pH changes can influence local blood flow, but the mechanisms of how acids and bases affect vascular tone is not fully clarified. Transient receptor potential vanilloid-1 (TRPV1) channels are expressed in vessels and can be activated by pH alterations. Thus, we hypothesized that TRPV1 channels are involved in the mediation of vascular responses to acid-base changes. Vasomotor responses to HCl, NaOH, and capsaicin were measured in isolated murine carotid and tail skin arteries. The function of TRPV1 was blocked by either of three approaches: Trpv1 gene disruption, pharmacological blockade with a TRPV1 antagonist (BCTC), and functional impairment of mainly neural TRPV1 channels (desensitization). In each artery type of control mice, HCl caused relaxation but NaOH contraction, and both responses were augmented after genetic or pharmacological TRPV1 blockade. In arteries of TRPV1-desensitized mice, HCl-induced relaxation did not differ from controls, whereas NaOH-induced contraction was augmented. All three types of TRPV1 blockade had more pronounced effects in carotid than in tail skin arteries. We conclude that TRPV1 channels limit the vasomotor responses to changes in pH. While base-induced arterial contraction is regulated primarily by neural TRPV1 channels, acid-induced arterial relaxation is modulated by TRPV1 channels located on nonneural vascular structures.

Keywords:
Transient receptor potential vanilloid-1, Capsaicin, Resiniferatoxin, BCTC, pH, Desensitization, Vascular biology
1.
Baretella O, Xu A, Vanhoutte PM: Acidosis prevents and alkalosis augments endothelium-dependent contractions in mouse arteries. Pflugers Arch 2014;466:295-305.
2.
Celotto C, Restini B, Capellini K, Bendhack M, Evora R: Acidosis induces relaxation mediated by nitric oxide and potassium channels in rat thoracic aorta. Eur J Pharmacol 2011;656:88-93.
3.
Balasubramanyan N, Halla TR, Ghanayem NS, Gordon JB: Endothelium-independent and -dependent vasodilation in alkalotic and acidotic piglet lungs. Pediatr Pulmonol 2000;30:241-248.
4.
Kinoshita H, Katusic ZS: Role of potassium channels in relaxations of isolated canine basilar arteries to acidosis. Stroke 1997;28:433-437.
5.
Toda N, Ayajiki K, Enokibori M, Okamura T: Monkey cerebral arterial relaxation caused by hypercapnic acidosis and hypertonic bicarbonate. Am J Physiol Heart Circ Physiol 1993;265:H929-H933.
6.
Ali TY, Broughton Pipkin F, Khan RN: The effect of pH and ion channel modulators on human placental arteries. PLoS One 2014;9:e114405.
7.
Austin C, Wray S: Interactions between Ca2+ and H+ and functional consequences in vascular smooth muscle. Circ Res 2000;86:355-363.
8.
Ludwig MG, Vanek M, Guerini D, Gasser JA, Jones CE, Junker U, Hofstetter H, Wolf RM, Seuwen K: Proton-sensing G-protein-coupled receptors. Nature 2003;425:93-98.
9.
Quinn SJ, Bai M, Brown EM: pH sensing by the calcium-sensing receptor. J Biol Chem 2004;279:37241-37249.
10.
Molliver DC, Immke DC, Fierro L, Pare M, Rice FL, McCleskey EW: ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons. Mol Pain 2005;1:8069-8061.
11.
Alvis A, Milesi V, Rebolledo A, Raingo J, Grassi de Gende A: Influence of calcitonin gene-related peptide release on pH-induced mechanical depression in rat atria. Jpn Heart J 2001;42:507-517.
12.
Franco-Cereceda A, Kallner G, Lundberg JM: Cyclo-oxygenase products released by low pH have capsaicin-like actions on sensory nerves in the isolated guinea pig heart. Cardiovasc Res 1994;28:365-369.
13.
Toth A, Czikora A, Pasztor ET, Dienes B, Bai P, Csernoch L, Rutkai I, Csato V, Manyine IS, Porszasz R, Edes I, Papp Z, Boczan J: Vanilloid receptor-1 (TRPV1) expression and function in the vasculature of the rat. J Histochem Cytochem 2014;62:129-144.
14.
