Abstract 337: Mechanisms of Reduced Aortic Relaxation Rate in Rats with Adenine-Induced Chronic Renal Failure

Abstract

We have previously shown that adenine-induced chronic renal failure (A-CRF) in rats causes a pronounced reduction in the rate of relaxation of the thoracic aorta, but not of mesenteric arteries. The aim of this study was to elucidate the mechanisms causing a decreased rate of relaxation in the thoracic aorta of rats with A-CRF and to examine if this abnormality was specific for this vascular bed or comprised also other conductance arteries. Male Sprague-Dawley rats received either chow containing adenine (0.5% week 1-3, 0.3% w. 4-5, and 0.15% thereafter) or were pair-fed an identical diet without adenine (controls). After 8-13 weeks segments of thoracic aorta, abdominal aorta, common carotid artery and common femoral artery were analyzed ex vivo with wire myograph. Data are means±SD. Plasma creatinine levels were markedly elevated in A-CRF animals (306±139 vs. 31±3 μM, P<0.001). The area under the curve for the initial 50 % reduction in force (reflecting relaxation rate) following wash-out of KCl was significantly elevated in A-CRF animals in the thoracic aorta (3.7-fold vs. controls, P<0.01), abdominal aorta (5.6-fold vs. controls, P<0.05), carotid artery (7.0-fold vs. controls, P<0.05), but was not significantly affected in the femoral artery. Removal of endothelium did not affect relaxation rate significantly in A-CRF thoracic aortas. However, aortic relaxation rate increased significantly (P<0.01), but was not normalized, in response to wash-out of KCl with Ca2+-free buffer. Thoracic aortas from A-CRF animals showed an increased sensitivity to KCl (log EC50 values -1.67±0.05 vs. -1.74±0.04 M in controls and A-CRF, respectively, P<0.01) but an unaltered sensitivity to Ca2+ during concentration-response experiments. In conclusion, rats with A-CRF show a pronounced reduction in the rate of relaxation of larger conductance arteries localized proximal to the common femoral artery. This abnormality, which could contribute to increased arterial stiffness, is independent of the endothelium but partly dependent on extracellular Ca2+. The increased sensitivity to KCl in the presence of a normal sensitivity to Ca2+ in A-CRF aortas could indicate that vascular smooth muscle cells of A-CRF aortas are more depolarized but this needs to be investigated further.