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Cat cerebral arterial smooth muscle cells express cytochrome P450 4A2 enzyme and produce the vasoconstrictor 20-HETE which enhances L-type Ca²⁺ current

Debebe Gebremedhin, Andrew R. Lange, Jayashree Narayanan, Mikael R. Aebly, Elizabeth R. Jacobs and David R. Harder

1. Cerebral arteries express cytochrome P450 4A enzymes (P450 4A) and produce 20- hydroxyeicosatetraenoic acid (20-HETE), a potent constrictor of pial arterioles. It is not known which cell type in the vessel wall is responsible for the formation of 20-HETE. We examined whether freshly isolated cerebral arterial muscle cells (VSMCs) express P450 4A and produce 20-HETE. We also studied the effect of 20-HETE on pressurized cerebral arteries and on whole-cell L-type Ca²⁺current (I_Ca) recorded in cat cerebral VSMCs.

2. Cat cerebral VSMCs incubated with [¹⁴C]arachidonic acid ([¹⁴C]AA) produced 20-HETE (3·9 ± 1·1 pmol min^-1 (mg protein)^-1).

3. Reverse transcription-polymerase chain reaction studies revealed that cat cerebral VSMCs express mRNA for P450 4A which metabolizes AA to 20-HETE. Cloning and sequencing of the cDNA amplified from mRNA isolated from VSMCs showed > 96 % amino acid homology to the rat and human P450 4A2 and 4A3.

4. 20-HETE (1-300 nM) induced a concentration-dependent constriction of cat cerebral arteries, which was inhibited by nifedipine.

5. Addition of 10 and 100 nM 20-HETE to the bath increased peak I_Ca by 50 ± 3 and 100 ± 10 %, respectively. This effect was not influenced by altering the frequency of depolarization. 20-HETE (100 nM) failed to increase I_Ca in the presence of nifedipine.

6. These results demonstrate that cat cerebral VSMCs express P450 4A enzyme, and produce 20-HETE which activates L-type Ca²⁺ channel current to promote cerebral vasoconstriction.

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