© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Signal transduction in spontaneous myogenic tone in isolated arterioles from rat skeletal muscle
Laboratory for Physiology, Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands
* Corresponding author. Tel.: +31-20-566-5179; fax: +31-20-691-7233.
Received 15 December 1997; accepted 12 May 1998
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Objective: The mechanism of spontaneous myogenic tone was investigated in isolated arteriolar segments. Methods: Arterioles were isolated from rat cremaster muscle. Segments were endothelium-denuded and mounted in a pressure myograph at 75 mmHg. Under this condition, segments spontaneously constricted from a passive diameter of 167±3 to 82±4 µm (n=41). The effects of several inhibitors were tested on the maintenance of myogenic tone. Results: Gadolinium (10–6–10–4 M), a putative inhibitor of stretch-activated cation channels, was ineffective. The phospholipase C (PLC) inhibitor 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC) induced a dose-dependent inhibition of tone. NCDC inhibited phenylephrine- (10–6 M), but not potassium buffer-induced (100 mM) constriction. The protein kinase C (PKC) inhibitors staurosporine, chelerythrine and calphostin C inhibited myogenic tone in a concentration-dependent manner. At an intermediate concentration, calphostin C selectively inhibited phenylephrine-induced constriction. However, all PKC inhibitors abolished responses to phenylephrine and potassium buffer at higher concentrations. The cytochrome P450 inhibitor 17-ODYA (0.3–3x10–6 M) did not inhibit myogenic tone. Conclusions: No evidence was found for a role of gadolinium-sensitive, stretch-activated cation channels or cytochrome P450 metabolites. On the other hand, both PLC and PKC contribute to the maintenance of myogenic tone.
KEYWORDS Arteries; Mechanotransduction; Protein kinases; Smooth muscle; Vasoconstriction/dilation
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Small arteries and arterioles isolated from various tissues spontaneously contract after pressurization. This maintained state of contraction is not dependent on the endothelium and, therefore, is often called myogenic tone. It is probably related to the myogenic response, but is not identical, since arteries without myogenic tone may show myogenic responses after precontraction [1]. A signal transduction pathway by which pressure induces constriction has been proposed by Meininger and Davis [2]. They proposed that pressure-induced stretch of smooth muscle cells causes depolarization and Ca2+ influx by the opening of stretch-activated channels. Depolarization opens voltage-operated Ca2+ channels (VOCs) and increases Ca2+ influx. Parallel to depolarization stretch may activate phospholipase C (PLC) and induce the breakdown of membrane phospholipids into 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). The second messengers IP3 and DAG elicit the release of Ca2+ from intracellular stores and activate protein kinase C (PKC), respectively.
Several reports have provided evidence for one or more steps in the mechanism proposed by Meininger and Davis [2]. Stretch-activated channels were involved in Ca2+ influx in cultured smooth muscle cells from rabbit pulmonary arteries [3]and in Ca2+ influx and PLC activation in rabbit aortic muscle during stretch [4]. However, a role for stretch-activated channels in the maintenance of myogenic tone remains to be established. The role of VOCs in myogenic tone is demonstrated more clearly. In isolated skeletal muscle arterioles, pressure caused a sustained increase in intracellular Ca2+ [5, 6]. This increase in cytosolic Ca2+ is inhibited by nifedipine, showing that it is mediated by VOCs [6]. An additional role in the regulation of cytosolic Ca2+ and tone may be performed by the sarcoplasmic reticulum [7]. Furthermore, myogenic tone was found to be dependent on PLC in small cerebral arteries [8]. Likewise, activation of PLC was suggested by a pressure-induced increase in IP3 and DAG in dog renal arteries [9]. One step further downstream, inhibition of PKC resulted in the loss of pressure-induced constriction of cremaster muscle arterioles in vivo [10]. In vitro, inhibition of PKC caused a dose-dependent loss of basal myogenic tone in human coronary arterioles [11]and rat cerebral arterioles [12].
Recently, a role for cytochrome P450 (P450) enzymes has been described in myogenic tone in renal and cerebral arteries [13, 14]. More specifically, arachidonic acid is thought to arise from the breakdown of DAG, which is used as a substrate by P450 enzymes. The P450 metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), may act as a second messenger and inhibit Ca2+-activated K+ channels. Inhibition of these channels by 20-HETE may play role in the maintenance of depolarization and constriction during myogenic tone.
