ANP-mediated cGMP signaling and phosphodiesterase inhibition in the rat cervical spinal cord

Journal of Chemical Neuroanatomy 31 (2006) 263–274 www.elsevier.com/locate/jchemneu

ANP-mediated cGMP signaling and phosphodiesterase inhibition in the rat cervical spinal cord J. de Vente a,*, M. Markerink-van Ittersum a, J.S.H. Vles b a

European Graduate School of Neuroscience (EURON), Maastricht University, Department of Psychiatry and Neuropsychology, UNS50, POB 616, 6200 MD Maastricht, The Netherlands b Department of Neurology, University Hospital Maastricht, POB 5800, 6202 AZ Maastricht, The Netherlands Received 28 October 2005; received in revised form 17 February 2006; accepted 20 February 2006 Available online 18 April 2006

Abstract Natriuretic peptides (NP) and the corresponding receptors are present in the rodent spinal cord. We have studied the structures which respond to atrial natriuretic peptide, brain natriuretic peptide, or C-type natriuretic peptide with an increased synthesis of cGMP. NP-responsive cGMPproducing structures were observed in laminae I–III, and X, and in addition in ependymal cells, astrocytes and a subpopulation of dorsal root ganglion cells. As the cGMP concentration is controlled by the rate of synthesis and the rate of breakdown by phosphodiesterases, we studied NPresponsive structures in spinal cord slices incubated in the presence of different phosphodiesterase inhibitors. We studied EHNA and BAY 60-7550 as selective PDE2 inhibitors, sildenafil as a selective PDE5 inhibitors, dipyridamole as a mixed type PDE5 and PDE10 inhibitor, rolipram as a PDE4 inhibitor, and SCH 81566 as a selective PDE9 inhibitor. Double immunostainings showed that cGMP-IR colocalized partial with the vesicular acetylcholine transporter molecule in lamina X, with Substance P in a subpopulation of neuronal fibers situated dorsolateral, and with a subpopulation of CGRP-IR dorsal root ganglion neurons. Colocalization of cGMP-IR was absent with parvalbumin, synaptophysin, and the vesicular transporter molecules for GABA and glutamate. It is concluded that NPs in the spinal cord are probably involved in integrating intersegmental sensory processing in the spinal cord although the greater part of the NP-responsive cGMP-producing fibers could not be characterized. PDE2, 5, and 9 are involved in regulating NP-stimulated cGMP levels in the spinal cord. NPs may have a role in regulating cerebrospinal fluid homeostasis. # 2006 Elsevier B.V. All rights reserved. Keywords: Natriuretic peptides; Phosphodiesterase; cGMP; Spinal cord; Intersegmental connections

1. Introduction In the spinal cord, cGMP synthesis can be catalyzed by two different isoforms of the enzyme gyanylyl cyclase (GC). The so-called soluble form of GC (sGC) is a heterodimeric protein and is activated by the binding of nitric oxide (NO) to a ferrous heme group complexed with the protein (Friebe and Koesling, 2003; Koesling et al., 2004). sGC is probably the physiological receptor of NO. The other GC is a homodimeric transmembrane receptor-activated protein and is designated the particulate GC (pGC) (Tamura et al., 2001). In the central nervous system, the ligands for this enzyme are the natriuretic peptides (NP). Three natriuretic peptides (NP) are known, atrial natriuretic peptide

* Corresponding author. Tel.: +31 43 3881022; fax: +31 43 3671096. E-mail address: [email protected] (J. de Vente). 0891-0618/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jchemneu.2006.02.005

(ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). In addition, also three NP receptors are known. The NP-A receptor has almost equal affinity toward ANP and BNP, whereas the NP-B receptor has a high affinity towards CNP. The NP-C receptor is not part of a pGC molecule and functions as a clearance receptor for all three NPs (Lucas et al., 2000; Wedel and Garbers, 2001). Natriuretic peptides were originally discovered in rat atria (see DeBold, 1985 for a review). Soon thereafter ANP binding sites were discovered in the brain (Quirion et al., 1984) and the presence of ANP in neurons was demonstrated (Jacobowitz et al., 1985; Kawata et al., 1985; Saper et al., 1985; Skofitsch et al., 1985; Zamir et al., 1986). Although the presence of NPs in the spinal cord of mice (Cameron et al., 1996), rats, and pigs has been described along with the distribution of NPs in the brain (Morii et al., 1987; Totsune et al., 1994; Ueda et al., 1988; Zamir et al., 1986), little is known about the localization and

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function. ANP- and BNP-immunoreactivity has been observed in fibers in laminae I/II and to a lesser extent in lamina X of the spinal cord of different species (Kawata et al., 1989; Nohr et al., 1989; Saper et al., 1989) with a distribution distinct from other neuropeptides (Kawata et al., 1989; Nohr et al., 1989). No somata have been observed in the spinal cord which are immunoreactive to NPs. This observation has led to the proposal that the NP-immunoreactive fibers in the spinal cord are of supraspinal origin, presumably originating from the hypothalamus (Cechetto and Saper, 1988; Nohr et al., 1989). In

addition, it was suggested that part of the ANP-immunoreactive fibers are of primary sensory origin (Nohr et al., 1989). We demonstrated ANP-mediated cGMP synthesis in fibers laminae I/II and in astrocytes of the rat spinal cord using a micropharmacological approach with spinal cord slices (Vles et al., 2000). In addition, we found that ANP stimulated cGMP synthesis in rat spinal cord slices was inhibited by baclofen, a GABAB agonist (De Louw et al., 2002) which is used as an analgesic and for the treatment of spasticity. This suggests that ANP-mediated cGMP synthesis might be part of a signaling

Fig. 1. Effect of non-selective inhibition of PDE activity on ANP-responsive, cGMP synthesizing structures in lamina X (a–c) and laminae I–III (d–f) of the rat cervical spinal cord. Slices were incubated in the presence of 1 mM IBMX and 100 nM ANP. Sections were double immunostained for cGMP-IR and EAAT3 (a and b) or cGMP-IR and vAChT (d and e). In (c) and (f) the merged photographs are presented. Bar in (a) represents 100 mm (similar for the other images).

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Fig. 2. Effect of non-selective inhibition of PDE activity by 1 mM IBMX on ANP-responsive, cGMP-IR ependymal cells lining the central canal of the cervical spinal cord. This effect has been observed in 4 out of 6 slices. Bar represents 100 mm.

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pathway involved controlling pain perception and/or spinal reflexes. However, we did not characterize the structures in which the ANP-mediated cGMP response in the rat spinal cord was observed in terms of known neurotransmitter pathways. Observations on the localization of the NP-receptors show that these are not confined to the laminae I/II. However, the literature is not unequivocal on this point. In the first report on ANP receptor binding, no specific binding was observed in the spinal cord (Quirion et al., 1984), and in addition, in another early report, ANP receptors were observed only in the pia/ arachnoid of the spinal cord (Mantyh et al., 1987). However, others reported ANP binding sites in the gray matter of the spinal cord together with ANP-immunoreactivity (Skofitsch and Jacobowitz, 1988). In addition, cGMP levels in cells are controlled by GC activity and by the activity of phosphodiesterases (PDE) which hydrolyze cGMP to GMP. Presently 11 subfamilies of PDEs are known (Beavo, 1995; Conti and Jin, 2000; Francis et al., 2001). These subfamilies differ in their affinities towards the substrates cAMP and cGMP and selective inhibitors have been developed towards most of these enzymes.

Fig. 3. Effect of PDE2 inhibition on ANP-responsive, cGMP-IR structures in laminae I–III of the rat cervical spinal cord. Slices were incubated in the presence 1 mM Bay 60-7550 (a–c) or 10 mM EHNA (d–i) in combination with 100 nM ANP. Sections were double immunostained for cGMP-IR and synaptophysin (a and b), cGMP-IR and parvalbumin (d and e), or cGMP-IR and vAChT (g and h). In (c), (f) and (i) the merged images are shown. Bar in (a) represents 100 mM (similar for the other images).

