Effects of Chronic Gap Junction Conduction–Enhancing Antiarrhythmic Peptide GAP-134 Administration on Experimental Atrial Fibrillation in Dogs

Laurent, Gabriel; Leong‐Poi, Howard; Mangat, Iqwal; Moe, Gordon W.; Hu, Xudong; So, Petsy Pui-Sze; Tarulli, Emidio; Ramadeen, Andrew; Rossman, Eric I.; Hennan, James K.; Dorian, Paul

doi:10.1161/circep.108.790212

Cited by 46 publications

(28 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results were comparable with the results obtained after IV administration of ZP123 in a dog model of mitral regurgitation. GAP-134 enhanced gap junctional communication probably by an indirect route, as there was no change in Cx43 and Cx40 mRNA levels, nor in the spatial distribution of Cx43 in the atria after 14 days of oral GAP-134 administration (Laurent et al, 2009). Interestingly, GAP-134 had no effect on the electrophysiological properties of the healthy tissue.…”

Section: Second Generation Antiarrhythmic Peptidesmentioning

confidence: 89%

“…Hereby, GAP-134 had a robust cardioprotective effect that limited infarct size . The effect of oral administration of GAP-134 (steady-state plasma concentration >100 nM) on conduction abnormalities and atrial fibrillation vulnerability was studied by Laurent et al (2009) in a model of pacinginduced atrial myopathy (Laurent et al, 2009). Simultanous pacing of the right atrium and ventricle induced severe left atrial dilation and increased atrial fibrillation vulnerability.…”

Section: Second Generation Antiarrhythmic Peptidesmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

Vuyst¹,

Boengler²,

Antoons³

et al. 2011

British J Pharmacology

View full text Add to dashboard Cite

Coordinated electrical activity in the heart is supported by gap junction channels located at the intercalated discs of cardiomyocytes. Impaired gap junctional communication between neighbouring cardiomyocytes contributes to the development of re-entry arrhythmias after myocardial ischaemia. Current antiarrhythmic therapy is hampered by a lack of efficiency and side effects, creating the need for a new generation of drugs. In this review, we focus on compounds that increase gap junctional communication, thereby increasing the conduction velocity and decreasing the risk of arrhythmias. Some of these compounds also inhibit connexin 43 (Cx43) hemichannels, thereby limiting adenosine triphosphate loss and volume overload following ischaemia/reperfusion, thus potentially increasing the survival of cardiomyocytes. The compounds discussed in this review are: (i) antiarrythmic peptide (AAP), AAP10, ZP123; (ii) GAP-134; (iii) RXP-E; and (vi) the Cx mimetic peptides Gap 26 and Gap 27. None of these compounds have effects on Na + , Ca 2+ and K + channels, and therefore have no proarrhythmic activity associated with currently available antiarrhythmic drugs. GAP-134, RXP-E, Gap 26 and Gap 27 are pharmalogical agents with a favorable clinical safety profile, as already confirmed in phase I clinical trials for GAP-134. These agents show an excellent promise for treatment of arrhythmias in patients with ischaemic cardiomyopathy.

show abstract

Section: Second Generation Antiarrhythmic Peptidesmentioning

confidence: 89%

Section: Second Generation Antiarrhythmic Peptidesmentioning

confidence: 99%

Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

Vuyst¹,

Boengler²,

Antoons³

et al. 2011

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…In a subset of dogs (n ϭ 3), AERP was measured, before and after GAP-134 administration, at cycle lengths of 300 and 200 ms. GAP-134 did not significantly alter the AERP at either cycle length (300 ms, 106.7 Ϯ 4.4 versus 105.0 Ϯ 6.3 ms; 200 ms, 109.2 Ϯ 4.2 versus 113.3 Ϯ 1.7 ms). Although the small sample size used to measure AERP in this study is a limitation, a recent study by Dr. Paul Dorian thoroughly explored the effect of GAP-134 on AERP, and other electrophysiological parameters, in a canine heart failure model of atrial fibrillation (Laurent et al, 2009). In this study, a very small reduction in AERP was observed with GAP-134 at only one cycle length in combination with a large increase in conduction velocity.…”

