Role of cGMP versus 20-HETE in the vasodilator response to nitric oxide in rat cerebral arteries

1 Department of Physiology and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and 2 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235 This study examined the response to nitric oxide (NO) in rat middle cerebral arteries (MCA). NO donors increased the activity of a 205-pS K + channel recorded from vascular smooth muscle (VSM) cells isolated from MCA 10-fold. Blockade of guanylyl cyclase activity with 1 H -[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ, 10 5 M) did not alter the effect of NO on this channel. In contrast, adding 20-hydroxyeicosatetraenoic acid (20-HETE) to the bath (10 7 M) abolished the response to NO. NO donors also increased the diameter of serotonin-preconstricted MCA to 85% of control. Blockade of K + channels with iberiotoxin or a high-K + medium reduced this response by 50%. ODQ (10 5 M) reduced this response by 47 ± 3%, whereas preventing the fall of 20-HETE levels reduced the response by 59 ± 2% ( n = 5). Blockade of both pathways eliminated the response to NO donors. These results indicate that activation of K + channels contributes 50% to vasodilator response to NO in rat MCA. This is mediated by a fall in 20-HETE levels rather than a rise in cGMP levels or a direct effect of NO. vascular smooth muscle; cytochrome P -450; potassium ion channels; cerebral circulation; 20-hydroxyeicosatetraenoic acid