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In the accompanying paper (De Vente et al., 2000) we showed that PDE2, PDE5, and PDE9 are expressed in all laminae of the rat spinal cord. We concluded that the majority of these cells express more than one of these PDEs. The aims of the present study were twofold. First, we wanted to study NP-mediated cGMP synthesis in the rat cervical spinal cord under conditions of selective inhibition of PDE2, PDE5, or PDE9, not only on the segmental level but also axial in longitudinal sections. Secondly, we wanted to characterize the ANP-responsive, cGMP-producing structures in the spinal cord under these conditions.

CGRP and NP-stimulated cGMP-synthesis was never observed in the ANP-responsive fibers (Figs.7a–c and 9a–c). No colocalization was observed between ANP-stimulated cGMP-IR and IB4 (Fig. 9d–f). NP-responsive cells were also observed in the dorsal roots (Figs. 4a and 9a), and here we observed a partial colocalization between cGMP-IR and CGRP (Fig. 7, arrows). Weak stimulation of cGMP synthesis by ANP was observed throughout the gray matter in astrocytes. No cGMP-IR was observed in ventral motor neurons in slices incubated in the presence of ANP, BNP, or CNP, in combination with any of the PDE inhibitors.

2. Materials and methods

4. Discussion

rANP1–28, rBNP and rCNP were all from Sigma. Peptides were dissolved in distilled water (100 mM) and stored as aliquots at
80 8C. Animals, tissue handling, and immunocytochemistry was exactly as described in the accompanying paper (De Vente et al., 2000).

3. Results Incubation of cervical spinal cord slices in vitro in the presence of 1 mM IBMX and 100 nM rANP resulted in the appearance of cGMP-immunoreactivity (cGMP-IR) in fibers in laminae I/III and in fibers and a few somata in lamina X (Fig. 1). In addition, the ependymal cells lining the central canal showed cGMP-IR although this was somewhat varying between experiments (compare Fig. 1a with Fig. 2). ANP-stimulated cGMP-IR is visualized in short fibers, which have few varicosities, and in a dot like immunostaining, probably arising from transversally cut fibers (Figs. 1e and 5a). In the presence of IBMX we did not observe colocalization of ANP-stimulated cGMP-IR with vAChT, EAAT3, synaptophysin, parvalbumin, vGAT, vGlu1, vGlu 2, CGRP or isolectin B4 (IB4). Replacing IBMX in the incubation medium by the selective PDE2 inhibitors BAY 60-7550 (Fig. 3a–c) or EHNA (Fig. 3d– i), the PDE5 inhibitor sildenafil (Fig. 4), the PDE4 inhibitor rolipram (Fig. 5), the mixed PDE2 and PDE10 inhibitor dipyridamole (Fig. 6), or the somewhat selective PDE9 inhibitor SCH 51866 (Fig. 7), resulted in a similar pattern of cGMP-IR in laminae I/III as observed with IBMX. Colocalization studies with the vAChT, parv or vGLU2, did not show any colocalization with the NP-stimulated cGMP-IR. Sildenafil presented an exception in that we observed ANP-stimulated cGMP-IR in ependymal cells (Fig. 4g–i; see also Fig. 2), and in addition, we observed some colocalization between ANPstimulated cGMP-IR van vAChT in lamina X (Fig. 4i). When slices were incubated in the presence of IBMX we observed partial colocalization between NP-stimulated (ANP, BNP and CNP) cGMP-IR and substance P. This colocalization was observed in the dorsolateral parts of the gray and white matter (compare Fig. 7d–f with Fig. 8). Colocalization between

