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. 1996 Aug 15;98(4):899–905. doi: 10.1172/JCI118872

Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery.

M R Tschudi 1, M Barton 1, N A Bersinger 1, P Moreau 1, F Cosentino 1, G Noll 1, T Malinski 1, T F Lüscher 1
PMCID: PMC507503  PMID: 8770860

Abstract

Aging is an important determinant of vascular disease. Endothelium-derived nitric oxide (NO) is protective as a vasodilator and inhibitor of platelet function. This study was designed to directly measure effects of prolonged aging on endotheliai NO release in isolated blood vessels and to delineate differences between the systemic and pulmonary circulation. Aortas and pulmonary arteries from 5-6-mo-old (young), 18-19-mo-old (middle-aged), and 32-33-mo-old (old) normotensive female rats were used. Blood pressure and plasma estradiol-17beta (E2) remained unchanged. In isolated blood vessels, NO release was induced by the receptor-independent agonist calcium ionophore A23187 (10 micromol/liter) and measured in situ on the endothelial surface of vessels using a porphyrinic microsensor. In vessels suspended in organ chambers isometric tension was recorded. In the aorta, the initial rate of NO release and peak NO concentration were reduced in middle-aged and old rats (P < 0.0006 vs. young rats, n = 6). Furthermore, endothelium-dependent relaxations to calcium ionophore and acetylcholine (both 10(-10) - 10(-5) mol/liter) were also reduced in aortas from old as compared with young rats (n = 6, P < 0.05). The initial rate of NO release and peak NO concentration significantly correlated with maximal relaxation to calcium ionophore A23187 (correlation coefficients r - 0.916, P < 0.0018 and r = 0.961, P < 0.0001, respectively, n = 7). In pulmonary arteries, however, the initial rate of NO release as well as peak NO concentration did not decrease with age (n = 6 for each age group, NS). In both blood vessels, the NO release was unaffected by superoxide dismutase in all age groups (n = 6, NS). Thus, aging specifically reduces initial rate and peak concentrations of endothelial NO release from aorta but not pulmonary artery indicating reduced NO production. As arterial pressure did not change with aging, the chronic exposure of the aorta to higher pressure and/or pulsatility than in the pulmonary artery may be the cause. This appears important as NO plays a protective role by preventing vasoconstriction, thrombosis and atherosclerosis.

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Selected References

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  1. Archer S. Measurement of nitric oxide in biological models. FASEB J. 1993 Feb 1;7(2):349–360. doi: 10.1096/fasebj.7.2.8440411. [DOI] [PubMed] [Google Scholar]
  2. Bath P. M., Hassall D. G., Gladwin A. M., Palmer R. M., Martin J. F. Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb. 1991 Mar-Apr;11(2):254–260. doi: 10.1161/01.atv.11.2.254. [DOI] [PubMed] [Google Scholar]
  3. Busse R., Mülsch A. Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett. 1990 Jun 4;265(1-2):133–136. doi: 10.1016/0014-5793(90)80902-u. [DOI] [PubMed] [Google Scholar]
  4. Dinerman J. L., Lowenstein C. J., Snyder S. H. Molecular mechanisms of nitric oxide regulation. Potential relevance to cardiovascular disease. Circ Res. 1993 Aug;73(2):217–222. doi: 10.1161/01.res.73.2.217. [DOI] [PubMed] [Google Scholar]
  5. Dohi Y., Thiel M. A., Bühler F. R., Lüscher T. F. Activation of endothelial L-arginine pathway in resistance arteries. Effect of age and hypertension. Hypertension. 1990 Aug;16(2):170–179. doi: 10.1161/01.hyp.16.2.170. [DOI] [PubMed] [Google Scholar]
  6. Flavahan N. A., Shimokawa H., Vanhoutte P. M. Pertussis toxin inhibits endothelium-dependent relaxations to certain agonists in porcine coronary arteries. J Physiol. 1989 Jan;408:549–560. doi: 10.1113/jphysiol.1989.sp017475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Folkow B., Svanborg A. Physiology of cardiovascular aging. Physiol Rev. 1993 Oct;73(4):725–764. doi: 10.1152/physrev.1993.73.4.725. [DOI] [PubMed] [Google Scholar]
  8. Furchgott R. F., Vanhoutte P. M. Endothelium-derived relaxing and contracting factors. FASEB J. 1989 Jul;3(9):2007–2018. [PubMed] [Google Scholar]
  9. Garg U. C., Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989 May;83(5):1774–1777. doi: 10.1172/JCI114081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hayashi T., Fukuto J. M., Ignarro L. J., Chaudhuri G. Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: implications for atherosclerosis. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11259–11263. doi: 10.1073/pnas.89.23.11259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hogg N., Kalyanaraman B., Joseph J., Struck A., Parthasarathy S. Inhibition of low-density lipoprotein oxidation by nitric oxide. Potential role in atherogenesis. FEBS Lett. 1993 Nov 15;334(2):170–174. doi: 10.1016/0014-5793(93)81706-6. [DOI] [PubMed] [Google Scholar]
  12. Hongo K., Nakagomi T., Kassell N. F., Sasaki T., Lehman M., Vollmer D. G., Tsukahara T., Ogawa H., Torner J. Effects of aging and hypertension on endothelium-dependent vascular relaxation in rat carotid artery. Stroke. 1988 Jul;19(7):892–897. doi: 10.1161/01.str.19.7.892. [DOI] [PubMed] [Google Scholar]
  13. Hynes M. R., Duckles S. P. Effect of increasing age on the endothelium-mediated relaxation of rat blood vessels in vitro. J Pharmacol Exp Ther. 1987 May;241(2):387–392. [PubMed] [Google Scholar]
  14. Ignarro L. J. Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein. Circ Res. 1989 Jul;65(1):1–21. doi: 10.1161/01.res.65.1.1. [DOI] [PubMed] [Google Scholar]
  15. Kiechle F. L., Malinski T. Nitric oxide. Biochemistry, pathophysiology, and detection. Am J Clin Pathol. 1993 Nov;100(5):567–575. doi: 10.1093/ajcp/100.5.567. [DOI] [PubMed] [Google Scholar]
  16. Küng C. F., Lüscher T. F. Different mechanisms of endothelial dysfunction with aging and hypertension in rat aorta. Hypertension. 1995 Feb;25(2):194–200. doi: 10.1161/01.hyp.25.2.194. [DOI] [PubMed] [Google Scholar]
  17. Liao J. K., Zulueta J. J., Yu F. S., Peng H. B., Cote C. G., Hassoun P. M. Regulation of bovine endothelial constitutive nitric oxide synthase by oxygen. J Clin Invest. 1995 Dec;96(6):2661–2666. doi: 10.1172/JCI118332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Malinski T., Radomski M. W., Taha Z., Moncada S. Direct electrochemical measurement of nitric oxide released from human platelets. Biochem Biophys Res Commun. 1993 Jul 30;194(2):960–965. doi: 10.1006/bbrc.1993.1914. [DOI] [PubMed] [Google Scholar]
  19. Malinski T., Taha Z., Grunfeld S., Patton S., Kapturczak M., Tomboulian P. Diffusion of nitric oxide in the aorta wall monitored in situ by porphyrinic microsensors. Biochem Biophys Res Commun. 1993 Jun 30;193(3):1076–1082. doi: 10.1006/bbrc.1993.1735. [DOI] [PubMed] [Google Scholar]
  20. Malinski T., Taha Z. Nitric oxide release from a single cell measured in situ by a porphyrinic-based microsensor. Nature. 1992 Aug 20;358(6388):676–678. doi: 10.1038/358676a0. [DOI] [PubMed] [Google Scholar]
  21. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  22. Moncada S. The 1991 Ulf von Euler Lecture. The L-arginine: nitric oxide pathway. Acta Physiol Scand. 1992 Jul;145(3):201–227. doi: 10.1111/j.1748-1716.1992.tb09359.x. [DOI] [PubMed] [Google Scholar]
  23. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  24. Nohl H. Involvement of free radicals in ageing: a consequence or cause of senescence. Br Med Bull. 1993 Jul;49(3):653–667. doi: 10.1093/oxfordjournals.bmb.a072638. [DOI] [PubMed] [Google Scholar]
  25. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  26. Pautler E. L. The possible role and treatment of deficient microcirculation regulation in age-associated memory impairment. Med Hypotheses. 1994 Jun;42(6):363–366. doi: 10.1016/0306-9877(94)90153-8. [DOI] [PubMed] [Google Scholar]
  27. Radomski M. W., Palmer R. M., Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol. 1987 Nov;92(3):639–646. doi: 10.1111/j.1476-5381.1987.tb11367.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Shaul P. W., Wells L. B. Oxygen modulates nitric oxide production selectively in fetal pulmonary endothelial cells. Am J Respir Cell Mol Biol. 1994 Oct;11(4):432–438. doi: 10.1165/ajrcmb.11.4.7522486. [DOI] [PubMed] [Google Scholar]
  29. Tschudi M. R., Lüscher T. F. Age and hypertension differently affect coronary contractions to endothelin-1, serotonin, and angiotensins. Circulation. 1995 May 1;91(9):2415–2422. doi: 10.1161/01.cir.91.9.2415. [DOI] [PubMed] [Google Scholar]
  30. Tschudi M. R., Mesaros S., Lüscher T. F., Malinski T. Direct in situ measurement of nitric oxide in mesenteric resistance arteries. Increased decomposition by superoxide in hypertension. Hypertension. 1996 Jan;27(1):32–35. doi: 10.1161/01.hyp.27.1.32. [DOI] [PubMed] [Google Scholar]
  31. Vallet B., Winn M. J., Asante N. K., Cain S. M. Influence of oxygen on endothelium-derived relaxing factor/nitric oxide and K(+)-dependent regulation of vascular tone. J Cardiovasc Pharmacol. 1994 Oct;24(4):595–602. doi: 10.1097/00005344-199410000-00010. [DOI] [PubMed] [Google Scholar]
  32. Weiner C. P., Lizasoain I., Baylis S. A., Knowles R. G., Charles I. G., Moncada S. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci U S A. 1994 May 24;91(11):5212–5216. doi: 10.1073/pnas.91.11.5212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zeiher A. M., Drexler H., Saurbier B., Just H. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993 Aug;92(2):652–662. doi: 10.1172/JCI116634. [DOI] [PMC free article] [PubMed] [Google Scholar]

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