ANTIHYPERTENSIVE EFFECTS OF A NEW TRANSDERMAL DELIVERY SYSTEM FOR CLONIDINE IN GENETIC AND EXPERIMENTAL HYPERTENSIVE RATS

The antihypertensive effects of a new transdermal delivery system for clonidine (GAS 4205-90-7, clonidine tape, M-5041T) were investigated i n spontaneously hypertensive rats (SHR), 2-kidney, 1-clip renal hypert ensive rats (RHR) and deoxycorticosterone acetate (DOCA)-salt hyperten sive rats. M-5041T (0.5-4.5 mg/kg) elicited a long-lasting hypotensive effect that was accompanied by bradycardia in a dose-dependent manner during 24-h patching on the backs of rats in all three hypertensive r at models. The hypotensive effect of M-5041T was more persistent than that of oral administration of clonidine (50 and 100 mu g/kg) in both SHR and RHR. The most pronounced hypotensive effect of M-5041T was obs erved in DOCA salt hypertensive rats. Plasma clonidine concentrations following transdermal application of M-5041T (1.5 mg/kg) were approxim ately 2-3 fold higher in DOCA-salt hypertensive rats compared with SHR . Electrical conductance of the skin surface, an index of the water co ntent of the stratum corneum, was greater in DOCA-salt hypertensive ra ts than in SHR, suggesting that the delivery of clonidine may have bee n enhanced as a result of an increase in skin permeability due to the increase in water content of the stratum corneum in DOCA-salt hyperten sive rats. Co-administration of M. 5041T (0.5 mg/kg) with either trich loromethiazide (1 mg/kg, orally) or nifedipine (3 mg/kg, orally) at ea ch sub-dose which affected both systolic blood pressure and heart rate produced significant hypotensive and bradycardic effects in SHR. Foll owing repeated daily applications of M-5041T (1.5 mg/kg) for 7 consecu tive days in SHR, significant hypotensive and bradycardic effects were produced at 6 h post-patching and then disappeared at 24 h post-patch ing in each trial. The plasma clonidine concentrations at 6 and 24 h p ost-patching were similar from the first to the seventh trial. No sign ificant changes in blood pressure and heart rate were observed after t ermination of the regimen. These findings suggest that M-5041T could s erve as an efficient and useful antihypertensive transdermal delivery system in humans without producing tolerance to the hypotensive effect and withdrawal syndrome after abrupt cessation of the treatment when used alone or with either a diuretic or a calcium channel blocker.