Rotigaptide
A stable six-amino-acid peptide designed to keep heart cells electrically coupled by reopening connexin-43 gap junctions, tested against ischaemic arrhythmias and then shelved
Rotigaptide, also written ZP-123 and GAP-486, is a short peptide built entirely from D-amino acids so that it resists the enzymes that destroy natural peptides. It was made by Zealand Pharma as a stable version of a natural 'antiarrhythmic peptide', AAP10, and its job is unusual: instead of blocking an ion channel, it widens the electrical connections, the connexin-43 gap junctions, that let neighbouring heart cells pass current to one another. Those connections close down during a heart attack, and the idea was that keeping them open would stop the chaotic rhythms that follow. In animals it prevented ischaemic ventricular and atrial arrhythmias and reduced infarct size, but in people it did little to healthy blood vessels, and the phase 2 trials its licensee Wyeth started in 2005 were all terminated without results. It was never approved, and the work moved on to an oral follow-on, danegaptide.
Used in human trials: 0.25-25 nmol/min, Continuous infusion, Intra-brachial (intra-arterial) (Forearm mechanistic study: healthy volunteers) Details ↓
Recommended Dosing
Used in human trials
Typical range0.25–25 nmol/min · continuous intra-brachial infusion Human studyPMID 18789901compare across peptides →
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
Every heartbeat depends on cells passing an electrical signal from one to the next. They do this through gap junctions, clusters of channels that bridge touching cells, and in the working parts of the heart those channels are built mostly from a protein called connexin-43. When a region of heart muscle loses its blood supply, connexin-43 channels close and the cells become electrically isolated. Signals then travel slowly and unevenly, which is the setting in which a normal beat can break down into the fast, disorganised rhythms that cause sudden death. Rotigaptide was built around the opposite idea: a drug that keeps those channels open might hold the tissue together electrically and head off the arrhythmia.
The starting point was a natural substance. In the 1980s researchers described 'antiarrhythmic peptides' from the heart that improved cell-to-cell coupling, and a synthetic version, AAP10, became the lead. AAP10 was far too fragile to use as a medicine, so chemists at Zealand Pharma rebuilt it from D-amino acids, the mirror-image forms that the body's enzymes do not recognise, and capped both ends. The result was rotigaptide, Ac-D-Tyr-D-Pro-D-Hyp-Gly-D-Ala-Gly-NH2, whose half-life in rat and human plasma is roughly 1,700 times that of AAP10 (PMID 12829724).
How it works was pinned down in cells. In HeLa cells engineered to make different connexins, 50 nanomolar rotigaptide increased dye transfer only when the cells carried connexin-43, not connexin-32 or connexin-26, and it raised coupling in heart muscle cells and an atrial cell line without changing how much connexin-43 was present or, in that study, its phosphorylation (PMID 16415913). Work in whole hearts filled in the trigger: during ischaemia connexin-43 is stripped of phosphate at two sites, Ser297 and Ser368, over the fifteen to thirty minutes when coupling fails, and rotigaptide slowed that loss and delayed the heart's arrest (PMID 16678851). A telling feature is that it did almost nothing to normal tissue; its effect appeared only when cells were already stressed and partly uncoupled (PMID 15877626).
In animal hearts it did what the theory predicted, with limits. In anaesthetised dogs with a blocked coronary artery it prevented reentrant ventricular tachycardia across a wide dose range without changing blood pressure, the ECG or infarct size (PMID 12776869), and in a reperfusion model it cut ventricular arrhythmias and reduced infarct size at the higher doses (PMID 16344331). On the atrial side the effect depended on the model: it suppressed atrial fibrillation brought on by acute ischaemia or mitral regurgitation, but not the fibrillation of chronic heart failure or long-term atrial pacing (PMIDs 16818812, 17224477). Several studies drew a blank, which the literature records honestly: it did not prevent focal (non-reentrant) ventricular tachycardia (PMID 15650154), and in a five-day-old dog infarct it only partly restored connexin-43 and did not stop the arrhythmia (PMID 21493965).
The human evidence is thin and almost entirely mechanistic. A phase 1 programme gave rotigaptide intravenously to about 200 healthy people with no drug-related side effects reported (PMID 17845503). Two careful forearm studies in Edinburgh then asked what it did to blood vessels: infused into the artery of 27 healthy volunteers it had no effect on resting blood flow or on the vessels' response to several dilators (PMID 18789901), and in a later study it did not change the healthy forearm but did protect the lining of the artery from the damage caused by a bout of ischaemia and reperfusion, alongside a parallel pig experiment in which it shrank infarcts (PMID 26750458). No trial ever tested whether it prevents arrhythmias in patients.
