A method for determining whether hypotension caused by novel compounds in preclinical development results from histamine release.
BACKGROUND
Many therapeutic agents stimulate histamine release from mast cells, which results in a decrease in blood pressure. The purpose of this study is to establish a method to determine if the mechanism of action, or one of the mechanisms, of hypotensive compounds is related to the release of histamine. The method was developed using a novel hypotensive compound, SC-372.


METHODS
In Inactin anesthetized rats, after intravenous administration of SC-372 (0.3-7 mg/kg), the 2 and 7 mg/kg resulted in a dose-dependent decrease in blood pressure. Histamine (0.1 and 1 mg/kg) was injected intravenously to establish whether histamine release was the mechanism of action for the hypotension induced by SC-372. Compound 48/80 (0.1 mg/kg, promotes histamine release) and Cromolyn (1 mg/kg/min, [5 min], prevents histamine release from mast cells) were characterized and used intravenously in combination with/or compared to SC-372.


RESULTS
Histamine resulted in a decrease in blood pressure that was unaffected by Cromolyn (1 mg/kg). Administration of Compound 48/80 resulted in a rapid reduction of systemic blood pressure. Intravenous infusion of Cromolyn prior to the injection of Compound 48/80 significantly attentuated the hypotensive response and the increase in histamine levels in the plasma. Intravenous administration of SC-372 resulted in a rapid reduction in blood pressure with a profile similar to that of Compound 48/80. When the rats were treated with Cromolyn prior to the administration of SC-372, both the blood pressure and plasma histamine levels were maintained at their pretreatment control levels.


CONCLUSIONS
These data indicate that Compound 48/80 and Cromolyn can be used in rats to screen for histamine release-dependent drug-induced hypotension and suggest that the rapid decrease in blood pressure caused by SC-372 may result from histamine release from mast cells.
Blom
Jason D
JD
Department of Discovery Biology, Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. jason.d.blom@pfizer.com
Yang
Po-Chang
PC
Nicholson
Nancy S
NS
Case
Brenda L
BL
Parlow
John J
JJ
South
Michael S
MS
Wegner
Craig D
CD
D000818:Animals; D004205:Cromolyn Sodium / Q000009:adverse effects / Q000494:pharmacology; D006146:Guanidines / Q000009:adverse effects* / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D007022:Hypotension / Q000139:chemically induced* / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D003189:p-Methoxy-N-methylphenethylamine / Q000009:adverse effects / Q000494:pharmacology
D006146:Guanidines; C494413:N-(4-(amino(imino)methyl)benzyl)-2-(6-(3-aminophenyl)-5-chloro-3-(cyclobutylamino)-2-oxopyrazin-1(2H)-yl)acetamide; D011719:Pyrazines; D003189:p-Methoxy-N-methylphenethylamine; D004205:Cromolyn Sodium