The aim of the present study was to investigate the mechanism of myogenic tone in a skeletal muscle arteriole. Based on the mechanism proposed by Meininger and Davis [2]and a possible role for cytochrome P450-derived metabolites, we proposed a scheme, as depicted in Fig. 1. Inhibitors were chosen to inhibit successive or parallel steps in this scheme. To activate pathways selectively, a high potassium buffer was used to induce depolarization and stimulate VOCs, and the 
1-adrenergic agonist phenylephrine was used to activate PLC. The effect of the inhibitors on myogenic tone, and on the contractile responses to high potassium buffer and phenylephrine, was studied. The study was performed on isolated arterioles from the cremaster muscle, as these arterioles develop spontaneous tone in vitro [15, 16]. We used gadolinium as an inhibitor of stretch-activated ion channels [17]. The compound 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC) was used to inhibit PLC. The role of PKC was studied using staurosporine, chelerythrine [18]and calphostin C [19]. To inhibit the formation of 20-HETE, we used 17-octadecynoic acid (17-ODYA) [14].
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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2.1 Preparation and set-up
The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985). Procedures were approved by the local ethics committee for animal experimentation. Male Wistar rats, 268±10 g (n=33), were anaesthetized with sodium pentobarbital (50 mg/kg i.p.). The right cremaster muscle was exposed by a ventral incision of the scrotal sac and cleared from connective tissue. The muscle was opened by an incision, after which, the testis was removed. The cremaster was then excised and pinned to a dissecting dish containing MOPS buffer (for composition, see Section 2.3) at 5°C. The first order arteriole was dissected from the surrounding muscle and a 1- to 2-mm long segment was transferred to a pressure myograph. The myograph consisted of a vessel chamber with two glass cannulas (tip O.D. approx. 100 µm), a circular heating coil, a thermistor and a glass cover. A video camera was mounted on a microscope and connected to an electronic measurement system, to monitor inner arteriolar diameters continuously. The vessel chamber was filled with Krebs buffer (see Section 2.3) except for group two, where Hepes buffer (see Section 2.3) was used. The vessel segment was mounted on one cannula and secured with a single strand of a 20-µm suture. Then, the segment was endothelium-denuded by perfusion of 1 ml of air. The lumen was flushed with buffer and the vessel was mounted on the second cannula. This cannula was connected to a column filled with buffer. The pressure inside the vessel was set to 75 mmHg by increasing the height of the column. A pump (Gilson, Minipuls 3) was used to superfuse the vessel with the indicated buffer without recirculation. All vasoactive substances were applied to the vessel by adding them to the superfusate. The temperature was raised gradually to 33°C, the in vivo temperature of the cremaster muscle. Experiments were performed under no-flow conditions, to prevent flow-induced responses [15]. Vessels were equilibrated for at least 30 min. At the end of each experiment, the passive (maximally dilated) diameter was assessed by adding papaverine (0.1 mM).
2.2 Protocol
During equilibration, vessels developed spontaneous tone, leading to an 
50% reduction in diameter with respect to the passive diameter. First, endothelial denudation was confirmed with 10–7 M acetylcholine. Segments that did not develop spontaneous tone or significantly dilate in the presence of acetylcholine were not used. Concentration–response relations to inhibitors were obtained by cumulative addition to the superfusate. Most compounds required a 10-min period to obtain steady-state responses. Only calphostin C required a 1-h incubation period for each concentration.
In group one (n=6), a concentration–response relation (10–6–10–4M) for gadolinium was obtained first. After a washout period of 30 min, a concentration–response relation (10–6–3x10–4 M) for the PLC inhibitor NCDC was obtained. Maximal responses to a high potassium buffer (100 mM) and phenylephrine (10–6 M) were obtained in the absence of and at the highest concentration of NCDC. In group two (n=9), the effect of gadolinium was studied in Hepes buffer. Hepes buffer was used because of the possible interference with bicarbonate [2]and because of the visible precipitation at higher concentrations of gadolinium in Krebs buffer. In groups three, four and five, the effects of the PKC inhibitors chelerythrine (10–7–10–5 M; n=5), staurosporine (10–10–10–7 M; n=5) and calphostin C (10–9–10–7 M; n=4) on myogenic tone were studied. In addition, the specificity of the inhibitors was tested. Responses to a high potassium buffer (100 mM) and phenylephrine (10–6 M) were obtained in the absence and presence of the inhibitors. In group six (n=6), the effect of 17-ODYA (3x10–7–3x10–6 M), an inhibitor of the cytochrome P450 pathway, on myogenic tone was studied. The efficacy of this compound was tested in group seven (n=6). For this purpose, the response of endothelium-intact arterioles to arachidonic acid was recorded in the presence and absence of 10–6 M 17-ODYA.
