Dopamine D2-receptor-mediated increase in vascular and endothelial NOS activity ameliorates cerebral vasospasm after subarachnoid hemorrhage in vitro.
BACKGROUND
Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a serious complication resulting in delayed neurological deficit, increased morbidity, mortality, longer hospital stays, and rehabilitation time. It afflicts approximately 35 per 100,000 Americans per year, and there is currently no effective therapy. We present in vitro data suggesting that increasing intrinsic nitric oxide relaxation pathways in vascular smooth muscle via dopaminergic agonism ameliorates cerebral vasospasm after SAH.


METHODS
Cerebrospinal fluid (CSF) from patients with cerebral vasospasm after SAH (CSF(V)) was used to induce vasospasm in porcine carotid artery in vitro. Dopamine was added to test its ability to reverse spasm, and specific dopamine receptor antagonists were used to determine which receptor mediated the protection. Immunohistochemical techniques confirmed the presence of dopamine receptor subtypes and the involvement of NOS in the mechanism of dopamine protection.


RESULTS
Dopamine receptor 1, 2, and 3 subtypes are all present in porcine carotid artery. Dopamine significantly reversed spasm in vitro (67% relaxation), and this relaxation was prevented by Haloperidol, a D(2)R antagonist (10% relaxation, P < 0.05), but not by D(1) or D(3)-receptor antagonism. Both eNOS and iNOS expression were increased significantly in response to CSF(V) alone, and this was significantly enhanced by addition of dopamine, and blocked by Haloperidol.


CONCLUSIONS
Cerebral vasospasm is significantly reversed in a functional measure of vasospasm in vitro by dopamine, via a D(2)R-mediated pathway. The increase in NOS protein seen in both the endothelium and vascular smooth muscle in response to CSF(V) is enhanced by dopamine, also in a D(2)R-dependent mechanism.
Pyne-Geithman
Gail J
GJ
Department of Neurology, University of Cincinnati, 3125 Eden Avenue, 2324 Vontz Center, Cincinnati, OH 45267-0536, USA. pynegj@ucmail.uc.edu
Caudell
Danielle N
DN
Cooper
Matthew
M
Clark
Joseph F
JF
Shutter
Lori A
LA
D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism; D002555:Cerebrospinal Fluid; D004298:Dopamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000378:metabolism*; D034421:Sus scrofa; D014664:Vasodilation / Q000502:physiology; D020301:Vasospasm, Intracranial / Q000378:metabolism*
D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D004298:Dopamine