That test was meant to come from Wyeth, which licensed the peptide as GAP-486 and registered three phase 2 trials in 2005: one in people with non-sustained ventricular tachycardia after a heart attack (NCT00124891, 500 planned) and two electrophysiology studies (NCT00137293, NCT00137332). All three were terminated in 2005-2006, and none posted results. Rather than push the injectable peptide further, the same group used it as the template for an orally active small molecule, danegaptide (GAP-134), which has its own entry; danegaptide reached a larger phase 2 heart-attack trial, which was negative. Rotigaptide itself has not been in an industry trial since.
Interest in the molecule did not stop, but it moved into the laboratory, where its clean, specific action on connexin-43 makes it a useful tool. Recent papers have used it to probe arrhythmia during therapeutic cooling (PMIDs 26188250, 34588996), scar healing after infarction (PMIDs 27807593, 33870715), bone loss (PMID 16109789), insulin-making islet cells (PMID 32560352), diabetic stomach muscle (PMID 39400417) and even egg-cell quality in ageing mice (PMID 42174667). None of this is clinical use, and this page keeps those studies in their place: they describe what the molecule does to cells and animals, not a treatment for anyone.
Mechanism of Action
Rotigaptide does not block an ion channel the way most antiarrhythmic drugs do. It works on the connections between heart cells, keeping the connexin-43 gap junctions open so that the electrical signal spreads evenly even when ischaemia is trying to shut them down.
Opens connexin-43 gap junctions
It increases coupling only in cells that carry connexin-43, not connexin-32 or connexin-26, and raises dye and electrical transfer between heart cells without changing how much connexin-43 is present (PMIDs 16415913, 12776869).
Protects connexin-43 from ischaemic dephosphorylation
During ischaemia connexin-43 loses phosphate at Ser297 and Ser368 as coupling fails; rotigaptide slows that loss and delays the heart's electrical arrest (PMID 16678851). Its parent review ties the effect to maintained connexin-43 phosphorylation (PMID 19943035).
Speeds and evens conduction under stress
In stressed or ischaemic tissue it restores conduction velocity and reverses the one-way conduction block that lets a reentry circuit form (PMIDs 16531322, 12776869), while leaving normal tissue, heart rate, blood pressure and the ECG unchanged (PMIDs 15877626, 16344331).
Acts only where coupling is already failing
Its effect is largest in partly uncoupled cells and absent under normal conditions (PMIDs 15877626, 16109789), and it depends on the disease model: it helps ischaemic atrial fibrillation but not the fibrillation of chronic heart failure (PMID 17224477).
Published Research
These are the studies of rotigaptide read from their PubMed abstracts on November 4, 2026. The two human studies come first, both small and mechanistic rather than tests of arrhythmia in patients, followed by the cell and isolated-tissue work that shows how it acts on connexin-43, two reviews from its developers, and then the large body of animal work. Most of the animal studies are in dogs, rabbits, pigs and rats and are described here in plain terms; several report that the peptide did nothing, which is kept in. Where a study's title names only gap junctions or a model and not the drug, the note says how the paper identifies it. Papers about the parent peptide AAP10 and the follow-on danegaptide are listed under References, not carded, because they are different molecules.
Protection of heart and artery from ischaemia-reperfusion injury
A two-part randomised, double-blind study. In pigs, a left-anterior-descending artery was blocked to cause a heart attack and rotigaptide (n = 9) or placebo (n = 10) was given into a vein before and during two hours of reperfusion; the treated pigs had a much smaller infarct, 18.7% of the area at risk against 43.6% (P = 0.006). In the human part, a short period of forearm ischaemia and reperfusion blunted the arteries' response to acetylcholine in people given placebo but not in those given rotigaptide into the artery, while the response to sodium nitroprusside was unchanged in both. The authors read this as protection of the artery lining.
No effect on healthy forearm blood vessels in 27 volunteers
Forearm blood flow was measured in 27 healthy men during infusion of rotigaptide into the brachial artery at 0.25 to 25 nmol/min, given alone and together with vessel-dilating agents (acetylcholine, bradykinin, sodium nitroprusside), with and without aspirin and a technique that clamps nitric oxide. Rotigaptide did not change resting blood flow and did not alter the response to any of the dilators, nor did it change the release of the clot-dissolving factor t-PA that bradykinin triggers. The authors concluded that opening connexin-43 coupling does nothing to normal forearm vessels and left open whether it helps in vascular disease.
