Role of Nitric Oxide and Prostaglandins in the Long-term Control of Renal Function

Abstract

Abstract-Previous studies have reported evidence of an important interaction between nitric oxide (NO) and prostaglandins in the acute regulation of renal function. The objective of this study was to determine in conscious dogs whether the renal effects of the prolonged administration of a cyclooxygenase inhibitor are enhanced when NO synthesis is reduced. Meclofenamate infusion (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) during 4 consecutive days (nϭ8) elicited a continuous decrease (PϽ0.05) in renal blood flow and plasma renin activity and a transitory decrease in sodium excretion. N G -Nitro-Larginine methyl ester (L-NAME) infusion (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) during 6 days (nϭ8) produced a significant increase in arterial pressure and a transitory decrease (PϽ0.05) in both renal blood flow and plasma renin activity. The simultaneous inhibition of NO and prostaglandin synthesis (nϭ7) led to an increase in arterial pressure and a decrease in renal blood flow similar to those observed during the administration of either L-NAME or meclofenamate. In contrast, this simultaneous inhibition produced a decrease in glomerular filtration rate, which was not observed in the previous groups, and also induced an increase in renal vascular resistance and a decrease in sodium excretion greater (PϽ0.05) than those found during the inhibition of either NO or prostaglandins. Only a transitory decrease in plasma renin activity was found during meclofenamate infusion in this group. The results of this study present new evidence that the renal vasoconstrictor and antinatriuretic effects induced by the prolonged infusion of a cyclooxygenase inhibitor are significantly enhanced when NO synthesis is reduced. These results suggest that renal function may be more sensitive to the prolonged administration of a cyclooxygenase inhibitor in situations where NO production is reduced. (Hypertension. 1998;32:33-38.) Key Words: vasoconstriction Ⅲ nitric oxide Ⅲ prostaglandins Ⅲ sodium Ⅲ plasma renin activity T he role of NO and PG in the acute and long-term regulation of arterial pressure and renal function has been examined in many studies (see References 1 through 4 for review). It has been reported that acute and long-term NO synthesis inhibition induces a significant elevation in arterial pressure and RVR and a decrease in the renal excretory ability.1-3 The results obtained during the acute administration of a cyclooxygenase inhibitor are contradictory, but it is generally accepted that it can induce small changes in RVR and sodium excretion.2,4 The effects of the prolonged PG synthesis inhibition on renal function have been evaluated, but changes in RBF during the first days of cyclooxygenase inhibition have been only partly examined. 2,4Results obtained in previous studies performed in anesthetized dogs suggest that an important interaction exists between NO and PG in the acute regulation of renal hemodynamic and excretory function. 5,6 It was found that the renal effects induced by acute intrarenal L-NAME administration are significantly potentiated when PG s...

Role of Cyclooxygenase-2 in the Prolonged Regulation of Renal Function

“…21 Prolonged COX-2 inhibition in dogs with normal sodium load did not induce changes in GFR and elicited a mild decrease in RBF. When comparing the renal hemodynamic effects of a nonselective COX inhibitor 10,11 with those reported in the present study, it can be proposed that the metabolites derived from both COX isoforms are involved in the regulation of renal hemodynamic. This notion is supported by results obtained in healthy adults 17 and suggests the preferential use of selective COX-2 inhibitors for treatment of inflammatory processes, as opposed to nonselective inhibitors, when sodium intake is normal.…”

“…10,11,15 PRA and PAC were measured using commercial RIA (DiaSorin). Urinary concentration of PGE 2 , 6-keto-PGF 1␣ , TXB 2 , and 11-dehydro-TXB 2 were measured using commercial EIA kits (Cayman Chemical).…”

“…Previous studies 10,14 have also proposed that endogenous PG modulate the renal vasoconstriction elicited by a reduction in NO synthesis. However, it has not been elucidated if these PG are COX-1-or COX-2-dependent.…”

“…The studies to accomplish this objective were performed in dogs with normal and high sodium load, because it has been proposed that NO synthesis is enhanced during elevations in sodium load. 15,16 were surgically instrumented as previously described 10,11,15 for the continuous intravenous infusions and mean arterial pressure (MAP) and RBF measurements. MAP and RBF data were obtained every minute and subsequently averaged over a 20-hour period (1:00 PM to 9:00 AM).…”

Role of prostaglandins in hypertension

“…23 It is now appreciated that NO, a reactive oxidation product of nitrogen, is produced normally by many cell types, including endothelial cells, and has functions ranging from neurotransmission to vasodilation; also, there is a complex association between PGs, NO, and cytokine pointing to the regulation of the inflammatory process: proinflammatory cytokine interleukin-1␤ (IL) stimulates inducible nitric oxide synthase (iNOS) mRNA, protein, and NO production in neonatal ventricular myocytes 34 and, in other types of cells, it also activates phospolipase A 2 , which liberates AA (Figure 1), but it also induces the cyclo-oxygenase isoform (COX), 17 and NO has been shown to directly stimulate COX activity and AA metabolites other than COX products, possibly being products of the lipoxygenase pathway, which are involved in IL regulation of iNOS 17 (Figure 1). Moreover, it has been suggested that the renal vasoconstriction and antinatriuretic effects induced by a prolonged infusion of a COX inhibition are significantly enhanced when NO synthesis is blocked; 20 additionally, a chronic NO inhibition may contribute to systemic HT and play a pivotal role in the development of renal structural injury. Finally, the association of NO-PGs contributes to the regulation of RBF and renal funcJournal of Human Hypertension tion and structure, suggesting that both NO and PGs control a similar percentage or rat renal papillary blood flow, but NO seems to be more important than PGs as a mediator of the pressure-blood flow relationship; 21,30,34 also, a relationship between bradykinin receptors and PGs has been suggested, and they have a steroidogenic effect.…”