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Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries

  • Muscle physiology
  • Published:
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Abstract

Arterial hypertension (AHT) affects the voltage dependency of L-type Ca2+ channels in cardiomyocytes. We analyzed the effect of angiotensin II (AngII)-induced AHT on L-type Ca2+ channel-mediated isometric contractions in conduit arteries. AHT was induced in C57Bl6 mice with AngII-filled osmotic mini-pumps (4 weeks). Normotensive mice treated with saline-filled osmotic mini-pumps were used for comparison. Voltage-dependent contractions mediated by L-type Ca2+ channels were studied in vaso-reactive studies in vitro in isolated aortic and femoral arteries by using extracellular K+ concentration-response (KDR) experiments. In aortic segments, AngII-induced AHT significantly sensitized isometric contractions induced by elevated extracellular K+ and depolarization. This sensitization was partly prevented by normalizing blood pressure with hydralazine, suggesting that it was caused by AHT rather than by direct AngII effects on aortic smooth muscle cells. The EC50 for extracellular K+ obtained in vitro correlated significantly with the rise in arterial blood pressure induced by AngII in vivo. The AHT-induced sensitization persisted when aortic segments were exposed to levcromakalim or to inhibitors of basal nitric oxide release. Consistent with these observations, AngII-treatment also sensitized the vaso-relaxing effects of the L-type Ca2+ channel blocker diltiazem during K+-induced contractions. Unlike aorta, AngII-treatment desensitized the isometric contractions to depolarization in femoral arteries pointing to vascular bed specific responses of arteries to hypertension. AHT affects the voltage-dependent L-type Ca2+ channel-mediated contraction of conduit arteries. This effect may contribute to the decreased vascular compliance in AHT and explain the efficacy of Ca2+ channel blockers to reduce vascular stiffness and central blood pressure in AHT.

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Abbreviations

AHT:

Arterial hypertension

AngII:

Angiotensin II

KDR:

Extracellular K+ concentration-response

(V)SMC:

(Vascular) smooth muscle cell

BP:

Blood pressure

L-NAME:

N Ω-nitro-l-arginine methyl ester

NO:

Nitric oxide

E max :

Maximum contraction or relaxation

EC50 or log IC50 :

Concentration (log concentration) exerting 50 % of the maximal response

References

  1. Bellien J, Favre J, Iacob M, Gao J, Thuillez C, Richard V, Joannides R (2010) Arterial stiffness is regulated by nitric oxide and endothelium-derived hyperpolarizing factor during changes in blood flow in humans. Hypertension 55:674–680

    Article  PubMed  CAS  Google Scholar 

  2. Bratz IN, Falcon R, Partridge LD, Kanagy NL (2002) Vascular smooth muscle cell membrane depolarization after NOS inhibition hypertension. Am J Physiol Heart Circ Physiol 282:H1648–H1655

    Article  PubMed  CAS  Google Scholar 

  3. Choi H, Allahdadi KJ, Tostes RC, Webb RC (2011) Augmented S-nitrosylation contributes to impaired relaxation in angiotensin II hypertensive mouse aorta: role of thioredoxin reductase. J Hypertens 29:2359–2368

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Cox RH, Fromme S (2015) Expression of calcium channel subunit variants in small mesenteric arteries of WKY and SHR. Am J Hypertens. doi:10.1093/ajh/hpv024

    PubMed  Google Scholar 

  5. Crauwels HM, Van Hove CE, Herman AG, Bult H (2000) Heterogeneity in relaxation mechanisms in the carotid and the femoral artery of the mouse. Eur J Pharmacol 404:341–351

    Article  PubMed  CAS  Google Scholar 

  6. Dal-Ros S, Bronner C, Schott C, Kane MO, Chataigneau M, Schini-Kerth VB, Chataigneau T (2009) Angiotensin II-induced hypertension is associated with a selective inhibition of endothelium-derived hyperpolarizing factor-mediated responses in the rat mesenteric artery. J Pharmacol Exp Ther 328:478–486

    Article  PubMed  CAS  Google Scholar 

  7. Fransen P, Van Hove CE, van Langen J, Schrijvers DM, Martinet W, De Meyer GR, Bult H (2012) Contribution of transient and sustained calcium influx, and sensitization to depolarization-induced contractions of the intact mouse aorta. BMC Physiol 12:9. doi:10.1186/1472-6793-12-9-

