Non-technical summary: Activation of the sympathetic nervous system hastens the rate of progression and severity of chronic heart failure (CHF). Chemically sensitive nerves in the carotid body (CB) that stimulate sympathetic nerve activity become overly active in CHF and contribute to this phenomenon. The stimulus for activation of these CB chemoreceptors is not known. Blood supply to tissues is impaired due to the failing heart. In this study we tested whether a chronic reduction in blood flow to the CB may contribute to altered CB chemoreceptor function. The results show that changes that occur in CB chemoreceptor function during CHF are identical to those that occur if blood flow is simply reduced to the CB for several weeks. The results suggest that chronic impairment of blood flow may be the key step in the pathophysiological events that cause sympathetic nervous system activation in heart failure.Peripheral chemoreflex sensitivity is potentiated in clinical and experimental chronic heart failure (CHF). Blood supply to tissues is inevitably reduced in CHF. However, it remains poorly understood whether the reduced blood flow is the cause of increased peripheral chemoreflex sensitivity in CHF. This work highlights the effect of chronically reduced blood flow to the carotid body (CB) on peripheral chemoreflex function in rabbits. In pacing-induced CHF rabbits, blood flow in the carotid artery was reduced by 36.4 ± 5.2% after 3 weeks of pacing. For comparison, a similar level of blood flow reduction was induced by carotid artery occlusion (CAO) over a similar 3 week time course without pacing. CB blood supply was reduced by similar levels in both CHF and CAO rabbits as measured with fluorescent microspheres. Compared with sham rabbits, CAO enhanced peripheral chemoreflex sensitivity in vivo, increased CB chemoreceptor activity in an isolated CB preparation and decreased outward potassium current (Ik) in CB glomus cells to levels similar to those that were observed in CHF rabbits. In CAO CB compared to sham, neural nitric oxide (NO) synthase (nNOS) expression and NO levels were suppressed, and angiotensin II (Ang II) type 1 receptor (AT1-R) protein expression and Ang II concentration were elevated; these changes were similar to those seen in the CB from CHF rabbits. A NO donor and AT1-R antagonist reversed CAO-enhanced chemoreflex sensitivity. These results suggest that a reduction of blood flow to the CB is involved in the augmentation of peripheral chemoreflex sensitivity in CHF.
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