Effect of hypoxia on vasodilator responses to S-nitroso-N-acetylpenicillamine and levcromakalim in guinea pig basilar artery.
Ischaemic stroke is characterised by reduction of blood flow, tissue hypoxia, energy depletion and neuronal death. Drugs causing vasodilatation of cerebral arteries may potentially enhance blood supply to the ischaemic area and improve clinical outcome. However, vasodilators could also reduce cerebral blood flow in the ischaemic region by acting on blood vessels in non-ischaemic tissue, a phenomenon known as blood flow steal. To explore whether these drugs could act selectively on cerebral blood vessels in a hypoxic environment, we examined the effect of hypoxia on vasodilator responses to the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) and the ATP-dependent potassium channel (K(ATP)) opener levcromakalim in guinea-pig basilar arteries contracted by endothelin-1. Hypoxia considerably enhanced the vasodilator responses to SNAP, while those to levcromakalim were unaffected. In the presence of the NO synthase inhibitor N(G)-nitro-L-arginine, hypoxia no longer enhanced the vasodilator response to SNAP and suppressed responses to levcromakalim. The results show that the NO donor SNAP, but not the K(ATP) opener levcromakalim, is a more effective vasodilator of cerebral arteries contracted by endothelin-1 during hypoxia than under control conditions. Hypoxia-induced inhibition of basal NO synthesis could explain this enhancement of the vasodilator response to SNAP. Thus, NO donors may have a selective effect on blood vessels in ischaemic brain areas and therefore warrant further evaluation as therapeutic agents in cerebral ischaemia.
Movahed
Pouya
P
Department of Clinical Pharmacology, Lund University Hospital, 221 85 Lund, Sweden.
Högestätt
Edward D
ED
Petersson
Jesper
J
D000109:Acetylcholine / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000503:physiopathology; D001685:Biological Factors / Q000378:metabolism; D019806:Cromakalim / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D019335:Nitroarginine / Q000008:administration & dosage / Q000493:pharmacokinetics; D026423:S-Nitroso-N-Acetylpenicillamine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D019806:Cromakalim; D019335:Nitroarginine; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D000109:Acetylcholine