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1 Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA2 Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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Abstract |
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-nitro-L-arginine (L-NNA, NO synthase inhibitor) decreased Ik in sham rabbits but not in HF rabbits. The guanylate cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) inhibited the effect of SNAP on Ik. These results demonstrate that IK is reduced in CB glomus cells from HF rabbits. This effect is due mainly to the suppression of KCa channel activity caused by decreased availability of NO. In addition, intracellular cGMP is necessary for the KCa channel modulation by NO.
(Received 30 October 2003;
accepted after revision 10 December 2003;
first published online 12 December 2003)
Corresponding author H. D. Schultz: Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA. Email: hschultz{at}unmc.edu
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Introduction |
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The carotid body (CB) is the primary sensor site of the peripheral chemoreflex, and is composed of neurotransmitter-enriched glomus cells and glial-like sustentacular cells among other neuronal structures. Currently it is believed that glomus cells, which lie in synaptic apposition with the afferent nerve ending, are the initial sites of sensory transduction in the CB. The glomus cell membrane contains many voltage-gated ion channels. The suppression of outward K+ channels is proposed to contribute sequentially to the initial depolarization, activation of voltage-gated Ca2+ channels, release of neurotransmitter, and activation of discharge in the carotid sinus nerve (Gonzalez et al. 1994; Prabhakar, 1994).
NO is a gas molecule that functions as a transmitter in both the peripheral and central nervous systems. It is synthesized during the catalytic conversion of arginine to citrulline by the enzyme nitric oxide synthase (NOS) (Snyder, 1992). The extensive plexus of nerve fibres and vessels surrounding glomus cells contains neuronal NOS (nNOS) and endothelial NOS (eNOS) (Prabhakar et al. 1993; Wang et al. 1993), but NOS is not found in detectable levels in glomus and type II cells. However, these other neural and vascular cells may produce paracrine effects of their NO production on neighbouring glomus cells.
Our previous study has shown that a down-regulation of NO synthesis in the CB in HF rabbits contributes to the enhancement of CB chemoreceptor sensitivity (Sun et al. 1999b). We hypothesize that NO affects IK, which contributes to the altered peripheral chemoreceptor function in HF. To test this hypothesis, we compared IK of CB glomus cells in sham and pacing-induced HF rabbits and examined the effects of NO on IK. Our results show that IK was attenuated in CB glomus cells from HF rabbits and that down-regulation of NO attenuated IK via the inhibition of Ca2+-dependent K+ (KCa) channels. Furthermore, the ability of NO to activate IKCa in glomus cells appears to be mediated by a cGMP-dependent pathway. Preliminary results from this study have been published in an abstract form (Li & Schultz, 2003).
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Methods |
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All experiments were carried out on male New Zealand White rabbits weighing 2.5–3.5 kg. Experiments were approved by the University of Nebraska Medical Center Institutional Animal Care and Use Committee and were carried out in accordance with the National Institutes of Health and the American Physiological Society's Guides for the Care and Use of Laboratory Animals.
Rabbits were anaesthetized with a cocktail consisting of 1.2 mg acepromazine, 5.9 mg xylazine and 58.8 mg ketamine, given as an I.M. injection. Using sterile technique, a left thoracotomy was performed as previously described (Sun et al. 1999a). The pericardium was opened and wire loop electrodes were attached to the left ventricle for pacing. Two sonomicrometer crystals (Sonometrics Corp., London, ON, Canada) were attached to opposing walls of the lateral left ventricle for measuring external diameter. All leads exited the chest between the 3rd and 4th ribs. The chest was closed in layers and evacuated. Rabbits were placed on an antibiotic regimen consisting of 5 mg kg-1 Baytril I.M. for 5 days. After the rabbits recovered from the thoracotomy (about 2 weeks), baseline left-ventricular end-systolic and end-diastolic external diameter (D), fractional shortening, and shortening velocity (dD/dtmax) were measured by sonomicrometry (Triton Technology Inc., San Diego, CA, USA). An arterial blood gas sample (0.25 ml) was taken by needle puncture of an ear artery periodically to monitor arterial blood gases. The pacing was started at 320 beats min-1, which was held for 7 days, and then the rate was gradually increased to 380 beats min-1, with an increment of 20 beats min-1 each week. The pacemaker was of our design, with its output usually being set at 4–5 V and 0.5 ms. Sonograms and blood gas (ABL5, Radiometer, Copenhagen) were done weekly, with the rabbits sitting quietly in a Plexiglas box and with the pacemaker turned off for at least 30 min before recordings were made. Sham-operated animals underwent a similar period of sonographic measurements with the pacemaker turned off. Rabbits with >40% reductions in dD/dtmax and shortening fraction were considered in HF (generally after 3–4 weeks). Any rabbit exhibiting abnormal arterial blood gases (Pa,O2 < 85 mmHg; 45 mmHg <Pa,CO2 < 30 mmHg) were excluded from study (Sun et al. 1999a).
