The Acute Effects and Mechanism of Ketamine on Nicotine-Induced Neurogenic Relaxation of the Corpus Cavernosum in Mice

Abstract

The present study aimed to investigate the acute effects and the mechanism of ketamine on nicotine-induced relaxation of the corpus cavernosum (CC) in mice. This study measured the intra-cavernosal pressure (ICP) of male C57BL/6 mice and the CC muscle activities using an organ bath wire myograph. Various drugs were used to investigate the mechanism of ketamine on nicotine-induced relaxation. Direct ketamine injection into the major pelvic ganglion (MPG) inhibited MPG-induced increases in ICP. D-serine/L-glutamate-induced relaxation of the CC was inhibited by MK-801 (N-methyl-D-aspartate (NMDA) receptor inhibitor), and nicotine-induced relaxation was enhanced by D-serine/L-glutamate. NMDA had no effect on CC relaxation. Nicotine-induced relaxation of the CC was suppressed by mecamylamine (a non-selective nicotinic acetylcholine receptor antagonist), lidocaine, guanethidine (an adrenergic neuronal blocker), Nw-nitro-L-arginine (a non-selective nitric oxide synthase inhibitor), MK-801, and ketamine. This relaxation was almost completely inhibited in CC strips pretreated with 6-hydroxydopamine (a neurotoxic synthetic organic compound). Ketamine inhibited cavernosal nerve neurotransmission via direct action on the ganglion and impaired nicotine-induced CC relaxation. The relaxation of the CC was dependent on the interaction of the sympathetic and parasympathetic nerves, which may be mediated by the NMDA receptor.

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“…Our previous study demonstrated that nicotine induces NO-dependent neurogenic relaxation in the CC. This relaxation is dependent on the interaction of the sympathetic and parasympathetic nerves (axo-axonal interaction), which may be mediated by the NMDA receptor [25]. In this study, our results show that tyrosine hydroxylase (TH)-/nNOS-immunoreactive fibers are localized in the CC, and nicotine-induced relaxation is inhibited by Nω-nitro-L-arginine and lidocaine.…”

“…Our recent results show that NMDAR plays an essential role in the sympatheticparasympathetic nerve interaction transmission pathway [25]. In Figure 5C, the TH-/nNOSimmunoreactive fibers and NMDAR/nNOS-immunoreactive fibers appear to be co-localized in the same nerve fibers.…”

“…In addition, we observed that ketamine directly targets the major pelvic ganglia (MPG) in vivo, leading to the inhibition of cavernosal nerve neurotransmission. Furthermore, our in vitro experiments demonstrated that ketamine impairs the ability of nicotine to reduce relaxation in the CC [25]. Notably, our investigations involving chronic ketamine use did not yield positive results with respect to reversing LUTD in mice subjected to SS [26].…”

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“…However, other reports on ketamine are mixed, even in the perioperative setting, where its use was first reported, and standard treatment protocols remain to be established. Recent investigations have attempted to elucidate the mechanism by which ketamine might affect erectile function in mice and concluded that N -methyl- d -aspartate receptor antagonism may be responsible via decreased parasympathetic transmission and decreased relaxation of the corpus cavernosum smooth muscle tissue . Further studies are needed to validate these findings, not only mechanistically, but also to confirm efficacy, and to discern optimal timing and dosing schedules for ketamine.…”