An investigation into the origin and generation of spontaneous activity in the guinea-pig prostate

Abstract

Spontaneous basal contractions may contribute to an enhanced smooth muscle tone as seen in benign prostatic hyperplasia (BPH). However, spontaneous activity is not neurogenic in origin, making the basal contractions impervious to current α1-adrenoceptor antagonist pharmacotherapeutics. Rather, the aging prostate generates myogenic contractions that are thought to be dependent on a network of prostatic interstitial cells (PICs) that propagate electrical currents to smooth muscle cells, stimulating Ca2+ release and causing contractions. PICs are a crucial component in the generation of spontaneous Ca2+ transients that are likely to contribute to spontaneous contractions. Yet pacemaker-independent electrical activity have been recorded from a population of uncoupled, asynchronous smooth muscle cells in the aging animals which suggests that the functional properties of the guinea-pig prostate may change with age. How spontaneous activity is generated in the prostate is not clearly understood though pacemaking PICs have been identified in the guinea-pig (Exintaris et al., 2002) and human prostate (Shafik et al., 2005; Van der Aa et al., 2003). Isolated PICs loaded with Ca2+ dye Fluo-4 exhibited spontaneous Ca2+ transients and morphological properties typical of similar interstitial cells in other urogenital smooth muscle organs concur with those observed in PICs including the presence of c-Kit, a protooncogene typically found in interstitial cells. The role of c-Kit itself in generating spontaneous activity appears to be limited to regulating smooth muscle tone since spontaneous electrical activity persists after blocking the c-Kit receptor. It is likely that c-Kit affects smooth muscle tone via another pathway or mechanism that affects Ca2+ mobilisation leading to contractility. One finding that was unexpected upon isolating PICs was the abolition of spontaneous Ca2+ currents after blockade of L-type Ca2+ channels. This does not conform to previous pacemaker potential electrical recordings which presumably arise from PICs and are resistant to L-type Ca2+ channel blockade. However, spontaneous Ca2+ currents from isolated PICs are heavily reliant on intracellular Ca2+ store release especially since PICs possess an abundance of mitochondria and a well-developed SR Ca2+ store system. It has been established that the mitochondria and inositol triphosphate (IP3) receptors are important regulators in the modulation of spontaneous activity in the young guinea-pig prostate but it is likely the mitochondria and IP3 receptors play a lesser role in Ca2+ mobilisation during the regulation of spontaneous activity with age. Instead, ryanodine receptors and external Ca2+ entry via L-type Ca2+ channels could feature more prominently in generating spontaneous activity of the aging guinea-pigs. Therefore results from this thesis suggest that an enhanced smooth muscle tone results from a heavier reliance on voltage-dependent Ca2+ entry in the aging animal model. Further investigation into the functional role of PICs and potential age-related changes involved in generating spontaneous contractions will provide a better understanding of the aetiology of BPH and perhaps leading to the discovery of a novel target that could relieve an enhanced prostate smooth muscle tone and improve the quality of life in BPH patients.