Epidural administration of large dose of opioid µ receptor agonist may impair cardiac functions and myocardial viability via desensitizing transient receptor potential vanilloid 1.

The incidence of postoperative myocardial injury remains high as the underlying pathogenesis is still unknown. The dorsal root ganglion (DRG) neurons express transient receptor potential vanilloid 1 (TRPV1) and its downstream effector, calcitonin gene-related peptide (CGRP) participating in transmitting pain signals and cardiac protection. Opioids remain a mainstay therapeutic option for moderate-to-severe pain relief clinically, as a critical component of multimodal postoperative analgesia via intravenous and epidural delivery. Evidence indicates the interaction of opioids and TRPV1 activities in DRG neurons. Here, we verify the potential impairment of myocardial viability by epidural usage of opioids in postoperative analgesia. We found that large dose of epidural morphine (50 µg) significantly worsened the cardiac performance (+dP/dtmax reduction by 11% and -dP/dtmax elevation by 24%, all P < 0.001), the myocardial infarct size (morphine vs Control, 0.54 ± 0.09 IS/AAR vs. 0.23 ± 0.06 IS/AAR, P < 0.001) and reduced CGRP in the myocardium (morphine vs. Control, 9.34 ± 2.24 pg/mg vs. 21.23 ± 4.32 pg/mg, P < 0.001), while induced definite suppression of nociception in the postoperative animals. It was demonstrated that activation of µ-opioid receptor (µ-OPR) induced desensitization of TRPV1 by attenuating phosphorylation of the channel in the dorsal root ganglion neurons, via inhibiting the accumulation of cAMP. CGRP may attenuated the buildup of ROS and the reduction of mitochondrial membrane potential in cardiomyocytes induced by hypoxia/reoxygenation. The findings of this study indicate that epidurally giving large dose of µ-OPR agonist may aggravate myocardial injury by inhibiting the activity of TRPV1/CGRP pathway.

Independent roles of CGRP in cardioprotection and hemodynamic regulation in ischemic postconditioning.

Calcitonin gene-related peptide (CGRP) may participate in ischemic post-conditioning (IPost) attenuating myocardial ischemia/reperfusion injury. However, the molecular mechanism underlying the effect of CGRP is still elusive. In this study, we evaluated the difference in hemodynamics, infarct size and CGRP in myocardium and serum of rats after acute myocardial ischemia/reperfusion with and without IPost. A specific antagonist of CGRP receptor, CGRP8-37 was employed to testify the role of endogenous CGRP in IPost. The underlying mechanism was investigated by evaluation of the effect of CGRP on the changes in cytosolic reactive oxygen species, mitochondrial membrane potential and myocyte apoptosis induced by hypoxia/reoxygenation in cultured cardiomyocytes of neonatal rats. The results showed that IPost significantly upgraded CGRP in myocardium and serum with reduced infarct size, independent of the reductions in blood pressures observed in this study. The effects were significantly reversed by CGRP8-37, indicating an involvement of intrinsic CGRP. It was further demonstrated that CGRP effectively reversed the hypoxia/reoxygenation-induced reduction of mitochondrial membrane potential and attenuated the increases of cytosolic reactive oxygen species and cardiomyocyte apoptosis. The findings may demonstrate that CGRP mediates the cardioprotective and vasoactive effects of IPost. Homeostasis of cytosolic reactive oxygen species and mitochondrial membrane potential may be underlying the cardioprotective effect of CGRP.

Preservation of CGRP in myocardium attenuates development of cardiac dysfunction in diabetic rats.

BACKGROUND: Calcitonin gene-related peptide (CGRP) plays an important role in cardiovascular regulation, which was found reduced in serum of diabetic patients. To test the hypothesis that lack of CGRP in myocardium is associated with diabetic cardiac dysfunction, which may be improved by preservation of CGRP in diabetic rats. METHODS AND RESULTS: Diabetes was induced in male Sprague-Dawley rats by streptozotocin (50mg/kg). Two groups of the diabetic rats, one fed with standard laboratory chew and another with the laboratory food plus hot pepper (containing 0.0174% of capsaicin), to stimulate production and release of CGRP. Cardiac functions were evaluated by measurements of intraventricular pressures after 8weeks of development of diabetes. Transient receptor potential vanilloid type 1 (TRPV1), CGRP, ß1-adreneregic receptor and norepinephrine were analyzed. Significantly lower levels of TRPV1 and CGRP were detected in the thoracic dorsal root ganglia (DRG) and myocardium of the diabetic animals, along with significant decline in left ventricular systolic pressure (by 24%) and heart rate (by 25%) and increase of the end-diastolic pressure (by 83%) with obvious reduction of CGRP in the DRG, by 41%, the myocardium (by 30%) and the serum (by 20%). The cardiac performance, the TRPV1 and the CGRP in the diabetic animals fed with hot pepper were well preserved. No any significant change in ß1-adreneregic receptor and norepinephrine was detected. CONCLUSION: The findings may suggest a novel mechanism underlying diabetic cardiac dysfunctions via impairing TRPV1-CGRP pathway in myocardium. Preservation of the TRPV1-CGRP mechanism may prevent the development of cardiac dysfunction in diabetes.