CHRONIC ISCHEMIA ALTERS PROSTATE STRUCTURE AND REACTIVITY IN RABBITS

Abstract

Autopsy studies performed in men older than 80 years old have demonstrated that 90% have histological evidence of benign prostatic hyperplasia. Despite this fact pressure flow studies in men of this age who are referred for the evaluation of lower urinary tract symptoms have shown that only 40% have evidence of bladder outlet obstruction. To our knowledge the specific features of benign prostatic hyperplasia responsible for bladder outlet obstruction are not known. To investigate the possible etiological factors responsible for bladder outlet obstruction we determined whether chronic ischemia alters the structural and functional properties of the prostate. Male New Zealand White rabbits weighing 3.5 to 4 kg. were divided into a chronic prostate ischemia (12), hypercholesterolemia (8) and age matched control (8) group. The chronic prostate ischemia group underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet, the hypercholesterolemia group received a 0.5% cholesterol diet only and controls received a regular diet. After 12 weeks using anesthesia iliac artery and prostatic blood flow was measured by an ultrasonic and laser Doppler flowmeter, respectively. The animals were then sacrificed and the prostate was processed for histological evaluation, immunohistochemical staining for vascular endothelial growth factor expression and organ bath studies. Iliac artery and prostatic blood flow was significantly decreased in the chronic prostate ischemia compared with the hypercholesterolemia and control groups. Histological findings included thickening and fibrosis of the prostatic stroma and cystic atrophy of the epithelium in the chronic prostate ischemia group as well as minor thickening of the stroma in the hypercholesterolemia group. These structural changes correlated with decreased vascular endothelial growth factor expression. Organ bath studies showed that chronic ischemia and to a lesser extent hypercholesterolemia impaired electrical field stimulation induced neurogenic relaxation of the prostatic tissue. Neurogenic relaxation of the prostatic tissue was improved by combined treatment with indomethacin and L-arginine in the hypercholesterolemia but not in the chronic prostate ischemia group. Nitric oxide donor sodium nitroprusside produced comparable relaxation in all 3 groups. Chronic ischemia causes marked changes in prostatic structure and contractility. Ischemia induced glandular atrophy was consistently associated with decreased vascular endothelial growth factor expression. Decreased relaxation of the ischemic tissue to electrical field stimulation appears to involve the nitric oxide pathway. The nitric oxide precursor L-arginine reversed hypercholesterolemia induced impairment of prostatic tissue relaxation. Our study suggests that chronic ischemia results in thickening and fibrosis of the prostate, changing its mechanical properties. Chronic ischemia also impairs neurogenic relaxation in the prostate. We discuss the possible relationship of these changes to clinical bladder outlet obstruction.