© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Protein expression, vascular reactivity and soluble guanylate cyclase activity in mice lacking the endothelial cell nitric oxide synthase: contributions of NOS isoforms to blood pressure and heart rate control
aCardiology Division, Department of Medicine, Emory University School of Medicine and Atlanta Veterans Administration Medical Center, Atlanta, GA, USA
bInstitut für Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Germany
cDivision of Hypertension and Vascular Research, Henry Ford-Hospital, Detroit, USA
* Corresponding author. Tel.: +49-221-811-2518; fax: +49-221-811-4781. E-mail address: kojda@uni-duesseldorf.de (G. Kojda)
Objective: Both disruption of the endothelial nitric oxide synthase (eNOS) gene and pharmacological inhibition of the NOS produce modest hypertension. It is unclear if and to what extent NOS isoforms other than eNOS contribute to this effect and how loss of one copy of the eNOS gene might impact on vascular reactivity or eNOS protein expression. Methods: We examined protein expression, vascular reactivity, activity of soluble guanylate cyclase, blood pressure and heart rate in mice completely lacking the eNOS gene (eNOS–/–), wild-type mice (eNOS+/+) and mice heterozygotic for the eNOS gene (eNOS+/–). Results: While eNOS–/– mice had mild hypertension and bradycardia, eNOS+/– mice were normotensive. In control mice, oral administration of L-NAME (approximately 100 mg/kg/dayx21 days) increased blood pressure to levels observed in eNOS–/– mice. In eNOS–/– mice, chronic oral administration of L-NAME had no effect on blood pressure, suggesting that inhibition of other NOS isoforms unlikely contribute to hypertension. L-NAME treatment induced bradycardia in both control and eNOS–/– mice, suggesting that both eNOS and other isoforms of NOS might be involved in heart rate control. Studies of aortic rings from eNOS–/– mice revealed a complete lack of endothelium-dependent vascular relaxation in response to acetylcholine and the calcium ionophore A23187 [GenBank] and an increase in sensitivity to phenylephrine, serotonin and nitroglycerin. Aortic rings from eNOS+/– mice demonstrated only minor alterations of responses to nitroglycerin and a normal relaxation to either acetylcholine or A23187 [GenBank] compared to vessels from eNOS+/+. Western analysis demonstrated that eNOS expression was virtually identical between eNOS+/+ and eNOS+/– mice and was absent in eNOS–/– mice. The activity of lung-isolated soluble guanylate cyclase was identical in the three strains of mice. Conclusions: We conclude that loss of one copy of the eNOS gene, as observed in heterozygotic animals, has no effect on vascular reactivity, blood pressure or eNOS protein expression. Isoforms of NOS, other than eNOS are unlikely involved in blood pressure regulation but may participate in heart rate control.
KEYWORDS Endothelial nitric oxide synthase; Gene disruption; Soluble guanylate cyclase; Nitroglycerin; Phenylephrine; Serotonine; Heart rate; Blood pressure
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. C. Chuang, Z. Yang, D. G. Westbrook, M. Pompilius, C. A. Ballinger, C. R. White, D. M. Krzywanski, E. M. Postlethwait, and S. W. Ballinger Pulmonary ozone exposure induces vascular dysfunction, mitochondrial damage, and atherogenesis Am J Physiol Lung Cell Mol Physiol, August 1, 2009; 297(2): L209 - L216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mujoo, V. G. Sharin, N. S. Bryan, J. S. Krumenacker, C. Sloan, S. Parveen, L. E. Nikonoff, A. Y. Kots, and F. Murad Role of nitric oxide signaling components in differentiation of embryonic stem cells into myocardial cells PNAS, December 2, 2008; 105(48): 18924 - 18929. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Daiber, D. G. Harrison, and T. Munzel Doubt about an essential role for constitutive nitric oxide synthase in nitroglycerin-mediated vasodilation PNAS, November 25, 2008; 105(47): E92 - E92. [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Ingram, S. C. Newcomer, E. M. Price, K. E. Eklund, R. M. McAllister, and M. H. Laughlin Chronic nitric oxide synthase inhibition blunts endothelium-dependent function of conduit coronary arteries, not arterioles Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2798 - H2808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Gill, J. C. Braz, N. Jin, G. J. Etgen, and W. Shen Restoration of impaired endothelium-dependent coronary vasodilation in failing heart: role of eNOS phosphorylation and