Section: Gap-134 Limits Af In the Canine Sterile Pericarditis Model 1129mentioning

confidence: 96%

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

Rossman¹,

Liu²,

Morgan³

et al. 2009

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Gap junction uncoupling can alter conduction pathways and promote cardiac re-entry mechanisms that potentiate many supraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL). Our objective was to determine whether GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], a small dipeptide gap junction modifier, can improve conduction and ultimately prevent AF/AFL. In rat atrial strips subjected to metabolic stress, GAP-134 prevented significantly conduction velocity slowing at 10 nM compared with vehicle (p Ͻ 0.01). In the canine sterile pericarditis model, conduction time (CT; n ϭ 5), atrial effective refractory period (AERP; n ϭ 3), and AF/AFL duration/inducibility (n ϭ 16) were measured 2 to 3 days postoperatively in conscious dogs. CT was significantly faster after GAP-134 infusion (average plasma concentration, 250 nM) at cycle lengths of 300 ms (66.2 Ϯ 1.0 versus 62.0 Ϯ 1.0 ms; p Ͻ 0.001) and 200 ms (64.4 Ϯ 0.9 versus 61.0 Ϯ 1.3 ms; p Ͻ 0.001). No significant changes in AERP were noted after GAP-134 infusion. The mean number of AF/AFL inductions per animal was significantly decreased after GAP-134 infusion (2.7 Ϯ 0.6 versus 1.6 Ϯ 0.8; p Ͻ 0.01), with total AF/AFL burden being decreased from 12,280 to 6063 s. Western blot experiments showed no change in connexin 43 expression. At concentrations exceeding those described in the AF/AFL experiments, GAP-134 had no effect on heart rate, blood pressure, or any electrocardiogram parameters. In conclusion, GAP-134 shows consistent efficacy on measures of conduction and AF/AFL inducibility in the canine sterile pericarditis model. These findings, along with its oral bioavailability, underscore its potential antiarrhythmic efficacy.

show abstract

“…Eventually, several of these drugs may not necessarily work, at least under the same concentration and exposure conditions, in all cell types. It is also intriguing that, so far, few connexin channel "openers" have been clearly identified (117,119,124,206,292,432), which delays the development of future strategies aimed at developing a connexin-targeted therapy of several diseases, specifically in humans.…”

Section: G the Pharmacologymentioning

confidence: 99%

Connexins: Key Mediators of Endocrine Function

Bosco

Haefliger

Meda

2011

Physiological Reviews

158

185

View full text Add to dashboard Cite

The appearance of multicellular organisms imposed the development of several mechanisms for cell-to-cell communication, whereby different types of cells coordinate their function. Some of these mechanisms depend on the intercellular diffusion of signal molecules in the extracellular spaces, whereas others require cell-to-cell contact. Among the latter mechanisms, those provided by the proteins of the connexin family are widespread in most tissues. Connexin signaling is achieved via direct exchanges of cytosolic molecules between adjacent cells at gap junctions, for cell-to-cell coupling, and possibly also involves the formation of membrane “hemi-channels,” for the extracellular release of cytosolic signals, direct interactions between connexins and other cell proteins, and coordinated influence on the expression of multiple genes. Connexin signaling appears to be an obligatory attribute of all multicellular exocrine and endocrine glands. Specifically, the experimental evidence we review here points to a direct participation of the Cx36 isoform in the function of the insulin-producing β-cells of the endocrine pancreas, and of the Cx40 isoform in the function of the renin-producing juxtaglomerular epithelioid cells of the kidney cortex.

show abstract

Effects of Chronic Gap Junction Conduction–Enhancing Antiarrhythmic Peptide GAP-134 Administration on Experimental Atrial Fibrillation in Dogs

Cited by 46 publications

References 29 publications

Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

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

Connexins: Key Mediators of Endocrine Function

Contact Info

Product

Resources

About