Abstract
The aim of this work was to study the influence of aging, obesity, metabolic syndrome (MS), hypertension (HT), and type 2 diabetes (T2D) on the endogenous rhythmic activity and the development acetylcholine resistance in aorta rings of male rats. T2D was produced by a free access to fat (lard). It was shown that phenylephrine (PE) or 5-hydroxytryptamine (5-HT) induces two types of rhythmic contractions: with periods T 1 = 3–10 s and T 2 = 50–70 s and amplitudes A 1 = 1–5% and A 2 = 20–40% of the maximal contraction force (F max), respectively. Such periodic modes can be caused by the operation of two known positive feedback loops (PFL) based on the Ca2+-induced activation of IP3 receptor (IP3R) or phospholipase C PFL1 and PFL2, respectively, and are not eliminated by L-NAME. Slow rhythmic activity induced by acetylcholine (Ach) with period T 3 = 7–20 min and amplitude A 3 = 20–30% of F max was observed only in young animals (under 6 months) and can be determined by the operation of PFL3, involving Ca2+, NO, kinase G, cADP-ribose, and the ryanodine receptor (RyR). Fast mode of contractions (T 1, A 1) is maintained regardless of age and the presence of MS and HT (140 mm Hg and higher) and disappears only at later stages of the T2D development. Probability of intermediate mode of contractions (T 2, A 2) decreases to 0.20–0.25 at the age of 14–16 months or during the development of HT and MS. In these circumstances, Ach could cause relaxation of preconstricted rings only to 40 and 60% of F max, respectively. At the stages of the T2D development characterized by high values of arterial pressure (above 150 mm Hg) and of the glucose (10–12 mM), ammonium (120–180 μM), and blood lipid levels, as well as by liver dysfunction (fibrosis/cirrhosis), the rhythmic activity of any type is lost and dysfunction of the initial part of the signaling cascade with the participation of PFL3 is manifested by the absence of responses to Ach or L-NAME. Coenzyme NAD (agonist of the P2Y receptors, К+ channel activator and a precursor of cADP-ribose) can exert a partial relaxation of aorta rings from healthy animals and animals with MS. Nicotinamide (product and an inhibitor of ADP-ribosyl cyclase) and SNP (donor of NO) produce an effective relaxation of aorta rings from healthy animals and animals with T2D. Relaxing effect of nicotinamide may suggest a tandem operation of IP3R and RyR in the control of intracellular Ca2+ stores in vascular cells.
Similar content being viewed by others
Abbreviations
- MS:
-
metabolic syndrome
- T2D:
-
type 2 diabetes
- HT:
-
vascular hypertension
- BP:
-
arterial blood pressure
- Ach:
-
acetylcholine
- PE:
-
phenylephrine
- 5-HT:
-
5-hydroxytryptamine
- CD38:
-
ADP-ribosyl cyclase
- NAM:
-
nicotinamide
- L-NAME:
-
an inhibitor of the endothelial NO-synthase
References
Kobayashi T., Taguchi K., Nemoto S., Nogami T., Matsumoto T., Kamata K. 2009. Activation of the PDK-1/Akt/eNOS pathway involved in aortic endothelial function differs between hyperinsulinemic and insulin-deficient diabetic rats. Am. J. Physiol. Heart Circ. Physiol. 297 (5), H1767–H1775.
Ishida K., Matsumoto T., Taguchi K., Kamata K., Kobayashi T. 2013. Mechanisms underlying reduced P2Y(1)-receptor-mediated relaxation in superior mesenteric arteries from long-term streptozotocin-induced diabetic rats. Acta Physiol. (Oxf). 207 (1), 130–141.
Potenza M.A., Marasciulo F.L., Chieppa D.M., Brigiani G.S., Formoso G., Quon M.J., Montagnani M. 2005. Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production. Am. J. Physiol. Heart Circ. Physiol. 289 (2), H813–H822.
Andreeva L.A., Nakipova O.V., Sergeev A.I., Rykov V.A., Chemeris N.K., Dynnik V.V. 2013. Dysregulation of No/cGMP/cADPr/Ca2+ signaling pathway in the vessels and the myocardium of spontaneously hypertensive rats. Basic Research. 6, 1397–1401.
Ishida K., Taguchi K., Matsumoto T., Kobayashi T. 2014. Activated platelets from diabetic rats cause endothelial dysfunction by decreasing Akt/endothelial NOsynthase signaling pathway. PLoS One. 9 (7), e102310.
Ravier M.A., Sehlin J., Henquin J.C. 2002. Disorganization of cytoplasmic Ca2+ oscillations and pulsatile insulin secretion in islets from ob/ob mice. Diabetologia. 45 (8), 1154–1163.
Hellman B., Gylfe E., Grapengiesser E., Dansk H., Salehi A. 2007. Insulin oscillations–clinically important rhythm. Antidiabetics should increase the pulsative component of the insulin release. Lakartidningen. 104 (32–33), 2236–2239.
Lefer D.J., Lynch C.D., Lapinski K.C., Hutchins P.M. 1990. Enhanced vasomotion of cerebral arterioles in spontaneously hypertensive rats. Microvasc. Res. 39, 129–139.
Nilsson H., Aalkjaer C. 2003. Vasomotion: Mechanisms and physiological importance. Mol. Interv. 2, 79–89.
Tikhonova I.V., Tankanag A.V., Chemeris N.K. 2010. Age-related features in the amplitude dynamics of the skin blood flow oscillations during post-occlusive reactive hyperemia. Human Physiology. 2, 114–120.
Jacob R., Merritt J.E., Hallam T.J., Rink T.J. 1988. Repetitive spikes in cytoplasmic calcium evoked by histamine in human endothelial cells. Nature. 335 (6185), 40–45.
Rooney T.A., Sass E.J., Thomas A.P. 1989. Characterization of cytosolic calcium oscillations induced by phenylephrine and vasopressin in single fura-2-loaded hepatocytes. J. Biol. Chem. 264 (29), 17131–17141.
Akata T., Kodama K., Takahashi S. 1995. Role of endothelium in oscillatory contractile responses to various receptor agonists in isolated small mesenteric and epicardial coronary arteries. Jpn. J. Pharmacol. 68 (3), 331–343.
Willmott N., Sethi J.K., Walseth T.F., Lee H.C., White A.M., Galione A. 1996. Nitric oxide-induced mobilization of intracellular calcium via the cyclic ADP-ribose signaling pathway. J. Biol. Chem. 271 (7), 3699–3705.
Prakash Y.S., Kannan M.S., Sieck G.C. 1997. Regulation of intracellular calcium oscillations in porcine tracheal smooth muscle cells. Am. J. Physiol. 272 (3 Pt 1), C966–C975.
White T.A., Kannan M.S., Walseth T.F. 2003. Intracellular calcium signaling through the cADPR pathway is agonist specific in porcine airway smooth muscle. FASEB J. 17 (3), 482–484.
Olson M.L., Sandison M.E., Chalmers S., McCarron J.G. 2012. Microdomains of muscarinic acetylcholine and Ins(1,4,5)P3 receptors create 'Ins(1,4,5)P3 junctions' and sites of Ca2+ wave initiation in smooth muscle. J. Cell Sci. 125, 5315–5328.
Berridge M.J., Galione A. 1988. Cytosolic calcium oscillators. FASEB J. 2 (15), 3074–3082.
Thomas A.P., Bird G.S., Hajnóczky G., Robb-Gaspers L.D., Putney J.W. 1996. Spatial and temporal aspects of cellular calcium signaling. FASEB J. 10 (13), 1505–1517.
Gilon P., Henquin J.C. 2001. Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function. Endocr. Rev. 22 (5), 565–604.
Sergeev A.I., Sirota N.P., Turovsky E.A., Dynnik V.V. 2013. Dysregulation of Ca2+ signaling systems in white adipocytes of rodents with obesity and type 2 diabetes. Fundamental’nye issledovania (Rus.). 6 (6), 1436–1441.
Islam M.Z., Watanabe Y., Nguyen H.T., Yamazaki-Himeno E., Obi T., Shiraishi M., Miyamoto A. 2014. Vasomotor effects of acetylcholine, bradykinin, noradrenaline, 5-hydroxytryptamine, histamine and angiotensin II on the mouse basilar artery. J. Vet. Med. Sci. 76 (10), 1339–1345.
Moneer Z., Pino I., Taylor E.J., Broad L.M., Liu Y., Tovey S.C., Staali L., Taylor C.W. 2005. Different phospholipase-C-coupled receptors differentially regulate capacitative and non-capacitative Ca2+ entry in A7r5 cells. Biochem. J. 389 (Pt 3), 821–829.
Burns D.M., Ruddock M.W., Walker M.D. 1999. Nicotinamide-inhibited vasoconstriction: Lack of dependence on agonist signalling pathways. Eur. J. Pharmacol. 374 (2), 213–220.
Ge Z.D., Zhang D.X., Chen Y.F., Yi F.X., Zou A.P., Campbell W.B., Li P.L. 2003. Cyclic ADP-ribose contributes to contraction and Ca2+ release by M1 muscarinic receptor activation in coronary arterial smooth muscle. J. Vasc. Res. 40 (1), 28–36.
Ruddock M.W., Hirst D.G. 2004. Nicotinamide relaxes vascular smooth muscle by inhibiting myosin light chain kinase-dependent signaling pathways: Implications for anticancer efficacy. Oncol. Res. 14 (10), 483–489.
Perez-Zoghbi J.F., Bai Y., Sanderson M.J. 2010. Nitric oxide induces airway smooth muscle cell relaxation by decreasing the frequency of agonist-induced Ca2+ oscillations. J. Gen. Physiol. 135 (3), 247–259.
Dimmeler S., Fleming I., Fisslthaler B., Hermann C., Busse R., Zeiher A.M. 1999. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 399 (6736), 601–605.
Bredt D.S., Snyder S.H. 1990. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. USA. 87 (2), 682–685.
Turovsky E.A., Turovskaya M.V., Dolgacheva L.P., Zinchenko V.P., Dynnik V.V. 2013. Acetylcholine promotes Ca2+ and NO oscillations in adipocytes implicating Ca2+ NO cGMP cADP-ribose Ca2+ positive feedback loop–modulatory effects of norepinephrine and atrial natriuretic peptide. PLoS One. 16 (5), e63483.
Archer S.L., Huang J.M., Hampl V., Nelson D.P., Shultz P.J., Weir E.K. 1994. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxinsensitive K channel by cGMP-dependent protein kinase. Proc. Natl. Acad. Sci. USA. 91 (16), 7583–7587.
Tertyshnikova S., Yan X., Fein A. 1998. cGMP inhibits IP3-induced Ca2+ release in intact rat megakaryocytes via cGMP- and cAMP-dependent protein kinases. J. Physiol. 512 (1), 89–96.
Huang J., Zhou H., Mahavadi S., Sriwai W., Murthy K.S. 2007. Inhibition of Galphaq-dependent PLC-beta1 activity by PKG and PKA is mediated by phosphorylation of RGS4 and GRK2. Am. J. Physiol. Cell Physiol. 292 (1), 200–208.
Colyer J. 1998. Phosphorylation states of phospholamban. Ann. NY Acad. Sci. 853, 79–91.
Yoshida Y., Sun H.T., Cai J.Q., Imai S. 1991. Cyclic GMP-dependent protein kinase stimulates the plasma membrane Ca2+ pump ATPase of vascular smooth muscle via phosphorylation of a 240-kDa protein. J. Biol. Chem. 266 (29), 19819–19825.
Koitabashi N., Aiba T., Hesketh G.G., Rowell J., Zhang M., Takimoto E., Tomaselli G.F., Kass D.A. 2010. Cyclic GMP/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation. Novel mechanism of cardiac stress modulation by PDE5 inhibition. J. Mol. Cell Cardiol. 48 (4), 713–724.
Palacios J., Vega J.L., Paredes A., Cifuentes F. 2013. Effect of phenylephrine and endothelium on vasomotion in rat aorta involves potassium uptake. J. Physiol. Sci. 63 (2), 103–111.
Mutafova-Yambolieva V.N., Hwang S.J., Hao X., Chen H., Zhu M.X., Wood J.D., Ward S.M., Sanders K.M. 1991. ß-Nicotinamide adenine dinucleotide is an inhibitory neurotransmitter in visceral smooth muscle. Proc. Natl. Acad. Sci. USA. 104 (41), 16359–16364.
Klein C., Grahnert A., Abdelrahman A., Müller C.E., Hauschildt S. 2009. Extracellular NAD+ induces a rise in [Ca2+]i in activated human monocytes via engagement of P2Y(1) and P2Y(11) receptors. Cell Calcium. 46 (4), 263–272.
Hwang S.J., Durnin L., Dwyer L, Dwyer L., Rhee P.L., Ward S.M., Koh S.D., Sanders K.M., Mutafova-Yambolieva V.N. 2011. ß-Nicotinamide adenine dinucleotide is an enteric inhibitory neurotransmitter in human and nonhuman primate colons. Gastroenterology. 140 (2), 608–617.
Kilfoil P.J., Tipparaju S.M., Barski O.A., Bhatnagar A. 2013. Regulation of ion channels by pyridine nucleotides. Circ. Res. 112 (4), 721–741.
Zinchenko V.P., Turovsky E.A., Turovskaya M.V., Berezhnov A.V., Dynnik V.V. 2015. NAD selectively inhibits hyperactivity of calbindin-expressing interneurons induced by NH4Cl. In: Receptors and intracellular signaling. Zinchenko V.P. and Berezhnov A.V., Eds. Pushchino: Fix-Print, vol. 1, p. 252–258.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © L.A. Andreeva, E.V. Grishina, A.I. Sergeev, A.V. Lobanov, G.A. Slastcheva, V.A. Rykov, A.V. Temyakov, V.V. Dynnik, 2016, published in Biologicheskie Membrany, 2016, Vol. 33, No. 3, pp. 213–222.
Rights and permissions
About this article
Cite this article
Andreeva, L.A., Grishina, E.V., Sergeev, A.I. et al. Emergence of acetylcholine resistance and loss of rhythmic activity associated with the development of hypertension, obesity, and type 2 diabetes. Biochem. Moscow Suppl. Ser. A 10, 199–206 (2016). https://doi.org/10.1134/S1990747816020033
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1990747816020033