Explanted human heart-failure hearts: faster but sometimes unstable conduction
Six hearts removed from people with end-stage heart failure were perfused and mapped before and after 50 nM of the peptide. It shortened the refractory period slightly (476 to 453 ms) without changing the spread of recovery times, and it sped conduction when the wavefront ran along the muscle fibres. Across the fibres it was different: conduction curves settled in five of six hearts running parallel, but in three of six hearts running perpendicular the peptide destabilised conduction with local delays near the stimulus. The title names enhanced gap-junctional conductance and failing hearts, not the drug.
Works only in cells that carry connexin-43
Dye passed between cells was measured in heart muscle cells, an atrial cell line and HeLa cells engineered to make one connexin at a time. The peptide raised transfer only where connexin-43 was present: HeLa cells making connexin-43 showed a 40% increase after 50 nM for five hours, while cells making connexin-32 or connexin-26 showed none. It raised coupling in the heart and atrial cells without changing their beating rate, and western blots showed no change in how much connexin-43 was present or, in this study, its phosphorylation.
Protects human insulin-making islet cells from cytokine damage
In human pancreatic islets, which make connexin-43, the peptide cut the cell death caused by inflammatory cytokines by about 40%. In an insulin-making cell line that lacks connexin-43 the protection was largely, but not entirely, lost: a modest effect remained, with less nitric oxide, lower iNOS and blunted NF-κB signalling. The authors suggest rotigaptide has a second, connexin-43-independent action on inflammatory signalling, and raise islet protection in diabetes as a question worth study.
The developer's overview of a new antiarrhythmic principle
A review from Zealand Pharma presenting rotigaptide as the first drug built to prevent arrhythmias by restoring gap-junction coupling rather than blocking ion channels. It summarises that during acute ischaemia the peptide prevents the induction of both ventricular and atrial tachyarrhythmia and prevents reperfusion arrhythmias, that it blocks ischaemic dephosphorylation of connexin-43 at Ser297 and Ser368, and that it reduced infarct size in rats and dogs. It reports no drug-related toxicity at plasma levels 77,000 times the active concentration and that phase 1 trials gave it intravenously to about 200 healthy people with no drug-related side effects.
Antiarrhythmic peptides as a class: how they act
A review of the antiarrhythmic peptides, which improve electrical and metabolic coupling through gap junctions. It traces the lead peptide AAP10 and describes rotigaptide as its stable D-amino-acid derivative and GAP-134 as a small-molecule analogue. The peptides act on connexin-43 and connexin-45 channels but not connexin-40, their effect is larger in partly uncoupled cells and is tied to maintained connexin-43 phosphorylation, and whether they help atrial fibrillation is, in the authors' words, still debated. The title names the class, not a single drug.
A stable peptide: pharmacology against the fragile parent AAP10
The characterisation study. In rat and human plasma the peptide's in vitro half-life was about 1,700 times that of the parent peptide AAP10, and its clearance was at least 140 times slower. In mice, both peptides delayed the heart block caused by ouabain in a dose-related way, with the peptide reaching maximum effect at a tenth of AAP10's dose. In isolated rabbit hearts under low-potassium ischaemia, only the stable peptide prevented the rise in the spread of action-potential duration that sets up arrhythmia.
Prevents reentrant ventricular tachycardia in ischaemic dogs
In pairs of guinea-pig heart cells, 10 nM of the peptide raised the conductance between them by about 69%. In anaesthetised dogs with a blocked coronary artery, reentrant ventricular tachycardia was induced by programmed stimulation and then re-tested after the peptide at three rising plasma levels; it prevented the tachycardia at every level against saline (6 of 12 vs 0 of 12; 7 of 13 vs 1 of 12; 9 of 13 vs 1 of 13), and the effect tracked the reversal of one-way conduction block. It did not change the refractory period, the surface ECG, blood pressure or infarct size.
No effect on focal (non-reentrant) ventricular tachycardia in dogs
A companion study testing whether gap-junction coupling matters for the focal kind of ischaemic ventricular tachycardia, which arises from a trigger rather than a reentry circuit. In 26 dogs the peptide, at three plasma levels, did not change how often focal tachycardia could be induced (77 vs 75%, 86 vs 77%, 77 vs 91%), and in isolated tissue it did not affect the delayed afterdepolarisations and triggered beats behind it. The authors concluded that coupling may not drive focal activity. The title names the mechanism, not the drug, which the abstract calls by its code.
