Abstract 1627: Molecular Substrates of Carotid Body Chemoreceptor Activation
Carotid bodies are powerful regulators of sympathetic nerve activity in response to acidosis, hypoxia and hypercarbia. They are hypersensitive in heart failure and hypertension. The molecular determinants of their responsiveness and hypersensitivity are not fully understood. We recently reported that the acid sensitive channels ASICs and TASKs mediate early and late depolarizations, respectively, in isolated glomus cells ( Circ. Res. 2007; 101 :1009–19). In these studies we addressed two questions. The first is whether the enhanced carotid body hypersensitivity known to occur in spontaneously hypertensive rats (SHR) reflects enhanced activity of ASICs and TASKs. The results indicate that low pH ranging from 7.0 to 6.0 induced both an early rapid and a late sustained depolarization of glomus cells isolated from young (4 – 6 weeks) SHR and WKY rats, however the response was markedly enhanced in SHR. The values for rapid and sustained depolarization at pH 6.0 were 24.4 ± 3.7 and 39.2 ± 2.3 mV for SHR cells (n = 16), and 12.7 ± 2.3 and 29.5 ± 2.6 mV for WKY cells (n = 26), respectively. The ASIC blocker amiloride (200 μM) suppressed significantly the early depolarization to a level of 2.0 ± 1.2 mV (n = 7), but not the sustained depolarization which remained at 33.6 ± 3.6 mV (n = 7). mRNAs encoding ASIC1b and 3 and TASK1 and 3 were augmented by 150%, 75%, 100% and 20% respectively in carotid bodies of SHR compared to WKY. The second question is whether glomus cells are selectively responsive to low pH vs. oxygen deprivation with cyanide. In contrast to the response to low pH, that to cyanide (2 mM) was not enhanced in SHR (13.9 ± 2.5 mV; n = 7) compared to WKY (11.8 ± 3.3 mV; n = 7). Moreover in six WKY cells, three were as sensitive to cyanide (20.0 ± 3.9 mV) as they were to low pH (29.3 ± 4.6 mV) whereas three other cells that were very sensitive to low pH (29.2 ± 1.9 mV) had negligible responses to cyanide (4.2 ± 0.9 mV).
that in a genetic model of neurogenic hypertension (SHR), overexpression of acid sensitive ion channels (ASICs and TASKs) causes selective carotid body chemoreceptor hypersensitivity to low pH and may contribute to the development of hypertension; and
that different glomus cell populations may be selectively sensitive to specific chemical stimuli (e.g. low pH vs. hypoxia).