Cyclooxygenases, the Kidney, and Hypertension

Abstract

Abstract-Selective cyclooxygenase (COX)-2 inhibitors that are in widespread clinical use were developed to avoid side effects of conventional NSAIDs, including gastrointestinal and renal toxicity. However, COX-2 is constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in maintenance of renal blood flow, mediation of renin release, and regulation of sodium excretion. COX-2 inhibition may transiently decrease urine sodium excretion in some subjects and induce mild to moderate elevation of blood pressure. Furthermore, in conditions of relative intravascular volume depletion and/or renal hypoperfusion, interference with COX-2 activity can have deleterious effects on maintenance of renal blood flow and glomerular filtration rate. In addition to physiological regulation of COX-2 expression in the kidney, increased renal cortical COX-2 expression is seen in experimental models associated with altered renal hemodynamics and progressive renal injury (decreased renal mass, poorly controlled diabetes), and long-term treatment with selective COX-2 inhibitors ameliorates functional and structural renal damage in these conditions. Key Words: COX-2 Ⅲ COX-1 Ⅲ hypertension Ⅲ renin Ⅲ sodium Ⅲ glomerular filtration rate Ⅲ kidney I n the kidney, prostaglandins are important mediators of vascular tone, salt and water balance, and renin release. The rate-limiting enzyme, cyclooxygenase (prostaglandin synthase G 2 /H 2 ) initiates the metabolism of arachidonic acid to prostaglandin (PG) G 2 and subsequently to PGH 2 , which is then further metabolized by tissue-specific isomerases to PGs and thromboxane. There are at least two distinct cyclooxygenases, COX-1 and COX-2, that share Ϸ60% homology 1 but are the products of different genes and have distinct patterns of expression and regulation. COX-1 has been termed "constitutive," because of its wide tissue distribution, while COX-2 has been designated as "inducible" because of its more restricted basal expression and its upregulation by inflammatory and/or proliferative stimuli and its central role in mediation of inflammatory conditions and malignancies. Recently, Chandrasekharan et al characterized a third potential cyclooxygenase isoform, COX-3, a 65-kDa membranebound protein with acetaminophen or paracetamol-sensitive cyclooxygenase activity that represents a splice variant of COX-1. 2 However, other investigators have not confirmed the existence of full-length, catalytically active COX-3 from human genomic clones. Therefore, it remains uncertain whether COX-3 in fact represents the elusive target of paracetamol.Inhibition of COX activity by NSAIDs has been widely used for the treatment of pain and inflammation. Because prostanoids are involved in renal function, nonselective NSAIDs exhibit adverse effects, including salt retention and decreases in glomerular filtration rate (GFR), which may elevate blood pressure (BP) or make pre-existing hypertension worse. 3 Based on the hypothesis...

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Therapeutic dose of Ginkgo biloba extract 761 may alter the urine excretion of Wistar rats

“…The importance of the cyclooxygenases pathways in the control of blood pressure is illustrated by the use of AINE'S in humans, which inhibit both cyclooxygenases 1 or 2 isoforms and cause Na + retention and hypertension. COX-1 is constitutively expressed in a variety of tissues, including the kidney (Cheng & Harris, 2004). Probably, our data could be explained by the inhibitory effects of GBE on the COX and PAF pathway of arachidonic metabolism, but future researches are necessary, to prove this possibilities.…”

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“…COX-2 has been implicated in maintenance of renal blood flow, mediation of renin release and regulation of sodium excretion (Cheng & Harris, 2004 Level IV; Kramer et al, 2004 Level IV).…”