Prevents stress-induced atrial conduction slowing, and nothing else
In isolated rat left atria, the peptide prevented the slowing of conduction caused by metabolic stress across a wide range (1 nM to 10 µM) but had no effect under normal conditions, on contractility, or on the rate-dependence of conduction. Screened against a panel of 80 ion channels and receptors it showed little or no binding, and it did not affect the hERG channel at concentrations that changed conduction; at 100 nM it reduced one outward potassium current by only 2.7%. The picture is of a drug that acts selectively on failing coupling.
Opens gap junctions in bone cells and protects bone in rats
Beyond the heart: in human osteoblasts the peptide produced a small rise in coupling under normal conditions (about 4.5%) and a larger rise under metabolic stress. In rats whose ovaries had been removed, a model of post-menopausal bone loss, the peptide given under the skin (300 nmol/kg twice daily) or by continuous infusion into the abdomen (158 nmol/kg a day) completely prevented the 20% loss of strength in the femoral head and the loss of bone mineral. The authors raise gap-junction modulation as a possible route for osteoporosis.
Fewer arrhythmias and smaller infarcts in dogs after reperfusion
Dogs had a coronary artery blocked for 60 minutes and then reopened for four hours, with the peptide given into a vein at four rising doses just before reperfusion. The two highest doses sharply cut ventricular tachycardia events (20.3 and 4.3 against 48.7 in controls) and premature beats (11.0% and 1.7% against 25.1%), and the top dose reduced infarct size to 7.1% of the left ventricle from 13.2%. There were more gap junctions preserved in the area at risk, and no change in heart rate, blood pressure, the QT interval or left-ventricular pressure.
Reverses conduction slowing that is already established
In isolated rat atria, metabolic stress cut conduction velocity by about 30%. When the peptide was started only after 30 minutes of that stress, it restored conduction quickly, showing it could reverse slowing that had already set in rather than only prevent it. When the peptide was then washed out, conduction fell only slightly over the next 30 minutes, so its effect faded much more slowly than it appeared.
Reduces infarct size in rats with a chronic heart attack
Because drugs that close gap junctions can shrink infarcts, the authors expected a coupling enhancer to enlarge them. They tied off a coronary artery in 156 rats and treated them at three dose levels for three weeks. The peptide did not change survival, and rather than enlarging the infarct it reduced it, to 90%, 67% and 82% of the vehicle group's size; only the middle dose reached significance. The result ran against the prediction and showed that findings for non-selective junction blockers do not carry over to a selective enhancer.
Which connexin-43 sites ischaemia strips, and the peptide protects
Using mass spectrometry on connexin-43 from isolated perfused rat hearts, the authors mapped 13 serine phosphorylation sites, three of them new. In the first seven minutes of ischaemia one site lost phosphate and another gained it; between 15 and 30 minutes, the window when coupling fails, Ser297 and Ser368 were fully stripped, and all untreated hearts stopped beating in that time. The peptide lengthened the time to this arrest and held phosphate on Ser297 and Ser368, marking them as likely targets of its action.
Suppresses atrial fibrillation from mitral regurgitation but not heart failure in dogs
Twenty-one dogs were studied in three groups: healthy controls, chronic mitral regurgitation, and heart failure from rapid pacing. The peptide raised conduction velocity in both atria of the control and regurgitation dogs (up to 38% in the left atrium) but barely moved it in the failing hearts. At 50 nM it cut the duration of atrial fibrillation in the regurgitation dogs by 96%, down to the level of healthy animals, while leaving the failing-heart dogs unchanged. The benefit depended on the kind of atrial disease.
Model-dependent effect on atrial fibrillation in dogs
The peptide was tested in three dog models of atrial fibrillation: congestive heart failure from ventricular pacing, long-term atrial pacing, and acute atrial ischaemia. It raised conduction velocity slightly in the paced and failing hearts but did not shorten the refractory period, reduce fibrillation duration or lower vulnerability in those models. In acute ischaemia, by contrast, it prevented the conduction slowing and the rise in fibrillation duration. The authors concluded that gap-junction dysfunction matters more in ischaemic atrial fibrillation than in the remodelling of pacing or heart failure.
Makes the heart easier to defibrillate in rabbits
Thirty-two rabbits were left in ventricular fibrillation for four minutes and then shocked. Rabbits given the peptide needed less total shock energy to restore rhythm (average cumulative voltage 844 V against 1,206 V in controls). The peptide did not change heart rate, the QRS or QT intervals, the refractory period, action-potential duration or the amount of connexin-43 measured by staining, so the easier defibrillation was not explained by those.
