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J Dent Res 82(1): 33-37, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Role of K+ATP Channels, Endothelin A Receptors, and Effect of Angiotensin II on Blood Flow in Oral Tissues

E. Berggreen*, and K.J. Heyeraas

Department of Physiology, Årstadveien 19, University of Bergen, N-5009 Bergen, Norway;

*corresponding author, ellen.berggreen{at}fys.uib.no


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
K+ATP channels are involved in CGRP-mediated vasodilation and in the vasoconstriction induced by endothelin or angiotensin II. In this study, we examined the effects of a K+ATP channel antagonist and an ET(A) receptor antagonist on resting blood flow in the pulp and gingiva, and observed their role in the vasodilation induced by tooth stimulation. We also investigated whether receptors for angiotensin II exist in the pulp and gingiva. Blood flow was measured with laser-Doppler flowmetry. Under control conditions, the K+ATP channel antagonist and angiotensin II caused a significant drop in blood flow in both target tissues. Blocking of ET(A) receptor did not change basal blood flow. The vasodilation observed after tooth stimulation remained unchanged following blockade of K+ATP channels and ET(A) receptors. Analysis of the data shows that open K+ATP channels exist during resting conditions in the pulp and gingiva, but that CGRP seems to induce vasodilation mainly via mechanisms other than K+ATP channels. ET(A) and AT1 receptors are found in the pulp and gingiva, but ET(A) receptors are not involved in modulation of a basal vascular tone in these tissues or in the vasodilation observed after tooth stimulation.

KEY WORDS: laser-Doppler • tooth stimulation • vascular tone • arterial infusion


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Under normal physiological conditions, vascular tone in oral tissues is controlled by nervous, local, and humoral mechanisms. Such mechanisms keep the vessels in a state of partial constriction. In the dental pulp, nervous regulation of blood flow is extensive. However, basal blood flow is unaffected by the severing of the cervical sympathetic trunk, indicating that little or no vasoconstrictor tone is of sympathetic origin in this tissue (Tønder and Næss, 1978; Jacobsen and Heyeraas, 1997). Our previous study concluded that the neuropeptide calcitonin gene-related peptide (CGRP) and substance P (SP) contributed to a basal vasodilator tone of vessels in the dental pulp and gingiva in ferrets (Berggreen and Heyeraas, 2000). The sensory neuropeptide CGRP is the principal factor in the vasodilation that follows tooth stimulation (Berggreen and Heyeraas, 1999, 2000). ATP-sensitive K+ channels (K+ATP) are known to be involved in CGRP-induced vasodilation, which occurs by hyperpolarization of the smooth-muscle cells in the blood vessel wall (Nelson et al., 1990a; Quayle et al., 1994). Arteriolar tone might also be determined by K+ATP channels (Quayle et al., 1996). The vascular endothelium plays an important role in the regulation of vascular smooth-muscle tone. Nitric oxide (NO) maintains a vasodilatory tone on the vessels in several oral tissues, including the dental pulp and gingiva (Lohinai et al., 1995; Berggreen and Heyeraas, 1999), but does not participate in the vasodilation that follows tooth stimulation (Berggreen and Heyeraas, 1999).

The 21-amino-acid peptide, endothelin (ET), causes vasoconstriction when infused close intra-arterially into the pulpal circulation of dogs (Gilbert et al., 1992), demonstrating that receptors for endothelin exist in the dental pulp. Currently, it is unknown whether endothelin is released during resting conditions in oral tissues and, if released, whether it induces a basal tone in the vessels.

In cutanous microcirculation, a balance between the vasodilatory effect of CGRP and the vasoconstrictive effect of endothelin exists, and an imbalance between them has been postulated as the principal mechanism of Raynaud’s phenomena (Raynaud’s phenomenon, 1995). In rat skin microvasculature, blocking of the ET(A) receptor has been shown significantly to enhance blood flux responses after antidromic stimulation of sensory nerves (Merhi et al., 1998). In another study, SP-induced relaxation of the ophthalmic artery was diminished after ET-1 application, despite the fact that ET-1 itself did not further contract the vessel (Vincent et al., 1992). These observations suggest that ET-1 modulates the vasodilation in rat skin microvasculature and in the ocular-forehead circulation, the latter supplied with trigeminal sensory fibers. In the dental pulp, which is abundantly supplied with trigeminal sensory fibers, it is not known if the vasodilation induced by CGRP is modified by the release of endothelin.

