Neurokinin-1 receptor antagonism in a rat model of subarachnoid hemorrhage: prevention of upregulation of contractile ETB and 5-HT1B receptors and cerebral blood flow reduction

• Object. Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced cerebral blood flow (CBF) and to cerebral ischemia, in some cases even producing infarction and long-term disability. The goal of the present study was to investigate the hypothesis that inhibition of neurokinin-1 receptors (NK1Rs) by administration of L-822429 blunts the decrease in CBF as well as cerebrovascular receptor upregulation in an animal model of SAH. Methods. Subarachnoid hemorrhage was induced in rats by injection of 250 mu l of blood into the prechiasmatic cistern. The NK1R inhibitor L-822429 was injected intracisternally 30 minutes and 24 hours after the induction of SAH. Two days after SAH induction, the basilar arteries were harvested, and contractile responses to endothelin-1 (ET-1, an ETA- and ETB-receptor agonist) and 5-carboxamidotryptamine (a 5-hydroxytryptamine-1 [5-HT1]-receptor agonist) were investigated using sensitive myographs. To determine whether NK1R inhibition had an influence on local CBF after post-SAH, a quantitative autoradiographic technique was used. After SAH, the vascular receptor phenotype was changed in cerebral arteries through upregulation of contractile ET, and 5-HT1B receptors, while regional and total CBF were markedly reduced. Treatment with the selective NK1R inhibitor L-822429 prevented both the receptor upregulation and the reduction in regional and global CBF. Conclusions. The data reveal the coregulation of vascular receptor changes and blood flow effects, and also show that interaction with a small-molecule NK1R antagonist is a promising area Of focus for the development of specific treatments for SAH.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Annan klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Other Clinical Medicine (hsv//eng)

Nyckelord

Dose-Response Relationship

Animal

Receptors

5-HT1B: physiology

Muscle

Male

Drug

Injections

Intraventricular

Neurokinin-1: antagonists & inhibitors

Vasospasm

Vasodilator Agents: pharmacology

Up-Regulation: drug effects

Subarachnoid Hemorrhage: physiopathology

Subarachnoid Hemorrhage: drug therapy

Regional Blood Flow: physiology

Regional Blood Flow: drug effects

Intracranial: physiopathology

Intracranial: drug therapy

Neurokinin-1: physiology

Smooth

Vascular: drug effects

Rats

Sprague-Dawley

Receptor

Endothelin B: antagonists & inhibitors

Serotonin

5-HT1B: antagonists & inhibitors

Animals

Autoradiography

Brain: blood supply

Cerebral Infarction: physiopathology

Cerebral Infarction: prevention & control

Disease Models

Publikations- och innehållstyp

art (ämneskategori)

ref (ämneskategori)