Salvinorin A produces cerebrovasodilation through activation of nitric oxide synthase, κ receptor, and adenosine triphosphate-sensitive potassium channel.
BACKGROUND
Salvinorin A is a nonopioid, selective κ opioid-receptor agonist. Despite its high potential for clinical application, its pharmacologic profile is not well known. In the current study, we hypothesized that salvinorin A dilates pial arteries via activation of nitric oxide synthase, adenosine triphosphate-sensitive potassium channels, and opioid receptors.


METHODS
Cerebral artery diameters and cyclic guanosine monophosphate in cortical periarachnoid cerebrospinal fluid were monitored in piglets equipped with closed cranial windows. Observation took place before and after salvinorin A administration in the presence or absence of an opioid antagonist (naloxone), a κ opioid receptor-selective antagonist (norbinaltorphimine), nitric oxide synthase inhibitors (N(G)-nitro-L-arginine and 7-nitroindazole), a dopamine receptor D2 antagonist (sulpiride), and adenosine triphosphate-sensitive potassium and Ca-activated K channel antagonists (glibenclamide and iberiotoxin). The effects of salvinorin A on the constricted cerebral artery induced by hypocarbia and endothelin were investigated. Data were analyzed by repeated measures ANOVA (n = 5) with statistical significance set at a P value of less than 0.05.


RESULTS
Salvinorin A induced immediate but brief vasodilatation that was sustained for 30 min via continual administration every 2 min. Vasodilatation and the associated cyclic guanosine monophosphate elevation in cerebrospinal fluid were abolished by preadministration N(G)-nitro-L-arginine, but not 7-nitroindazole. Although naloxone, norbinaltorphimine, and glibenclamide abolished salvinorin A-induced cerebrovasodilation, this response was unchanged by iberiotoxin and sulpiride. Hypocarbia and endothelin-constricted pial arteries responded similarly to salvinorin A, to the extent observed under resting tone.


CONCLUSIONS
Salvinorin A dilates cerebral arteries via activation of nitric oxide synthase, adenosine triphosphate-sensitive potassium channel, and the κ opioid receptor.
Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
Diansan
D
Su
John
J
Riley
Willis J
WJ
Kiessling
William M
WM
Armstead
Renyu
R
Liu
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D005260:Female; D008297:Male; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D045785:Diterpenes, Clerodane; D015221:Potassium Channels; D017473:Receptors, Opioid, kappa; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; C090499:salvinorin A
Neuroscience. 2007 Feb 23;144(4):1509-15
17175112
Stroke. 2008 Jan;39(1):205-12
18048856
J Cereb Blood Flow Metab. 2006 Mar;26(3):414-20
16049424
Clin Exp Pharmacol Physiol. 2010 Feb;37(2):243-52
19413600
Psychopharmacology (Berl). 2001 Sep;157(2):151-62
11594439
Xenobiotica. 2009 May;39(5):391-8
19280383
Synapse. 2009 Aug;63(8):698-704
19391150
Psychopharmacology (Berl). 2010 Jun;210(2):263-74
20358363
IUBMB Life. 2009 Oct;61(10):971-8
19787700
J Neurosci Res. 2010 Feb 1;88(2):428-37
19746425
Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11934-9
12192085
Eur J Clin Pharmacol. 1994;46(3):203-7
8070500
J Smooth Muscle Res. 2008 Apr;44(2):65-81
18552454
CNS Drugs. 2004;18(15):1085-104
15581380
Stroke. 2003 Jun;34(6):1533-8
12738895
Neuroimage. 2008 Jul 1;41(3):1044-50
18434204
Mol Interv. 2006 Oct;6(5):257-65
17035666
Neuroscience. 2008 Dec 10;157(4):884-94
18951957
Eur J Pharm Biopharm. 2009 Jun;72(2):471-7
19462483
Dev Neurosci. 2006;28(4-5):380-7
16943661
Br J Pharmacol. 2009 Jul;157(5):844-53
19422370
Sheng Li Xue Bao. 2003 Feb 25;55(1):91-5
12598942
Brain Res. 1995 Mar 27;675(1-2):257-63
7796137
Lancet Neurol. 2010 May;9(5):504-19
20398858
Neuropharmacology. 2009 Oct-Nov;57(5-6):523-30
19628000
Life Sci. 2004 Oct 15;75(22):2615-9
15369697