We investigated the localization and characterization of NPresponsive, cGMP producing structures in the cervical spinal cord of the rat. We were especially interested in the role of PDEs in the accumulation of cGMP. In this respect it was somewhat surprising that regardless of the PDE inhibitor present, ANP and BNP increased cGMP in fibers in laminae I/ III and X. In this respect, the PDE9 inhibitor SCH 51866 proved to be the least potent. In lamina X we observed cGMP-IR also in somata in the gray matter using IBMX or sildenafil, and in ependymal cells lining the central canal. In addition, we observed NP-stimulated cGMP-IR in lamina X in structures which were also immunoreactive for vAChT. We observed that a subpopulation of the cGMP-producing, NP-responsive fibers in the laminae I/III were immunoreactive for substance P- but not for CGRP-IR. These latter findings point to involvement of NP-signaling in sensory neurotransmission. This suggestion is strengthened by the observation of NP-responsive, cGMPproducing cells in the dorsal roots. The localization of ANP-IR fibers has been described in rats (Skofitsch et al., 1985) and guinea pigs (Nohr et al., 1989) in laminae I/II and X; Saper et al., 1989). BNP-IR fibers were also observed in laminae I/II and X of rats (Saper et al., 1989) and pigs (Kawata et al., 1989). The results of Kawata et al. showed especially BNP-IR in the spinal cord of pigs, whereas ANP-IR was considerably less. It is not known if the same situation exists in the rat. In mice spinal cord, the presence of all three natriuretic peptides has been reported (Cameron et al., 1996). Nevertheless, the receptor for ANP and BNP is for both cases GC-A (Wedel and Garbers, 2001), and we did not observe differences in the cGMP response to either ANP, BNP, or CNP, although the effect of the latter NP was less compared to ANP and BNP. Using selective inhibitors of PDE activity, we observed few differences in the localization of cGMP-IR after incubation of the slices with ANP. It is to be expected that inhibition of PDE2, PDE5, or PDE9 should result in accumulation of cGMP in structures that are also observed when using IBMX as a non-

Fig. 4. Effect of PDE5 inhibition on ANP-responsive, cGMP-IR structures in the rat cervical spinal cord. Sections were incubated in the presence of 10 mM sildenafil and 100 nM ANP. cGMP-IR double immunostained with vAChT in laminae I–III (a, b, merged in c), and lamina X (g, h, merged in i). cGMP-IR double immunostained with synaptophysin in laminae I–III (e, f merged in d) did not show colocalization. Bar in (a) represents 100 mm for (a–f). Bar in (g) represent 100 mm for (g–i).

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Fig. 5. Effect of inhibition of PDE4 on ANP-responsive cGMP-IR structures in laminae I–III of the rat cervical spinal cord. Slices were incubated in the presence of 10 mM rolipram and 100 nM ANP. Sections were double immunostained for cGMP-IR and EAAT3 (d, e, merged in f), or cGMP-IR and synaptophysin (g, h, and merged in i). Bar in (a) represents 100 mm (similar for the other images).

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Fig. 6. Effect of mixed inhibition of PDE5 and PDE10 on ANP-responsive, cGMP-IR structures in laminae I–III of the rat cervical spinal cord. Slices were incubated in the presence of 10 mM dipyridamole and 100 nM ANP. Double immunostaining for cGMP-IR and parvalbumin (a, b, and merged in c). Bars in (a) and (c) represent 100 mm.

specific inhibitor. IBMX has been reported to be a poor inhibitor of PDE9 (Soderling et al., 1998), however, using SCH 51866, which has been reported to be somewhat selective for PDE9 (Soderling et al., 1998), we only observed weak cGMPIR in laminae I–III. Inhibition of PDE4 by 10 mM rolipram resulted in a surprisingly large effect on ANP-stimulated cGMP accumulation. It might be that the concentration of rolipram used already results in appreciable inhibition of other PDEs when cGMP concentration are high, as has been suggested (Bellamy and Garthwaite, 2001). Strong cGMP-IR was observed in ependymal cells when the slices were incubated in the presence of sildenafil and ANP. The accumulation of cGMP in ependymal cells seems to be regulated by PDE5, because, next to sildenafil, no effect was observed in these cells when other selective PDE inhibitors were used, but only and often rather weak using IBMX. Recently, it has been reported that cGMP levels were raised in cultured ependymal cells by ANP, even in the absence of IBMX, and CNP was reported to be equally potent after short incubation periods (Wellard et al., 2003). We did not observe an effect of CNP on cGMP levels in ependymal cells, however,

this might be related to differences in the protocol and especially the incubation period. Characterization of the cGMP-IR structures after challenging the spinal cord slices with NPs did not result in a positive identification of structures with parvalbumin or vGAT as markers for GABA, EAAT3, vGlu1, or vGlu2 for glutamate, or synaptophysin as a general presynaptic marker. Only after incubation of the slices in the presence of sildenafil did we observe ANP-stimulated cGMP synthesis in lamina III in small somata and in lamina X in cells which were also immunoreactive for vAChT. It is known that cholinergic cells are present in lamina X (Feng-Chen and Wolpaw, 1996; Wilson et al., 2004) and also ANP receptors have been observed in lamina X (Skofitsch and Jacobowitz, 1988). These initial observations warrant further investigation into a possible connection between the ANP and the cholinergic innervation in the spinal cord. NP-responsive fibers were never CGRP-IR and did not show binding of IB4. In addition, only a partial colocalization was observed with Substance P-IR in the more lateral parts of laminae I-III. A remarkable observation was the presence of

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Fig. 7. Effect of inhibition of PDE9 on ANP-responsive, cGMP-IR structures in laminae I–III of the rat cervical spinal cord. Longitudinal sections were incubated in the presence of 10 mM SCH 51866 in combination with 100 nM ANP. Sections were double immunostained for cGMP-IR and CGRP (a, b, merged in c) or cGMP-IR and Substance P (d, e, merged in f). Bar in (a) represents 100 mm (similar for all images).

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Fig. 8. Effect of non-specific inhibition of PDE activity on NP-responsive, cGMP-IR structures in the rat cervical spinal cord. Longitudinal slices were incubated in the presence of 1 mM IBMX and 100 nM ANP (dorsolateral aspect: a, b, merged in c) or with 100 nM BNP (dorsal aspect, e, f, merged in d). Sections were double immunostained for cGMP-IR and substance P. Bar in (a) represents 100 mm (similar for all images).

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Fig. 9. Effect of non-specific inhibition of PDE activity on CNP-responsive (a–c) and ANP responsive (d–f) cGMP-IR structures in the rat cervical spinal cord. Longitudinal (a–c) or transverse (d–f) slices were incubated in the presence of 1 mM IBMX and 100 nM CNP (a–c) (dorsal aspect with part of the dorsal root visible) or 100 nM ANP (d–f). Sections were double immunostained for cGMP-IR (a) and CGRP (b). Merging of part of (a) and (b) is shown in (c). Double-labeling for cGMP-IR (d) and IB4 (e) does not show any colocalization (f). Arrows point to dorsal root ganglion cells with colocalization of cGMP-IR and CGRP. Bars represent 50 mm in all images.

CNP-responsive cells in the dorsal root which were CGRP-IR. NP responsive cells were observed frequently in the event that dorsal roots were still visible in the sections (e.g. Figs. 1e, 3d, 4a and 9a). This observation suggests that the NP-responsive, cGMP-producing network in laminae I–III is part of the neuronal network entering the spinal cord through the dorsal

roots. For a large part, the NP-reponsive network has a longitudinal orientation, which is obvious from our sections of longitudinal slices. There is evidence that natriuretic peptides are involved in the central regulation of blood pressure (Standaert et al., 1988). Thus, ANP receptors are found in highest density in

