Cardiovascular actions of buflomedil and possible mechanisms involved
Kushiku, K.; Ohba, M.; Mikagi, T.; Nuki, S.; Araki, Y.; Furukawa, T.
Arzneimittel-Forschung 39(6): 670-677
1989
ISSN/ISBN: 0004-4172 PMID: 2775333 Document Number: 330520
Cardiovascular effects of buflomedil (Bufedil) were studied in dogs, rabbits and guinea pigs. 1. In pentobarbital-anesthetized dogs, buflomedil (0.32-5.12 mg/kg i.v.) induced a dose-dependent fall of blood pressure and a slight increase of heart rate at 0.32-1.28 mg/kg but a heart rate decrease at 2.56 and 5.12 mg/kg. 2. Buflomedil administered into the maxillary (10-320 .mu.g/kg), internal carotid (40-320 .mu.g/kg) and vertebral artery (20-640 .mu.g/kg) increased respective blood flows dose-dependently. 3. Buflomedil (i.v.) also produced dose-dependent increases of the maxillary blood flow at 0.08-0.64 mg/kg, internal carotid flow at 1.28-5.12 mg/kg and vertebral flow at 0.32-5.12 mg/kg, respectively. These increasing effects were attenuated at larger doses because of marked hypotension. 4. Buflomedil (10 mg/kg i.v.) reduced pressor responses to norepinephrine (noradrenaline) and enhanced depressor responses to isoprenaline (isoproterenol), without affecting depressor responses to acetylcholine and positive chronotropic responses to norepinephrine and isoprenaline. 5. After buflomedil (i.v.), the femoral and coronary blood flow increased dose-dependently while renal blood flow decreased. These increasing effects were also reduced at larger doses because of hypotension. 6. Buflomedil (i.v.) induced a dose-dependent increase of cardiac output at 0.16-0.64 mg/kg, biphasic changes at 1.28 and 2.56 mg/kg and a marked decrease and subsequent slight increase at a large dose of 5.12 mg/kg. 7. 4-Desmethylbuflomedil (i.v.), elicited dose-dependent biphasic changes of blood pressure at 0.64-5.12 mg/kg, and a slight increase of heart rate at 0.32-2.56 mg/kg but decreases at 5.12 mg/kg. It also elevated, dose-dependently, the maxillary blood flow at 0.16-5.12 mg/kg and vertebral flow at 1.28-5.12 mg/kg. This metabolite, injected into respective arteries at smaller doses, also increased arterial blood flow. 8. Blood pressure rise induced by the carotid sinus occlusion and heart rate changes elicited by the vagus stimulation as well as pre- and postganglionic stimulation of stellate ganglia were not affected after buflomedil. 9. In an isolated rabbit pulmonary artery, buflomedil, 10-4 to 10-3 mol/l reduced the contraction induced by nonepinephrine and KCL. The reduction of KCl-induced contraction was enhanced by decreasing Ca++ concentration in the medium. 10. In isolated guinea pig papillary muscle, buflomedil inhibited action potential-dependent Ca++ channel. 11. Thus, buflomedil increases the cerebral, femoral and coronary blood flow, but systemic hypotension and cardiac inhibition occurs at large doses. Buflomedil does not extent actions on sympathetic and parasympathetic functions, except for blocking .alpha.-adrenoceptor. The .alpha.-receptor and Ca++ channel blocking seems to be involved in cardiovascular responses to buflomedil. 4-Desmethylbuflomedil is an active buflomedil metabolite and has a similar pharmacological profile.