Selected Contribution: Effects of aging on cerebrovascular tone and [Ca2+]i

Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, California 92350 Submitted 27 March 2003 ; accepted in final form 17 June 2003 The lower limits of cerebral blood flow autoregulation shift toward high pressures in aged compared with young rats. Intraluminal pressure stimulates contractile mechanisms in cerebral arteries that might, in part, cause an age-dependent shift in autoregulation. The present project tested two hypotheses. First, cerebral artery tone is greater in isolated arteries from aged compared with mature adult rats. Second, aging decreases the modulatory effect of endothelium-derived nitric oxide (NO) and increases vascular smooth muscle Ca 2+ sensitivity. Isolated segments of middle cerebral arteries from male 6-, 12-, 20-, and 24-mo-old Fischer 344 rats were cannulated and loaded with fura-2. Diameter and Ca 2+ responses to increasing pressure were measured in HEPES, during NO synthase inhibition [ N G -nitro- L -arginine methyl ester ( L -NAME)], and after removal of the endothelium. Cerebral artery tone (with endothelium) increased with age. Only at the lowest pressure (20 and 40 mmHg) was intracellular Ca 2+ concentration ([Ca 2+ ] i ) greater in arteries from 24-mo-old rats compared with the other age groups. L -NAME-sensitive constriction increased significantly in arteries from 6- to 20-mo-old rats but declined significantly thereafter in arteries from 24-mo-old rats. [Ca 2+ ] i was less in arteries from 24-mo-old rats compared with the other groups after treatment with L -NAME. Another endothelial-derived factor, insensitive to L -NAME, also decreased significantly with age. For example, at 60 mmHg, the L -NAME-insensitive constriction decreased from 47 ± 10, 42 ± 5, 21 ± 2, and 3 ± 1 µm in 6-, 12-, 20-, and 24-mo-old rats, respectively. Our data suggest that aging alters cerebral artery tone and [Ca 2+ ] i responses through endothelial-derived NO synthase-sensitive and -insensitive mechanisms. The combined effect of greater cerebral artery tone with less endothelium-dependent modulation may in part contribute to the age-dependent shift in cerebral blood flow autoregulation. endothelium; nitric oxide; calcium sensitivity; rat; pressure; intracellular calcium concentration Address for reprint requests and other correspondence: G. G. Geary, Depts. of Physiology and Pharmacology, School of Medicine, Loma Linda Univ., Loma Linda, CA 92350 (E-mail: ggeary{at}som.llu.edu ).