Ischemia NSAIDs

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. 

NSAID-induced acute renal deterioration occurs in the setting of severe vasoconstrictive renal ischemia and can be attributed to interruption of the delicate balance between hormonally mediated pressor mechanisms and prostaglandin-associated vasodilatory effects (Figure 3). During NSAID inhibition of renal... 

NSAIDs have an overall favorable safety profile resulting in OTC availability in the United States of ibuprofen, naproxen, and keto-profen for short-term therapy. WWle potential adverse renal effects from OTC NSAIDs have been a concern, activity of vasodilatory prostaglandins is not necessary to maintain renal function in healthy individuals. NSAIDs are unlikely to impair renal function in the absence of renal ischemia or excess renal vasoconstrictor activity. Nevertheless, given the fact that 50 million U.S. citizens report NSAID use, it has been estimated that 500,000 to 2.5 million people will develop NSAID nephrotoxicity in this country annually. ... 

Finally, prostaglandins from COX-2 may play an important role in certain neurological disorders. For example, the prevalence of Alzheimer s disease seems to be lower in those patients that take NSAIDs [51]. COX-2 im-munoreactivity increases in certain brain tissues following cerebral ischemia and the upregulation of COX-2 has been implicated in delayed neuronal death. In rodent studies, selective COX-2 inhibitors attenuated the infarct volume in the hemisphere where the injury was induced. The mechanism by which selective inhibitors showed activity in this model was attributed to inhibition of prostaglandin E2 (PGE2) formation by COX-2 [52]. 

On the other hand, gastric mucosal injury has also been associated with periods of ischemia in several different clinical settings, including trauma [166], ethanol exposure [167], acetic acid [168], NSAID [169], or ischemia-reperfusion [170]. When a tissue is subjected to ischemia, a sequence of chemical reactions is initiated which may ultimately lead to cellular dysfunction and necrosis [171]. 

COX-2 is constitutively present in the brain, mainly in neurons, and has been shown to play a key role in brain-specific inflammatory episodes linked to the progression of Alzheimer s disease (AD). Epidemiological and clinical studies have observed the influence of NSAID on the evolution of AD, with recent studies showing an inverse correlation between the use of NSAID and the risk of developing AD (Bazan et al., 2002). In the central nervous system, prostanoid levels are normally very low, but they can substantially increase in a variety of pathological conditions such as trauma, ischemia, HIV infection and multiple sclerosis. COX-1 and COX-2 are expressed in the spinal cord. It has been suggested that the antihyperalgesic mechanism of COX-2 inhibitors lies with the modulation of constitutive COX-2 present at the spinal level (S vensson and Yaksh, 2002). 

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