm. Gap junction modulation is a promising and novel mechanism of action for the treatment of cardiovascular disorders. Its peptide sequence is Ac-D-Tyr-D-Pro-D-Hyp-Gly-D-Ala-Gly-NH2.

Indications

Rotigaptide is being studied for its antiarrhythmic effects, specifically for treating atrial fibrillation.Guerra J, Everett T, Lee K, Wilson E, Olgin J (2006). Effects of the Gap Junction Modifier Rotigaptide (ZP123) on Atrial Conduction and Vulnerability to Atrial Fibrillation. ''Circulation''. 114: 110-118. Atrial fibrillation is an irregular and often rapid heart rhythm. The irregular rhythm, results from abnormal electrical impulses in the heart. The irregularity can be continuous or intermittent. In atrial fibrillation, multiple impulses travel through the atria at the same time. Instead of a coordinated contraction, the atrial contractions are irregular, disorganized and very rapid. These irregular impulses reach the

AV node The atrioventricular node or AV node electrically connects the heart's atria and ventricles to coordinate beating in the top of the heart; it is part of the electrical conduction system of the heart. The AV node lies at the lower back section of t ...

in rapid succession, but not all of them make it past the AV node. Therefore, the ventricles beat slower in an irregular rhythm. The resulting rapid, irregular heartbeat causes an irregular pulse and sometimes a sensation of fluttering in the chest.

Mechanism of action

The exact

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular tar ...

of rotigaptide is not completely understood. However, rotigaptide is believed to exert its effects on

cardiomyocyte Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

gap junctions through

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

events. Each gap junction is composed of a series of

connexons In biology, a connexon, also known as a connexin hemichannel, is an assembly of six proteins called connexins that form the pore for a gap junction between the cytoplasm of two adjacent cells. This channel allows for bidirectional flow of ions an ...

in close proximity to each other. Each connexon is made up of 6 functional units (

connexins Connexins (Cx)TC# 1.A.24, or gap junction proteins, are structurally related transmembrane proteins that assemble to form vertebrate gap junctions. An entirely different family of proteins, the innexins, form gap junctions in invertebrates. Each ...

) that associate together to form a channel between adjacent cells. Rotigaptide acts at connexins, preferentially to connexin 43 (Cx43). Treatment with rotigaptide has been shown to activate various

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 ...

(PKC) isoforms to cause the phosphorylation of Cx43, which aids in proper function of the connexon. This allows for a smoother conduction to pass through the myocytes to propagate a synchronous contraction. This has been shown to reduce the occurrence of atrial fibrillation.

Limitations

A potential limitation for this drug is that animals being used for studies are most commonly anesthetized with

isoflurane Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia rather than isoflurane, due to airway irritation w ...

, which has been shown to be a partial gap junction uncoupler and thus would negate the effects of rotigaptide. However, this effect can be only minor, as one study showed that a low dose of isoflurane was kept continuous over the progression of the study, indicating that the dose was not high enough to uncouple rotigaptide. Therefore, it may be unlikely that isoflurane plays a role in the results presented.

References

{{Reflist, 2 Peptides Antiarrhythmic agents