CGMP/cGK-I signaling Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2782 - H2790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Vongpatanasin, G. D. Thomas, R. Schwartz, L. A. Cassis, S. Osborne-Lawrence, L. Hahner, L. L. Gibson, S. Black, D. Samols, and P. W. Shaul C-Reactive Protein Causes Downregulation of Vascular Angiotensin Subtype 2 Receptors and Systolic Hypertension in Mice Circulation, February 27, 2007; 115(8): 1020 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Adlam, J. K. Bendall, J. P. De Bono, N. J. Alp, J. Khoo, T. Nicoli, M. Yokoyama, S. Kawashima, and K. M. Channon Cardiovascular Control: Relationships between nitric oxide-mediated endothelial function, eNOS coupling and blood pressure revealed by eNOS-GTP cyclohydrolase 1 double transgenic mice Exp Physiol, January 1, 2007; 92(1): 119 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Mullins, M. A. Bailey, and J. J. Mullins Hypertension, Kidney, and Transgenics: A Fresh Perspective Physiol Rev, April 1, 2006; 86(2): 709 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Liu, O. A. Carretero, O. H. Cingolani, T.-D. Liao, Y. Sun, J. Xu, L. Y. Li, P. J. Pagano, J. J. Yang, and X.-P. Yang Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2616 - H2623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Suvorava, N. Lauer, S. Kumpf, R. Jacob, W. Meyer, and G. Kojda Endogenous Vascular Hydrogen Peroxide Regulates Arteriolar Tension In Vivo Circulation, October 18, 2005; 112(16): 2487 - 2495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhou, S. Varadharaj, X. Zhao, N. Parinandi, N. A. Flavahan, and J. L. Zweier Acetylcholine causes endothelium-dependent contraction of mouse arteries Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1027 - H1032. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Kojda and R. Hambrecht Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy? Cardiovasc Res, August 1, 2005; 67(2): 187 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Lauer, T. Suvorava, U. Ruther, R. Jacob, W. Meyer, D. G. Harrison, and G. Kojda Critical involvement of hydrogen peroxide in exercise-induced up-regulation of endothelial NO synthase Cardiovasc Res, January 1, 2005; 65(1): 254 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Landmesser, N. Engberding, F. H. Bahlmann, A. Schaefer, A. Wiencke, A. Heineke, S. Spiekermann, D. Hilfiker-Kleiner, C. Templin, D. Kotlarz, et al. Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase Circulation, October 5, 2004; 110(14): 1933 - 1939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Li, G. G. Geary, R. J. Gonzales, D. N. Krause, and S. P. Duckles Effect of estrogen on cerebrovascular prostaglandins is amplified in mice with dysfunctional NOS Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H588 - H594. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. F. Danson, K. S. Mankia, S. Golding, T. Dawson, L. Everatt, S. Cai, K. M. Channon, and D. J. Paterson Impaired regulation of neuronal nitric oxide synthase and heart rate during exercise in mice lacking one nNOS allele J. Physiol., August 1, 2004; 558(3): 963 - 974. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Budzyn, P. D. Marley, and C. G. Sobey Chronic mevastatin modulates receptor-dependent vascular contraction in eNOS-deficient mice Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R342 - R348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Laufs, N. Werner, A. Link, M. Endres, S. Wassmann, K. Jurgens, E. Miche, M. Bohm, and G. Nickenig Physical Training Increases Endothelial Progenitor Cells, Inhibits Neointima Formation, and Enhances Angiogenesis Circulation, January 20, 2004; 109(2): 220 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Day, D. Duquaine, L. V. Mundada, R. G. Menon, B. V. Khan, S. Rajagopalan, and W. P. Fay Chronic Iron Administration Increases Vascular Oxidative Stress and Accelerates Arterial Thrombosis Circulation, May 27, 2003; 107(20): 2601 - 2606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N Van Vliet, L. L Chafe, and J.-P. Montani Characteristics of 24 h Telemetered Blood Pressure in eNOS-Knockout and C57Bl/6J Control Mice J. Physiol., May 15, 2003; 549(1): 313 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sabrane, S. Gambaryan, R. P. Brandes, R. Holtwick, M. Voss, and M. Kuhn Increased Sensitivity to Endothelial Nitric Oxide (NO) Contributes to Arterial Normotension in Mice with Vascular Smooth Muscle-selective Deletion of the Atrial Natriuretic Peptide (ANP) Receptor J. Biol. Chem., May 9, 2003; 278(20): 17963 - 17968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P B Massion and J-L Balligand Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): lessons from genetically modified mice J. Physiol., January 1, 2003; 546(1): 63 - 75. