Cyclo‐oxygenase‐2 inhibition increases blood pressure in rats

Abstract

1 It is known that nonselective cyclo-oxygenase (COX) inhibitors have small but signi®cant eects on blood pressure (BP), most notably in hypertensive patients on antihypertensive medication. Whether selective COX-2 inhibitors also interfere with BP regulation is not well understood. Therefore, we aimed to examine the eect of chronic treatment with a selective COX-2 inhibitor (rofecoxib) on systolic blood pressure (sBP) in normotensive Wistar-Kyoto rats (WKY) and on the developmental changes of sBP in young spontaneously hypertensive rats (SHR). In addition, we investigated a possible in¯uence of salt intake on the eects of COX-2 inhibition on BP in these two rat strains. 2 Rofecoxib dose dependently increased sBP and decreased plasma levels of 6-keto prostaglandin (PG)F 1a in WKY rats fed a normal salt diet (0.6% NaCl, wt wt 71 ), without aecting serum thromboxane (TX)B 2 levels. 3 Rofecoxib signi®cantly elevated sBP in both rat strains fed normal salt or high salt diet (8% NaCl, wt wt 71), but not in rats on low salt intake (0.02% NaCl, wt wt 71). 4 Rofecoxib signi®cantly decreased plasma levels of 6-keto PGF 1a in both rat strains fed normal or high salt diet, but not in rats during low salt intake. 5 Rofecoxib exerted no in¯uence on the changes of body weight nor on water intake. Plasma renin activity (PRA) and renocortical renin mRNA abundance were not changed by rofecoxib, but plasma aldosterone concentration (PAC) was signi®cantly reduced. 6 These results suggest that chronic inhibition of COX-2 causes an increase of blood pressure that depends on prostacyclin synthesis. Furthermore, this increase is independent on genetic predisposition and can be prevented by salt deprivation. Since water intake and body weight gain were not changed by rofecoxib,¯uid retention appears not to be a major reason for the development of hypertension. Similarly, an activation of the renin-angiotensin-aldosterone axis appears to be an unlikely candidate mechanism.

Are All COX-2 Inhibitors Created Equal?

“…The differential effects of celecoxib and rofecoxib on blood pressure in the study from Hermann et al are consistent with previous animal studies in rodent models of hypertension 17,18 and also parallel clinical findings seen in elderly patients treated with the different COX-2-selective inhibitors. 19 Although celecoxib attenuated further increases in systolic blood pressure (SBP) in week 8 compared with the other treatment groups, the difference in mean SBP was still small (9 to 12 mm Hg) relative to the severe hypertension (mean SBP Ͼ200 mm Hg) found in these Dahl salt-sensitive animals.…”

Selective cyclooxygenase-2 inhibitor use and progression of renal function in patients with chronic kidney disease: a single-center retrospective cohort study

“…The previous case report in 2002 clearly demonstrated that sCOX-2 inhibitors caused acute tubulointerstitial nephritis (ATIN). 2 Moreover, other studies 9 have revealed that sCOX-2 inhibitors also caused acute ischemic tubular necrosis, nephrotic syndrome due to minimal change disease, acute papillary necrosis, 1,10 hyperkalemia, and type 4 renal tubular acidosis. The previous study showed that conventional NSAIDs increased the risk of renal progression and end-stage renal disease in CKD.…”

“…A subsequent clinical study has also provided evidence that COX-2 inhibitors affect renal hemodynamics. 9 Acute kidney injury caused by sCOX-2 inhibitors was encountered several days after starting drug use. The previous case report in 2002 clearly demonstrated that sCOX-2 inhibitors caused acute tubulointerstitial nephritis (ATIN).…”

Cyclooxygenases, the Kidney, and Hypertension

“…Rofecoxib significantly elevated systolic BP (SBP) in SHR or WKY rats with normal-salt or high-salt diet, but not in rats on low-salt intake, which suggested that the hypertension induced by COX-2 inhibition can occur independently of a genetic predisposition to hypertension and can be prevented by salt deprivation. 50 In mice COX-2 inhibition enhanced the pressure effect of angiotensin II. 31 In double-blind, randomized, controlled, clinical trials, conflicting results have been obtained about the influence of COX-2 inhibitor treatment on BP.…”