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Fransen P, Van Hove C, van Langen J, Bult H (2012) Contraction by Ca2+ influx via the L-type Ca2+ channel voltage window in mouse aortic segments is modulated by nitric oxide. In: Sugi H (ed) Current basic and pathological approaches to the function of muscle cells and tissues—from molecules to humans. Rijeka, Croatia: Intech (www.intech.com) 69–92

  9. Hermsmeyer K, Rusch NJ (1989) Calcium channel alterations in genetic hypertension. Hypertension 14:453–456

    Article  PubMed  CAS  Google Scholar 

  10. Hofmann F, Flockerzi V, Kahl S, Wegener JW (2014) L-type CaV1.2 calcium channels: from in vitro findings to in vivo function. Physiol Rev 94:303–326

  11. Kanagy NL (1997) Increased vascular responsiveness to alpha 2-adrenergic stimulation during NOS inhibition-induced hypertension. Am J Physiol 273:H2756–H2764

    PubMed  CAS  Google Scholar 

  12. Kanaide H, Ichiki T, Nishimura J, Hirano K (2003) Cellular mechanism of vasoconstriction induced by angiotensin II: it remains to be determined. Circ Res 93:1015–1017

    Article  PubMed  CAS  Google Scholar 

  13. Kane MO, Etienne-Selloum N, Madeira SV, Sarr M, Walter A, Dal-Ros S, Schott C, Chataigneau T, Schini-Kerth VB (2010) Endothelium-derived contracting factors mediate the Ang II-induced endothelial dysfunction in the rat aorta: preventive effect of red wine polyphenols. Pflugers Arch 459:671–679

    Article  PubMed  CAS  Google Scholar 

  14. Kisters K, Wessels F, Kuper H, Tokmak F, Krefting ER, Gremmler B, Kosch M, Barenbrock M, Hausberg M (2004) Increased calcium and decreased magnesium concentrations and an increased calcium/magnesium ratio in spontaneously hypertensive rats versus Wistar-Kyoto rats: relation to arteriosclerosis. Am J Hypertens 17:59–62

    Article  PubMed  CAS  Google Scholar 

  15. Knot HJ, Nelson MT (1998) Regulation of arterial diameter and wall [Ca2+] in cerebral arteries of rat by membrane potential and intravascular pressure. J Physiol 508(Pt 1):199–209

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Koch WJ, Ellinor PT, Schwartz A (1990) cDNA cloning of a dihydropyridine-sensitive calcium channel from rat aorta. Evidence for the existence of alternatively spliced forms. J Biol Chem 265:17786–17791

    PubMed  CAS  Google Scholar 

  17. Koumaras C, Tzimou M, Stavrinou E, Griva T, Gossios TD, Katsiki N, Athyros VG, Mikhailidis DP, Karagiannis A (2012) Role of antihypertensive drugs in arterial ‘de-stiffening’ and central pulsatile hemodynamics. Am J Cardiovasc Drugs 12:143–156

    Article  PubMed  CAS  Google Scholar 

  18. Liao P, Yu D, Li G, Yong TF, Soon JL, Chua YL, Soong TW (2007) A smooth muscle Cav1.2 calcium channel splice variant underlies hyperpolarized window current and enhanced state-dependent inhibition by nifedipine. J Biol Chem 282:35133–35142

    Article  PubMed  CAS  Google Scholar 

  19. Liao P, Yu D, Lu S, Tang Z, Liang MC, Zeng S, Lin W, Soong TW (2004) Smooth muscle-selective alternatively spliced exon generates functional variation in Cav1.2 calcium channels. J Biol Chem 279:50329–50335

    Article  PubMed  CAS  Google Scholar 

  20. Mahmud A, Feely J (2004) Arterial stiffness and the renin-angiotensin-aldosterone system. J Renin-Angiotensin-Aldosterone Syst 5:102–108

    Article  PubMed  CAS  Google Scholar 

  21. McFarlane SI, Kumar A, Sowers JR (2003) Mechanisms by which angiotensin-converting enzyme inhibitors prevent diabetes and cardiovascular disease. Am J Cardiol 91:30H–37H

