Role of endothelium in hyperemia during cortical spreading depression (CSD) in the rat.
The purpose of this study was to examine whether endothelium-mediated dilation is responsible for the cortical hyperemia that occurs during cortical spreading depression (CSD) in rats using three different approaches. The first approach taken was the acute pharmacological inhibition of the predominant endothelium-centered dilator systems, using indomethacin, a cyclooxygenase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, and miconazole, a cytochrome P-450 epoxygenase inhibitor. The second approach used was the acute general pharmacological impairment of endothelial function by the intravascular administration of phorbol 12, 13-dibutyrate (PDBu). The third approach taken was the chronic impairment of endothelium-dependent dilator responses by diet in insulin resistant (IR) rats. Cerebral blood flow (CBF) was measured using laser Doppler flowmetry. CSD was elicited by the topical application of potassium chloride. Pharmacological inhibition of endothelium-dependent dilator factors did not affect CSD. For example, with 20 mg/kg L-NAME, CBF peak of the first series of CSDs was 377 +/- 67% of baseline CBF. After drug administration, CBF peaks of the second and the third series of CSDs were 451 +/- 67% and 390 +/- 69% (n=5, P=n.s.), respectively. Control and IR animals and those treated with indomethacin, miconazole and PDBu showed similar results. We also calculated the area under the CBF curve to fully represent the extent of hyperemia during CSD. However, there were no significant differences in the CBF area with any treatment compared to control animals. Thus, our results provide strong evidence that endothelium-mediated mechanisms have minimal effects on the CSD-associated hyperemia.
Shimizu
Katsuyoshi
K
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1083, USA.
Miller
Allison W
AW
Erdös
Benedek
B
Bari
Ferenc
F
Busija
David W
DW
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000098:blood supply* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D013181:Cortical Spreading Depression / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005632:Fructose / Q000009:adverse effects; D006940:Hyperemia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D009599:Nitroprusside; D005632:Fructose; D015240:Phorbol 12,13-Dibutyrate; D000109:Acetylcholine; D001920:Bradykinin