Hyperpolarization‐activated current, I_h, in inspiratory brainstem neurons and its inhibition by hypoxia

Abstract

A hyperpolarization-activated current, Ih, is often implied in pacemaker-like depolarizations during rhythmic oscillatory activity. We describe Ih in the isolated respiratory centre of immature mice (P6-P11). Ih was recorded in 15% (22/146) of all inspiratory neurons examined. The mean half-maximal Ih activation occurred at -78 mV and the reversal potential was -40 mV. Ih was inhibited by Cs+ (1-5 mM) and by organic blockers N-ethyl-1,6-dihydro-1, 2-dimethyl-6-(methylimino)-N-phenyl-4-pyrimidinamine (ZD 7288; 0.3-3 microM) and N,N'-bis-(3,4-dimethylphenylethyl)-N-methylamine (YS 035, 3-30 microM), but not by Ba2+ (0.5 mM). The organic Ih blockers did not change the inspiratory bursts recorded from the XIIth nerve and synaptic drives in inspiratory neurons. Hypoxia reversibly inhibited Ih but, in the presence of organic blockers, the hypoxic reaction remained unchanged. We conclude that although Ih channels are functional in a minority of inspiratory neurons, Ih does not contribute to respiratory rhythm generation or its modulation by hypoxia.

Noradrenergic modulation of XII motoneuron inspiratory activity does not involve α2-receptor inhibition of theIhcurrent or presynaptic glutamate release

“…Thus it was not possible to determine whether the effect on XII output was due to an action at the XII premotor-toinspiratory motoneuron synapse or further upstream at the level of the rhythm generator or premotor network. Nevertheless, our data in which ZD7288 was focally applied at 100 M to the XII nucleus (approximately equivalent to 10 M bath application) are consistent with data from late neonatal mice (P6 -P11), indicating that bath application of 1-10 M ZD7288 is without effect on rhythm or motor output (41). These data, however, are inconsistent with data from slightly older mice (P7-P22) in which bath application of 100 M ZD7288 increased frequency and potentiated burst amplitude (64).…”

“…3B) revealed an inwardly rectifying conductance. As described elsewhere (41), this difference between I steady and I inst was defined as the I h current on the basis of its voltage dependence and sensitivity to the organic blocker, ZD7288 (see Fig. 4B).…”

“…On the basis of this hypothesis, one would not predict a major influence of I h or its modulation on excitatory inspiratory motoneuron activity in neonates in vitro. Only two studies have examined the role of I h in modulating rhythmic inspiratory activity (41,64). However, these studies yielded conflicting results.…”

“…However, the effects on respiratory-related behavior recorded from rhythmically active medullary slices of blocking I h are controversial. At low concentrations the I h blocker ZD7288 has no effect on rhythm or motor output (41), whereas at higher concentrations it potentiates both frequency and burst amplitude (64). Because ZD7288 was applied to the bath in these experiments where it would affect both rhythm generating and drive transmission elements, it remains to be determined whether block of I h solely within the motoneuron pool has any impact on inspiratory output.…”

Expression of Functional Tyrosine Kinase B Receptors by Rhythmically Active Respiratory Neurons in the Pre-Bötzinger Complex of Neonatal Mice

“…No leak subtraction was performed. Activation curves were obtained by converting peak current to peak conductance, assuming a reversal potential of Ϫ28 mV [assessed by the extrapolation method of Mironov et al (2000)]. These values were then normalized to the calculated g max , and the resulting conductancevoltage curves were fitted to a first order Boltzmann equation ( g/g max ϭ 1/(1 ϩ exp (V1/2 Ϫ V)/s ) in which V 1/2 is the mean voltage for half-maximal activation and s the slope.…”