Three Gaseous Neurotransmitters, Nitric oxide, Carbon Monoxide, and Hydrogen Sulfide, Are Involved in the Neurogenic Relaxation Responses of the Porcine Internal Anal Sphincter

Abstract

Background/AimsThe internal anal sphincter (IAS) plays an important role in maintaining continence and a number of neurotransmitters are known to regulate IAS tone. The aim of this study was to determine the relative importance of the neurotransmitters involved in the relaxant and contractile responses of the porcine IAS. MethodsResponses of isolated strips of IAS to electrical field stimulation (EFS) were obtained in the absence and presence of inhibitors of neurotransmitter systems. ResultsContractile responses of the sphincter to EFS were unaffected by the muscarinic receptor antagonist, atropine (1 mM), but were almost completely abolished by the adrenergic neuron blocker guanethidine (10 mM). Contractile responses were also reduced (by 45% at 5 Hz, P < 0.01) following desensitisation of purinergic receptors with α,β-methylene-ATP (10 mM). In the presence of guanethidine, atropine, and α,β-methylene-ATP, the remaining relaxatory responses to EFS were examined. These responses were not altered by the cyclooxygenase inhibitor, indomethacin (5 mM), the vasoactive intestinal polypeptide receptor antagonist, [D-p-Cl-Phe 6 ,Leu 17 ]-vasoactive intestinal peptide (PheLeu-VIP; 100 nM), or the purinoceptor antagonists, 8-phenyltheophyline (P1 receptors) or suramin (P2 receptors). However, relaxation responses were reduced by Nω-nitro-L-arginine (L-NNA; 100 mM), an inhibitor of nitric oxide synthesis (40-50% reduction), zinc protoprophyrin IX (10 mM), an inhibitor of carbon monoxide synthesis (20-40% reduction), and also propargylglycine (30 mM) and aminooxyacetic acid (30 mM), inhibitors of hydrogen sulphide synthesis (15-20% reduction). ConclusionsStimulation of IAS efferent nerves releases excitatory and inhibitory neurotransmitters: noradrenaline is the predominant contractile transmitter with a smaller component from ATP, whilst 3 gases mediate relaxation responses to EFS, with the combined contributions being nitric oxide > carbon monoxide > hydrogen sulfide.

Control of Motility in the Internal Anal Sphincter

“…Nitric oxide (NO) plays a prominent role in inhibitory NMT in the IAS of all species studied including man. 15,45,93,[123][124][125] Although the IAS lacks a myenteric plexus there are numerous varicose nicotinamide adenine dinucleotide phosphate/nNOS neurons located within the circular muscle layer. 15,16 Since first proposed in 1996, a number of studies have provided evidence that ICC-IM participate in nitrergic NMT in GI muscles.…”

A systematic review of translation and experimental studies on internal anal sphincter for fecal incontinence

“…McDonnell et al [ 60 ] reported that a purinergic pathway significantly contributes to inhibitory motor innervation in the IAS by hyperpolarization of the postjunctional membrane to produce inhibitory junction potentials. Folasire et al [ 61 ] also reported that hydrogen sulfide possibly contributes relaxation of the porcine IAS, and its potency is lower than that of CO. In addition, recombinant hemoglobin 1.1 (rHb1.1) could be caused specific obliteration of NO-induced relaxation of the IAS [ 77 ].…”

Neurotransmitters—Key Factors in Neurological and Neurodegenerative Disorders of the Central Nervous System

“…Among other molecules recognized as NTs, there can be enumerated purines, such as adenosine triphosphate (ATP) [ 64 ], soluble gases (known as gasotransmitters), such as carbon monoxide (CO) [ 65 , 66 ], nitric oxide (NO) [ 65 , 66 ], and hydrogen sulfide (H 2 S) [ 66 ], and various neuropeptides [ 8 , 9 ], including somatostatin [ 67 ], β-endorphins [ 68 ], vasopressin [ 69 ], neurotensin [ 70 ], substance P [ 70 ], and neuropeptide Y [ 71 ]. One representative example from each category was chosen and briefly discussed.…”