K ATP channels and NO dilate redundantly intramuscular arterioles during electrical stimulation of the skeletal muscle in mice.

Publisher: Springer Country of Publication: Germany NLM ID: 0154720 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-2013 (Electronic) Linking ISSN: 00316768 NLM ISO Abbreviation: Pflugers Arch Subsets: MEDLINE

Original Publication: Berlin, New York, Springer.

Adenosine Triphosphate/*metabolism ; Arterioles/*metabolism ; KATP Channels/*metabolism ; Muscle, Skeletal/*metabolism ; Nitric Oxide/*metabolism; Acetylcholine/pharmacology ; Adenosine/metabolism ; Animals ; Arterioles/drug effects ; Dilatation/methods ; Electric Stimulation/methods ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Contraction/drug effects ; Muscle Contraction/physiology ; Muscle, Skeletal/drug effects ; Prostaglandins/metabolism ; Vasodilation/drug effects ; Vasodilation/physiology

Functional hyperemia is fundamental to provide enhanced oxygen delivery during exercise in skeletal muscle. Different mechanisms are suggested to contribute, mediators from skeletal muscle, transmitter spillover from the neuromuscular synapse as well as endothelium-related dilators. We hypothesized that redundant mechanisms that invoke adenosine, endothelial autacoids, and K ATP channels mediate the dilation of intramuscular arterioles in mice. Arterioles (maximal diameter: 20-42 µm, n = 65) were studied in the cremaster by intravital microscopy during electrical stimulation of the motor nerve to induce twitch or tetanic skeletal muscle contractions (10 or 100 Hz). Stimulation for 1-60 s dilated arterioles rapidly up to 65% of dilator capacity. Blockade of nicotinergic receptors blocked muscle contraction and arteriolar dilation. Exclusive blockade of adenosine receptors (1,3-dipropyl-8-(p-sulfophenyl)xanthine) or of NO and prostaglandins (nitro-L-arginine and indomethacin, LN + Indo) exerted only a minor attenuation. Combination of these blockers, however, reduced the dilation by roughly one-third during longer stimulation periods (> 1 s at 100 Hz). Blockade of K ATP channels (glibenclamide) which strongly reduced adenosine-induced dilation reduced responses upon electrical stimulation only moderately. The attenuation was strongly enhanced if glibenclamide was combined with LN + Indo and even observed during brief stimulation. LN was more efficient than indomethacin to abrogate dilations if combined with glibenclamide. Arteriolar dilations induced by electrical stimulation of motor nerves require muscular contractions and are not elicited by acetylcholine spillover from neuromuscular synapses. The dilations are mediated by redundant mechanisms, mainly activation of K ATP channels and release of NO. The contribution of K ⁺ channels and hyperpolarization sets the stage for ascending dilations that are crucial for a coordinated response in the network.
(© 2021. The Author(s).)

