In vivo measurements of the cerebral perfusion and cardiovascular effects of the novel guanidine ME10092 in the non-human primate, Papio ursinus.
The novel guanidines N-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine (ME 10092) and N-(3,4-dimethoxy-2-chlorobenzylideneamino)-N1-hydroxyguanidine (PR5) were recently reported to exhibit promising cardioprotective activities in myocardial ischaemia and reperfusion in rats. The current study investigated for the first time pharmacological effects of ME10092 in the primate, viz. the Cape baboon Papio ursinus. The effects of ME10092 (1 and 2 mg/kg doses) on the cerebral blood flow, heart rates and the systolic and diastolic blood pressure were investigated after intravenous injection to the baboon under anaesthesia. The cerebral perfusion effects of ME10092 were assessed using Single Photon Emission Computed Tomography according to the split-dose approach and 99mTc-hexamethyl-propylene amine oxime as brain perfusion tracer. The observation that the recovery times from the anaesthesia were unacceptably prolonged excluded doses beyond 2 mg/kg. The data indicate that no cerebral perfusion changes were induced at both the 1 and 2 mg/kg doses of ME10092. Both these doses of ME10092 showed blood pressure and heart rate effects, with the latter being more significant. Decreases in heart rate were seen directly after ME10092 administration reaching levels of about 20% for the 2 mg/kg dose and about 15% for the 1 mg/kg dose at around 6 min post drug administration. A transient decrease in both systolic and diastolic blood pressure was observed for the higher dose. The blood pressure data further suggest an attenuation of the anaesthesia induced increase in pressure usually present in non-intervention studies. ME10092 clearly exhibits mycocardial effects in the non-human primate, similar to the effects previously observed in the ischaemia-reperfusion rat model, where ME10092 showed strong protection.
Oliver
D W
DW
Pharmacology, Faculty of Health Sciences, Potchefstroom University for CHE, 2520, South Africa. fkldwo@puknet.puk.ac.za
Dormehl
I C
IC
Wikberg
J E S
JE
Louw
W K A
WK
Dambrova
M
M
van Gelder
A
A
Kilian
E
E
van Rensburg
E Jansen
EJ
D000758:Anesthesia / Q000662:veterinary; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010215:Papio / Q000502:physiology*; D013019:South Africa; D019690:Technetium Tc 99m Exametazime; D013687:Telencephalon / Q000098:blood supply / Q000187:drug effects*; D013997:Time Factors; D014055:Tomography, Emission-Computed
C408693:1-(3,4-dimethoxy-2--chlorobenzylideneamino)guanidine; D006146:Guanidines; D019690:Technetium Tc 99m Exametazime