Nitric Oxide Synthase Inhibition and Acute Renal Ischemia: Effect on Systemic Hemodynamics and Mortality
AbstractThis study was designed to examine if acute systemic blockade of nitric oxide (NO) production by inhibition of nitric oxide synthase (NOS) with N-ω-nitro-L-arginine methyl ester (L-NAME) would worsen the severity of ischemic acute renal failure (ARF). Initially three groups of rats, were studied: 45 min of bilateral renal ischemia (I) alone, Group I; L-NAME (L; 10 mg/kg BW, i.v.) alone, Group L; and L-NAME administered 15 min before renal ischemia, Group L+I. We observed, however, a 60% mortality in Group I+L during the first 4 h of reflow. Captopril, administered acutely 15 min before L-NAME in an attempt to offset any detrimental effects of increased angiotensin II generation in response to renal ischemia, failed to obviate the mortality because 67% of rats in this group (Group C+L+I) also died. Therefore, additional studies were performed in rats instrumented for cardiovascular studies to evaluate the acute hemodynamic responses during the first 90 min of reperfusion following renal ischemia in rats pretreated with L-NAME. As expected, L-NAME injection was accompanied by a 25–30 mm Hg increase in mean systemic arterial pressure (SAP) (p < 0.05), a bradycardia (p < 0.02), and a decrease in cardiac output (CO) (p < 0.02). The increase in SAP was due exclusively to an increase in systemic vascular resistance (SVR) (p < 0.01). Ischemia and reflow in the L-NAME-treated rats were attended by a progressive increase in SVR and a progressive decrease in CO such that by the end of 45 min of reperfusion SVR had increased 10-fold and CO had decreased to one third of its initial rate (both p < 0.02). Pulmonary artery pressure (PAP) increased promptly following L-NAME injection. Total pulmonary resistance (PRT) increased significantly by the end of reperfusion. L-NAME in combination with renal ischemia and reflow induces a large increase in both SVR and PRT, and is accompanied by a 70% reduction in CO and substantial mortality.