Armstrong ML, Dua AK, Murrant CL (2007) Time course of vasodilation at the onset of repetitive skeletal muscle contractions. Am J Physiol Regul Integr Comp Physiol 292:R505–R515. https://doi.org/10.1152/ajpregu.00381.2006. (PMID: 10.1152/ajpregu.00381.200616931651)
Brähler S, Kaistha A, Schmidt VJ, Wölfle SE, Busch C, Kaistha BP, Kacik M, Hasenau AL, Grgic I, Si H, Bond CT, Adelman JP, Wulff H, de Wit C, Hoyer J, Köhler R (2009) Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension. Circulation 119:2323–2332. https://doi.org/10.1161/CIRCULATIONAHA.108.846634. (PMID: 10.1161/CIRCULATIONAHA.108.84663419380617)
Cohen KD, Sarelius IH (2002) Muscle contraction under capillaries in hamster muscle induces arteriolar dilatation via K(ATP) channels and nitric oxide. J Physiol 539:547–555. https://doi.org/10.1113/jphysiol.2001.013388. (PMID: 10.1113/jphysiol.2001.013388118826862290146)
Copp SW, Hirai DM, Hageman KS, Poole DC, Musch TI (2010) Nitric oxide synthase inhibition during treadmill exercise reveals fiber-type specific vascular control in the rat hindlimb. Am J Physiol Regul Integr Comp Physiol 298:R478–R485. https://doi.org/10.1152/ajpregu.00631.2009. (PMID: 10.1152/ajpregu.00631.200920007515)
Danialou G, Vicaut E, Sambe A, Aubier M, Boczkowski J (1997) Predominant role of A(1) adenosine receptors in mediating adenosine induced vasodilatation of rat diaphragmatic arterioles: Involvement of nitric oxide and the ATP-dependent K ⁺ channels. Br J Pharmacol 121:1355–1363. https://doi.org/10.1038/sj.bjp.0701247. (PMID: 10.1038/sj.bjp.070124792579141564813)
de Wit C (2004) Connexins pave the way for vascular communication. News Physiol Sci 19:148–153. https://doi.org/10.1152/nips.01520.2004. (PMID: 10.1152/nips.01520.200415143212)
de Wit C (2010) Different pathways with distinct properties conduct dilations in the microcirculation in vivo. Cardiovasc Res 85:604–613. https://doi.org/10.1093/cvr/cvp340. (PMID: 10.1093/cvr/cvp34019820254)
Dua AK, Dua N, Murrant CL (2009) Skeletal muscle contraction-induced vasodilator complement production is dependent on stimulus and contraction frequency. Am J Physiol Heart Circ Physiol 297:H433–H442. https://doi.org/10.1152/ajpheart.00216.2009. (PMID: 10.1152/ajpheart.00216.200919465553)
Duncker DJ, Bache RJ (2008) Regulation of coronary blood flow during exercise. Physiol Rev 88:1009–1086. https://doi.org/10.1152/physrev.00045.2006. (PMID: 10.1152/physrev.00045.200618626066)
Duza T, Sarelius IH (2003) Conducted dilations initiated by purines in arterioles are endothelium dependent and require endothelial Ca ²⁺ . Am J Physiol Heart Circ Physiol 285:H26–H37. https://doi.org/10.1152/ajpheart.00788.2002. (PMID: 10.1152/ajpheart.00788.200212637357)
Hein TW, Kuo L (1999) cAMP-independent dilation of coronary arterioles to adenosine - role of nitric oxide, G proteins, and K-ATP channels. Circ Res 85:634–642. https://doi.org/10.1161/01.res.85.7.634. (PMID: 10.1161/01.res.85.7.63410506488)
Hein TW, Wang W, Zoghi B, Muthuchamy M, Kuo L (2001) Functional and molecular characterization of receptor subtypes mediating coronary microvascular dilation to adenosine. J Mol Cell Cardiol 33:271–282. https://doi.org/10.1006/jmcc.2000.1298. (PMID: 10.1006/jmcc.2000.129811162132)
Hein TW, Xu W, Ren Y, Kuo L (2013) Cellular signalling pathways mediating dilation of porcine pial arterioles to adenosine A(2)A receptor activation. Cardiovasc Res 99:156–163. https://doi.org/10.1093/cvr/cvt072. (PMID: 10.1093/cvr/cvt072235395023687749)
