Endogenous methyl palmitate modulates nicotinic receptor-mediated transmission in the superior cervical ganglion

Abstract

Nitric oxide (NO) is identified as the endothelium-derived relaxing factor and a neurotransmitter with a superfusion bioassay cascade technique. By using a similar technique with rat superior cervical ganglion (SCG) as donor tissue and rabbit endothelium-denuded aortic ring as detector tissue, we report here that a vasodilator, which is more potent than NO, is released in the SCG upon field electrical stimulation (FES) or addition of nicotine. Release of this vasodilator was enhanced by arginine analogs, including N ω -nitro- l -arginine (a NO synthase inhibitor), suggesting that it is not NO. Analysis by gas chromatography/mass spectrometry identified 2 saturated fatty acids, palmitic acid methyl ester (PAME) and stearic acid methyl ester (SAME), being released from the SCG upon FES in the presence of arginine analogs. Exogenous PAME but not SAME induced significant aortic dilation (EC 50 = 0.19 nM), indicating that PAME is the potent vasodilator. Release of PAME and SAME was significantly diminished in chronically decentralized SCG but not denervated SCG, suggesting the preganglionic origin. Furthermore, release of both fatty acids was calcium- and myosin light chain kinase-dependent, suggesting that both were released from axoplasmic vesicular stores. Electrophysiological studies further demonstrated that PAME but not SAME inhibited nicotine-induced inward currents in cultured SCG and the α7-nicotinic acetylcholine receptor-expressing Xenopus oocytes. Endogenous PAME appears to play a role in modulation of the autonomic ganglionic transmission and to complement the vasodilator effect of NO.

Fatty Acid Methyl Esters and Solutol HS 15 Confer Neuroprotection after Focal and Global Cerebral Ischemia

“…Cortical CBF was not measured in the MCAO model due to the technical complexity with the focal ischemia technique coupled with intravital TPLSM. Consistent with our previous findings [1], our results suggest that PAME, but not SAME (18 carbon fatty acid) can cause vasodilation to enhance CBF after global ischemia (asphyxial cardiac arrest) (Figures 2D and E). Since SAME, an 18 carbon fatty acid, did not cause vasodilation/constriction nor changes in CBF, we did not pursue this study further with similar 18 carbon fatty acids, Solutol HS15 or 12-HS.…”

“…vasodilatory actions of PAME), the neuroprotective actions of PAME can be attributed to its’ inherent anti-inflammatory properties during cellular stress [30, 31]. However, the role of SAME-induced neuroprotection (not a vasodilator) [1] remains unknown. Interestingly, SAME is released at twice the concentration as compared to PAME upon depolarization of the SCG [1].…”

“…This was based on the fact that PAME produces maximum rabbit aortic vasorelaxation at 1 μM ex vivo [1]. Therefore, we hypothesized that utilizing 1 μM (This translates to 0.02 mg/kg in vivo in the 300g rat.)…”

“…Exogenous and endogenous application of PAME but not SAME induced potent rabbit aortic vasodilation (EC 50 = 0.19 nM) and is 3000 times more potent than some nitric oxide (NO) donors [1]. Since the vast majority of vasodilators [i.e.…”

Differential Effects of Delta and Epsilon Protein Kinase C in Modulation of Postischemic Cerebral Blood Flow

“…Vasoactive factors that influence vasoconstriction/vasodilation during reperfusion have been highly debated over the years. Nonetheless, a recent development in cerebral vascular physiology describes a novel and highly potent vasodilator (palmitic acid methyl ester) that may be involved in PKC regulation during cerebral ischemia [11]. …”