Only partly reverses gap-junction remodelling in a healing dog infarct
In the epicardial border zone of dog hearts five days after a heart attack, connexin-43 had fallen, spread to the sides of the cells and gained phosphate at Ser368. The peptide partly restored the amount of connexin-43 but did not change the Ser368 phosphorylation or the sideways redistribution. It did not prevent the slowed conduction in the border zone and did not reduce how readily sustained ventricular tachycardia could be induced, though it did shorten the refractory period. A negative result in a healing infarct.
Lowers the shock needed after prolonged fibrillation in pigs
Twenty pigs were put into ventricular fibrillation and left untreated for eight minutes before resuscitation. In the pigs given the peptide beforehand, the fibrillation ran at a higher frequency but lower amplitude, the energy needed to defibrillate was lower (92 against 133 joules) and successful defibrillation was more common (90% against 30%). The rate of return of a spontaneous circulation did not differ (40% against 30%), which the authors linked to the lower fibrillation amplitude.
Reduces arrhythmia vulnerability in rabbits with heart failure
Heart failure was produced in rabbits by chronic volume and pressure overload, which lengthened the refractory period, lowered the fibrillation threshold and made ventricular arrhythmia easier to provoke. The peptide shortened the refractory period (113 against 132 ms), raised the fibrillation threshold (15.0 against 6.3 V) and reduced vulnerability to ventricular tachycardia and fibrillation, without changing action-potential duration or the amount of connexin-43 messenger RNA.
Reduces arrhythmia during therapeutic cooling in isolated rabbit hearts
Cooling the body is used after cardiac arrest but can itself provoke arrhythmia by slowing conduction. In isolated rabbit hearts cooled to 33°C and 30°C, 300 nM of the peptide raised conduction velocity, reduced the spread of action-potential duration, raised the threshold for the alternating beat-to-beat pattern that precedes fibrillation, and made pacing-induced fibrillation less likely, all without changing the amount or distribution of connexin-43. The authors offer it as a way to make cooling safer.
One week of treatment at the time of infarction leaves a less arrhythmic scar in rats
Rats were given the peptide or saline by an implanted pump for the first seven days around a surgically induced heart attack, then studied four weeks later. Infarct size was the same, but the treated hearts were less easily provoked into arrhythmia (an inducibility score of 2.4 against 5.0), had a more uniform scar in the border zone and conducted faster there (43.1 against 34.8 cm/s). The authors propose early, short-term gap-junction enhancement as a way to shape a safer healed scar. The title names the mechanism, not the drug, which the abstract identifies in the treated group.
A week of treatment after reperfusion reduces later arrhythmia in rats
Rats had a heart attack with reperfusion followed by seven days of the peptide or saline, and were tested three weeks later. Ventricular tachycardia or fibrillation could be induced in 20% of treated rats against 53% of controls, and the overall arrhythmia score was lower. Imaging and histology showed a remodelled, less complex layered structure in the border zone of the healed scar. There was no change in the ECG, in spontaneous arrhythmias or in survival. The work echoes the 2016 study from the same group.
Helpful electrically, but cannot stop fibrillation in failing, cooled rabbit hearts
In failing rabbit hearts with fresh ischaemia-reperfusion injury, therapeutic cooling worsened the electrical disarray and made fibrillation easier to provoke. The peptide, at 300 nM, improved several measures, reducing the spread and beat-to-beat swing of action-potential duration, improving conduction and deferring the alternating pattern that precedes fibrillation, and raised the pacing threshold for it. Even so, its effect on how readily cooling-driven fibrillation could be induced was not statistically significant, a frank negative in a difficult model.
Calms overactive stomach muscle in diabetic rats
In rats with diabetes, the spontaneous contractions of stomach muscle were weaker and slower than normal, and the peptide reduced them further. In the treated muscle, connexin-43 shifted from the cell membrane into the cytoplasm and an active form of the enzyme PKCα rose, lowering the share of connexin-43 at the membrane. The authors describe the effect as working through a PKCα-connexin-43 pathway that steadies calcium inside the muscle cells, a laboratory finding in a disease model, not a treatment.
Restores egg-cell support in ageing mice
Egg quality falls with age partly because the gap junctions linking the egg to its surrounding granulosa cells, built from connexin-43, weaken. In ageing mice, connexin-43 in the ovary fell with age, and giving the peptide into the abdomen restored the gap junctions between granulosa cells and improved follicle development. The treated mice had better egg maturation, mitochondrial function, ovulation and early-embryo development, and in a granulosa cell line the peptide raised dye transfer without raising connexin-43, a research finding in reproductive ageing.
