Deficiency of COX-1 causes natriuresis and enhanced sensitivity to ACE inhibition

Background. Prostanoid products of the cyclo-oxygenase (COX) pathway of ara chidonic acid metabolism modulate blood pressure (BP) and sodium homeostasi s. Conventional non-steroidal anti-inflammatory drugs (NSAIDs), which inhib it both COX isoforms (COX-1 and -2), cause sodium retention, exacerbate hyp ertension, and interfere with the efficacy of certain anti-hypertensive age nts such as angiotensin-converting enzyme (ACE) inhibitors. While a new cla ss of NSAIDs that specifically inhibit COX-2 is now widely used, the relati ve contribution of the individual COX isoforms to these untoward effects is not clear. Methods. To address this question, we studied mice with targeted disruption of the COX-1 (Ptgs1) gene. Blood pressure, renin mRNA expression, and aldo sterone were measured while dietary sodium was varied. To study interaction s with the renin-angiotensin system, ACE inhibitors were administered and m ice with combined deficiency of COX-1 and the angiotensin II subtype 1A (AT (1A)) receptor were generated. Results. On a regular diet, BP in COX-1-/- mice was near normal. However, d uring low salt feeding, BP values were reduced in COX-1-/- compared to +/animals, and this reduction in BP was associated with abnormal natriuresis despite appropriate stimulation of renin and aldosterone. Compared to COX-1 +/+ mice, the actions of ACE inhibition were markedly accentuated in COX-1- /- mice. Sodium sensitivity and BP lowering also were enhanced in mice with combined deficiency of COX-1 and AT(1A) receptor. Conclusions. The absence of COX-1 is associated with sodium loss and enhanc ed sensitivity to ACE inhibition, suggesting that COX-1 inhibition does not cause hypertension and abnormal sodium handling associated with NSAID use.