Novel roles of a local angiotensin‐generating system in the carotid body

Abstract

The carotid body is a highly vascularized network of chemoreceptor cells, which are located at the bifurcation of the internal and external carotid arteries arising from the common carotid artery. Carotid body chemoreceptors, called glomus (type 1, catechol-secreting) cells release dopamine in response to rapid changes in arterial PO2, PCO2 and pH, thus increasing carotid body sinus nerve activity and provoking centrally mediated cardiopulmonary responses (Gonzalez et al. 1994). The endocrine (circulating) renin–angiotensin system (RAS) plays a role in regulating the blood pressure, electrolyte and fluid homeostasis. The aspartyl protease renin cleaves the precursor of the system, angiotensinogen, to yield angiotensin I, which is subsequently cleaved by angiotensin converting enzyme (ACE) to yield the physiologically active octapeptide angiotensin II (Ang II). Pressor responses to Ang II are largely mediated through activation of the type 1 receptor (AT1R). It is now recognized that the RAS exists in diverse mammalian cells and organs, where it plays diverse roles in their respective tissues and organs. Apart from the haemodynamic function, they include, but are not limited to, cell proliferation, apoptosis, oxidative stress and inflammatory as well as fibrotic actions. This so-called local RAS which adds to and/or differs from the circulating RAS, frequently operated in a paracrine and/or autocrine manner (Lavoie & Sigmund, 2003). Newly discovered functions of locally generated Ang II in tissues and organs are of particular interest in the physiological and pathophysiological aspects. Such a system has recently been proposed to exist in the carotid body: here, key RAS components (including angiotensinogen, ACE, AT1R and AT2R) are expressed in the absence of renin, suggesting the existence of a renin-independent biosynthetic pathway for Ang II or an intrinsic angiotensin-generating system in the carotid body (Lam & Leung, 2002). This system may play a key role in modulating the carotid body response to hypoxia. Ang II itself increases carotid body efferent activity, presumably via AT1R activation (Allen, 1998). Meanwhile, chronic hypoxia up-regulates several key RAS components in the carotid body, including a time-course-dependent activity of ACE (Lam & Leung, 2003; Lam et al. 2004). Specifically, expression of the AT1R on glomus cells is enhanced, consistent with increased expression of the AT1R at gene and protein level (Leung et al. 2000). Chronic hypoxia thus enhances AT1R-mediated efferent activity (Leung et al. 2000). In addition, AT1R activation increases intracellular calcium levels in dissociated glomus cells, an effect which is enhanced three-fold by chronic hypoxaemia (Fung et al. 2002). Taken together, all data suggest that chronic hypoxia is a major factor that increases AT1R expression and function in the carotid chemoreceptor, with likely changes in cardiopulmonary function. Thus the excitatory action of Ang II on the glomus cells may increase the chemosensitivity of the carotid body and may counteract the blunting effect of chronic hypoxia. Notwithstanding this involvement of a local angiotensin-generating system in the carotid body, details of the molecular and cellular mechanisms underlying the modulation require extensive study. A paper by Li & Schultz (2006) in this issue of The Journal of Physiology adds valuable data to this story. Using a rabbit model of congestive heart failure (CHF), the authors demonstrate a role for local glomus Ang II/AT1R signalling in increasing the sensitivity of Kv channels to hypoxia. High concentrations of Ang II (> 1 nm) directly inhibit Kv currents (Ik) while changes in Kv channel protein expression may contribute to the suppression of Ik and enhanced sensitivity of Ik to hypoxia in the CHF state. This study has two significant implications: Ang II can enhance the oxygen sensitivity of Kv channels via the mediation of AT1R and the cellular Ang II–AT1R pathway is functional in carotid glomus cells of CHF but not normal animals. In spite of this solid evidence, the precise mechanism by which CHF up-regulates the Ang II–AT1R and its function in the carotid body have yet to be resolved. In this regard, chronically impaired cardiac output resulting from CHF might be sufficient to render a prolonged deprivation of oxygen delivery to carotid glomus cells, a state akin to chronic hypoxia, thus leading to activation of its cellular RAS pathway. These data indicate a paracrine/autocrine role of Ang II in the modulation of enhanced carotid chemoreceptor sensitivity to chronic hypoxia characterized in chronic heart failure. In summary, the carotid body is the major organ central to the physiological responses to various forms of hypoxic stress: acute, chronic and intermittent hypoxia. Thus, activation of the RAS by hypoxia might be commonly associated with chronic cardiopulmonary diseases and sleep apnoea. Of great interest in this context is the emerging data of evidence for the existence of a local carotid angiotensin-generating system, which is up-regulated by chronic hypoxia to alter carotid chemoreceptor sensitivity. The data of Li and Schultz thus support this concept.