Dosing Data
Rotigaptide was never approved, so there is no label and no recommended dose. The only amount a published human study gives is the Edinburgh forearm infusion below, a research dose used to study blood vessels, not to treat anyone. Phase 1 trials gave it intravenously to about 200 healthy people, and the terminated phase 2 trials posted no doses. The animal doses, given in nanomolar plasma concentrations or nanograms per kilogram, are described in the research cards and are not repeated here as if they were human amounts.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes Rotigaptide is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
No worked example: none of the doses on this page is a fixed amount in mg or mcg injected under the skin or into a muscle (the routes given are: intra-brachial (intra-arterial)). There is no home-mixing step to show. The reconstitution calculator does the arithmetic for any vial.
Source: the route and amount of each dose row in Dosing Data below.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Rotigaptide, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long Rotigaptide stays intact once mixed.
How it is taken
As it was given in human studies: Intra-brachial (intra-arterial) (Continuous infusion; Forearm mechanistic study: healthy volunteers).
For injection technique, sites and needle disposal, see the mixing guide.
Source: Used in human trials: the route and frequency of each row in Dosing Data below.
What to expect, and when
How long it stays in the body: not established by a measurement cited on this entry.
How long the doses were given: Forearm mechanistic study: healthy volunteers: During the study session.
When effects appear: unknown; no source on this page gives a time to effect for Rotigaptide. Results reported in the studies are under Published Research.
Source: Used in human trials, the duration of each row in Dosing Data below.
Side effects, and when to stop or get help
From the Side Effects section: No drug-related side effects reported in phase 1 trials that gave it intravenously to about 200 healthy people (PMID 17845503); No effect on resting forearm blood flow or on the vessels' responses in 27 healthy volunteers (PMID 18789901); In animals it did not change heart rate, blood pressure, the QT interval or left-ventricular pressure at antiarrhythmic doses (PMIDs 16344331, 12776869); No binding of note across a panel of 80 receptors and ion channels, and no effect on the hERG channel at active concentrations (PMID 15877626); A developer review reported no drug-related toxicity at plasma levels up to 77,000 times the active concentration (PMID 17845503); In one isolated human heart-failure heart study, enhanced coupling destabilised conduction across the fibre direction in three of six hearts (PMID 19139945). Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Rotigaptide. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“Human experience is small and was reassuring as far as it went; the animal findings on safety follow”).
Interactions
Unknown: a PubMed search for human interaction studies of Rotigaptide (reviewed 2026-11-04) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Rotigaptide products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Rotigaptide's expected mass, 617.6 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Discontinued (Never approved anywhere). Sport: Prohibited (S0 catch-all).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
Human experience is small and was reassuring as far as it went; the animal findings on safety follow.
Contraindications & Cautions
There is no approved label and so no official contraindications. These cautions come from the molecule's status and the studies read here.
Legal Status
Rotigaptide has never been approved by any regulator; its development reached phase 2 and stopped.
Frequently Asked Questions
?What is rotigaptide?
An experimental antiarrhythmic peptide, six amino acids long and built from D-amino acids for stability (ZP-123, GAP-486). It reopens the connexin-43 gap junctions that connect heart cells, which close during a heart attack, and was tested as a way to prevent dangerous rhythms.
?Is rotigaptide approved or available as a medicine?
No. It was never approved anywhere. Its maker's phase 2 trials were terminated in 2006, and later human work is limited to small academic studies of blood vessels. There is no approved product.
?Did it work?
In animals it prevented ischaemic ventricular and atrial arrhythmias and reduced infarct size in several models (PMIDs 12776869, 16344331, 26750458), but it failed in others (PMIDs 15650154, 17224477). No trial ever tested whether it prevents arrhythmias in patients, so its clinical value is unknown.
?How is it different from other antiarrhythmic drugs?
Most antiarrhythmic drugs block ion channels inside heart cells. Rotigaptide instead works on the connexin-43 gap junctions between cells, keeping them coupled; it left heart rate, blood pressure and the ECG unchanged in animals (PMID 16344331).
?How does it relate to danegaptide?
Danegaptide (GAP-134) is an orally active small molecule that Wyeth developed from rotigaptide to hit the same gap junctions. It was taken forward when the rotigaptide peptide programme stopped, and it has its own entry; its results are not rotigaptide's.
?Why do some studies call it ZP123?
ZP-123 was Zealand Pharma's development code and GAP-486 was Wyeth's; older papers use these names, and the peptide's INN is rotigaptide.
References
- [clinical-trial] Pedersen CM, et al. "Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury." Br J Clin Pharmacol, 2016;81(6):1037-45. PMID: 26750458.