2.3 Chemicals and buffer compositions
Mops buffer consisted of (in mM) 145 NaCl, 5 KCl, 2 CaCl2, 1 MgSO4, 1 NaH2PO4, 5 dextrose, 2 pyruvate, 0.02 EDTA and 3 3-(N-morpholino)propanesulfonic acid. Krebs buffer consisted of (in mM) 110 NaCl, 5 KCl, 2.5 CaCl2, 1 MgSO4, 24 NaHCO3, 1 KH2PO4, 0.02 EDTA and 10 dextrose. It was equilibrated with 5% CO2, 21% O2 and 74% N2 at 33°C. This resulted in a pH of 7.4, a pO2 of 150 mmHg and a pCO2 of 35 mmHg (at 33°C, measured by a blood gas analyzer, ABL-330, from Radiometer, Copenhagen, Denmark). High potassium (Krebs) buffer was obtained by equimolar exchange with NaCl. Hepes buffer consisted of (in mM) 110 NaCl, 5 KCl, 2.5 CaCl2, 1 MgCl2, 5 (N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]), and 10 dextrose. The pH was adjusted to pH 7.4 with NaOH. All salts, Mops and Hepes were of analytical grade and purchased from Merck (Darmstadt, Germany). Vasoactive compounds, inhibitors, Hepes and pyruvate were obtained from Sigma (St. Louis, MO, USA). Acetylcholine and phenylephrine solutions were prepared fresh daily and kept on ice. Staurosporine and calphostin C were dissolved in dimethylsulfoxide (DMSO), final concentration 
0.1%. 17-ODYA was dissolved in ethanol (EtOH); final concentration, 0.03%.
2.4 Statistics
Responses are expressed as diameter change from spontaneous tone. Data are expressed as mean±SEM from n different segments. When two segments were obtained from one animal, each segment was subjected to another group. Statistical analysis was done by a paired or unpaired t-test and the Bonferroni method, as appropriate. Differences were considered to be statistically significant at P<0.05.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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3.1 Vessel characteristics
Passive arteriolar diameters averaged 167±3 µm (n=41). Typically, segments developed spontaneous tone within 10 min after the start of the equilibration period. This resulted in an active diameter of 82±4 µm. Tone was dependent on the type of buffer. Segments developed significantly more tone in Krebs buffer: 78±4 µm (n=32) vs. 97±9 µm in Hepes buffer (n=9; p<0.05).
3.2 Effect of gadolinium on tone
The effect of the lanthanide, gadolinium, was studied in Krebs buffer and in Hepes buffer. Responses were more variable in Hepes buffer, but gadolinium did not significantly affect vascular diameters in either buffer. Concentration–response relations are shown in Fig. 2.
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3.3 Effect of NCDC on tone
The PLC inhibitor NCDC induced a concentration-dependent dilation with an EC50 concentration of 2.9±0.9x10–5 M. At the highest concentration, vessels were fully dilated. In Fig. 3, a typical experiment is shown. Mean data on the effect of NCDC on myogenic tone are shown in Fig. 4a. NCDC did not affect constriction induced by high potassium, but significantly impaired constriction induced by phenylephrine. Results are shown in Fig. 4b.
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3.4 Effects of chelerythrine, staurosporine and calphostin C on tone
The effect of the PKC inhibitor chelerythrine was dependent on the concentration. Lower concentrations showed a tendency to constriction, which was significant at 1 µM. Only the highest concentration induced a dilatory response, eliciting full dilation. This steep concentration–response relation had an EC50 concentration of 6.0±1.0x10–6 M (Fig. 5a). The second PKC inhibitor, staurosporine, did not induce constriction at lower concentrations. A steep concentration–response relation was observed with an EC50 concentration of 3.0±0.4x10–8 M (Fig. 5a). The third PKC inhibitor, calphostin C, also induced a concentration-dependent dilation with an EC50 concentration of 1.4±0.1x10–8 M (Fig. 5a). At an intermediate concentration, calphostin C selectively inhibited phenylephrine-induced constriction. However, at the highest dose, responses to both phenylephrine and high potassium were abolished. Similar results were obtained with the other PKC inhibitors, staurosporine and chelerythrine (Fig. 5b).
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3.5 Effect of 17-ODYA on tone
The control experiments showed that 17-ODYA significantly increases the response to exogenous arachidonic acid. This result suggests that exogenous arachidonic acid is at least partly metabolized by cytochrome P450 enzymes, producing a contractile factor (Fig. 6). However, the cytochrome P450 inhibitor did not reverse myogenic tone. In contrast, a small but significant increase in tone was observed. Results are shown in Fig. 7.
