Cyclo‐oxygenase‐2 inhibition increases blood pressure in rats

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Abstract
It is known that nonselective cyclo‐oxygenase (COX) inhibitors have small but significant effects 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 effect 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 influence of salt intake on the effects of COX‐2 inhibition on BP in these two rat strains. Rofecoxib dose dependently increased sBP and decreased plasma levels of 6‐keto prostaglandin (PG)F1α in WKY rats fed a normal salt diet (0.6% NaCl, wt wt−1), without affecting serum thromboxane (TX)B2 levels. Rofecoxib significantly elevated sBP in both rat strains fed normal salt or high salt diet (8% NaCl, wt wt−1), but not in rats on low salt intake (0.02% NaCl, wt wt−1). Rofecoxib significantly decreased plasma levels of 6‐keto PGF1α in both rat strains fed normal or high salt diet, but not in rats during low salt intake. Rofecoxib exerted no influence 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 significantly reduced. 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, fluid 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. British Journal of Pharmacology (2002) 136, 1117–1126. doi:10.1038/sj.bjp.0704821