Heinonen I, Saltin B, Hellsten Y, Kalliokoski KK (2017) The effect of nitric oxide synthase inhibition with and without inhibition of prostaglandins on blood flow in different human skeletal muscles. Eur J Appl Physiol 117:1175–1180. https://doi.org/10.1007/s00421-017-3604-2. (PMID: 10.1007/s00421-017-3604-228432421)
Hester RL, Eraslan A, Saito Y (1993) Differences in EDNO contribution to arteriolar diameters at rest and during functional dilation in striated muscle. Am J Physiol 265:H146–H151. https://doi.org/10.1152/ajpheart.1993.265.1.H146. (PMID: 10.1152/ajpheart.1993.265.1.H1468342626)
Jackson WF (1993) Arteriolar tone is determined by activity of ATP-sensitive potassium channels. Am J Physiol 265:H1797–H1803. https://doi.org/10.1152/ajpheart.1993.265.5.H1797. (PMID: 10.1152/ajpheart.1993.265.5.H17978238593)
Jobs A, Schmidt K, Schmidt VJ, Lubkemeier I, van Veen TAB, Kurtz A, Willecke K, de Wit C (2012) Defective Cx40 maintains Cx37 expression but intact Cx40 is crucial for conducted dilations irrespective of hypertension. Hypertension 60:1422–1429. https://doi.org/10.1161/HYPERTENSIONAHA.112.201194. (PMID: 10.1161/HYPERTENSIONAHA.112.20119423090768)
Kleppisch T, Nelson MT (1995) Adenosine activates ATP-sensitive potassium channels in arterial myocytes via A(2) receptors and cAMP-dependent protein kinase. Proc Natl Acad Sci U S A 92:12441–12445. https://doi.org/10.1073/pnas.92.26.12441. (PMID: 10.1073/pnas.92.26.12441861891740373)
Koller A, Bagi Z (2002) On the role of mechanosensitive mechanisms eliciting reactive hyperemia. Am J Physiol Heart Circ Physiol 283:H2250–H2259. https://doi.org/10.1152/ajpheart.00545.2002. (PMID: 10.1152/ajpheart.00545.200212427591)
Lamb IR, Novielli NM, Murrant CL (2018) Capillary response to skeletal muscle contraction: evidence that redundancy between vasodilators is physiologically relevant during active hyperaemia. J Physiol 596:1357–1372. https://doi.org/10.1113/JP275467. (PMID: 10.1113/JP275467294175895899980)
Lau KS, Grange RW, Isotani E, Sarelius IH, Kamm KE, Huang PL, Stull JT (2000) nNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle. Physiol Genomics 2:21–27. https://doi.org/10.1152/physiolgenomics.2000.2.1.21. (PMID: 10.1152/physiolgenomics.2000.2.1.2111015578)
Laughlin MH, Davis MJ, Secher NH, van Lieshout JJ, Arce-Esquivel AA, Simmons GH, Bender SB, Padilla J, Bache RJ, Merkus D, Duncker DJ (2012) Peripheral circulation Compr Physiol 2:321–447. https://doi.org/10.1002/cphy.c100048. (PMID: 10.1002/cphy.c10004823728977)
Maekawa K, Saito D, Obayashi N, Uchida S, Haraoka S (1994) Role of endothelium-derived nitric oxide and adenosine in functional myocardial hyperemia. Am J Physiol 267:H166–H173. https://doi.org/10.1152/ajpheart.1994.267.1.H166. (PMID: 10.1152/ajpheart.1994.267.1.H1668048581)
Marshall JM (2007) The roles of adenosine and related substances in exercise hyperaemia. J Physiol 583:835–845. https://doi.org/10.1113/jphysiol.2007.136416. (PMID: 10.1113/jphysiol.2007.136416176151002277189)
Merkus D, Haitsma DB, Fung TY, Assen YJ, Verdouw PD, Duncker DJ (2003) Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways. Am J Physiol Heart Circ Physiol 285:H424–H433. https://doi.org/10.1152/ajpheart.00916.2002. (PMID: 10.1152/ajpheart.00916.200212637354)
