Efficacy of Cyclooxygenase 2 Inhibitors on Tumor Anorexia-Cachexia Syndrome in Patients with Cancer of the Head and Neck and Gastrointestinal Tract

Abstract

Dietary sodium intake has been shown to influence ␤2-adrenergic receptor (␤2-AR) responsiveness, and the Gly allele of the Arg16/Gly ␤2-AR polymorphism has been associated with hypertension in a linkage analysis in Rochester, MN. We have also shown that Gly homozygotes (GG) have greater forearm ␤2-AR mediated vasodilation than Arg (AA) after a controlled Na + diet (150 mmol • day Ϫ1 ), and the difference is mediated by endothelial NO. The purpose of this study was to test the hypothesis that dietary Na + restriction affects forearm and systemic ␤2-mediated dilation in healthy normotensive humans GG (n = 17) vs AA (n = 15). We measured HR, MAP, and CO (acetylene breathing) responses to intravenous infusion of terbutaline (TRB) before and after 5 days of dietary Na + restriction (10 mmol • day Ϫ1 ). Also following the diet, a brachial artery catheter was placed to measure forearm blood flow (FBF, plethysmography) responses to isoproterenol (ISO) before and after NO inhibition with L-NMMA. There was a main effect of diet (p < .03) on weight loss, increased urine volume, and 24-hour urinary excretion of Na + but no influence from genotype. Diet significantly decreased baseline CO in GG (pre-vs postdiet mean Ϯ SD: 6.4 Ϯ 1.4 to 5.5 Ϯ 1.2 L • min Ϫ1 ; p = .003) but not in AA (5.8 Ϯ 1.3 to 5.6 Ϯ 1.0 L • min Ϫ1 , NS) and increased peripheral resistance in GG (p = .02) but not AA. Baseline HR, MAP, and stroke volume were similar between groups, and the responses of all cardiovascular measures to TRB were not influenced by genotype or diet. In contrast to previous findings after a normal Na + diet, the FBF dose response curves to ISO were not different based on genotype (p = .51). L-NMMA decreased baseline FBF and significantly blunted the response to ISO, but there was no evidence to suggest that the responses were influenced by genotype (p = .89, genotype-by-ISOby-L-NMMA interaction). We conclude that dietary Na + restriction negates the increased forearm NO-mediated, ␤2-AR responsiveness in GG subjects, which may explain the dietevoked baseline increase in peripheral resistance and decrease in CO in this group, providing evidence that Na + intake modulates cardiovascular indices based on the Arg16/Gly ␤2-AR polymorphism.