Role of Nitric Oxide in Hemodialysis-Related Hypotension in an Experimental Renal Dysfunction Dog Model

Abstract

ABSTRACT. To clarify the role of nitric oxide (NO) in hemodialysis (HD)-related hypotension, the relationship between plasma NO metabolites (NOx) and blood pressure changes, and the effect of N G -monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor, on changes in blood pressure were evaluated in an experimental renal dysfunctional dog model. In order to create a renal dysfunction model, gentamicin was administered to male beagles in which 7 of 8 renal artery branches had been ligated. Normal renal functional and dy sfunctional dogs underwent 3 hr of HD per day for 3 days. HD induced a transient decrease in mean blood pressure in the normal renal functional dogs. In renal dysfunctional dogs, a continuous hypotension occurred with a gradual increase in the plasma NOx conce ntration during HD. Although L-NMMA prevented the fall in blood pressure, it did not significantly change the plasma NOx concentration during HD. These results suggest that NO contributes to HD-related hypotension in renal dysfunctional dogs but the plasma NOx concentration does not reflect the change in blood pressure. KEY WORDS: hemodialysis-related hypotension, L-NMMA, nitric oxide, renal dysfunctional dog.J. Vet. Med. Sci. 66(1): 53-57, 2004 Hemodialysis (HD) is an established form of therapy for renal dysfunction which has developed since the first study was carried out on a rabbit in 1912 [1]. Nevertheless, HD causes many complications. Hypotension is a major complication of HD that often requires aggressive resuscitation and premature termination of HD. It is widely accepted that many factors influence HD-related hypotension [5].Nitric oxide (NO) is an endogenous vasodilator and an increase in NO synthesis is known to decrease the blood pressure [8,14]. There are some reports suggesting that NO may contribute to HD-related hypotension. It has been shown that there is a correlation between the increase in levels of plasma nitrates and nitrites (NOx) and the reduction in blood pressure in HD patients [12,15]. Methylene blue, a NO inhibitor, prevented hypotension in a few patients undergoing HD therapy [18], but it was conceivable that basic examination concerning an involvement of NO in HDrelated hypotension was insufficient. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are powerful inducers of the inducible form of NO synthase (iNOS) [6], which causes overproduction of NO [19], and activate constitutive endothelial NO synthase (eNOS) [3]. Plasma levels of these cytokines chronically increase in renal disease patients undergoing HD therapy [6]. The cause may be partly attributable to decreased renal clearance [20]. These results suggest that the ability to produce NO in renal dysfunction is greater than that in normal renal function.Therefore, the present study was devised to establish an experimental renal dysfunctional dog model and to compare this model with a normal animal as to the change in blood pressure in the case of HD. Furthermore, we studied the relationship of NO to HD-related hypotension in this model by measuri...

Effects of a Selective Inhibitor of Inducible Nitric Oxide Synthase, ONO-1714, on Experimental Hemodialysis-Related Hypotension in Renal Dysfunctional Dogs

“…We have previously demonstrated in a study using a non-selective inhibitor of NOS that an increase in NO contributed to hemodialysis-related hypotension (12). In the present study, ONO-1714, which displays a tenfold specificity in the inhibitory activity on iNOS compared with ecNOS (9), reversed hemodialysis-related hypotension of renal dysfunction dogs with doses of 0.03 mg / kg or more in a dose-dependent fashion.…”

“…On performing hemodialysis and ultrafiltration, the mean blood pressure gradually decreased, and a constant level (107 -128 mmHg) was almost established by 90 min after initiating ultrafiltration. We have demonstrated in our previous study that hemodialysis-related hypotension is merely a transient event, using a dialysis device for animal use (12). However, the hemodialysisrelated hypotension has been reported to behave in a persistent fashion in a clinical study (13).…”

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

“…Studies of NO functions have been aided by pharmacologic agents that raise or lower NO levels (4). A number of disease states including sepsis and hepatic failure are characterized by abnormally high NO production, and removing the excess NO could have salutary effects (5)(6)(7).…”

Intermittent hemodialysis in dogs with chronic kidney disease stage III

“…There was a slight reduction in the percentage of hypertensive patients throughout the study in both groups due to antihypertensive treatment with ACEI and CCB. In contrast, hypotension is the most serious complication that can occur near to the end of the hemodialysis session due to loss of the blood volume at the beginning of extracorporeal circulation or due to cytokines and other inflammatory mediators from the interaction of blood with the dialysis membrane (KOMENO et al, 2004). In two hemodialysis sessions, only one dog (8%) had hypotension (80mmHg).…”