Selective cyclo‐oxygenase‐2 inhibition with celecoxib elevates blood pressure and promotes leukocyte adherence

Abstract

1 Selective inhibitors of cyclo-oxygenase-2 have been shown to be e ective anti-in¯ammatory drugs with reduced gastrointestinal toxicity relative to conventional nonsteroidal anti-in¯ammatory drugs (NSAIDs). In the present study, we examined the possibility that selective COX-2 inhibition, by blocking prostacyclin synthesis, would increase blood pressure and cause leukocyte adherence and platelet aggregation. 2 Normal rats and rats with hypertension induced by chronic administration of N o -nitro-Larginine methylester were given celecoxib (10 mg kg 71 ) daily for 3 weeks. Celecoxib signi®cantly elevated of blood pressure in both the normal and hypertensive rats (mean increase of 433 mm Hg after 3 weeks). 3 In normal rats, celecoxib had no e ect on serum 6-keto prostaglandin (PG)F 1a levels. Hypertensive rats exhibited a signi®cant increase (82%) in serum 6-keto PGF 1a levels, and this was reduced to the levels of normal rats by treatment with celecoxib. 4 Rats treated with celecoxib exhibited signi®cant increases in weight gain (20%), plasma argininevasopressin levels (148%) and plasma urea (69%) relative to vehicle-treated controls. Plasma creatinine levels were una ected by treatment with celecoxib, while plasma renin levels were signi®cantly decreased (30%) relative to controls. 5 Superfusion of mesenteric venules with celecoxib (3 mM) in vivo resulted in signi®cant increases in leukocyte adherence to the endothelium in both normal and hypertensive rats. 6 These studies suggest that suppression of COX-2 signi®cantly in¯uences vascular and/or renal function, leading to elevated blood pressure and leukocyte adherence.

Structure–function properties of the apoE-dependent COX-2 pathway in vascular smooth muscle cells

“…The physiological consequences of eicosanoid metabolite production by the COX-2 enzyme are tissue and cellspecific. In vascular systems, COX-2-dependent production of prostacyclin can affect platelet coagulation [19][20][21] and leukocyte adhesion [22,23]. COX-2 activation in endothelial cells and vascular smooth muscle cells plays a vital role in the development and stability of atherosclerotic plaque.…”

Success of prostaglandin E 2 in structure–function is a challenge for structure-based therapeutics

“…These observations hint at potential additional counterregulatory roles for the enzyme and PGE 2 that may become evident with further investigations of the kinetics of complex inflammatory responses, such as delayed-type hypersensitivity, which require prominent contributions from the adaptive immune system for resolution (27). In several other models of inflammation, pharmacologic inhibition of COX-2 decreases PGE 2 , but not leukocyte infiltration (29,32 a striking protection from collageninduced arthritis, with diminished pannus formation, preservation of proteoglycan at articular surfaces, and less bony erosions. Antibodies against type II collagen were detected in both control and the mPGES1-deficient mice, but the titers were decreased in mPGES1-deficient animals.…”

The different patterns of blood pressure elevation by rofecoxib and nabumetone

“…Some studies have shown an increase in blood pressure for both drugs celecoxib and rofecoxib. 18,19 We did not find any other studies about the influence of nabumetone on blood pressure.…”