The effect of the isomers of cyclo(Trp-Pro) on heart and ion-channel activity.
Cyclo(L-Trp-L-Pro) has shown potential for use in the treatment of cardiovascular dysfunction. The aim of the study was to determine the effects of the isomers of cyclo(Trp-Pro) - cyclo(L-Trp-L-Pro), cyclo(L-Trp-D-Pro), cyclo(D-Trp-L-Pro) and cyclo(D-Trp-D-Pro) - on heart and ion-channel activity. The effects on L-type Ca(2+)-channel, Na(+)-channel and inward rectifier K(+)-channel activity were determined by using the whole-cell patch-clamp technique on myocytes of guinea-pig origin. Dependence on the membrane potential in terms of Ca(2+)-channel activity was also investigated. A modified Langendorff method was used to determine the effects of the isomers on heart rate, coronary flow, duration of ventricular tachycardia and arrhythmia, time to sinus rhythm and QRS interval on the rat isolated heart. Cyclo(L-Trp-L-Pro), cyclo(L-Trp-D-Pro) and cyclo(D-Trp-D-Pro), 100 microM, showed agonism towards Ca(2+)-channel activity, while cyclo(D-Trp-L-Pro) caused a blockage of the current. The action of cyclo(D-Trp-L-Pro) was shown to be independent of membrane potential. No significant effect (P > 0.05) on the inward rectifier K(+) current was observed in the presence of cyclo(L-Trp-D-Pro) and cyclo(D-Trp-D-Pro), while antagonism was noted in the presence of cyclo(L-Trp-L-Pro) and cyclo(D-Trp-L-Pro). All isomers showed antagonist effects on the Na(+) channel. No adverse effects were noted on chronotropic effects in the presence of 200 microM cyclo(L-Trp-L-Pro) and cyclo(D-Trp-D-Pro) (P > 0.05), while cyclo(L-Trp-D-Pro) significantly increased the heart rate. Cyclo(D-Trp-L-Pro) significantly reduced the heart rate (P < 0.05). In addition, no significant effects were observed on the coronary flow rate in the presence of the isomers. All isomers significantly reduced the duration of ventricular tachycardia and arrhythmia, as well as the time to sinus rhythm. Furthermore, no change in the QRS intervals was noted in the presence of the isomers in comparison with the control, with a significant increase being noted for cyclo(D-Trp-D-Pro) (P < 0.05) in reference to the other isomers. The isomers thus show antiarrhythmic potential and may manifest as novel agents in the treatment of cardiovascular dysfunction, since a decrease in ventricular fibrillation may reduce the mortality rates in acute myocardial infarction.
Jamie
Hajierah
H
Cyclic Dipeptide Research Unit, Department of Pharmacy, Box 1600, University of Port Elizabeth, Port Elizabeth, 6000, South Africa.
Kilian
Gareth
G
Dyason
Karin
K
Milne
Pieter J
PJ
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology; D015220:Calcium Channels / Q000187:drug effects*; D003326:Coronary Circulation / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004562:Electrocardiography; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D015222:Sodium Channels / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017180:Tachycardia, Ventricular / Q000188:drug therapy; D013997:Time Factors
D015220:Calcium Channels; D004151:Dipeptides; D010456:Peptides, Cyclic; D024661:Potassium Channels, Inwardly Rectifying; D015222:Sodium Channels; C118539:cyclo(tryptophyl-prolyl)