Purinergic agonists flex vas deferens muscle.

The vas deferens is described typically as a muscular tube that functions as a conduit to move sperm from the epididymis to the urethra. A growing body of evidence, however, shows that the system is far more complex. Smooth muscle tone and contractions are affected by a number of neuocrine, endocrine and perhaps lumicrine agents. Likewise, epithelial activity is modified by a similar host of agents. Stimulation of the hypogastric nerve, which innervates the male reproductive ducts, results in the co-release of noradrenaline, ATP, and other neurotransmitters that induce or modulate smooth muscle contraction and can induce epithelial ion transport. In fact, it has been suggested that purinergic receptors in the reproductive duct might be targeted for the development of non-steroidal male contraceptives (Gur et al. 2007). Thus, there is great interest in determining regulatory cascades that link purinergic stimulation to smooth muscle contraction or relaxation. One caveat in exploiting purinergic pathways to manage male fertility is the apparently conflicting observations that ATP exposure can, depending upon conditions, lead to either smooth muscle contraction or relaxation. Thus, multiple receptors and signalling cascades are probably involved in these responses. Both ionotropic P2X and metabotropic P2Y receptors are present on vas deferens smooth muscle cells with rapid muscle contraction typically associated with P2X-mediated Ca2+ entry. The cascade accounting for relaxation appears to be more complex. In a recent issue of The Journal of Physiology, Ruan et al. (2008) provide keen insight on a mechanism that probably contributes to muscle relaxation, in vitro. Their work builds on the observation that vas deferens epithelium contributes to the response of smooth muscle to adrenergic stimuli (Okpalaugo et al. 2002). This observation suggests that vas deferens smooth muscle activity can be modified by paracrine agents released from the epithelium. It is becoming more widely recognized that neurotransmitters and hormones can modify the activity of epithelial cells lining the epididymes and vas deferens. Indeed, neurotransmitters, steroid hormones, peptide hormones and autocoids have been shown to modify epithelial ion transport. HCO3− secretion is particularly important because it initiates and supports increased sperm motility. Importantly, noradrenaline, ATP and adenosine have been shown to induce anion secretion. The Ruan paper adds purinergic modulation of smooth muscle tone to the activities probably mediated by the epithelium lining the reproductive duct. Prostaglandin E2 is a key element in the epithelium-dependent response to ATP. This observation has far-reaching impact because prostaglandin H synthase 2 (PGHS2; formerly known as COX2) expression in vas deferens epithelial cells is dependent upon testosterone. In both rats (McKanna et al. 1998) and humans (Kirschenbaum et al. 2000), vas deferens epithelial PGHS2 expression correlates with serum testosterone. PGHS2 immunoreactivity is present during gestation and following puberty, but absent pre-pubertally or following castration. Recently, Pierucci-Alves & Schultz (2007) demonstrated that testosterone exposure enhances bradykinin-induced vas deferens epithelial anion secretion in vitro, a response mediated by prostaglandins. Thus, testosterone-induced epithelial PGHS2 expression provides the basis for androgen-dependent sperm development and delivery. The results provided by Ruan and colleagues are the foundation of a model that brings many seemingly disparate elements together with the culmination of viable sperm delivery. ATP released from the hypogastric nerve can rapidly promote smooth muscle contraction by the activation of P2X receptors while co-released noradrenaline can promote a sustained response by activating α1 receptors on smooth muscles. These same neurotransmitters can affect epithelial HCO3− secretion by interacting with epithelial P2Y and β2 receptors, respectively. In epithelial cells exposed to testosterone, PGHS2 can be stimulated downstream from the P2Y receptor resulting in PGE2 production. PGE2 then interacts with sperm to promote motility, with prostanoid receptors on epithelial cells to further enhance anion secretion, and with prostanoid receptors on adjacent smooth muscle cells to promote hyperpolarization and smooth muscle relaxation. Thus, the work presented in this issue provides compelling evidence that the vas deferens is much more that just a muscular tube. The vas deferens is a complex tissue in which many component parts contribute to the timely delivery of mature active sperm. Dr Schultz receives research support from the National Institutes of Health (R01HD058398).