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The present study was designed to investigate signal transduction in spontaneous or myogenic tone in skeletal muscle arterioles. Based on the signal transduction pathway proposed by Meininger and Davis [2]and recent reports on a role for cytochrome P450 metabolites [13, 14], several compounds were used to inhibit steps in the scheme proposed in Fig. 1. To avoid interference of the endothelium, we perfused the segments with 1 ml of air. The absence of a dilatory response to acetylcholine (0.1 µM), a concentration that was previously found to induce half-maximal dilation [20], confirms functional loss of the endothelium. This procedure has been reported to affect pressure–diameter relations, whereas mechanical rubbing did not [21]. However, in isolated cremaster arterioles, endothelium denudation with air did not affect pressure–diameter relations, nor responses to endothelium-independent dilators in normal Wistar rats [16].
4.1 Stretch-activated channels
Stretch-activated channels may play a role in the initiation and/or maintenance of the myogenic response [2]. Gadolinium was found to be effective in a wide range of mechanogated processes at concentrations as used in our study [17]. However, the efficacy of this compound is difficult to verify as no agonist for these channels exists. Using electron microscopy, gadolinium has been shown to diffuse through all layers of rat aorta [22]. Thus, we used this as evidence that gadolinium would reach its site of action at the smooth muscle membrane. In rabbit aortic smooth muscle, gadolinium (0.1 mM) inhibited the transient activation of PLC induced by stretch [4]. In this report, aortic rings were incubated in Krebs buffer. The use of gadolinium in bicarbonate-buffered solutions, however, may affect the inhibitory effect of gadolinium [23]. Using a Hepes buffer, gadolinium (10 µM) was found to inhibit stretch-induced calcium fluxes in pulmonary arterial smooth muscle cells [3]. Therefore, we performed concentration–response relations to gadolinium both in Krebs and Hepes buffer, but found no effect on myogenic tone. Thus, our data do not support a role for gadolinium-sensitive ion channels in the maintenance of myogenic tone in cremaster arterioles.
4.2 Inhibitors of phospholipase C and protein kinase C
The PLC inhibitor NCDC [24–26]induced a complete loss of myogenic tone. It also inhibited phenylephrine-induced, but not potassium-induced, constriction. Given that phenylephrine stimulates PLC [27], these data indicate that the effect of NCDC on myogenic tone results from inhibition of PLC. These results point to an important role for PLC in myogenic tone in skeletal muscle arterioles, as was found in rat cerebral- [8]and dog renal arteries [9]. The PLC-derived second messengers, IP3 and DAG, release Ca2+ from intracellular stores and activate PKC, respectively. During sustained activation, PLC uses phophatidylcholine as substrate, resulting in the production of DAG only [28]. Activation of PKC by DAG may induce constriction without increasing cytosolic Ca2+ [28]. Pharmacological tools, like staurosporine and chelerythrine, can be used to study the role of PKC in constriction. We observed a steep concentration–response relation to both inhibitors, with a complete loss of myogenic tone at concentrations of 10–7 and 10–5 M, respectively. However, staurosporine and some other PKC inhibitors are known to be rather non-specific [28]. Chelerythrine is specific for PKC compared to other protein kinases [18], but this compound may interact with cyclic nucleotide phosphodiesterases [29]. Therefore, we also used calphostin C, an inhibitor of PKC that acts on the binding site for DAG [19]. A concentration-dependent dilation was observed, with a complete loss of myogenic tone at 10–7 M calphostin C. Taken together, these results indicate that PKC is essential in myogenic tone, consistent with reports on myogenic tone in rat cerebral arteries [11], arteries from rat gracilis muscle [6]and human coronary arteries [11]. PKC inhibitors were also found to inhibit myogenic responses in third order cremaster arterioles (15–25 µm) in vivo [10]. In our experiments, the PKC inhibitor calphostin C selectively impaired constriction induced by phenylephrine at an intermediate concentration of the inhibitor. However, at the highest concentration of calphostin C, responses to both phenylephrine and high potassium were abolished, as was the case with staurosporine and chelerythrine. In general, phenylephrine-induced constriction is associated with PKC activation, whereas high potassium-induced constriction is not [30]. Therefore, the inhibition of high potassium-induced constriction by calphostin C was unexpected. However, similar results have been described with PKC inhibitors in cerebral arteries [12]. These results appear to indicate that calphostin C has nonspecific actions at higher doses, but it could also be speculated that PKC activity is involved in high potassium-induced constriction also. A recent study on arterioles from gracilis muscle showed that PKC inhibitors abolish myogenic tone, but do not inhibit the increase in cytosolic Ca2+ induced by pressure [6]. The rise in cytosolic Ca2+ is abolished by nifedipine. Thus, these authors conclude that PKC activity is required to couple the cytosolic Ca2+ increase with actual smooth muscle contraction. In this perspective, it is not surprising that PKC inhibitors were found to impair phenylephrine as well as potassium-induced constriction. Taken together, these data indicate that PKC is essential in all of the contractile mechanisms relevant in this study.