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389:816-824.
15.
Dhaka A, Uzzell V, Dubin AE, Mathur J, Petrus M, Bandell M, Patapoutian A: TRPV1 is activated by both acidic and basic pH. J Neurosci 2009;29:153-158.
16.
Cavanaugh DJ, Chesler AT, Jackson AC, Sigal YM, Yamanaka H, Grant R, O'Donnell D, Nicoll RA, Shah NM, Julius D: Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. J Neurosci 2011;31:5067-5077.
17.
Kark T, Bagi Z, Lizanecz E, Pasztor ET, Erdei N, Czikora A, Papp Z, Edes I, Porszasz R, Toth A: Tissue-specific regulation of microvascular diameter: opposite functional roles of neuronal and smooth muscle located vanilloid receptor-1. Mol Pharmacol 2008;73:1405-1412.
18.
Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED: Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999;400:452-457.
19.
Romanovsky AA, Almeida MC, Garami A, Steiner AA, Norman MH, Morrison SF, Nakamura K, Burmeister JJ, Nucci TB: The transient receptor potential vanilloid-1 channel in thermoregulation: a thermosensor it is not. Pharmacol Rev 2009;61:228-261.
20.
Wong BJ, Fieger SM: Transient receptor potential vanilloid type-1 (TRPV-1) channels contribute to cutaneous thermal hyperaemia in humans. J Physiol 2010;588:4317-4326.
21.
Wong BJ, Fieger SM: Transient receptor potential vanilloid type 1 channels contribute to reflex cutaneous vasodilation in humans. J Appl Physiol 2012;112:2037-2042.
22.
Bolcskei K, Helyes Z, Szabo A, Sandor K, Elekes K, Nemeth J, Almasi R, Pinter E, Petho G, Szolcsanyi J: Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using gene-deficient mice. Pain 2005;117:368-376.
23.
Frassetto LA, Morris RC Jr, Sebastian A: Effect of age on blood acid-base composition in adult humans: role of age-related renal functional decline. Am J Physiol 1996;271:F1114-F1122.
24.
Tareen N, Zadshir A, Martins D, Nagami G, Levine B, Norris KC: Alterations in acid-base homeostasis with aging. J Natl Med Assoc 2004;96:921-925; quiz 925-926.
25.
Elkhair NM, Siegling-Vlitakis C, Radtke E, Willing A, Hartmann H: Age-dependent response of the acid-base parameters (Henderson-Hasselbalch, Stewart) in healthy calves with experimentally induced metabolic acidosis. Berl Munch Tierarztl Wochenschr 2009;122:63-69.
26.
Toffanello ED, Inelmen EM, Imoscopi A, Perissinotto E, Coin A, Miotto F, Donini LM, Cucinotta D, Barbagallo M, Manzato E, Sergi G: Taste loss in hospitalized multimorbid elderly subjects. Clin Interv Aging 2013;8:167-174.
27.
Garami A, Pakai E, Oliveira DL, Steiner AA, Wanner SP, Almeida MC, Lesnikov VA, Gavva NR, Romanovsky AA: Thermoregulatory phenotype of the Trpv1 knockout mouse: thermoeffector dysbalance with hyperkinesis. J Neurosci 2011;31:1721-1733.
28.
Wanner SP, Garami A, Pakai E, Oliveira DL, Gavva NR, Coimbra CC, Romanovsky AA: Aging reverses the role of the transient receptor potential vanilloid-1 channel in systemic inflammation from anti-inflammatory to proinflammatory. Cell Cycle 2012;11:343-349.
29.
Wanner SP, Garami A, Romanovsky AA: Hyperactive when young, hypoactive and overweight when aged: connecting the dots in the story about locomotor activity, body mass, and aging in Trpv1 knockout mice. Aging (Albany NY) 2011;3:450-454.
30.
Vamos Z, Cseplo P, Ivic I, Matics R, Hamar J, Koller A: Age determines the magnitudes of angiotensin II-induced contractions, mRNA, and protein expression of angiotensin type 1 receptors in rat carotid arteries. J Gerontol A Biol Sci Med Sci 2014;69:519-526.
31.
Joannides R, Bellien J, Thuillez C: Clinical methods for the evaluation of endothelial function - a focus on resistance arteries. Fundam Clin Pharmacol 2006;20:311-320.
32.
Pozsgai G, Sandor K, Perkecz A, Szolcsanyi J, Helyes Z, Brain S, Pinter E: Topical acetone treatment induces neurogenic oedema on the sensitized mouse ear: an in vivo study using transient receptor potential vanilloid 1 (TRPV1) receptor knockout mice. Inflamm Res 2007;56:459-467.
33.
Czikora A, Rutkai I, Pasztor ET, Szalai A, Porszasz R, Boczan J, Edes I, Papp Z, Toth A: Different desensitization patterns for sensory and vascular TRPV1 populations in the rat: expression, localization and functional consequences. PLoS One 2013;8:e78184.
34.
Kun J, Helyes Z, Perkecz A, Ban A, Polgar B, Szolcsanyi J, Pinter E: Effect of surgical and chemical sensory denervation on non-neural expression of the transient receptor potential vanilloid 1 (TRPV1) receptors in the rat. J Mol Neurosci 2012;48:795-803.
35.
Szolcsanyi J, Sandor Z: Multisteric TRPV1 nocisensor: a target for analgesics. Trends Pharmacol Sci 2012;33:646-655.
36.
Yang D, Luo Z, Ma S, Wong WT, Ma L, Zhong J, He H, Zhao Z, Cao T, Yan Z: Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension. Cell Metab 2010;12:130-141.
37.
Wang L-H, Luo M, Wang Y, Galligan JJ, Wang DH: Impaired vasodilation in response to perivascular nerve stimulation in mesenteric arteries of TRPV1-null mutant mice. J Hypertens 2006;24:2399-2408.
38.
Toth A, Boczan J, Kedei N, Lizanecz E, Bagi Z, Papp Z, Edes I, Csiba L, Blumberg PM: Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain. Brain Res Mol Brain Res 2005;135:162-168.
39.
Ralevic V, Kendall DA, Randall MD, Zygmunt PM, Movahed P, Hogestatt ED: Vanilloid receptors on capsaicin-sensitive sensory nerves mediate relaxation to methanandamide in the rat isolated mesenteric arterial bed and small mesenteric arteries. Br J Pharmacol 2000;130:1483-1488.
40.
Czikora A, Lizanecz E, Bako P, Rutkai I, Ruzsnavszky F, Magyar J, Porszasz R, Kark T, Facsko A, Papp Z, Edes I, Toth A: Structure-activity relationships of vanilloid receptor agonists for arteriolar TRPV1. Br J Pharmacol 2012;165:1801-1812.
41.
Toda N, Usui H, Nishino N, Fujiwara M: Cardiovascular effects of capsaicin in dogs and rabbits. J Pharmacol Exp Ther 1972;181:512-521.
42.
Toth A, Blumberg PM, Boczan J: Anandamide and the vanilloid receptor (TRPV1). Vitam Horm 2009;81:389-419.
43.
Bubb KJ, Wen H, Panayiotou CM, Finsterbusch M, Khan FJ, Chan MV, Priestley JV, Baker MD, Ahluwalia A: Activation of neuronal transient receptor potential vanilloid 1 channel underlies 20-hydroxyeicosatetraenoic acid-induced vasoactivity: role for protein kinase A. Hypertension 2013;62:426-433.
44.
Donnerer J, Lembeck F: Analysis of the effects of intravenously injected capsaicin in the rat. Naunyn Schmiedebergs Arch Pharmacol 1982;320:54-57.
45.
Petervari E, Garami A, Pakai E, Szekely M: Effects of perineural capsaicin treatment of the abdominal vagus on endotoxin fever and on a non-febrile thermoregulatory event. J Endotoxin Res 2005;11:260-266.
46.
Garami A, Balasko M, Szekely M, Solymar M, Petervari E: Fasting hypometabolism and refeeding hyperphagia in rats: effects of capsaicin desensitization of the abdominal vagus. Eur J Pharmacol 2010;644:61-66.
47.
Somjen GG, Tombaugh GC: pH modulation of neuronal excitability and central nervous system functions; in Kaila K, Ransom BR: pH and Brain Function. New York, Wiley-Liss, 1998, pp 373-393.
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