- [clinical-trial] Lang NN, et al. "The vascular effects of rotigaptide in vivo in man." Biochem Pharmacol, 2008;76(10):1194-200. PMID: 18789901.
- [pubmed] Wiegerinck RF, et al. "The effect of enhanced gap junctional conductance on ventricular conduction in explanted hearts from patients with heart failure." Basic Res Cardiol, 2009;104(3):321-32. PMID: 19139945.
- [pubmed] Clarke TC, et al. "The antiarrhythmic peptide rotigaptide (ZP123) increases gap junction intercellular communication in cardiac myocytes and HeLa cells expressing connexin 43." Br J Pharmacol, 2006;147(5):486-95. PMID: 16415913.
- [pubmed] Ghiasi SM, et al. "The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets." Int J Mol Sci, 2020;21(12). PMID: 32560352.
- [review] Kjølbye AL, et al. "Pharmacological modulation of gap junction function with the novel compound rotigaptide: a promising new principle for prevention of arrhythmias." Basic Clin Pharmacol Toxicol, 2007;101(4):215-30. PMID: 17845503.
- [review] Dhein S, et al. "Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides." Naunyn Schmiedebergs Arch Pharmacol, 2010;381(3):221-34. PMID: 19943035.
- [pubmed] Kjølbye AL, et al. "Pharmacological characterization of the new stable antiarrhythmic peptide analog Ac-D-Tyr-D-Pro-D-Hyp-Gly-D-Ala-Gly-NH2 (ZP123): in vivo and in vitro studies." J Pharmacol Exp Ther, 2003;306(3):1191-9. PMID: 12829724.
- [pubmed] Xing D, et al. "ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs." J Cardiovasc Electrophysiol, 2003;14(5):510-20. PMID: 12776869.
- [pubmed] Xing D, et al. "Pharmacological stimulation of cardiac gap junction coupling does not affect ischemia-induced focal ventricular tachycardia or triggered activity in dogs." Am J Physiol Heart Circ Physiol, 2005;288(2):H511-6. PMID: 15650154.
- [pubmed] Haugan K, et al. "The antiarrhythmic peptide analog ZP123 prevents atrial conduction slowing during metabolic stress." J Cardiovasc Electrophysiol, 2005;16(5):537-45. PMID: 15877626.
- [pubmed] Jørgensen NR, et al. "The antiarrhythmic peptide analog rotigaptide (ZP123) stimulates gap junction intercellular communication in human osteoblasts and prevents decrease in femoral trabecular bone strength in ovariectomized rats." Endocrinology, 2005;146(11):4745-54. PMID: 16109789.
- [pubmed] Hennan JK, et al. "Rotigaptide (ZP123) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs." J Pharmacol Exp Ther, 2006;317(1):236-43. PMID: 16344331.
- [pubmed] Haugan K, et al. "Treatment with the gap junction modifier rotigaptide (ZP123) reduces infarct size in rats with chronic myocardial infarction." J Cardiovasc Pharmacol, 2006;47(2):236-42. PMID: 16495761.
- [pubmed] Haugan K, et al. "Rotigaptide (ZP123) reverts established atrial conduction velocity slowing." Cell Commun Adhes, 2005;12(5-6):271-8. PMID: 16531322.
- [pubmed] Axelsen LN, et al. "Identification of ischemia-regulated phosphorylation sites in connexin43: A possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123)." J Mol Cell Cardiol, 2006;40(6):790-8. PMID: 16678851.
- [pubmed] Guerra JM, et al. "Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation." Circulation, 2006;114(2):110-8. PMID: 16818812.
- [pubmed] Shiroshita-Takeshita A, et al. "Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs." Circulation, 2007;115(3):310-8. PMID: 17224477.
- [pubmed] Zhong JQ, et al. "Effects of rotigaptide, a gap junction modifier, on defibrillation energy and resuscitation from cardiac arrest in rabbits." J Cardiovasc Pharmacol Ther, 2007;12(1):69-77. PMID: 17495260.
- [pubmed] Macia E, et al. "Characterization of gap junction remodeling in epicardial border zone of healing canine infarcts and electrophysiological effects of partial reversal by rotigaptide." Circ Arrhythm Electrophysiol, 2011;4(3):344-51. PMID: 21493965.
- [pubmed] Li JS, et al. "Effect of ZP123, a gap junction modifier, on prolonged ventricular fibrillation in swine." Cardiology, 2011;118(3):147-52. PMID: 21606647.
