Prostanoids renal

Kidney Function. Prostanoids influence a variety of kidney functions including renal blood flow, secretion of renin, glomerular filtration rate, and salt and water excretion. They do not have a critical role in modulating normal kidney function but play an important role when the kidney is under stress. Eor example, PGE2 and -I2 are renal vasodilators (70,71) and both are released as a result of various vasoconstrictor stimuli. They thus counterbalance the vasoconstrictor effects of the stimulus and prevent renal ischemia. The renal side effects of NSAIDS are primarily observed when normal kidney function is compromised. 

These findings from special renal studies and the clinical trial data indicate that inhibition of Cox-2 does not eliminate the renal effects of NSAIDs because Cox-2-derived prostanoids are involved in normal renal function. However, the kidney contains considerably more Cox-1 than Cox-2, and the localization of the two isoforms is different It is not yet known whether the Cox-2 inhibitors will be safer in subgroups of patients prone to develop acute renal failure with NSAIDs, such as those patients with severe volume depletion, congestive heart failure, or hepatic cirrhosis with ascites (Bosch-Marce et al., 1999). Also, it is not known whether rare events, such as interstitial nephritis or papillary necrosis, will occur with long-term use of Cox-2 inhibitors, although studies in animals suggest that such events may be related to Cox-1 inhibition, since only Cox-1 is found in the papilla. Therefore, Cox-2 inhibitors may not produce these serious adverse effects (Khan etal., 1998). 

The prostaglandin pathway Renal prostanoid receptors Cyclooxygenase isoforms 420 421 422... 

Dilger K, Herriinger C, Peters J et al. Effects of celecoxib and diclofenac on blood pressure, renal function, and vasoactive prostanoids in young and elderly subjects. Journal of Clinical Pharmacology 2002 42 985-994. 

Agmon Y, Peleg H, Greenfeld Z, Rosen S, Brezis M. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. J Clin invest 1994 94 1069-1075. 

Intraperitoneal administration of coptisine at dosages of 0.5, 1, and 5 mg/kg/day to original-type anti-GBM-induced nephritic rats was shown to be effective in the inhibition of urinary protein excretion, elevation of serum cholesterol, and creatinine contents, as well glomerular histopathological changes. The alkaloid inhibited platelet aggregation in both in vitro and in vivo assays. These results suggest that the antinephritic effect of coptisine may be due partly to antiplatelet action and improved renal hemodynamics, via the alteration of prostanoid synthesis [223]. 

COX-1 is expressed in all tissues and regulates the conversion of arachidonic acid to prostaglandin G0 (PGG,), which is the first step in prostanoid synthesis. The COX-2 isozyme is selectively expressed—it appears in renal, bone, brain, and reproductive tissues, as well as in some tumor types. The COX-2 enzyme is inducible by various mediators of inflammation (e.g., interleukins and superoxide radicals), whereas the COX-1 isomer is expressed constitutively. 

The inhibition of distal nephron Na" reabsorption by 5,6-EET " the induction of kidney CYP2C23 and EET biosynthesis by excess dietary salt 123 and EET-induced dilation of micro-circulatory beds " suggested antihypertensive functions for the EETs In agreement with this (a) clotrimazole inhibition of the rat kidney epoxygenases caused reductions in renal EET biosynthesis , and the development of clotrimazole-dependent, salt-sensitive hypertension , (b) high salt diets failed to induce the activity of the kidney AA epoxygenase in hypertensive DS rats , and (c) the EETs contribute to the prostanoid- and NO-independent dilation pf renal afferent arterioles " In summary,... 

Vasodilatory prostanoids tend to promote renal salt and water excretion. The natriuretic effect of PG is in part related to their positive influence on... 

Changes in the pattern of prostanoid production during obstructive uropathy affect renal function primarily through alterations in renal haemodynamics. In general, enhanced biosynthesis of vasodilatory prostanoids occurs with acute obstruction, while increases in thromboxane synthesis prevail in the later stages. The role of eicosanoids in obstruction will be discussed in detail below. 

Is it necessary to eat a diet exclusive of fish in the absence of vegetable or beef oil to reduce the intrarenal cyclo-oxygenase metabolism Studies show that a diet containing only 2.5% fish oil and 17.5% safflower oil is nearly as effective in lowering renal, cortical or medullary prostanoids as a diet limited to 20% fish oil (unpublished observation). Thus, a small proportion of fish oil in the presence of other lipid sources favourably competes and inhibits cyclooxygenase metabolite synthesis. 

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