Angiotensin II causes a drop in blood flow in the submandibular gland, but fails to have an effect in the tongue (Fazekas et al., 1991). It is unknown if receptors for angiotensin II exist in the dental pulp and gingiva. The objective of the present study was to observe the effects of a K+ATP channel antagonist and an ET(A) receptor antagonist on resting blood flow in the pulp and gingiva, and to observe their role in the vasodilation induced by tooth stimulation. The study also investigated whether receptors for angiotensin II exist in the dental pulp and gingiva.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Young female ferrets were used (n = 17; aged 3–7 months; body weight 0.8–1.2 kg). The University of Bergen, under the supervision of the Norwegian Experimental Animal Board, approved the animal experiments. Animals were anesthetized with 1 mL/kg ketamine hydrochloride (1 mg/mL) mixed with 0.1 mL/kg medetomidin hydrochloride (50 mg/mL) given intramuscularly. The ferrets were placed on a heating pad so that normal body temperature was maintained. A femoral vein was catheterized for supplemental anesthesia, while the femoral artery was catheterized for continuous systemic blood pressure (PA) recordings with a Gould pressure transducer and recorder. The left posterior auricular artery (a branch of the maxillary artery) was exposed and cannulated in the retrograde direction with a tube for regional drug infusion. The head was immobilized, and simultaneous measurements of systemic arterial pressure (PA), pulpal blood flow (PBF), and gingival blood flow (GBF) were then performed. Blood flow was recorded in the left maxillary canine pulp and in the gingiva during control conditions, alternating with periods of electrical stimulation of the canine crown before and after drug infusion.

Blood Flow Recordings
A Periflux Model 4001 Master laser-Doppler flowmeter (Perimed KB; Jarfalla, Sweden) with wavelength of 780 nm, equipped with two needleprobes PF 415:10 (fiber diameter 125 µm, with separation 500 µm), was used to measure PBF and GBF. One laser probe was positioned at the coronal part of the tooth, and the other probe was placed above the gingiva between the left first and second premolars 4 mm apical to the gingival margin. Both probes were rotated to the positions that gave the largest resting blood flow signals. The signals were recorded in arbitrary perfusion units (PU) and monitored in a computer equipped with the Perisoft 1.14 program. Motility standard calibration of the instruments and fiber-optic probes was carried out according to the manufacturers’ specifications. Zero blood flow was determined as the value recorded with the probes positioned at the tooth and at the gingiva after cardiac arrest. The flowmeter time constant was 0.03 sec, with an upper bandwidth at 20 kHz and lower bandwidth at 20 Hz. Since the laser flowmeter measures only relative changes in the flux of blood cells multiplied by their velocity, changes obtained during electrical stimulation and after drug infusion were calculated as percentages of the baseline values obtained during control conditions.

Electrical Tooth Stimulation
A negative electrode was placed in a shallow cavity at the canine tip. After being acid-etched with Scotchbond etching gel (3M Dental Products, St. Paul, MN, USA) for 30 sec, followed by a water rinse and air drying, the electrode was fixed into position with the composite material Herculite (Dental Materials Center, Santa Ana, CA, USA). The positive electrode was placed in the upper lip, and electrical stimulation was performed by means of a constant-current Grass stimulator (Quincy, MA, USA), which gave square-wave pulses of 2 msec at 10 Hz, 200–250 µA, for periods of 10 sec.

Experimental Protocol and Administration of Drugs
All drugs were administered by close intra-arterial infusion into the posterior auricular artery, and the animals received slow infusions over 1 min (0.3 mL/kg-1). Simultaneous measurements of PBF, GBF, and PA were performed during control conditions, infusions, and stimulation periods. The animals received a vehicle infusion (solvent minus drugs, 0.3 mL/kg-1) after measurements during control conditions and one stimulation period. After vehicle infusion, the tooth was stimulated, and drug infusions were given when the pre-stimulated flow levels were reached.

Group 1 (n = 8) received a K+ATP channel blocker (from 20 to 80 µM glibenclamid), and the ferrets’ canines were re-stimulated for 10 sec when the effect appeared. One hour later, 3 animals in this group received angiotensin II (1.1 µmol) infusions.

Group 2 (n = 9) received an ET(A) receptor antagonist BQ-123 (1 µmol). The animals were re-stimulated for 10 sec. Four animals in this group were infused with ET-1 (0.06 nmol) 1 hr after the BQ-123 administrations. Once they had recovered from the ET-1 effect, 2 of these animals received another infusion with BQ-123 (1 µmol), followed immediately by an ET-1 (0.06 nmol) infusion, to control the blocking effect of BQ-123.

Drug Preparation
Glibenclamid (Alexis Biochem., Grunberg, Germany) was dissolved in ethanol and diluted in saline to the concentration required. BQ-123 (Calbiochem-Novabiochem Corp., La Jolla, CA, USA). Human, porcine ET-1 (Sigma Chemical, St. Louis, MO, USA), and angiotensin II (Sigma Chemical, St. Louis, MO, USA) were dissolved in saline.