- [pubmed] Liu Y, et al. "Electrophysiological effect of rotigaptide in rabbits with heart failure." Arch Med Sci, 2014;10(2):374-80. PMID: 24904675.
- [pubmed] Hsieh YC, et al. "Gap junction modifier rotigaptide decreases the susceptibility to ventricular arrhythmia by enhancing conduction velocity and suppressing discordant alternans during therapeutic hypothermia in isolated rabbit hearts." Heart Rhythm, 2016;13(1):251-61. PMID: 26188250.
- [pubmed] Ng FS, et al. "Enhancement of Gap Junction Function During Acute Myocardial Infarction Modifies Healing and Reduces Late Ventricular Arrhythmia Susceptibility." JACC Clin Electrophysiol, 2016;2(5):574-582. PMID: 27807593.
- [pubmed] Chowdhury RA, et al. "Rotigaptide Infusion for the First 7 Days After Myocardial Infarction-Reperfusion Reduced Late Complexity of Myocardial Architecture of the Healing Border-Zone and Arrhythmia Inducibility." J Am Heart Assoc, 2021;10(9):e020006. PMID: 33870715.
- [pubmed] Lee HL, et al. "Beneficial Electrophysiological Effects of Rotigaptide Are Unable to Suppress Therapeutic Hypothermia-Provoked Ventricular Fibrillation in Failing Rabbit Hearts With Acute Ischemia-Reperfusion Injury." Front Physiol, 2021;12:726389. PMID: 34588996.
- [pubmed] Changri L, et al. "Rotigaptide inhibits spontaneous contractions of gastric smooth muscle in diabetic rats via the PKCα-Cx43 pathway." Cell Biol Int, 2025;49(1):92-100. PMID: 39400417.
- [pubmed] Teng H, et al. "Intraperitoneal ZP123 improves aged oocyte quality by restoring granulosa cell gap junctions and improving mitochondrial function." J Ovarian Res, 2026;19(1). PMID: 42174667.
- [pubmed] Skyschally A, et al. "The antiarrhythmic dipeptide ZP1609 (danegaptide) when given at reperfusion reduces myocardial infarct size in pigs." Naunyn Schmiedebergs Arch Pharmacol, 2013;386(5):383-91. PMID: 23397587.
- [pubmed] Rossman EI, et al. "The gap junction modifier, GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], improves conduction and reduces atrial fibrillation/flutter in the canine sterile pericarditis model." J Pharmacol Exp Ther, 2009;329(3):1127-33. PMID: 19252062.
- [pubmed] Butera JA, et al. "Discovery of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride (GAP-134)13, an orally active small molecule gap-junction modifier for the treatment of atrial fibrillation." J Med Chem, 2009;52(4):908-11. PMID: 19175320.
- [pubmed] "Molecule of the month. Rotigaptide." Drug News Perspect, 2005;18(9):585-6. PMID: 16421631.
- [other] FDA Global Substance Registration System, Rotigaptide, UNII GFA1W6KO7N (INN 8717; USAN RR-54; CAS 355151-12-1; MeSH C477643), read November 4, 2026: formula C28H39N7O9, molecular weight 617.65; Ac-D-Tyr-D-Pro-D-Hyp-Gly-D-Ala-Gly-NH2. https://gsrs.ncats.nih.gov/ginas/app/beta/substances/GFA1W6KO7N
- [other] ChEMBL molecule CHEMBL450656 (ROTIGAPTIDE), read November 4, 2026: synonyms Rotigaptide, Rotigaptida, ZP-123; highest clinical phase recorded 2. https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL450656/
- [registry] ClinicalTrials.gov API v2, read November 4, 2026: five studies name rotigaptide, ZP-123 or GAP-486. Wyeth's three phase 2 trials, NCT00124891 (non-sustained ventricular tachycardia, 500 planned), NCT00137293 and NCT00137332 (electrophysiology and ventricular-tachycardia induction), are all marked terminated (2005-2006) with no results posted; the University of Edinburgh forearm studies NCT00901563 and NCT07192744 are completed academic studies. https://clinicaltrials.gov/search?intr=rotigaptide
Sources & Citations
The studies carded above and the four References-only papers were read from their PubMed records on November 4, 2026. Identity comes from the FDA Global Substance Registration System (UNII GFA1W6KO7N) and ChEMBL (CHEMBL450656); trial registration and termination from ClinicalTrials.gov API v2; US status from Drugs@FDA, all read the same day. Rotigaptide was never approved, so no label was read. Papers about the parent peptide AAP10 and the follow-on danegaptide are listed under References as other molecules. Grey Peptides sells nothing and links to no vendor.
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