    Article  PubMed  CAS  Google Scholar 

  22. Moosmang S, Schulla V, Welling A, Feil R, Feil S, Wegener JW, Hofmann F, Klugbauer N (2003) Dominant role of smooth muscle L-type calcium channel Cav1.2 for blood pressure regulation. EMBO J 22:6027–6034

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Nakashima H, Suzuki H, Ohtsu H, Chao JY, Utsunomiya H, Frank GD, Eguchi S (2006) Angiotensin II regulates vascular and endothelial dysfunction: recent topics of angiotensin II type-1 receptor signaling in the vasculature. Curr Vasc Pharmacol 4:67–78

    Article  PubMed  CAS  Google Scholar 

  24. Navedo MF, Nieves-Cintron M, Amberg GC, Yuan C, Votaw VS, Lederer WJ, McKnight GS, Santana LF (2008) AKAP150 is required for stuttering persistent Ca2+ sparklets and angiotensin II-induced hypertension. Circ Res 102:e1–e11

    Article  PubMed  CAS  Google Scholar 

  25. Ohya Y, Tsuchihashi T, Kagiyama S, Abe I, Fujishima M (1998) Single L-type calcium channels in smooth muscle cells from resistance arteries of spontaneously hypertensive rats. Hypertension 31:1125–1129

    Article  PubMed  CAS  Google Scholar 

  26. Rusch NJ, Hermsmeyer K (1988) Calcium currents are altered in the vascular muscle cell membrane of spontaneously hypertensive rats. Circ Res 63:997–1002

    Article  PubMed  CAS  Google Scholar 

  27. Safar M, Chamiot-Clerc P, Dagher G, Renaud JF (2001) Pulse pressure, endothelium function, and arterial stiffness in spontaneously hypertensive rats. Hypertension 38:1416–1421

    Article  PubMed  CAS  Google Scholar 

  28. Swafford AN Jr, Harrison-Bernard LM, Dick GM (2007) Knockout mice reveal that the angiotensin II type 1B receptor links to smooth muscle contraction. Am J Hypertens 20:335–337

    Article  PubMed  CAS  Google Scholar 

  29. Tang ZZ, Hong X, Wang J, Soong TW (2007) Signature combinatorial splicing profiles of rat cardiac- and smooth-muscle Cav1.2 channels with distinct biophysical properties. Cell Calcium 41:417–428

    Article  PubMed  CAS  Google Scholar 

  30. Tang ZZ, Liao P, Li G, Jiang FL, Yu D, Hong X, Yong TF, Tan G, Lu S, Wang J, Soong TW (2008) Differential splicing patterns of L-type calcium channel Cav1.2 subunit in hearts of Spontaneously Hypertensive Rats and Wistar Kyoto Rats. Biochim Biophys Acta 1783:118–130

    Article  PubMed  CAS  Google Scholar 

  31. Tiwari S, Zhang Y, Heller J, Abernethy DR, Soldatov NM (2006) Atherosclerosis-related molecular alteration of the human Cav1.2 calcium channel alpha1C subunit. Proc Natl Acad Sci U S A 103:17024–17029

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Ushio-Fukai M, Yamamoto H, Toyofuku K, Nishimura J, Hirano K, Kanaide H (2000) Changes in the cytosolic Ca2+ concentration and Ca(2+)-sensitivity of the contractile apparatus during angiotensin II-induced desensitization in the rabbit femoral artery. Br J Pharmacol 129:425–436

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Van Hove CE, Van der Donckt C, Herman AG, Bult H, Fransen P (2009) Vasodilator efficacy of nitric oxide depends on mechanisms of intracellular calcium mobilization in mouse aortic smooth muscle cells. Br J Pharmacol 158:920–930

    Article  PubMed  PubMed Central  Google Scholar 

  34. van Langen J, Fransen P, Van Hove CE, Schrijvers DM, Martinet W, De Meyer GR, Bult H (2012) Selective loss of basal but not receptor-stimulated relaxation by endothelial nitric oxide synthase after isolation of the mouse aorta. Eur J Pharmacol 696:111–119

