a-317491 and Myocardial-Ischemia

Myocardial ischemia causes the production of a variety of chemical substances, which act on the cardiac afferent nerve to cause pain. Myocardial damage can affect cardiac vagal afferent activity. Survivors of myocardial infarction are often left with impaired activity of cardiac vagal sensory fibres. The nodose ganglia (NG) are lower ganglia of cardiac vagus nerve, which are chiefly visceral afferent in the sensation of heart. ATP as a possible damage signal may activate nociceptive sensory neurons. Activation of P2X(3), P2X(2/3) receptors by endogenous ATP contributes to the development of hyperalgesia. The present results have shown that the sensitivity of P2X(2/3) receptor in nodose ganglion neurons was increased after myocardial ischemic injury under electrophysiological observation. The inhibitive role of P2X(2/3) antagonist A-317491 on ATP-activated currents in myocardial ischemic rats was significantly increased, compared with that in control group at the same concentration of A-317491. The staining of P2X(2) and P2X(3) receptors in myocardial ischemic injury group appeared to be more intense than those in naive rats and myocardial ischemic rats treated with A-317491 with immunofluorescence double labeling methods. Therefore, the activity of P2X(2/3) receptors in NG neurons was involved in the transmission of myocardial ischemic nociceptive signal.

Topics: Angina Pectoris; Animals; Male; Myocardial Ischemia; Myocardium; Neural Pathways; Nociceptors; Nodose Ganglion; Phenols; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2X; Receptors, Purinergic P2X3; Signal Transduction

Adenosine 5'-triphosphate (ATP) is implicated in peripheral pain signaling through activation of P2X receptors. P2X(3) receptors have a high level of expression in, and selective location on sensory afferents. P2X receptors, particularly the P2X(3) subtype, are identified as targets for novel analgesics. The stellate ganglion (SG) is peripheral sympathetic ganglia involved in heart function. Surgical interventions of sympathetic afferent pathways abolish or relieve angina pectoris, so it is showed that cardiac pain is mediated by the activation of afferents in sympathetic nerves. The cervicothoracic sympathetic ganglia, including the stellate ganglion, are implicated in sensations associated with myocardial ischemia or cardiac pain. In the present study we have examined P2X(3) involvement in cardiac nociceptive transmission. P2X receptor agonists activated currents (I(ATP)) in SG neurons. The I(ATP) amplitude and P2X(3) mRNA expression in myocardial ischemic injury group were much larger than those obtained in control group. Prostaglandin E(2) (PGE(2)) and substance P (SP) increased ATP-activated currents. P2X(3) receptor antagonist A-317491 reduced P2X agonist activated currents and P2X(3) mRNA expression. The results revealed that the myocardial ischemia induced the upregulation of P2X(3) receptor in function and morphous and P2X(3) receptor antagonist A-317491 inhibited P2X agonist activated currents and P2X(3) mRNA expression. The facts indicated that P2X(3) receptor in SG neurons was involved in cardiac nociceptive transmission.

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Dinoprostone; Drug Interactions; Electric Stimulation; Female; Gene Expression Regulation; Male; Membrane Potentials; Myocardial Ischemia; Neuralgia; Neurons; Patch-Clamp Techniques; Phenols; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2X3; Signal Transduction; Stellate Ganglion; Substance P

Extracellular ATP acts on purinergic receptors as a potent agonist for a variety of different cell types, including cardiomyocytes and nodose ganglia. P2X3 receptor is the most abundant P2X-receptor subtype in heart and nodose ganglia. This study wants to observe the role of P2X3 receptor in myocardial ischemic injury and nociceptive transmission via nodose ganglia. The serum lactate dehydrogenase (LDH), creatine kinase (CK) and CK isoform MB (CK-MB) activities were measured by automatic biochemistry analyzer. The electrocardiogram (ECG) recorded ST-segment changes and cardiac arrhythmia. The expression of P2X3 immunoreactivity, mRNA and protein were analyzed by immunohistochemistry, in situ hybridization and western blotting. Myocardial ischemia enhanced the serum LDH, CK and CK-MB activities and caused premature beats. P2X3 receptor antagonist A-317491 decreased the serum enzyme activities and improved premature beats in myocardial ischemic rats. The expression of P2X3 mRNA and protein in the ischemic injury heart were higher than that in the naive heart as control. A-317491 reduced the expression of P2X3 mRNA and protein in the myocardial ischemic injury. The myocardial ischemic injury increased the expression of P2X3 immunoreactivity and mRNA in nodose ganglia. In rats treated with A-317491, the expression of P2X3 immunoreactivity and mRNA in nodose ganglia was reduced. Blocking the nociceptive transmission mediated by P2X3 receptor may protect the cardiac function. According to these results, P2X3 receptor could be thought of as a new target for treating myocardial ischemic injury and cardiac arrhythmia and inhibiting nociceptive transmission of myocardial ischemic injury.

Topics: Animals; Creatine Kinase; Creatine Kinase, MB Form; Disease Models, Animal; Electrocardiography; Female; Gene Expression Regulation; L-Lactate Dehydrogenase; Male; Myocardial Ischemia; Nodose Ganglion; Pain; Phenols; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2X3; Synaptic Transmission

In this work we have examined the effects of P2X3 receptor antagonist A-317491 on P2X3 expression in superior cervical ganglion (SCG) from naive and myocardial ischemic rats to observe the effect of P2X3 receptors in cardiac nociceptive transmission. A-317491 improved nociceptive behavior. In the ganglia neurons of rats at 14 days after myocardial ischemic injury, the staining of P2X3 receptor in myocardial ischemic groups appeared to be more intense than those of naive rats detected by immunohistochemistry. After myocardial ischemic rats treated with A-317491, the intensity of the P2X3 immunoreactivity was lower than that in myocardial ischemic rats. The signals of P2X3 and its protein and mRNA in myocardial ischemic groups were higher than those in control group measured by western blotting and in situ hybridization. After myocardial ischemic rats treated with A-317491, the intensity of the P2X3 and its mRNA was lower than that in myocardial ischemic rats. These results suggest the involvement of P2X3 receptors in cardiac nociceptive transmission and A-317491 may inhibit the transmission mediated by P2X3 receptors in rat SCG after myocardial ischemia.

Topics: Animals; Behavior, Animal; Female; Male; Myocardial Ischemia; Pain Measurement; Phenols; Polycyclic Compounds; Rats; Receptors, Purinergic P2; Receptors, Purinergic P2X3; Superior Cervical Ganglion; Synaptic Transmission