Isolation of CB glomus cells
The carotid bifurcations on both sides were removed surgically from sham or HF rabbits anaesthetized with the cocktail described above. The rabbits were then killed with an intravenous injection of 150 mg kg-1 sodium pentobarbital. The removed tissue was placed in ice-cold Ca2+/Mg2+-free solution (mM: NaCl, 140; KCl, 5; Hepes 10; glucose 5; pH 7.2), and then minced with microscissors. The CBs were then subjected to a two-step enzymatic digestion protocol. Each step lasted for 30 min at 37°C. The enzymatic solution for the first step of digestion contained trypsin (type II, 2 mg ml-1) and collagenase (type IV, 2 mg ml-1); and that for the second step contained collagenase (4 mg ml-1) and bovine serum albumin (BSA, 5 mg ml-1). Other solutes in the solutions used for enzymatic digestion were the same as the above Ca2+/Mg2+-free solution. The digested tissue fragments were gently triturated for 1 min every 10 min during the process of digestion. CB cells were obtained after centrifugation of the digested tissue at 150 g for 5 min. The isolated cells were then resuspended in culture medium and plated onto culture wells. The culture medium consisted of a 50/50 mixture of Delbecco's modified Eagle's medium (DMEM) and Ham's F12 medium supplemented with antibiotics and 10% fetal bovine serum. The CB cells including glomus cells, other neural cells and vascular cells were cocultured at 37°C in a humidified atmosphere of 95% air–5% CO2 (Zhong et al. 1997) and studied within 24 h of dissociation.
Identification of glomus cells
Short-term cultured cells freshly isolated from CB in sham and HF rabbits contain several cell types, including glomus and type II cells. It has been shown that rabbit glomus cells are excitable cells and they exhibit Ca2+, K+ and Na+ currents, but type II cells are non-excitable and exhibit only small outward K+ currents. Therefore, at the beginning of each experiment, cells were superfused with an extracellular solution containing Na+. Those cells that exhibited Na+ current were considered to be glomus cells (Overholt & Prabhakar, 1997). Once the presence of Na+ current was confirmed, the extracellular solution was changed to solution containing 0.5 µM TTX to record IK (see below).
Recording of whole cell K+ currents and resting membrane potential
K+ currents were measured in the whole-cell configuration of the patch-clamp technique (Hamill et al. 1981) using a Warner PC-501A patch-clamp amplifier (Warner Instrument Corp. Hamden, CT, USA), which allowed the same cell to be recorded in either the voltage-clamp or current-clamp mode. Patch pipettes had resistances of 4–6 M
when filled with (mM) 105 potassium aspartate, 20 KCl, 1 CaCl2, 10 EGTA, 5 Mg-ATP, 10 Hepes and 25 glucose, pH 7.2. In the perforated whole-cell configuration, nystatin was added to the patch-pipette solution at a final concentration of 300 µg ml-1 immediately before recording. The extracellular solution had the following composition (mM): 140 NaCl, 5.4 KCl, 2.5 CaCl2, 0.5 MgCl2, 5.5 Hepes, 11 glucose, 10 sucrose, pH 7.4. Na+ channels were blocked by TTX (0.5 µM).
Cell membrane capacitance (Cm) was determined by integrating the capacitive current evoked by a 5 mV voltage step and dividing the resulting charge by the voltage step. Mean series resistances, as determined from the decay of the capacitive transient, were 7.4 ± 0.5 M (conventional whole-cell mode) and 13.2 ± 0.7 M (perforated whole-cell mode), and were compensated electronically by 80–90%. Current traces were sampled at 10 kHz and filtered at 5 kHz. Holding potential was -80 mV. Current–voltage (I–V) relations were elicited by 400 ms test pulses from -80 mV to +80 mV applied in 10 mV increments (5 s between steps). Peak currents were measured for each test potential and were plotted against the corresponding test potential.
