Key result
Nitric oxide donors increased K+ channel activity 10-fold and dilated arteries, a response mediated by a fall in 20-HETE levels rather than a rise in cGMP.
The vasodilator response to nitric oxide in rat middle cerebral arteries is largely mediated by a reduction in 20-HETE levels activating K+ channels, rather than the classic cGMP pathway.
Questions cGMP primacy in cerebral NO vasodilation; leaves open 20-HETE targeting in human stroke models.
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 1H-[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.
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Sun et al. (2000) studied this question. Nitric oxide (NO) donors vs. Blockade of guanylyl cyclase (ODQ) or addition of 20-HETE was evaluated on Vasodilator response and K(+) channel activity. Nitric oxide donors increased K+ channel activity 10-fold and dilated arteries, a response mediated by a fall in 20-HETE levels rather than a rise in cGMP.
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