vasoactive-intestinal-peptide and Myocardial-Ischemia

Cardiac function is regulated by a balance of sympathetic and parasympathetic transmission. Neuropeptide Y (NPY) and galanin (GAL) released from cardiac sympathetic neurons inhibits parasympathetic transmission in the heart. Sympathetic peptides may contribute to autonomic imbalance, which is characterized by increased sympathetic and decreased parasympathetic transmission and contributes to life threatening cardiovascular pathologies. Several gp130 cytokines are increased in the heart after myocardial infarction (MI), and these cytokines stimulate neuropeptide expression in sympathetic neurons. We used mice whose sympathetic neurons lack the gp130 receptor (gp130(DBH-Cre/lox) mice) to ask if cytokine activation of gp130 regulated neuropeptide expression in cardiac sympathetic nerves after MI. Myocardial infarction decreased NPY mRNA through a gp130 independent mechanism and increased VIP and PACAP mRNA via gp130, while GAL mRNA was unchanged. Immunohistochemistry revealed a gp130-dependent increase in PACAP38 in cells of the stellate ganglion after MI, and PACAP was detected in pre-ganglionic fibers of all genotypes and surgical groups. VIP was identified in a few sympathetic nerve fibers in all genotypes and surgical groups. GAL and PACAP38 were not detected in sham hearts, but peptide immunoreactivity was high in the infarct three days after MI. Surprisingly, peptides were abundant in cells that co-labeled with macrophage markers F4/80 and MAC2, but were not detected in sympathetic axons. PACAP protects cardiac myocytes from apoptosis, and GAL stimulates axon regeneration in addition to inhibiting parasympathetic transmission. Thus, these peptides may play an important role in cardiac and neuronal remodeling after ischemia-reperfusion.

Topics: Animals; Cytokine Receptor gp130; Galanin; Heart; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Ischemia; Myocardium; Neuropeptide Y; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Reperfusion Injury; Sympathetic Nervous System; Vasoactive Intestinal Peptide

Cardiac ischemia-reperfusion alters sympathetic neurotransmission in the heart, but little is known about its effect on neuropeptide expression in sympathetic neurons. Ischemia followed by reperfusion induces the production of inflammatory cytokines in the heart, including interleukin-6 and cardiotrophin-1. These cytokines and related molecules inhibit the expression of neuropeptide Y (NPY), and stimulate the expression of vasoactive intestinal peptide (VIP), substance P (SubP), and galanin (GAL) in cultured sympathetic neurons. Therefore, we quantified NPY, VIP, SubP, and GAL mRNA in neurons of the stellate ganglia 1 week after ischemia-reperfusion to determine if neuropeptide expression was altered in cardiac sympathetic neurons. NPY, VIP, and SubP mRNAs were unchanged compared to unoperated control animals, but GAL mRNA was increased significantly. The increased GAL mRNA was not accompanied by elevated GAL peptide content in the stellate ganglia. Galanin content was increased significantly in the heart, however, indicating that elevated GAL mRNA led to increased peptide production. GAL content was increased in the left ventricle below the coronary artery ligation, but was not increased significantly in the atria or the base of the heart above the ligation. The buildup of GAL specifically in the damaged left ventricle is consistent with previous reports that GAL is transported to regenerating nerve endings after axon damage.

Topics: Animals; Coronary Vessels; Galanin; Gene Expression; Heart; Ligation; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Neurons; Neuropeptide Y; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; RNA, Messenger; Substance P; Sympathetic Nervous System; Vasoactive Intestinal Peptide

The present study sought to examine the interrelationship between nitric oxide (NO) and vasoactive intestinal peptide (VIP) in myocardial protection. Isolated rat hearts were perfused for 15 min with buffer only (Group I); 0.3 mM VIP (Group II); 3 mM L-arginine (a precursor of NO) (Group III); VIP and aminoguanidine (iNOS blocker) (Group IV); or L-arginine plus VIP 10-28 (VIP inhibitor) (Group V). Each heart was then made globally ischemic for 30 min followed by 2 h reperfusion. Both VIP and NO were found to provide cardioprotection during ischemia and reperfusion. However, the beneficial effects of VIP and NO were reduced by inhibition of NO and VIP, respectively, suggesting that cardioprotection by VIP is modulated by NO and vice versa. The results of this study suggested a coordinated regulation by cardioprotection by NO and VIP.

Topics: Animals; Arginine; Cardiotonic Agents; Enzyme Inhibitors; Guanidines; Heart; In Vitro Techniques; Models, Cardiovascular; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peptide Fragments; Rats; Signal Transduction; Stereoisomerism; Vasoactive Intestinal Peptide; Vasodilation

Vasoactive intestinal peptide (VIP) has been shown to exert vasodilatory action and positive ionotropic effect on the heart and to possess free radical-scavenging ability. Because these properties are likely to make this peptide a suitable agent for myocardial preservation, we examined the role of VIP in myocardial ischemia and reperfusion. Isolated rat heart perfused by the Langendorff technique was subjected to 30 min of normothermic ischemia followed by 60 min of reperfusion. A significant amount of VIP was found to be released from the ischemic reperfused heart. The amount of VIP released from the heart increased progressively with the duration of reperfusion and paralleled the release of creative kinase from the heart. In another set of experiments, hearts were divided into two groups. The experimental group received three different doses of VIP (0.1 microM, 0.3 microM and 1 microM) before ischemia. After perfusing the isolated heart with VIP for 15 min, ischemia was induced for 30 min by terminating the coronary flow, which was followed by 60 min of reperfusion. The results of our study indicated a significant improvement of myocardial functions by VIP (0.3 and 1 microM), as evidenced by enhanced left ventricular functions and coronary flow, and reduction of tissue injury, as judged by the decrease in creatine kinase release (0.3 microM only). Intracellular Ca++ ([Ca++]i) transients increased during ischemia and further increased during reperfusion. The increase in [Ca++]i transients was significantly reduced in the VIP-treated hearts. A significant amount of hydroxyl radical was detected in the ischemic reperfused heart, but the quantity of the hydroxyl radical was much lower in the VIP-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcium; Cats; Coronary Circulation; Creatine Kinase; Female; Hydroxyl Radical; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide