Skip to main content
SpringerLink
Log in

Different vasoactive effects of chronic endothelial and neuronal NO-synthase inhibition in young Wistar rats

  • Original Paper
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

While the unequivocal pattern of endothelial nitric oxide synthase (eNOS) inhibition in cardiovascular control is recognized, the role of NO produced by neuronal NOS (nNOS) remains unclear. The aim of this study was to compare the effects of chronic treatment with 7-nitroindazole (7-NI, nNOS inhibitor) and NG-nitro-l-arginine methylester (l-NAME, general and predominantly eNOS inhibitor) on cardiovascular system of young normotensive rats. Wistar rats (4 weeks old) were used: controls and rats administered either 7-NI (10 mg/kg bw/day) or l-NAME (50 mg/kg bw/day) in drinking water for 6 weeks. The systolic blood pressure (sBP) was measured by plethysmographic method, and the vasoactivity of isolated arteries was recorded. 7-NI-treatment did not affect sBP; however, the sBP was increased after l-NAME-treatment. l-NAME inhibited acetylcholine-induced relaxation of thoracic aorta (TA), whereas it remained unchanged after 7-NI-treatment. The response of TA to sodium nitroprusside was increased in both experimental groups. The expression of eNOS and nNOS in TA was unchanged in both experimental groups, whereas the activity of NOS was decreased in l-NAME-treated group. Noradrenaline- and angiotensin II-induced contractions of TA were reduced in l-NAME-treated group; however, the contractions remained unchanged in 7-NI-treated group. In all groups, the endogenous angiotensin II participated in adrenergic contraction of TA; this contribution was significantly increased in l-NAME-treated group. Neurogenic contractions in mesenteric artery (MA) remained unchanged after 7-NI-treatment, but increased after l-NAME-treatment. Results show that NO deficiency induced by administration of 7-NI and l-NAME had different cardiovascular effects: eNOS and nNOS triggered distinct signaling pathways in young normotensive rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Aleixandre A, Lopez-Miranda V, Ortega A (2001) Alpha-vascular responses after short-term and long-term inhibition of nitric oxide synthesis. J Cardiovasc Pharmacol 37:133–142

    Article  PubMed  CAS  Google Scholar 

  2. Ayajiki K, Fujioka H, Okamura T, Toda N (2001) Relatively selective neuronal nitric oxide synthase inhibition by 7-nitroindazole in monkey isolated cerebral arteries. Eur J Pharmacol 423:179–183

    Article  PubMed  CAS  Google Scholar 

  3. Benyo Z, Lacza Z, Hortobagyi T, Gorlach C, Wahl M (2000) Functional importance of neuronal nitric oxide synthase in the endothelium of rat basilar arteries. Brain Res 877:79–84

    Article  PubMed  CAS  Google Scholar 

  4. Bernatova I, Pechanova O, Babal P, Kysela S, Stvrtina S, Andriantsitohaina R (2002) Wine polyphenos improve cardiovascular remodeling and vascular function in NO-deficient hypertension. Am J Physiol 282:942–948

    Google Scholar 

  5. Cacanyiova S, Kristek F, Gerova M, Krenek P, Klimas J (2009) Effect of chronic nNOS inhibition on blood pressure, vasoactivity, and arterial wall structure in Wistar rats. Nitric Oxide 20:304–310

    Article  PubMed  CAS  Google Scholar 

  6. Charbit M, Blazy I, Gogusev J, Pouzet B, Brocart D, Sachs C, Dechaux M (1997) Nitric oxide and the renin angiotensin system: contributions to blood pressure in the young rat. Pediatr Nephrol 11:617–622

    Article  PubMed  CAS  Google Scholar 

  7. De Gennaro Colonna V, Fioretti S, Rigamonti A, Bonomo S, Manfredi B, Muller EE, Berti F et al (2006) Angiotensin II type 1 receptor antagonism improves endothelial vasodilator function in L-NAME-induced hypertensive rats by a kinin-dependent mechanism. J Hypertens 24:95–102

    Article  PubMed  Google Scholar 

  8. De Toledo Durand M, Castania JA, Fazan R Jr, Salgado MCO, Salgado HC (2011) Hemodynamic responses to aortic depressor nerve stimulation in conscious L-NAME-induced hypertensive rats. Am J Physiol 300:418–427

    Google Scholar 

  9. Dos Santos FM, Martins Dias DP, da Silva CA, Fazan R Jr, Salgado HC (2010) Sympathetic activity is not increased in L-NAME hypertensive rats. Am J Physiol 298:89–95

    Google Scholar 

  10. Dowell FJ, Henrion D, Duriez M, Michel JB (1996) Vascular reactivity in mesenteric resistance arteries following chronic nitric oxide synthase inhibition in Wistar rats. Br J Pharmacol 117:341–346

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Eshima K, Hirooka Y, Shigematsu H, Matsuo L, Koike G, Sakai K, Takeshita A (2000) Angiotensin in the nucleus tractus solitarii contributes to neurogenic hypertension caused by chronic nitric oxide synthase inhibition. Hypertension 36:259–263

    Article  PubMed  CAS  Google Scholar 

  12. Fitch RM, Rutledge JC, Wang YX, Powers AF, Tseng JL, Clary T, Rubanyi GM (2005) Synergistic effect of angiotensin II and aortic nitric oxide synthase inhibitor in increasing aortic stiffness in mice. Am J Physiol 290:1190–1198

    Google Scholar 

  13. Förstermann U, Nakane M, Tracey WR, Pollock JS (1993) Isoforms of nitric oxide synthase: Functions in the cardiovascular system. Eur Heart J 14(Suppl I):10–15

    PubMed  Google Scholar 

  14. Gao Y, Zhou H, Raj JU (1995) Endothelium-derived nitric oxide plays a larger role in pulmonary veins than in arteries of newborn lambs. Circ Res 76:559–565

    Article  PubMed  CAS  Google Scholar 

  15. Henrion D, Dowell FJ, Levy BI, Michel JB (1996) In vitro alteration of aortic vascular reactivity in hypertension induced by chronic N-nitro-L-arginine methyl ester. Hypertens 28:361–366

    Article  CAS  Google Scholar 

  16. Kalliovalkama J, Jolma P, Tolvanen JP, Kahonen M, Hutri-Kahonen N, Wu X, Holm P et al (1999) Arterial function in nitric oxide-deficient hypertension: Influence of long-term angiotensin II receptor antagonism. Cardiovasc Res 42:773–782

    Article  PubMed  CAS  Google Scholar 

  17. Kopincova J, Puzserova A, Bernatova I (2002) L-NAME in the cardiovascular system–nitric oxide synthase activator? Pharmacol Rep 64:511–520

    Article  Google Scholar 

  18. Kristek F, Cacanyiova S, Gerova M (2009) Hypotrophic effect of long-term neuronal NO-synthase inhibition on heart and conduit arteries of the Wistar rats. J Physiol Pharmacol 60:21–27

    PubMed  CAS  Google Scholar 

  19. Kristek F, Gerova M, Devat L, Varga I (1996) Remodelling of septal branch of coronary artery and carotid artery in L-NAME treated rats. Physiol Res 45:329–333

    PubMed  CAS  Google Scholar 

  20. Kristek F, Gerova M (2004) Hypotrophy of conduit artery walls of the offspring of nitric oxide-defective rats. Braz J Med Biol Res 37:601–606

    Article  PubMed  CAS  Google Scholar 

  21. Kristek F (2000) Pentaerythrityl tetranitrate attenuates structural changes in conduit arteries evoked by long-term NO-synthase inhibition. Br J Pharmacol 130:450–456

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Kubota Y, Umegaki K, Kagota S, Tanaka N, Nakamura K, Kunimoto M, Shinozuka K (2006) Evaluation of bood pressure measured by tail-cuff methods (without heating) in spontaneously hypertensive rats. Biol Pharm Bull 29:1756–1758

    Article  PubMed  CAS  Google Scholar 

  23. Kung CF, Moreau P, Takase H, Luscher TF (1995) L-NAME hypertension alters endothelial and smooth muscle function in rat aorta: prevention by trandolapril and verapamil. Hypertension 26:744–751

    Article  PubMed  CAS  Google Scholar 

  24. Li JS, Schiffrin EL (1994) Resistance artery structure and neuroeffector mechanisms in hypertension induced by inhibition of nitric oxide synthase. Am J Hypertens 7:996–1004

    PubMed  CAS  Google Scholar 

  25. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  26. Lopez RM, Ortiz CS, Ruiz A, Velez JM, Castillo C, Castillo EF (2004) Impairment of smooth muscle function of rat thoracic aorta in anendothelium-independent manner by long-term administration of N(G)-nitro-L-arginine methyl ester. Fundam Clin Pharmacol 18:669–677

    Article  PubMed  CAS  Google Scholar 

  27. Moore PK, Wallace P, Gaffen Z, Hart SL, Babbedge RC (1993) Characterisation of the novel nitric oxide synthase inhibitor 7-nitro indazole and related indazoles: Antinociceptive and cardiovascular effects. Br J Pharmacol 110:219–224

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Morton JJ, Beattie EC, Speirs A, Gulliver F (1993) Persistent hypertension following inhibition of nitric oxide formation in the young Wistar rat: Role of renin and vascular hypertrophy. Hypertens 11:1083–1088

    Article  CAS  Google Scholar 

  29. Nakmareong S, Kukongviriyapan U, Pakdeechote P, Kukongviriyapan V, Kongyingyoes B, Donpunha W, Prachaney P et al (2012) Tetrahydrocurcumin alleviates hypertension, aortic stiffening and oxidative stress in rats with nitric oxide deficiency. Hypertens Res 35:418–425

    Article  PubMed  CAS  Google Scholar 

  30. Ollerstam A, Pittner J, Persson EG, Thorup C (1997) Increased blood pressure in rats after long-term inhibition of the neuronal isoform of nitric oxide synthase. J Clin Invest 99:2212–2218

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Paulis L, Becker ST, Lucht K, Schwengel K, Slavic S, Kaschina E, Thone-Reineke C et al (2012) Direct angiotensin II type 2 receptor stimulation in Nω-nito-L-arginine-methyl ester-induced hypertension: the effect on pulse wave velocity and aortic remodelling. Hypertens 59:485–492

    Article  CAS  Google Scholar 

  32. Pechanova O, Bernatova I, Babal P, Martinez MC, Kysela S, Stvrtina S, Andriantsitohaina R (2004) Red wine polyphenols prevent cardiovascular alterations in L-NAME-induced hypertension. J Hypertens 22:1551–1559

    Article  PubMed  CAS  Google Scholar 

  33. Ribeiro MO, Antunes E, DeNucci G, Lovisolo SM, Zatz R (1992) Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension 20:298–303

    Article  PubMed  CAS  Google Scholar 

  34. Ruiz-Marcos FM, Ortiz MC, Fortepiani LA, Nadal FJ, Atucha NM, Garcia-Estao J (2001) Mechanisms of the increased pressor response to vasopressor in the mesenteric bed of nitric oxide-deficient hypertensive rats. Eur J Pharmacol 412:273–279

    Article  PubMed  CAS  Google Scholar 

  35. Scrogin KE, Hatton DC, Chi Y, Luft FC (1998) Chronic nitric oxide inhibition with L-NAME: Effects on autonomic control of the cardiovascular system. Am J Physiol 274:367–37

    Google Scholar 

  36. Torok J, Kristek F (2001) Functional and morphological pattern of vascular responses in two models of experimental hypertension. Exp Clin Cardiol 6:142–148

    PubMed  CAS  PubMed Central  Google Scholar 

  37. Torok J, Gerova M (1997) Developmental dynamics of endothelial and neurogenic control of canine thoracic aorta. Mech Ageing Dev 95:143–152

    Article  PubMed  CAS  Google Scholar 

  38. Wangensteen R, Sainz J, Rodriguez-Gomez I, Moreno JM, Alvarez-Guerra M, Osuna A, Vargas F (2006) Effects of chronic treatment with 7-nitroindazole in hyperthyroid rats. Am J Physiol 291:1376–1382

    Google Scholar 

  39. Wangensteen R, Sainz J, Rodriguez-Gomez I, Moreno JM, Osuna A, Vargas F (2003) Chronic blockade of neuronal nitric oxide synthase does not affect long-term control of blood pressure in normal, saline-drinking or deoxycorticosterone-treated rats. Exp Physiol 88:243–250

    Article  PubMed  CAS  Google Scholar 

  40. Yoneyama T, Ohkawa S, Watanabe T, Odamaki M, Kumagai H, Kimura M, Hishida A (1998) The contribution of nitric oxide to renal vascular wall thickening in rats with L-NAME-induced hypertension. Virchows Arch 433:549–557

    Article  PubMed  CAS  Google Scholar 

  41. Zagvazdin Y, Sancesario G, Wang XY, Share L, Fitzgerald MEC, Reiner A (1996) Evidence from its cardiovascular effects that 7-nitroindazole may inhibit endothelial nitric oxide synthase in vivo. Eur J Pharmacol 303:61–69

    Article  PubMed  CAS  Google Scholar 

  42. Zicha J, Kunes J (1999) Ontogenetic aspects of hypertension development: Analysis in the Rat. Physiol Rev 79:1227–1282

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants VEGA 2/0074/14, 2/0067/14, 1/0981/12 and by Ministry of Health of the Slovak Republic under the project registration number 2012/51-SAV-1. We thank L. Kosnacova for her technical assistance.

Author information

Authors and Affiliations

  1. Institute of Normal and Pathological Physiology, Centre of Excellence for Examination of Regulatory Role of Nitric Oxide in Civilization Diseases, Slovak Academy of Sciences, Bratislava, Slovak Republic

    Sona Cacanyiova, Andrea Berenyiova, Magdalena Malekova, Frantisek Kristek, Ima Dovinova & Ivana Pifkova

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Odbojárov 1, 832 32, Bratislava, Slovak Republic

    Peter Krenek & Lenka Pivackova

Authors
  1. Sona Cacanyiova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea Berenyiova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Magdalena Malekova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frantisek Kristek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ima Dovinova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Krenek
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lenka Pivackova
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ivana Pifkova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sona Cacanyiova.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cacanyiova, S., Berenyiova, A., Malekova, M. et al. Different vasoactive effects of chronic endothelial and neuronal NO-synthase inhibition in young Wistar rats. J Physiol Biochem 70, 749–760 (2014). https://doi.org/10.1007/s13105-014-0343-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-014-0343-2

Keywords

Search

Navigation