To study steady-state inactivation, we used two-step pulse protocols from a holding potential of -80 mV. First, a 10 s prepulse was applied at various potentials ranging from -110 to -10 mV (10 mV step) followed by a 400 ms test pulse to +20 mV. Inactivation curves were constructed from currents at the corresponding prepulse voltages and fit to the Boltzmann function:
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Test chemicals were all delivered to the recording bath through a fast-flow apparatus consisting of a linear array of borosilicate glass tubes (Overholt et al. 1995). Chemicals were added into syringe reservoirs, which contained extracellular solution and connected to the fast-flow apparatus. All chemicals were obtained from Sigma (St. Louis, MO, USA).
Data analysis
All data are presented as means ±S.E.M. Statistical significance was determined by Student's paired or unpaired t test for haemodynamic parameters, or a two-way ANOVA, with a Bonferroni procedure for post hoc comparisons of IK. Statistical significance was accepted when P < 0.05.
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Results |
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Rapid left ventricular pacing induced HF by the 3rd or 4th week of pacing. In paced rabbits, LV dD/dtmax and LV shortening fraction were reduced after 3 or 4 weeks of pacing, compared with prepaced baselines (P < 0.05, Table 1). There was no significant change in the LV dD/dtmax and LV shortening fraction between the baseline and the 3rd or 4th week in sham rabbits (Table 1).
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The resting membrane potential of glomus cells in HF rabbits (-34.7 ± 1.0 mV, n= 21 cells from 20 rabbits) was depolarized (P < 0.05), compared with that in sham rabbits (-47.2 ± 1.9 mV, n= 18 cells from 18 rabbits). There was no significant difference in the whole-cell capacitance between sham (2.59 ± 0.18 pF) and HF rabbits (3.23 ± 0.35 pF). Thus, absolute currents measured in our recordings reflected current density in the cells and were not normalized.
Figure 1Aa–c illustrates typical IK recordings and I–V curves obtained from glomus cells from sham and HF rabbits, with voltage steps from -80 mV under conventional whole-cell patch conditions. As illustrated in current traces in Fig. 1Aa and b, IK was attenuated in HF rabbits, compared with those in sham rabbits. Figure 1Ac shows the peak current–voltage relationships evoked by 400 ms depolarizing test pulses from -80 mV to +80 mV in 10 mV increments. From this curve, the attenuated IK in HF rabbits began near -30 mV and appeared to be voltage dependent.
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Steady-state inactivation was evaluated with a two-pulse protocol (Fig. 2A). The inactivating prepulse was 10 s in duration in order to reach a steady state of inactivation. The interpulse interval was 60 s to allow full recovery of inactivation. Figure 2B illustrates the mean inactivation curves obtained in eight cells from sham and HF rabbits. The mean inactivation curve exhibited a threshold at about -100 mV and failed to reach full inactivation at values greater than 0 mV. There was no difference in the inactivation curves between sham and HF rabbits (sham, V1/2=-45.6 mV, K1= 13.56, S= 0.16; HF, V1/2=-47.5 mV, K1=-15.44, S= 0.18).
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It has been shown that an IKCa component exists in rabbit carotid body glomus cells (Lopez-Lopez et al. 1993). Therefore, IKCa in glomus cells was further characterized by using the selective IKCa blocker, iberiotoxin (IbTx). In glomus cells from sham rabbits, 100 nM IbTx (saturated concentration) decreased IK (P < 0.05, Fig. 4A and C). However IbTx had no effect on IK in glomus cells from HF rabbits (Fig. 4B and D). These results suggested that the decrease of IK in glomus cells from HF rabbits was due to suppression of the KCa channel.
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The modulation of IK by NO was investigated by application of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and a NOS inhibitor, L-NNA, to the recording bath. As shown in Fig. 5, 100 µM SNAP significantly increased IK of glomus cells from HF rabbits and IbTx completely inhibited this effect (P < 0.05, Fig. 5B and D). Similarly, SNAP also enhanced the IK of glomus cells from sham rabbits (P < 0.05, Fig. 5A and C). At the same time, following the changes of IK induced by SNAP and IbTx, corresponding changes were induced in resting membrane potential. In glomus cells from both sham and HF rabbits, SNAP increased the resting membrane potential and IbTx inhibited this effect of SNAP (Fig. 6). However, in conventional whole-cell mode, SNAP did not change IK (Fig. 7) or membrane potential in either group (data not shown).
