These findings suggest that COX-2-derived prostanoids are of major relevance in modulating the renal effects of diuretics. COX-2 inhibitors might be valuable drugs to treat salt and water wasting during Bartter and Gitelman diseases.
Our findings suggest that inhibition of salt transport in the loop of Henle, but not in the distal tubule, causes a selective stimulation of COX-2 expression in the macula densa region. This up-regulation may be of relevance for macula densa signaling, which links tubular salt transport rate with glomerular filtration rate and renin secretion.
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.
Cardiovascular morbidity and mortality is high in patients following renal transplantation. The present analysis assessed major cardiovascular risk factors and estimated the risk of coronary artery disease in the largest present-day comparative trial of tacrolimus vs. microemulsified cyclosporine A.In this 6-month study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) or cyclosporine A (n = 271) concomitantly with azathioprine and corticosteroids. The primary endpoint was the incidence of and time to acute rejection. Blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose were measured at baseline, and at months 1, 3, and 6. Ten-year risk of coronary heart disease was estimated according to the Framingham risk algorithm.Tacrolimus resulted in significantly lower summary measures (time-weighted average) of serum cholesterol (p = 0.0004) and mean arterial blood pressure (p = 0.0156), but in a higher summary measure of blood glucose (p = 0.0028) than cyclosporine. The summary measure of serum triglycerides was not different between treatment groups (p = 0.368). The mean 10-year coronary artery disease risk estimate was significantly lowered in men (p = 0.0032) treated with tacrolimus, but was unchanged in women.Tacrolimus and cyclosporine A microemulsion exert a compound-specific impact on cardiovascular risk factors and appear to affect the predicted rate of cardiovascular morbidity in different manners.
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