Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic kidney disease.
Left ventricular systolic dysfunction (LVSD) in patients with chronic kidney disease (CKD) is associated with poorer prognosis. Because patients with CKD often exhibit progressively decreased nitric oxide (NO) availability and inhibition of NO production can reduce cardiac output, we hypothesized that loss of NO availability in CKD contributes to pathogenesis of LVSD. Subtotally nephrectomized (SNX) rats were treated with a low dose of the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA; 20 mg/l water; SNX+L-NNA) and compared with relevant control groups. To study permanent changes separate from hemodynamic effects, L-NNA was stopped after week 8 and rats were followed up to week 15, until blood pressure was similar in SNX+L-NNA and SNX groups. To study effects of NO depletion alone, a control group with high-dose L-NNA (L-NNA-High: 100 mg/l) was included. Mild systolic dysfunction developed at week 13 after SNX. In SNX+L-NNA, systolic function decreased by almost 50% already from week 4 onward, together with markedly reduced whole body NO production and high mortality. In L-NNA-High, LVSD was not as severe as in SNX+L-NNA, and renal function was not affected. Both LVSD and NO depletion were reversible in L-NNA-High after L-NNA was stopped, but both were persistently low in SNX+L-NNA. Proteinuria increased compared with rats with SNX, and glomerulosclerosis and cardiac fibrosis were worsened. We conclude that SNX+L-NNA induced accelerated and permanent LVSD that was functionally and structurally different from CKD or NO depletion alone. Availability of NO appears to play a pivotal role in maintaining cardiac function in CKD.
Bongartz
L G
LG
Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands.
Braam
B
B
Verhaar
M C
MC
Cramer
M J
MJ
Goldschmeding
R
R
Gaillard
C A
CA
Doevendans
P A
PA
Joles
J A
JA
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006400:Hematocrit; D006977:Hypertension, Renal / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D031261:Poult Enteritis Mortality Syndrome; D011507:Proteinuria / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011917:Rats, Inbred Lew; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D013599:Systole / Q000502:physiology*; D014556:Urine; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism
D004791:Enzyme Inhibitors; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase