Inhibition by ketamine and amphetamine analogs of the neurogenic nitrergic vasodilations in porcine basilar arteries.
The abuse of ketamine and amphetamine analogs is associated with incidence of hypertension and strokes involving activation of sympathetic activities. Large cerebral arteries at the base of the brain from several species receive dense sympathetic innervation which upon activation causes parasympathetic-nitrergic vasodilation with increased regional blood flow via axo-axonal interaction mechanism, serving as a protective mechanism to meet O2 demand in an acutely stressful situation. The present study was designed to examine effects of ketamine and amphetamine analogs on axo-axonal interaction-mediated neurogenic nitrergic vasodilation in porcine basilar arteries using techniques of blood-vessel myography, patch clamp and two-electrode voltage clamp, and calcium imaging. In U46619-contracted basilar arterial rings, nicotine (100μM) and electrical depolarization of nitrergic nerves by transmural nerve stimulation (TNS, 8Hz) elicited neurogenic nitrergic vasodilations. Ketamine and amphetamine analogs concentration-dependently inhibited nicotine-induced parasympathetic-nitrergic vasodilation without affecting that induced by TNS, nitroprusside or isoproterenol. Ketamine and amphetamine analogs also concentration-dependently blocked nicotine-induced inward currents in Xenopus oocytes expressing α3β2-nicotinic acetylcholine receptors (nAChRs), and nicotine-induced inward currents as well as calcium influxes in rat superior cervical ganglion neurons. The potency in inhibiting both inward-currents and calcium influxes is ketamine>methamphetamine>hydroxyamphetamine. These results indicate that ketamine and amphetamine analogs, by blocking nAChRs located on cerebral perivascular sympathetic nerves, reduce nicotine-induced, axo-axonal interaction mechanism-mediated neurogenic dilation of the basilar arteries. Chronic abuse of these drugs, therefore, may interfere with normal sympathetic-parasympathetic interaction mechanism resulting in diminished neurogenic vasodilation and, possibly, normal blood flow in the brainstem.
Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; Tzu Chi Center for Vascular Medicine, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; Tzu Chi University of Science and Technology, Hualien, Taiwan.
Mei-Fang
MF
Chen
Department of Pharmacology and Toxicology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
Su-Yu
SY
Lai
Department of Pharmacology and Toxicology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
Po-Cheng
PC
Kung
Department of Pharmacology and Toxicology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
Yo-Cheng
YC
Lin
Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
Hui-I
HI
Yang
Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; Department of Pharmacology and Toxicology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
Po-Yi
PY
Chen
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan.
Ingrid Y
IY
Liu
Department of Laboratory Medicine and Biotechnology & Graduate Institute of Medical Biotechnology, Tzu Chi University, Hualien, Taiwan.
Ahai Chang
AC
Lua
Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; Tzu Chi Center for Vascular Medicine, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; Department of Life Sciences, College of Life Sciences, Tzu Chi University, Hualien, Taiwan; Department of Pharmacology and Toxicology, College of Medicine, Tzu Chi University, Hualien, Taiwan; Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA. Electronic address: tlee@mail.tcu.edu.tw.
Tony Jer-Fu
TJ
Lee
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002941:Circle of Willis / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007649:Ketamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology; D009865:Oocytes; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D017783:Superior Cervical Ganglion / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D014981:Xenopus
D000662:Amphetamines; D011978:Receptors, Nicotinic; D014662:Vasoconstrictor Agents; D007649:Ketamine; D009538:Nicotine; D002118:Calcium
Amphetamine; Basilar artery; Ketamine; Methamphetamine; Nicotinic acetylcholine receptor; Nitrergic neurogenic vasodilation; Sympathetic-parasympathetic interaction