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To test whether enhancement of IK by NO is related to activation of guanylate cyclase, we examined the effects of SNAP on IK in the presence of 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. As shown in the current traces in Fig. 9A and B, and I–V curves in Fig. 9C and D, ODQ (1 µM) alone reduced IK in glomus cells from sham rabbits (P < 0.05) but not in those from HF rabbits. More importantly, ODQ inhibited the effects of SNAP on IK in cells from both sham and HF rabbits (P < 0.05, Fig. 10). We further inferred that if the effects of NO were mediated by cGMP, then 8-bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP), a cGMP analogue, should mimic the effects of SNAP on IK. Therefore we tested this possibility in seven additional cells from each group. Treatment with 8-Br-cGMP (1 mM) for 20 min increased IK in glomus cells from sham and HF rabbits by 132 ± 11% and 176 ± 19% of control, respectively (P < 0.01), at a test potential of +70 mV. These results support the idea that NO enhanced IK via a cGMP-dependent pathway.
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Discussion |
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Functionally, K+ channels are classified into five families: (1) voltage-gated K+ (KV) channels, (2) KCa channels, which are intracellular Ca2+-sensitive and also voltage-sensitive, (3) ATP-sensitive K+ channels, (4) inward rectifier K+ channels, and (5) voltage-insensitive background K+ channels (Jan & Jan, 1997; Lesaga & Lazdunski, 2000). These channels are extraordinarily diverse and are expressed in many different cell types. In adult rabbits to the extent known, carotid body glomus cells express KV channels, KCa channels and HERG-like K+ channels (inward rectifier K+ channel; Lopez-Lopez et al. 1993, 1997; Overholt et al. 2000).
Of these K+ channels, which type is likely to account for attenuated IK in carotid body glomus cells from HF rabbits, and what regulates the change of resting membrane potential observed? The present study showed that IbTx inhibited IK in sham rabbits but had no effect in HF rabbits. These results suggest that KCa channel activity is markedly suppressed in glomus cells from HF rabbits, and the attenuated IK in HF rabbits is mainly due to decreased activity of these KCa channels. On the other hand, our results also do not imply that suppressed KCa channel activity exclusively caused the attenuated IK in HF rabbits. After administration of KV channel blockers, 4-AP and TEA, IK was reduced to the same level in both sham and HF rabbits (Fig. 3). However, in sham rabbits IbTx did not reduce the IK level to that seen in HF rabbits (Fig. 4). These results suggest that other KV channels are also involved in the attenuated IK in HF rabbits, but to a lesser extent.
Our results also suggest that the attenuated KCa activity contributed to the elevation in resting membrane potential observed in the HF glomus cells. SNAP lowered the resting potential to normal levels in HF cells, and this effect was reversed by IbTx. However, a HERG-like K+ channel has been reported in rabbit glomus cells which could also influence the resting membrane potential (Overholt et al. 2000). The contribution of HERG channels to the elevated membrane potential in the HF glomus cells remains to be determined.
Much evidence indicates that NO produced within the CB is an inhibitory modulator of chemoreception (Prabhakar et al. 1993; Chugh et al. 1994; Wang et al. 1994; Alcayaga et al. 1997; Prabhakar, 1999; Sun et al. 1999b; Iturriaga et al. 2000a). The administration of the precursor L-arginine, NO donors (Prabhakar et al. 1993; Chugh et al. 1994; Wang et al. 1994; Iturriaga et al. 2000b), and NO gas (Iturriaga et al. 2000a) to the cat carotid body perfused in vitro reduces the chemosensory response to hypoxia. Non-specific NOS inhibitors, such as 
-nitro-L-arginine methyl ester (L-NAME), enhance the chemosensory response to hypoxia (Wang et al. 1994) or nicotine and NaCN (Valdes et al. 2003). In a previous study we demonstrated that the NO donor (SNAP) inhibited the baseline discharge of the carotid sinus nerve (CSN) and the chemosensitivity in sham and HF rabbits (Sun et al. 1999b). Our present results confirmed that SNAP enhanced IK and hyperpolarized the resting membrane potential in glomus cells from sham and HF rabbits, and IbTx completely abolished the effects of SNAP. We have shown that NO production and protein expression of NOS in CB from HF rabbits is lower than that from sham rabbits (Sun et al. 1999b; Zeng et al. 2002). From these data, we propose that decreased NO production contributed to the attenuated the IK in glomus cells from HF rabbits by preventing the activation of KCa channels.