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Brunner, R. Maier, P. Andrew, G. Wolkart, R. Zechner, and B. Mayer Attenuation of myocardial ischemia/reperfusion injury in mice with myocyte-specific overexpression of endothelial nitric oxide synthase Cardiovasc Res, January 1, 2003; 57(1): 55 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Sutliff, S. Dikalov, D. Weiss, J. Parker, S. Raidel, A. K. Racine, R. Russ, C. P. Haase, W. R. Taylor, and W. Lewis Nucleoside reverse transcriptase inhibitors impair endothelium-dependent relaxation by increasing superoxide Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2363 - H2370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Godecke, M. Ziegler, Z. Ding, and J. Schrader Endothelial dysfunction of coronary resistance vessels in apoE-/- mice involves NO but not prostacyclin-dependent mechanisms Cardiovasc Res, January 1, 2002; 53(1): 253 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kaikita, A. B. Fogo, L. Ma, J. A. Schoenhard, N. J. Brown, and D. E. Vaughan Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition Circulation, August 14, 2001; 104(7): 839 - 844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Li, V. E. Laubach, and R. A. Johns Upregulation of lung soluble guanylate cyclase during chronic hypoxia is prevented by deletion of eNOS Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L369 - L376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Kojda, Y. C. Cheng, J. Burchfield, and D. G. Harrison Dysfunctional Regulation of Endothelial Nitric Oxide Synthase (eNOS) Expression in Response to Exercise in Mice Lacking One eNOS Gene Circulation, June 12, 2001; 103(23): 2839 - 2844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Laursen, M. Somers, S. Kurz, L. McCann, A. Warnholtz, B. A. Freeman, M. Tarpey, T. Fukai, and D. G. Harrison Endothelial Regulation of Vasomotion in ApoE-Deficient Mice : Implications for Interactions Between Peroxynitrite and Tetrahydrobiopterin Circulation, March 6, 2001; 103(9): 1282 - 1288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Hussain, R. J. MacAllister, and A. J. Hobbs Reciprocal regulation of cGMP-mediated vasorelaxation by soluble and particulate guanylate cyclases Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1151 - H1159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Schnermann, Y. G Huang, and J. P Briggs Angiotensin II blockade causes acute renal failure in eNOS-deficient mice Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S199 - S203. [Abstract] [PDF]
|
|
|
|
|
|
K. G. Lamping, D. W. Nuno, E. G. Shesely, N. Maeda, and F. M. Faraci Vasodilator mechanisms in the coronary circulation of endothelial nitric oxide synthase-deficient mice Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1906 - H1912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Lentz, R. A. Erger, S. Dayal, N. Maeda, M. R. Malinow, D. D. Heistad, and F. M. Faraci Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta -synthase-deficient mice Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H970 - H975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Muller-Strahl, K. Kottenberg, H.-G. Zimmer, E. Noack, and G. Kojda Inhibition of nitric oxide synthase augments the positive inotropic effect of nitric oxide donors in the rat heart J. Physiol., January 15, 2000; 522(2): 311 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Brandes, D.-y. Kim, F.-H. Schmitz-Winnenthal, M. Amidi, A. Godecke, A. Mulsch, and R. Busse Increased Nitrovasodilator Sensitivity in Endothelial Nitric Oxide Synthase Knockout Mice : Role of Soluble Guanylyl Cyclase Hypertension, January 1, 2000; 35(1): 231 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Faraci and C. D. Sigmund Vascular Biology in Genetically Altered Mice : Smaller Vessels, Bigger Insight Circ. Res., December 3, 1999; 85(12): 1214 - 1225. [Full Text] [PDF]
|
|
|
|
|
|
G. Kojda Reply to Letter to the editor Cardiovasc Res, October 1, 1999; 44(1): 224 - 224. [Full Text] [PDF]
|
|
|
|
|
|
U. Laber, T. Kober, V. Schmitz, A. Schrammel, W. Meyer, B. Mayer, M. Weber, and G. Kojda Effect of Hypercholesterolemia on Expression and Function of Vascular Soluble Guanylyl Cyclase Circulation, February 19, 2002; 105(7): 855 - 860. [Abstract] [Full Text] [PDF]
|
|