Ocular and Systemic Effects of WIN 55-212-2 in Normotensive Rabbits

Abstract

Abstract: : Purpose: Published studies on the intraocular pressure (IOP) effect of WIN 55-212-2, a potent synthetic cannabinoid, are conflicting and have not included cardiovascular monitoring. Our aim was to: (1) determine a dose-response relationship between IOP and both topical and intravenous WIN 55-212-2, in conscious rabbits, (2) measure systemic blood pressure and pulse changes associated with i.v. and topical WIN 55-212-2 administration, and (3) extrapolate whether these changes were responsible in part for changes in IOP. Methods: After acclimatization to calibrated pneumotonometry, adult albino New Zealand rabbits (2-3kg.) were given baseline exams including IOP, pupil size, external ocular assessment, pulse, and mean blood pressure. WIN 55-212-2 was dissolved in combinations of ethanol, emulphor, DMSO, or saline and administered i.v. in concentrations ranging from 0.01-0.3 mg/kg. For topical application 200 µl of a 0.5% solution was utilized. Following administration of drugs, exams were repeated at 15, 30, 60, 120, and 180 minutes. Results: Using 0.05 mg/kg of i.v.drug, IOP was reduced from 19.2 ± 1.7 (SEM) mmHg to 15.7 ± 0.6 mmHg and 16.7 ± 0.7 mmHg at 30 and 60 minutes respectively. This was statistically significant (p<0.02) as was the reduction with 0.2mg/kg, from 19.3 ± 1.2 mmHg to 14.5 ± 0.6 mmHg at 60 minutes (p<0.05). Peak changes in pulse and blood pressure occurred after 15-60 minutes. With i.v. drug at a concentration of 0.1 mg/kg, mean blood pressure dropped from a baseline of 64.3 ± 0.3 mmHg to 29.8 ± 2.3 mmHg. Higher concentrations gave profound reductions and excitatory behavioral changes were also noted. Topical WIN 55-212-2 produced a small but significant IOP drop from 17.8 ± 0.4 mmHg to 16.4 ± 0.7 mmHg at 30 minutes (p<0.02). There was no observed ocular toxicity and there were no significant blood pressure (p=0.22) or pulse (p=0.92) changes. Conclusions: In rabbits, both topical and systemic WIN 55-212-2 cause reductions in IOP without apparent ocular toxicity. Changes in blood pressure may have contributed slightly to the IOP reduction seen with i.v. administration but topical application had no attendant cardiovascular changes.

Keywords: drug toxicity/drug effects • pharmacology • animal model