Statistical Analyses
Data are presented as means ± SEM. Differences were tested with the Wilcoxon ranked test or paired t test, and a p value of less than 0.05 was considered as statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effects of K+ATP Channel Blockade by Glibenclamid
Group 1 received doses of glibenclamid in the range from 20 to 80 µM. Under control conditions, glibenclamid infusions resulted in a consistently significant fall in both pulpal and gingival blood flow (Fig. 1Go). The changes in blood flow appeared almost immediately after the start of infusion and were followed by an increase in systemic pressure from 99.5 ± 5.65 mm Hg to 104.7 ± 6.47 mm Hg (p < 0.05) (Figs. 1Go,2Go). On average, PBF was reduced to 70.43 ± 4.74% of control (p < 0.001) and GBF to 75.5 ± 6.4% (p < 0.01) (Fig. 2Go). Three animals were left unstimulated so that we could explore the persistence of the effect of glibenclamid. The blood flow remained lowered over the three- to 12-minute interval. Individual irregular differences in duration between the pulp and gingiva over this interval were frequently observed (as illustrated in Fig. 1Go). Tooth stimulation before the infusion of glibenclamid caused an increase in PBF of 39.36 ± 5.5%. This vasodilation was not blocked by glibenclamid (27.6 ± 8.7%; p = 0.33) (Fig. 3Go). Infusion of a vehicle (solvent minus glibenclamid) gave no changes in any of the measured parameters.



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  		Figure 1. Original simultaneous recordings of systemic arterial pressure (PA), pulpal blood flow (PBF), and gingival blood flow (GBF), before, during, and after infusion of glibenclamid. Start of infusion of glibenclamid (40 µM, 0.3 mL, 1 min) indicated with an arrow. To observe the duration of the drop in PBF, we omitted electrical tooth stimulation in this experiment.

 


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  		Figure 2. Effects of glibenclamid infusions on pulpal blood flow (PBF), gingival blood flow (GBF), and mean arterial pressure (MAP) as % of control measurements (8 animals, 14 observations). Values are mean ± SEM. ***p < 0.001, **p < 0.01, *p < 0.05.

 


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  		Figure 3. Effects of electrical tooth stimulation on pulpal blood flow (PBF) and mean arterial pressure (MAP) before and after glibenclamid infusions. Values are mean ± SEM as % of control measurements (5 animals, 9 observations). No significant difference was observed between the measurements before and those after glibenclamid infusions.

 
Effect of Angiotensin II
Infusion of 1.1 µmol angiotensin II significantly reduced both PBF and GBF, as demonstrated in Fig 4Go. PBF dropped to 19.01 ± 6% (p < 0.001) of control measurements, and GBF to 33.1 ± 4.9% (p < 0.001). The decrease in blood flow appeared immediately after the start of the infusions, whereas systemic arterial pressure remained unchanged. The duration of the angiotensin II effect varied from 1 to 6 min.



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  		Figure 4. Original simultaneous recordings of phasic systemic arterial pressure (PA), pulpal blood flow (PBF), and gingival blood flow (GBF). Arrow points at start of infusion of angiotensin II.

 
Effects of ET-1 and Endothelin A Receptor Antagonist BQ-123
ET-1 infusion (n = 4) induced a drop in both pulpal and gingival blood flow. Pulpal blood flow dropped to 42.1 ± 7.65% and GBF to 49.52 ± 11.2% of control measurements, whereas mean arterial pressure (MAP) increased (27.8 ± 11.8%). The vasoconstriction induced by ET-1 persisted for more than 1 hr in both the pulp and the gingiva. After a return of blood flow to control levels, 2 animals in this group received an infusion of BQ-123 immediately prior to another dose of ET-1. BQ-123 infusions eliminated the drop in PBF and GBF observed when ET-1 was infused alone, and no more than a slight increase in MAP was observed (5.75 ± 0.49%) (data not shown). Infusions of 1 µmol BQ-123 alone (n = 9) did not significantly change any of the measured parameters. PBF responses after tooth stimulation were not altered after BQ-123 infusions; the increase in PBF averaged 133.9 ± 8.9% before BQ-123 infusions compared with 133 ± 6.6% after (p = 0.83). MAP remained unchanged during tooth stimulations.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the current investigation, basal blood flow in the dental pulp and gingiva was reduced by nearly 30% after glibenclamid infusion. The result clearly demonstrates that open K+ATP channels exist in the dental pulp during resting conditions, which can be closed by glibenclamid to cause a vasoconstriction. This complements previous findings of a resting vasodilator tone in the dental pulp and gingiva due to release of CGRP (Berggreen and Heyeraas, 2000). However, the vasodilation observed after tooth stimulation was unaffected by glibenclamid infusion, suggesting that K+ATP channels are not involved in CGRP-induced vasodilation in the dental pulp. Other mechanisms for CGRP-mediated vasodilation have been observed in several studies. CGRP may inhibit calcium influx via activation of large-conductance Ca2+-activated potassium channels and thereby reduce cytosolic Ca2+ concentrations [Ca2+]i (Sheykhzade and Berg Nyborg, 2001). A reduction in [Ca2+]i, lowering tension of the vessels, has also been shown to be mediated through elevation of cyclic AMP content in vascular smooth muscles (Kageyama et al., 1993; Yoshimoto et al., 1998). Cyclic AMP stimulates Ca2+ uptake into the sarcoplasmic reticulum, a mechanism demonstrated for, e.g., vasoactive intestinal peptide. This sequestering of cytosolic Ca2+ into intracellular storage sites has also been postulated as a mechanism for CGRP-mediated vasodilation (Sheykhzade and Berg Nyborg, 2001). Additionally, CGRP reduces the Ca2+ sensitivity of the contractile apparatus in coronary arteries (Fukuizumi et al., 1996; Sheykhzade and Berg Nyborg, 2001).

