Hydrogen sulphide: an endogenous stimulant of capsaicin-sensitive primary afferent neurons?

Abstract

Hydrogen sulphide (H₂S) is a gas best known for its rotten egg smell. The toxic effects of high concentrations of H₂S have been extensively investigated. It is known that H₂S is generated in mammalian systems, but little is known of its effects in physiological concentrations. In the present issue of this journal, Patacchini et al. present evidence that H₂S stimulates capsaicin-sensitive primary afferent neurons to release tachykinins in the rat urinary bladder. The possible significance of this finding is discussed in this commentary.

Hydrogen sulphide (H₂S) is a gas with a characteristic rotten egg smell. It is a chemical hazard in certain industries and its toxic effects on the central respiratory centres have been extensively investigated (see Reiffenstein et al., 1992). However, H₂S is also generated in considerable amounts enzymatically, and to a lesser extent nonenzymatically, by mammalian tissues (see Wang, 2002). The enzymes involved in the enzymatic production of H₂S are cystathionine β-synthase (CBS) and cystathionine γ-lyase. The expression of these enzymes is tissue specific. Using CBS knockout mice, Eto et al. (2002) established that in brain tissue the main enzyme involved is CBS. Furthermore, it was found that the production of H₂S was greatly enhanced by activation of glutamate receptors and by electrical stimulation. H₂S has also been shown to enhance long-term potentiation (LTP) in rat hippocampal slices by enhancing the NMDA-induced inward current (Abe & Kimura, 1996). These observations have led to the proposal that H₂S might be a third endogenous gaseous transmitter or modulator which, like nitric oxide and carbon monoxide, regulates synaptic activity (Eto et al., 2002; Wang, 2002; Boehning & Snyder, 2003).

Zhao et al. (2001) studied the effect of physiologically relevant concentrations of H₂S on the rat cardiovascular system in vivo and showed that it had a vasorelaxant effect and caused a decrease in blood pressure that mimicked the K_ATP channel opener pinacidil, and was antagonized by the K_ATP channel blocker glibenclamide. Studies on vascular tissues in vitro and on isolated smooth muscle cells have established H₂S as a K_ATP channel opener in these cells (Zhao et al., 2001). Interestingly, the relaxant effect of H₂S on nonvascular smooth muscle occurred by a mechanism independent of K_ATP channels (Teague et al., 2002).

In the present issue, Patacchini et al. (2004) present evidence that in the detrusor muscle of the rat urinary bladder H₂S produced contractile responses. These responses exhibited marked tachyphylaxis similar to responses to capsaicin, the active principle from chillies that stimulates certain primary afferent neurons to release neuropeptides, in particular tachykinins and calcitonin gene-related peptide (CGRP) (Maggi, 1995). On investigation of this response to H₂S, they found that desensitization of capsaicin-sensitive primary afferent neurons by pretreatment with a high concentration of capsaicin, or pretreatment of tissues with a combination of tachykinin NK₁ and NK₂ receptor antagonists, abolished the response to H₂S. These results provide definitive evidence that in the detrusor muscle the dominant effect of physiologically relevant concentrations of H₂S involves stimulation of capsaicin-sensitive primary afferent neurons with consequent release of tachykinins, which in turn produce contractile responses of the detrusor muscle.

From the results reported by Patacchini et al. (2004), the site of action of H₂S cannot be determined with certainty. However, the observation that the responses to H₂S exhibited a similar resistance to tetrodotoxin as those to capsaicin indicates that H₂S predominantly activates the primary afferent nerve terminals directly rather than indirectly via axonal conduction, which involves fast tetrodotoxin-sensitive sodium channels. The intriguing possibility that H₂S activates the transient receptor potential vanilloid receptor 1 (TRPVR1) receptors that are activated by capsaicin (Caterina et al., 1997) awaits future investigation.

The response to activation of capsaicin-sensitive primary afferent neurons in a tissue or organ depends upon the complement of neuropeptides in the primary afferent neurons in that tissue, and the effect of the released neuropeptides. Thus capsaicin may produce stimulation of some smooth muscles and relaxation of others. Therefore, previous studies on the actions of H₂S, such as its vasorelaxant effect, may need re-evaluation in light of the findings reported by Patacchini et al. (2004) that H₂S activates primary afferent neurons. Furthermore, the toxicology of H₂S may require further investigation in light of these new findings.

H₂S is a very potent stimulant of olfactory afferents. It is possible that it might also activate a number of other chemosensitive neurons. Indeed, one important aspect that remains to be investigated is the selectivity of H₂S for capsaicin-sensitive primary afferent neurons. The study of Patacchini et al. (2004) has opened a new field of research into the pharmacology of H₂S and of primary afferent neurons, which should lead to new advances in understanding the physiological and pathophysiological roles of this putative endogenous gaseous neurotransmitter.

Abbreviations

CBS

cystathionine β-synthase

H₂S

hydrogen sulphide