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Am J Physiol Heart Circ Physiol 277: H1546-H1552, 1999;
0363-6135/99 $5.00
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Vol. 277, Issue 4, H1546-H1552, October 1999

Role of cytochrome P-450 4A in oxygen sensing and NO production in rat cremaster resistance arteries

Cornel J. M. Kerkhof1, Erik N. T. P. Bakker2, and Pieter Sipkema1

1 Laboratory for Physiology, Institute for Cardiovascular Research, Vrije Universiteit, 1071 BT Amsterdam; and 2 Academic Medical Center, Department of Medical Physics, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

The role of arachidonic acid metabolism and nitric oxide (NO) in hypoxia-induced changes of vascular tone was investigated in first-order cannulated rat cremaster muscle resistance arteries. Spontaneous tone reduced arterial diameter from 179 ± 2 µm (fully dilated) to 98 ± 3 µm under normoxia (PO2 = 150 mmHg). Hypoxia (PO2 5-10 mmHg) had no significant effect on arterial diameter under conditions of spontaneous tone. The effect of hypoxia was not changed after blockade of cyclooxygenase with indomethacin or after blockade of lipoxygenase with nordihydroguaiaretic acid. However, after partial blockade of cytochrome P-450 4A enzymes with 17-octadecynoic acid (17-ODYA), hypoxia increased the diameter by 65 ± 6 µm (P < 0.05). This increase could be inhibited by NG-nitro-L-arginine (L-NNA) or 20-hydroxyeicosatetraenoic acid (20-HETE). 17-ODYA induced a concentration-dependent dilation under normoxia, which could be blocked by endothelium removal or L-NNA. 17-ODYA did not increase smooth muscle sensitivity to NO. We conclude that, under conditions of spontaneous tone and in the absence of luminal flow, hypoxia (5-10 mmHg) has no effect on the diameter of resistance arteries from the rat cremaster muscle. Inhibition of the cytochrome P-450 4A pathway of arachidonic acid metabolism under normoxia induces NO production by the endothelium. Hypoxia induces an NO-mediated dilation when cytochrome P-450 4A enzymes are partially inhibited.

hypoxia; arachidonic acid metabolism; 17-octadecynoic acid; endothelium; spontaneous tone


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