4.3 Cytochrome P450 enzymes
Recently, evidence has been provided for a role of cytochrome P450-derived metabolites of arachidonic acid in myogenic tone in rat renal and cat cerebral microcirculation [13, 14]. Arachidonic acid may be derived from the breakdown of DAG by DAG lipase [28]and other pathways. Cytochrome P450 enzymes may convert arachidonic acid to 20-HETE, a potent inhibitor of Ca2+-activated K+ channels. These channels are activated by depolarization and calcium, and may provide a feedback mechanism in myogenic tone [31]. The compound 17-ODYA is an inhibitor of 20-HETE formation, in the concentration range we used in this study [14].
Evidence for a role of cytochrome P450 in the cremaster muscle is provided by a study by Harder et al. [32]. Homogenates of cremaster muscle were found to produce 20-HETE when incubated with arachidonic acid. Furthermore, 20-HETE constricts third order arterioles in vivo [32]. The formation of 20-HETE was found to be oxygen-dependent and inhibited by 17-ODYA. Thus, cytochrome P450 enzymes are present in cremaster muscle and play a role in the regulation of arteriolar diameter. Our control experiments using 17-ODYA showed that dilation induced by arachidonic acid is increased in the presence of this inhibitor. Thus, these results indicate that arachidonic acid is metabolized by cytochrome P450 enzymes in our preparation, possibly resulting in the formation of 20-HETE. The formation of this contractile factor is inhibited by 17-ODYA. However, using a similar concentration of 17-ODYA, we found no evidence for a role of P450-derived contractile factors in the maintenance of myogenic tone in first order arterioles.
In conclusion, in arterioles from cremaster muscle, the maintenance of spontaneous myogenic tone is not dependent on gadolinium-sensitive, stretch-activated cation channels. These data do not exclude a role for depolarization and activation of VOCs in myogenic tone. Inhibition of VOCs with felodipine (10–8 M) inhibited myogenic tone by 43±6% in our preparation (n=3; data not shown). In cremaster arterioles, myogenic tone resembles 1-adrenergic constriction as it is highly dependent on phospholipase C and protein kinase C. Furthermore, we found no evidence for a role of cytochrome P450 metabolites in myogenic tone in this arteriole.
Time for primary review 31 days.
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G. Lagaud, N. Gaudreault, E. D. W. Moore, C. van Breemen, and I. Laher Pressure-dependent myogenic constriction of cerebral arteries occurs independently of voltage-dependent activation Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2187 - H2195. [Abstract] [Full Text] [PDF]
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Y. P. R. Jarajapu and H. J. Knot Role of phospholipase C in development of myogenic tone in rat posterior cerebral arteries Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2234 - H2238. [Abstract] [Full Text] [PDF]
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R. Schubert, V. U. Kalentchuk, and U. Krien Rho kinase inhibition partly weakens myogenic reactivity in rat small arteries by changing calcium sensitivity Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2288 - H2295. [Abstract] [Full Text] [PDF]
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V. V. Matchkov, O. S. Tarasova, M. J. Mulvany, and H. Nilsson Myogenic response of rat femoral small arteries in relation to wall structure and [Ca2+]i Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H118 - H125. [Abstract] [Full Text] [PDF]
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X. Wu and M. J. Davis Characterization of stretch-activated cation current in coronary smooth muscle cells Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1751 - H1761. [Abstract] [Full Text] [PDF]
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 Z. Ungvari and A. Koller Endothelin and Prostaglandin H2/Thromboxane A2 Enhance Myogenic Constriction in Hypertension by Increasing Ca2+ Sensitivity of Arteriolar Smooth Muscle Hypertension, November 1, 2000; 36(5): 856 - 861. [Abstract] [Full Text] [PDF]
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C. Dessy, N. Matsuda, J. Hulvershorn, C. L. Sougnez, F. W. Sellke, and K. G. Morgan Evidence for involvement of the PKC-alpha isoform in myogenic contractions of the coronary microcirculation Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H916 - H923. [Abstract] [Full Text] [PDF]
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E. N. T. P. Bakker, E. T. van der Meulen, J. A. E. Spaan, and E. VanBavel Organoid culture of cannulated rat resistance arteries: effect of serum factors on vasoactivity and remodeling Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1233 - H1240. [Abstract] [Full Text] [PDF]
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