Decreased Plasma Concentration of Nitric Oxide Metabolites in Dogs with Untreated Mitral Regurgitation

Abstract

Endothelium-dependent (nitric oxide [NO]-mediated) vasodilation is impaired in humans with heart failure. This dysfunction is an important therapeutic target. The plasma concentration of the NO metabolites nitrate and nitrite (collectively referred to as NOx) is a measure of whole-body NO production, provided that the dietary intake of the ions is low. Fifty clinically healthy dogs older than 1 year (median 5.0 years; interquartile interval 2.6-8.2 years) were studied, including 9 controls of various breeds, 23 Cavalier King Charles Spaniels (CKCSs) with no or minimal mitral regurgitation (MR), 9 CKCSs with mild MR (regurgitant jet occupying 15-50% of the left atrial area), and 9 CKCS with moderate to severe MR (jet Ͼ50%) due to myxomatous valve disease. None of the dogs received medication. The dogs were given NOx-free water and a diet with a low concentration of NOx for 96 hours before blood sampling. Multiple linear regression analysis revealed that dog group, but not gender, age, serum creatinine concentration, and platelet count, was associated with NOx concentrations. Control dogs had the same NOx concentration (median 20.0 M; interquartile interval 15.1-25.5 M) as CKCSs without MR (median 18.7 M; interquartile interval 15.5-25.9 M). Compared to CKCSs without MR, the NOx concentration was lower in CKCSs with mild (median 12.9 M; interquartile interval 11.0-13.5 M; P ϭ .04) and moderate to severe (median 11.2 M; interquartile interval 6.9-17.1 M; P ϭ .02) MR. In conclusion, CKCSs with mild to severe, clinically silent MR have decreased plasma NOx concentrations, suggesting that endothelial dysfunction develops early in the course of developing MR in dogs.

Serum nitrotyrosine concentration in dogs with myxomatous mitral valve disease

“…This result is similar to that of Pedersen et al [19] in which as MMVD severity increased serum nitrotyrosine levels decreased. Medications for congestive heart failure resulting in MMVD, such as pimobendan and ACE-inhibitors, may regulate inflammatory mediators and iNOS expressions.…”

“…Nakazawa et al [17] reported that nitrotyrosine concentration was related to cytokine-induced myocardial dysfunction in a canine model, while Cunningham et al [4] reported that mono-nitrogen oxides (NOx) level was positively correlated with NT-pro BNP concentration in dogs with mitral valvular disease or DCM [4,17]. Another study reported that NOx concentration was high in dogs with chronic valvular disease [19].…”

Aldosterone receptor antagonists - how cardiovascular actions may explain their beneficial effects in heart failure

“…Nevertheless, a reduction in circulating concentrations of nitrate ⁄ nitrite has been reported in dogs in the sub-clinical stages of naturally occurring heart disease (Pedersen et al, 2003). The assumption was that circulating nitrate ⁄ nitrite is reflective of endothelial cell production although the mechanism of this proposed endothelial cell dysfunction has not been investigated.…”

“…Aldosterone participates in the development of structural (remodelling) and functional (endothelial dysfunction) vascular alterations induced by AngII Spironolactone (25 mg ⁄ kg ⁄ day) partially reduces the increased media ⁄ lumen ratio and the impaired response to acetylcholine of resistance arteries in AngII-infused rats Aortic NADPH oxidase activity is increased by AngII and aldosterone and reduced by spironolactone Falk et al (2006) In vivo, dogs with naturally occurring CHF Dogs with naturally occurring myxomatous mitral valve disease have significantly more arterial narrowing in the myocardium, lung and kidney than control dogs Pedersen et al (2003) In vivo, dogs (Cavalier King Charles Spaniels with mitral regurgitation)…”

Systemic Inflammation and Endothelial Dysfunction in Dogs with Congestive Heart Failure

“…However, investigations of endothelial function in this population have been limited. 14 Noninvasive evaluation of endothelial function can be accomplished via measurement of plasma biomarkers, 6,[15][16][17][18][19][20] endothelium-dependent flow-mediated vasodilation (FMD), 21,22 or assessment of reactive hyperemia (RH). [23][24][25][26] Potential plasma markers of endothelial function include markers of systemic inflammation such as C-reactive protein (CRP) [27][28][29][30] ; markers of nitric oxide (NO) bioavailability such as nitrate and nitrite (NO x ), 15,16,31 L-arginine (L-Arg), asymmetric dimethylarginine (ADMA), and symmetric Abbreviations: 18,19,32,33 ; and indicators of endothelial damage or repair such as von Willebrand factor (vWF) 17,34 or circulating endothelial progenitor cells, 35 respectively.…”