Influence of different routes of administration on the cardiovascular effects of dihydrexidine (DHX) in rats

The intranasal (IN) route of administration may provide more rapid and complete delivery of various pharmacological agents to the CNS, while minimizing the peripherally-mediated non-therapeutic actions of such agents. We demonstrated previously that IN administration of the dopaminergic agonist DHX produced robust contralateral turning behavior in a 6-hydroxydopamine unilateral striatal lesioned rat model. Here, we evaluate the hypotensive side effects of DHX administered IN or IV. Male Sprague-Dawley rats were anesthetized with urethane and the right carotid artery and left jugular vein cannulated for mean arterial pressure (MAP) measurement and IV drug delivery, respectively. Rats then received either IN or IV DHX or vehicle. The peak changes in MAP following 0.5, 1.0, 2.0 and 6.0 mg/kg of IN DHX were -5 ± 2, -6 ± 3, -12 ± 3 and -7 ± 3 mmHg, respectively, while following 0.25, 0.5, 0.75 mg/kg of IV DHX peak MAP changes were -22 ± 2, -25 ± 3, -28 ± 3 mmHg, respectively. The IN doses of DHX used, while previously shown to produce robust CNS effects, produced significantly less unwanted cardiovascular effects compared with the IV route. The potential utility of IN DHX should be further explored in human disorders that benefit from CNS dopaminergic stimulation such as Parkinson's disease.