Milkau M, Köhler R, de Wit C (2010) Crucial importance of the endothelial K ⁺ channel SK3 and connexin40 in arteriolar dilations during skeletal muscle contraction. FASEB J 24:3572–3579. https://doi.org/10.1096/fj.10-158956. (PMID: 10.1096/fj.10-15895620427707)
Mishra RC, Belke D, Wulff H, Braun AP (2013) SKA-31, a novel activator of SKCa and IKCa channels, increases coronary flow in male and female rat hearts. Cardiovasc Res 97:339–348. https://doi.org/10.1093/cvr/cvs326. (PMID: 10.1093/cvr/cvs32623118129)
Mortensen SP, Gonzalez-Alonso J, Damsgaard R, Saltin B, Hellsten Y (2007) Inhibition of nitric oxide and prostaglandins, but not endothelial-derived hyperpolarizing factors, reduces blood flow and aerobic energy turnover in the exercising human leg. J Physiol 581:853–861. https://doi.org/10.1113/jphysiol.2006.127423. (PMID: 10.1113/jphysiol.2006.127423173472732075180)
Murrant CL, Dodd JD, Foster AJ, Inch KA, Muckle FR, Ruiz DA, Simpson JA, Scholl JHP (2014) Prostaglandins induce vasodilatation of the microvasculature during muscle contraction and induce vasodilatation independent of adenosine. J Physiol 592:1267–1281. https://doi.org/10.1113/jphysiol.2013.264259. (PMID: 10.1113/jphysiol.2013.264259244690743961086)
Murrant CL, Sarelius IH (2002) Multiple dilator pathways in skeletal muscle contraction-induced arteriolar dilations. Am J Physiol Regul Integr Comp Physiol 282:R969–R978. https://doi.org/10.1152/ajpregu.00405.2001. (PMID: 10.1152/ajpregu.00405.200111893599)
Murrant CL, Sarelius IH (2015) Local control of blood flow during active hyperaemia: what kinds of integration are important? J Physiol 593:4699–4711. https://doi.org/10.1113/JP270205. (PMID: 10.1113/JP270205263143914626542)
Mutafova-Yambolieva VN, Keef KD (1997) Adenosine-induced hyperpolarization in guinea pig coronary artery involves A(2b) receptors and K-ATP channels. Am J Physiol 273:H2687–H2695. https://doi.org/10.1152/ajpheart.1997.273.6.H2687. (PMID: 10.1152/ajpheart.1997.273.6.H26879435605)
Philp A, Macdonald AL, Watt PW (2005) Lactate - a signal coordinating cell and systemic function. J Exp Biol 208:4561–4575. https://doi.org/10.1242/jeb.01961. (PMID: 10.1242/jeb.0196116326938)
Pohl U, Holtz J, Busse R, Bassenge E (1986) Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension 8:37–44. https://doi.org/10.1161/01.hyp.8.1.37. (PMID: 10.1161/01.hyp.8.1.373080370)
Poucher SM, Nowell CG, Collis MG (1990) The role of adenosine in exercise hyperaemia of the gracilis muscle in anaesthetized cats. J Physiol 427:19–29. https://doi.org/10.1113/jphysiol.1990.sp018158. (PMID: 10.1113/jphysiol.1990.sp01815822135961189917)
Proctor KG (1984) Reduction of contraction-induced arteriolar vasodilation by adenosine deaminase or theophylline. Am J Physiol 247:H195–H205. https://doi.org/10.1152/ajpheart.1984.247.2.H195. (PMID: 10.1152/ajpheart.1984.247.2.H1956465328)
Radtke J, Schmidt K, Wulff H, Köhler R, de Wit C (2013) Activation of KCa3.1 by SKA-31 induces arteriolar dilation and lowers blood pressure in normo- and hypertensive connexin40-deficient mice. Br J Pharmacol 170:293–303. https://doi.org/10.1111/bph.12267. (PMID: 10.1111/bph.12267237346973834754)
Randall MD (1995) The involvement of ATP-sensitive potassium channels and adenosine in the regulation of coronary flow in the isolated perfused rat heart. Br J Pharmacol 116:3068–3074. https://doi.org/10.1111/j.1476-5381.1995.tb15965.x. (PMID: 10.1111/j.1476-5381.1995.tb15965.x86807451909199)