    Article  PubMed  Google Scholar 

  35. Virdis A, Neves MF, Amiri F, Touyz RM, Schiffrin EL (2004) Role of NAD(P)H oxidase on vascular alterations in angiotensin II-infused mice. J Hypertens 22:535–542

    Article  PubMed  CAS  Google Scholar 

  36. Wang D, Chabrashvili T, Borrego L, Aslam S, Umans JG (2006) Angiotensin II infusion alters vascular function in mouse resistance vessels: roles of O and endothelium. J Vasc Res 43:109–119

    Article  PubMed  CAS  Google Scholar 

  37. Wang W, Pang L, Palade P (2011) Angiotensin II upregulates Ca(V)1.2 protein expression in cultured arteries via endothelial H(2)O(2) production. J Vasc Res 48:67–78

    Article  PubMed  CAS  Google Scholar 

  38. Wang WZ, Saada N, Dai B, Pang L, Palade P (2006) Vascular-specific increase in exon 1B-encoded CAV1.2 channels in spontaneously hypertensive rats. Am J Hypertens 19:823–831

    Article  PubMed  CAS  Google Scholar 

  39. Wang J, Thio SS, Yang SS, Yu D, Yu CY, Wong YP, Liao P, Li S, Soong TW (2011) Splice variant specific modulation of CaV1.2 calcium channel by galectin-1 regulates arterial constriction. Circ Res 109:1250–1258

    Article  PubMed  CAS  Google Scholar 

  40. Wellman GC, Cartin L, Eckman DM, Stevenson AS, Saundry CM, Lederer WJ, Nelson MT (2001) Membrane depolarization, elevated Ca(2+) entry, and gene expression in cerebral arteries of hypertensive rats. Am J Physiol Heart Circ Physiol 281:H2559–H2567

    PubMed  CAS  Google Scholar 

  41. Wynne BM, Chiao CW, Webb RC (2009) Vascular smooth muscle cell signaling mechanisms for contraction to angiotensin II and endothelin-1. J Am Soc Hypertens 3:84–95

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wynne BM, Labazi H, Tostes RC, Webb RC (2012) Aorta from angiotensin II hypertensive mice exhibit preserved nitroxyl anion mediated relaxation responses. Pharmacol Res 65:41–47

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Zhou Y, Chen Y, Dirksen WP, Morris M, Periasamy M (2003) AT1b receptor predominantly mediates contractions in major mouse blood vessels. Circ Res 93:1089–1094

    Article  PubMed  CAS  Google Scholar 

  44. Zhou Y, Dirksen WP, Babu GJ, Periasamy M (2003) Differential vasoconstrictions induced by angiotensin II: role of AT1 and AT2 receptors in isolated C57BL/6J mouse blood vessels. Am J Physiol Heart Circ Physiol 285:H2797–H2803

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We acknowledge the support by the University of Antwerp (grant 29887, GOA-BOF 2407) and the Fund for Scientific Research (FWO) Flanders (grant G.0293.10N). Tail-cuff blood pressure measurements were performed by Mrs. Annie Van Weert.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Physiopharmacology, Campus Drie Eiken, University of Antwerp, T2, Universiteitsplein 1, 2610, Antwerp, Belgium

    Paul Fransen, Arthur J. A. Leloup, Dorien M. Schrijvers, Guido R. Y. De Meyer & Gilles W. De Keulenaer

  2. Faculty of Medicine & Health Sciences, Pharmacology, Campus Drie Eiken, University of Antwerp, T2, Universiteitsplein 1, 2610, Antwerp, Belgium

    Cor E. Van Hove

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  1. Paul Fransen
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  2. Cor E. Van Hove
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  5. Guido R. Y. De Meyer
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  6. Gilles W. De Keulenaer
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Correspondence to Paul Fransen.

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There are no conflicts of interest and other sources of funding unlike these mentioned under acknowledgments. All research involving animals were approved by the Ethical Committee of the University of Antwerp, and the investigations conform to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

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Fransen, P., Van Hove, C.E., Leloup, A.J.A. et al. Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries. Pflugers Arch - Eur J Physiol 468, 257–267 (2016). https://doi.org/10.1007/s00424-015-1737-x

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