科研之友
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摘要
A locally generating, angiotensinII (ANGII) system is present in the rat carotid body (CB) and up-regulation of this system occurs in certain pathophysiological situations, enhancing sympathetic activity. Here, we show that, similar to chemoreceptor type I cells, glial-like typeII cells also express functional AT(1)Rs, stimulation of which causes release of Ca2+ from intracellular stores. ANGII-AT(1)R signalling in typeII cells activates an inward current carried by pannexin-1 (Panx-1) channels which are known to act as conduits for release of ATP, a key CB excitatory neurotransmitter. Combined effects of ANGII and ATP, which also activates Panx-1 currents via P2Y2 receptors, were synergistic; chelating intracellular Ca2+ with BAPTA prevented Panx-1 current activation. We propose that the excitatory function of ANGII in the CB involves dual actions at both type I and type II cells. %26lt;br%26gt;AbstractA local angiotensin-generating system is present in the carotid body (CB) and increased angiotensinII (ANGII) signalling contributes to enhanced CB excitation in chronic heart failure (CHF) and after chronic or intermittent hypoxia. ANGII actions have thus far been attributed solely to stimulation of AT(1) receptors (AT(1)Rs) on chemoreceptor typeI cells. Here, we show that in dissociated rat CB cultures, ANGII also stimulates glial-like typeII cells, identified by P2Y2-receptor-induced intracellular Ca2+ elevation ([Ca2+](i)). ANGII induced a dose-dependent (EC50 approximate to 8nm), robust [Ca2+](i) in type II cells that was reversibly abolished by the AT(1)R blocker losartan (1m). The ANGII-induced [Ca2+](i) persisted in Ca2+-free medium but was sensitive to store depletion with cyclopiazonic acid (1m). Similar to P2Y2 receptor agonists, ANGII (20-1000nm) activated pannexin-1 (Panx-1) current that was reversibly abolished by carbenoxolone (5m). This current arose with a variable delay and was reversibly inhibited by losartan. Repeated application of ANGII often led to current run-down, attributable to AT(1)R desensitization. When applied to the same cell the combined actions of ANGII and ATP on Panx-1 current were synergistic. Current induced by either ligand was inhibited by BAPTA-AM (1m), suggesting that intracellular Ca2+ signalling contributed to Panx-1 channel activation. Because open Panx-1 channels release ATP, a key CB excitatory neurotransmitter, it is plausible that paracrine stimulation of type II cells by ANGII contributes to enhanced CB excitability, especially in pathophysiological conditions such as CHF and sleep apnoea.
- 出版日期2014-11-1