Rhoden A, Speiser J, Geertz B, Uebeler J, Schmidt K, de Wit C, Eschenhagen T (2019) Preserved cardiovascular homeostasis despite blunted acetylcholine-induced dilation in mice with endothelial muscarinic M3 receptor deletion. Acta Physiol (Oxf) 226:e13262. https://doi.org/10.1111/apha.13262. (PMID: 10.1111/apha.13262)
Rosendal L, Blangsted AK, Kristiansen J, Sogaard K, Langberg H, Sjogaard G, Kjaer M (2004) Interstitial muscle lactate, pyruvate and potassium dynamics in the trapezius muscle during repetitive low-force arm movements, measured with microdialysis. Acta Physiol Scand 182:379–388. https://doi.org/10.1111/j.1365-201X.2004.01356.x. (PMID: 10.1111/j.1365-201X.2004.01356.x15569099)
Saito Y, Eraslan A, Hester RL (1994) Role of EDRFs in the control of arteriolar diameter during increased metabolism of striated muscle. Am J Physiol 267:H195–H200. https://doi.org/10.1152/ajpheart.1994.267.1.H195. (PMID: 10.1152/ajpheart.1994.267.1.H1958048585)
Saito Y, Eraslan A, Hester RL (1994) Role of endothelium-derived relaxing factors in arteriolar dilation during muscle contraction elicited by electrical field stimulation. Microcirculation 1:195–201. https://doi.org/10.3109/10739689409148274. (PMID: 10.3109/107396894091482748790590)
Sarelius I, Pohl U (2010) Control of muscle blood flow during exercise: local factors and integrative mechanisms. Acta Physiol (Oxf) 199:349–365. https://doi.org/10.1111/j.1748-1716.2010.02129.x. (PMID: 10.1111/j.1748-1716.2010.02129.x)
Segal SS (2005) Regulation of blood flow in the microcirculation. Microcirculation 12:33–45. https://doi.org/10.1080/10739680590895028. (PMID: 10.1080/1073968059089502815804972)
Si H, Heyken WT, Wölfle SE, Tysiac M, Schubert R, Grgic I, Vilianovich L, Giebing G, Maier T, Gross V, Bader M, de Wit C, Hoyer J, Köhler R (2006) Impaired endothelium-derived hyperpolarizing factor-mediated dilations and increased blood pressure in mice deficient of the intermediate-conductance Ca ²⁺ -activated K ⁺ channel. Circ Res 99:537–544. https://doi.org/10.1161/01.RES.0000238377.08219.0c. (PMID: 10.1161/01.RES.0000238377.08219.0c16873714)
Sun D, Huang A, Kaley G (2004) Mechanical compression elicits NO-dependent increases in coronary flow. Am J Physiol Heart Circ Physiol 287:H2454–H2460. https://doi.org/10.1152/ajpheart.00364.2004. (PMID: 10.1152/ajpheart.00364.200415308477)
Welsh DG, Segal SS (1997) Coactivation of resistance vessels and muscle fibers with acetylcholine release from motor nerves. Am J Physiol 273:H156–H163. https://doi.org/10.1152/ajpheart.1997.273.1.H156. (PMID: 10.1152/ajpheart.1997.273.1.H1569249486)
Wölfle SE, de Wit C (2005) Intact endothelium-dependent dilation and conducted responses in resistance vessels of hypercholesterolemic mice in vivo. J Vasc Res 42:475–482. https://doi.org/10.1159/000088101. (PMID: 10.1159/00008810116155363)
Wölfle SE, Schmidt VJ, Hoyer J, Köhler R, de Wit C (2009) Prominent role of KCa3.1 in endothelium-derived hyperpolarizing factor-type dilations and conducted responses in the microcirculation in vivo. Cardiovasc Res 82:476–483. https://doi.org/10.1093/cvr/cvp060. (PMID: 10.1093/cvr/cvp06019218287)

Keywords: Active hyperemia; Adenosine; Endothelial autacoids; Glibenclamide; KATP channels

0 (KATP Channels)
0 (Prostaglandins)
31C4KY9ESH (Nitric Oxide)
8L70Q75FXE (Adenosine Triphosphate)
K72T3FS567 (Adenosine)
N9YNS0M02X (Acetylcholine)

Date Created: 20210813 Date Completed: 20220307 Latest Revision: 20220307

20240829

PMC8528760

10.1007/s00424-021-02607-1

34386847