An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats

Abstract

Soluble epoxide hydrolase (sEH) inhibitors have been demonstrated to have cardiovascular protective actions. This hydrolase enzyme converts fatty acid epoxides to their corresponding diols, and this conversion can alter the biologic activity of these metabolites. We hypothesized that 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), a sEH inhibitor, would protect stroke-prone spontaneously hypertensive rats from cerebral ischemia. AUDA was administered to 6-week-old male rats for 6 weeks, during which blood pressure was measured by telemetry. Cerebral ischemia was induced by middle cerebral artery occlusion, the size of the cerebral infarct was assessed after 6 hours of ischemia, and the results were expressed as a percentage of the hemisphere infarcted (%HI). Vascular structure and function were assessed using a pressurized arteriograph. Plasma levels of AUDA at the end of the treatment period averaged 5.0 +/- 0.4 ng/mL, and the urinary excretion rate was 99 +/- 21 ng/d. AUDA-treated rats had significantly smaller cerebral infarcts than control rats (36 +/- 4% vs 53 +/- 4% HI, treated versus control, P < 0.05, n = 6). This difference occurred independently of changes in blood pressure. AUDA treatment increased the passive compliance of the cerebral vessels but had no effect on vascular structure. The results of this study provide novel evidence suggesting that the sEH inhibitor AUDA is a possible therapeutic agent for ischemic stroke.

FIGURE 1.

A, Mean arterial pressure measured by radiotelemetry in the AUDA-treated and control rats. The average 12-hour day and night pressures are shown for the 5 days before and for the duration of the treatment. B, Heart rate over the same time (n = 6 in each group).

FIGURE 2.

The upper panel shows representative cerebral infarcts for AUDA-treated and control rats; the gray area is viable tissue; and the white area is tissue damaged by ischemia. The lower panel shows the percentage of the hemisphere infarcted (n = 6 in each group ^*P < 0.05).

FIGURE 3.

A, Relaxation of the MCA in response to bradykinin (10^-9-10^-5 M); the results are expressed as a percentage of the maximum dilation otained in response to SNP (10^-5 M). B, Constriction of the MCA in response to serotonin (10^-9-10^-5 M); the results are expressed as a percentage of the maximum lumen diameter as described above (n = 10 for AUDA and 8 for control).

FIGURE 4.

A, Lumen diameter in micrometerss of the MCA over a range of intraluminal pressures (0-180 mm Hg) for the AUDA-treated and the control rats. B, Wall/lumen ratio (n = 10 for AUDA and 8 for control).

FIGURE 5.

A, Average stress-strain curves generated for the MCAs from AUDA-treated and control SHRSP (n = 8). B, β-Coefficients calculated from the individual stress-strain curves for the MCAs from AUDA-treated and control SHRSP.