Selective impairment of myogenic constriction and endothelial function of small renal arteries precedes the development of renal damage in the hypertensive Fawn-Hooded rat

Background: Chronic kidney disease is associated with abnormal regulation of arterial tone throughout various vascular beds. It is however unknown whether generalized vascular dysfunction precedes the development of kidney disease. We studied myogenic constriction and endothelium-mediated dilatory responses in two inbred Fawn-Hooded (FH) rat strains, one of which (FHH) spontaneously develops hypertension, proteinuria and glomerulosclerosis, whereas other (FHL) does not. Methods: Small renal, mesenteric resistance arteries and aorta isolated from FH rats prior to (7 weeks old) and following the development of mild proteinuria (12 weeks old), were mounted in perfused and isometric set-ups, respectively. Myogenic response, acetylcholineinduced endothelium-dependent relaxation and the contribution of nitric oxide (NO), cyclooxygenase (COX)-derived prostaglandins and endothelium-derived hyperpolarizing factor (EDHF) were studied using the inhibitors L-NMMA, indomethacin and charybdotoxin+apamin, respectively. Results: In small renal arteries, markedly impaired myogenic reactivity and endothelial dysfunction due to excessive COX1-mediated production of constrictive prostaglandins were selectively present in FHH as compared to FHL even prior to the development of proteinuria. In contrast, myogenic reactivity was intact in mesenteric resistance artery of FHH. In addition, meseneteric endothelial dysfunction was observed attributed to the loss of EDHF. Renal myogenic and peripheral EDHF alterations were further attenuated after the development of proteinuria. Aortic reactivity did not differ between FHL and FHH at the time points studied. Conclusion: The present study shows that vascular dysfunction in both small renal and systemic arteries precedes renal end-organ damage in a spontaneous model of hypertensionassociated renal damage. Renal and peripheral vasomotor mechanisms are affected heterogeneously and differentially modulated by renal disease. These early vascular changes might be potentially involved in the increased susceptibility of FHH rats to renal injury. Vascular dysfunction in spontaneous renal disease 71