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hypothalamic nuclei involved in the control of blood pressure (Saavedra, 1987). In addition ANP receptors are found in the area postrema and the nucleus of the solitary tract (Quirion et al., 1986; Saavedra, 1987), both areas that are involved in blood pressure regulation. As ANP receptors have been demonstrated in circumventricular organs such as the subfornical organ and in the choroid plexus, a role for ANP in fluid homeostasis has been suggested also (Gibson et al., 1986; Herbert, 1993; Ryan and Gundlach, 1997; Saavedra, 1987) and evidence has been presented that cGMP has a role in this process (Israel et al., 1988). NPs have a modulating role in the release of hormones from the hypothalamus (Dumont et al., 2004; Ryan and Gundlach, 1997), the firing of vasopressin neurons in the paraventricular nucleus (Standaert et al., 1987), and on certain learning and memory processes (Bhattacharya et al., 1996; Telegdy et al., 2000). Recently, it was demonstrated that CNP might have effects which are opposite to those of ANP or BNP on anxiety (Montkowski et al., 1998) and water intake (Samson et al., 1991). This may find its cause in the different receptors involved in the responses to ANP and CNP (Lucas et al., 2000; Wedel and Garbers, 2001). Unfortunately, we were unsuccessful in our attempts to localize ANP-IR structures in our spinal cord sections. Nevertheless, ANP-receptors in the spinal cord have been described in all laminae (Skofitsch and Jacobowitz, 1988). We observed an effect of ANP in neuronal structures of the spinal cord only in laminae I–III and in lamina X. In addition to the ependymal cells lining the central canal which were responsive to ANP we observed ANP responsive cells situated just beneath the ependymal cells layer (Fig. 1a). These cells showed fingerlike protrusion through the ependymal cell layer, apparently contacting the cerebrospinal fluid. As cGMP is involved in regulating ciliary beat in rat tracheal epithelial cells (Li et al., 2000), cGMP may also play a role in regulating ependymal cilia, either in a positive or negative way. Recently, an effect of ANP on ependymal cells lining the third ventricle and on the choroid plexus ependymal epithelium has been reported (Wellard et al., 2006). These data, together with our observations suggest that ANP has a role in regulating cerebrospinal fluid in the spinal cord. The podocytes appear to express functional pGC and sGC as they are also responsive to DEANO and have been described in the accompanying paper (De Vente et al., 2006). Expression of both isoforms of GC in the same cell has been described before for hippocampal astrocytes (Teunissen et al., 2001). In addition, we observed ANP-stimulated cGMP synthesis in astrocytes in all gray matter layers, and also in the dorsal and lateral white matter columns. These observations are in agreement with our previous observations (Vles et al., 2000) and reports by others (Deschepper and Picard, 1994; De Vente et al., 1989, 1990; Friedl et al., 1989; Ho¨sli and Ho¨sli, 1992). The effect of NPs on cGMP synthesis in astrocytes of the spinal cord is variable from one experiment to the other. In the CNS the effect of both three peptides is rather consistent although there exists a considerable heterogeneity exists between astrocytes from different regions of the central nervous system when NP mediated cGMP synthesis is studied (De Vente et al., 1990; Teunissen et al., 2001).

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The function of NP-receptors in the spinal cord is unknown. Our observation that ANP and BNP stimulate cGMP synthesis in substance P in a subpopulation of neuronal fibers and CGRP in a subpopulation of dorsal root ganglion neurons indicates that NPs have a role in the processing of sensory information. Our finding that the cGMP-synthesizing, NO-responsive fibers do not bind IB4 implies that the C-fibers (Plenderleith et al., 1989; Breese et al., 2005) are not involved in this processing. Further interpretation of the data is hampered by the fact that the origin of the NP innervation of the spinal cord is not well known, although there are indications that this innervation is of (partly) supraspinal origin (Cechetto and Saper, 1988). In conclusion, NP-stimulated cGMP sythesis in the rat cervical spinal cord is regulated by at least three PDEs, i.e. PDE2, 5, and 9. As the NP-responsive cGMP-synthesizing fibers are organized in a longitudinal direction, it is suggested that NPs are involved in the intersegmental processing of sensory information. In addition, NPs might be involved in regulating aspects of cerebrospinal fluid homeostasis.

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