In contrast to our study, Hatton & Peers (1996) found that SNAP did not affect IK recorded in CB glomus cells. One possibility for this discrepancy is that their study employed the conventional whole-cell patch-clamp technique. The present study also found that SNAP did not change the IK of glomus cells in the conventional whole-cell mode, but SNAP was effective in the perforated-patch mode. Taken together these results suggest that some intracellular factor(s) that is dialysed in conventional whole-cell recording is necessary for KCa channel modulation by SNAP. This notion is supported by Silva & Lewis's study (2002), in which KCa channel activity in rat CB glomus cells was enhanced by SNAP in cell-attached mode.
Our results indicate that this intracellular factor is cGMP. NO activates soluble guanylate cyclase, and many of its effects are mediated by stimulation of cGMP production (Snyder, 1992). cGMP is well known to activate K+ channels in vascular smooth muscle, and is the major mediator of NO-induced vasodilatation in many vascular beds (Vaandrager & de Jonge, 1996). The NO donor nitroglycerine has been shown to elevate cGMP levels in glomus cells (Wang et al. 1994). In rat CB glomus cells, NO enhances KCa channel activity through cGMP-dependent protein kinase G (Silva & Lewis, 2002). However, recently it has been shown that NO inhibits L-type Ca2+ channels in rabbit type I cells via a cGMP-independent mechanism (Summers et al. 1999). In rabbit aortic smooth muscle cells (Bolotina et al. 1994) and rat brain (Shin et al. 1997), NO activates KCa channels directly. The heterogeneity of these results could be due to the difference of species and tissues. Our results confirmed that the effect of NO on the IK in CB glomus cells was cGMP-dependent because ODQ inhibited the effects of SNAP on the IK and 8-Br-cGMP could mimic the effect of SNAP on the IK in both sham and HF rabbits.
It is known that NOS isoforms (eNOS, nNOS and iNOS) exist in the extensive plexus of nerve fibres and vessels surrounding glomus cells (Wang et al. 1993) but not in detectable levels in CB glomus cells and type II cells. Thus, a reasonable question is how NO production and NOS inhibitors can influence IK in isolated CB glomus cells. There may be at least two possible explanations for this phenomenon. First, NOS may be present in glomus cells at low levels that are difficult to detect (Prabhakar et al. 1993), but sufficient to influence K+ channel activity, or sequestered in mitochondria inaccessible to immunofluorescence antibodies (Alvarez et al. 2003). Secondly, even though glomus cells are dispersed in cell culture, they continue to coexist with other neural and vascular cells of the CB that possess substantial amounts of NOS. These cells may produce sufficient NO to exert a paracrine effect on the neighbouring glomus cells from which we recorded. This notion is supported by other electrophysiological studies in which paracrine effects can be observed from neighbouring cells in the recording media (Chapleau et al. 2001). Although we cannot ascertain the cellular origin of NOS activity in the present study, we observed that L-NNA reduced the IK in glomus cells from sham rabbits but not from HF rabbits, which demonstrated that lower activation of NOS was responsible for the attenuated IK in glomus cells from HF rabbits.
Our previous study has shown that the baseline discharge of CB chemoreceptor afferents in the normoxic state and their response to hypoxia are enhanced in pacing-induced HF rabbits as compared with sham rabbits (Sun et al. 1999b). Our present results indicate that IK is attenuated in CB glomus cells from HF rabbits in the normoxic state and the resting membrane potential of glomus cells from HF rabbits is depolarized as compared with that in sham rabbits. The depression in IK from the CB glomus cells in HF rabbits is consistent with the enhanced peripheral chemoreceptor function observed for CB afferent responses in HF rabbits. NO donors inhibited the baseline discharge of CSN (Sun et al. 1999b) and enhanced the IK in glomus cells in sham and HF rabbits. L-NNA increased the baseline discharge of CSN in sham rabbits but not HF rabbits (Sun et al. 1999b) and attenuated the IK in sham rabbits but not in HF rabbits. Based on these results, it is reasonable to assume that the attenuated IK in glomus cells induced by HF contributes to the enhancement of CB chemoreceptor function. Nevertheless, it is important to point out that other ion channels in glomus cells may be altered in HF due to changes in NO or other neuro-endocrine factors. These effects must be taken into consideration when fully assessing the functional significance of the results we describe here.
In conclusion, our results indicate that IK is attenuated in CB glomus cells from HF rabbits, and the attenuated IK is due mainly to the decreased activity of KCa channels. In the normal state, NO maintains this KCa channel activity via a cGMP-dependent signalling pathway, and during HF a decrease in NO induced by an attenuated NOS activity is responsible for the inactivation of the KCa channels.
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, HF.
, SNAP + IbTx.