The mechanisms behind the CGRP-induced vasodilation in the dental pulp remain unclear and require further investigation.

Open K+ATP channels in the dental pulp and gingiva during resting conditions have been identified in the current investigation. K+ATP channels appear to be the target of several vasodilators linked to the phosphokinase A pathway, and its activity may be set by the combined effects of different activators. Activation of K+ATP channels has been shown to occur in response to adenosine, isoprenaline, vasoactive intestinal peptide, and prostacyclin (Nelson et al., 1990b; Quayle et al., 1997), and activation in the pulp and gingiva might be due to one or some of them. The involvement of K+ATP channels in the regulation of basal blood flow is strongly supported by investigations into coronary circulation (Mori et al., 1995). Such involvement may be a consequence of K+ATP channels’ contributions to the resting membrane conductance of the smooth-muscle cell (Klieber and Daut, 1994).

Vasoconstriction induced by ET-1 in the pulp and gingiva is mediated through ET(A) receptors, since the induced vasoconstriction was almost abolished with the selective ET(A) receptor antagonist BQ-123 in the current investigation.

Angiotensin II mediates vasoconstriction through AT1 receptors. This study identifies both ET(A) and AT1 receptors in the vascular bed in the dental pulp and gingiva, since both ET-1 and angiotensin II infusions caused a decrease in resting blood flow. Both endothelin and angiotensin II can constrict blood vessels through closure of K+ATP channels (Miyoshi et al., 1992). Endothelin constricts blood vessels through ET(A) receptors and also through ET(B) receptors in some vascular beds (Sudjarwo et al., 1993; Leseth et al., 1999). However, whether the vasoconstriction observed in this study was due to closure of K+ATP channels remains to be determined.

BQ-123 infusions did not change any of the measured parameters under either control conditions or after tooth stimulation. This shows that ET(A) receptors are not involved in either the regulation of resting blood flow in the target tissues in this study or in the vasodilation induced by tooth stimulation. ET(A) receptors may play a role in signaling acute or neuropathic pain, indicating a possible interaction between sensory nerves and endothelin (Davar et al., 1998; Jarvis et al., 2000). In the dorsal root ganglion, ET(A) receptor-immunoreactivity is present in a subset of small-sized peptidergic and non-peptidergic sensory neurons and their axons (Pomonis et al., 2001). Thus, when ETs are released in peripheral tissues, they could act directly on ET(A) receptor-expressing sensory neurons and affect the release of neurotransmitters from the nerve endings. Furthermore, after neonatal sensory denervation, a significant reduction in the thrombin-stimulated release of endothelin from vascular endothelium was observed (Milner and Burnstock, 1996), indicating a trophic effect of sensory nerves on the expression of endothelin in the endothelium. Whether ET(A) receptors are localized in axons in the dental pulp and gingiva is unknown, but the present study gave no evidence for involvement of the ET(A) receptor in neurogenic inflammation in the dental pulp. Endothelin immunoreactivity (IR) has been detected only in the endothelium in the dental pulp (Casasco et al., 1991), in contrast to other tissues where IR has been detected in nerves (Franco-Cereceda et al., 1991; Loesch et al., 1998). The role of endogenous endothelin and angiotensin II in the regulation of blood flow in the dental pulp and gingiva is still unclear and requires further investigation.

In conclusion, open K+ATP channels exist during resting conditions in both the dental pulp and gingiva, but CGRP seems to induce vasodilation via mechanisms other than the K+ATP channels. Furthermore, ET(A) and AT1 receptors exist in the dental pulp and gingiva, but ET(A) receptors are not involved in modulation of a basal vascular tone in these tissues, or in the vasodilation observed after tooth stimulation.


   ACKNOWLEDGMENTS
 
We thank Aase R. Eriksen for technical assistance. This study was financed by a post-doctoral fellowship from the University of Bergen (to E. Berggreen) and by the Norwegian Research Council.

Received January 14, 2002; Last revision August 22, 2002; Accepted October 10, 2002


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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