Peripheral haemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and interactions with captopril.

Abstract

Objectives-To investigate the role of prostaglandins in maintaining circulatory homoeostasis in chronic heart failure and the hypothesis that an increase in vasodilatory prostaglandin synthesis may contribute to the actions of angiotensin converting enzyme inhibitors in heart failure. Design-Randomised, double blind, placebo controlled studies. Cardiac output and renal and limb blood flow were measured after oral indomethacin 50 mg or placebo followed by "open" intravenous infusion of prostaglandin E, (study A). In a second study the same measurements were made after oral indomethacin 50 mg or placebo was given 30 min before "open" captopril (study B). Methods-Blood pressure was measured using a mercury sphygmomanometer. Cardiac output was determined by Doppler interrogation ofblood flow in the ascending aorta and echocardiographic measurement of aortic root diameter. Renal blood flow was calculated from the effective renal plasma flow measured by p-aminohippurate clearance and the haematocrit, and glomerular filtration rate by endogenous creatinine clearance. Limb blood flow was measured by venous occlusion plethysmography using mercury in silastic strain gauges. The concentration of plasma prostaglandin E, was measured by radioimmunoassay. Prostaglandins are 21 carbon fatty acids synthesised from arachidonic acid by all body tissues including the kidney and vascular endothelium. Stimuli to prostaglandin production include ischaemia, catecholamines, angiotensin II, bradykinin, and vasopressin.' 2 Prostaglandins E2 and I2 are potent vasodilators and are thought to act locally to increase blood flow.2 Many of the factors known to stimulate prostaglandin synthesis are present in heart failure and circulating concentrations of metabolites of prostaglandins E2 and I2 are increased in some patients with heart failure.3 It has been suggested that vasodilatory prostaglandins have an important role in maintaining circulatory homoeostasis in heart failure when tissue perfusion is reduced.4 In parallel with the activation of nervous and humoral vasoconstrictor systems, increased prostaglandin synthesis may act as a "counter regulatory" mechanism to limit local vasoconstriction and maintain local blood flow. Uncontrolled studies have shown adverse renal and systemic haemodynamic effects after inhibition of prostaglandin synthesis in chronic heart failure.3 5Angiotensin converting enzyme and kininase II are structurally identical so that angiotensin converting enzyme inhibitors not only inhibit the renin angiotensin system but also inhibit the degradation of kinins. Bradykinin is a potent vasodilator and also a stimulus to the synthesis of prostaglandins.6 This pivotal position of the angiotensin converting enzyme means that angiotensin converting enzyme inhibitors not only inhibit the vasoconstrictor renin angiotensin system but may also facilitate the production of vasodilators such as bradykinin and prostaglandin.

Cyclooxygenase-2 Inhibitor Treatment Improves Left Ventricular Function and Mortality in a Murine Model of Doxorubicin-Induced Heart Failure

“…14 Conversely, in a more recent study in humans, indomethacin caused adverse hemodynamic and renal effects. 15 To clarify this question, we used a mouse model of drug-induced heart failure to test the hypothesis that the progression of heart failure can be attenuated by selective COX-2 inhibition after initial injury and that this may have a beneficial effect on cardiac function and mortality.…”

Interaction between cyclooxygenase and the renin-angiotensin-aldosterone system: rationale and clinical relevance

“…38 In CHF, NSAIDs' deleterious effects are more predominant, since PG and bradykinin are stimulated in order to counteract water retention and vasoconstriction. Indeed, administration of NSAIDs results in decreased renal plasma flow and glomerular filtration rate, 18,39 and adversely affects cardiac index, left ventricular filling pressure and systemic vascular resistance, particularly in hyponatraemic patients. 4,8,18 Townend et al demonstrated that this deleterious effect was…”

“…16,18 These PGs have both vasodilatator (PGE2 and PGI2) and vasoconstrictor properties (PGH2 and TxA2), but the overall effect of COX blockade is an increase in systemic vascular resistance, which may result in a reduction in organ perfusion. 18 Bradykinin also has cardioprotective effects and the removal of bradykinin receptors in mice results in hypertension, left ventricular remodelling and functional impairment.…”

“…16,18 These PGs have both vasodilatator (PGE2 and PGI2) and vasoconstrictor properties (PGH2 and TxA2), but the overall effect of COX blockade is an increase in systemic vascular resistance, which may result in a reduction in organ perfusion. 18 Bradykinin also has cardioprotective effects and the removal of bradykinin receptors in mice results in hypertension, left ventricular remodelling and functional impairment. 19 COX pathway blockade inhibits PG synthesis and may be, deleterious and/or counteract part of the ACE-Is' efficacy, 18,20 especially in CHF, in which bradykinins are stimulated in order to limit vasoconstriction and maintain local blood flow.…”

“…18 Bradykinin also has cardioprotective effects and the removal of bradykinin receptors in mice results in hypertension, left ventricular remodelling and functional impairment. 19 COX pathway blockade inhibits PG synthesis and may be, deleterious and/or counteract part of the ACE-Is' efficacy, 18,20 especially in CHF, in which bradykinins are stimulated in order to limit vasoconstriction and maintain local blood flow.…”