Abstract
The effects of a new transdermal delivery system for clonidine (M-5041T) on hypotensive effect, urine volume, plasma renin activity (PRA) and antidiuretic hormone (ADH) in spontaneously hypertensive rats (SHRs) were compared to the effects of the continuous infusion of clonidine. Both M-5041T (1.5 and 4.5 mg/kg) and the continuous infusion of clonidine (250 micrograms/kg/24 h) elicited hypotensive effects persisting for 12 hours or more. These effects were based on consistent plasma concentrations of clonidine. These two treatments produced diuresis followed by antidiuresis, which was remarkably observed by continuous infusion of clonidine. Single subcutaneous injection of clonidine (50 micrograms/kg) produced diuresis accompanied by increases in electrolytes corresponding to plasma levels of clonidine. M-5041T at 1.5 mg/kg did not affect PRA until 12 h, and produced an increase in PRA at 24 h. M-5041T at 4.5 mg/kg and the continuous infusion of clonidine resulted in a decrease in PRA at 2 and 1 h followed by an increase at 12 and 24 h, respectively. M-5041T at 1.5 mg/kg did not affect plasma levels of ADH. Plasma ADH did increase at 2 and 4 h accompanied by diuresis following M-5041T at 4.5 mg/kg or the continuous infusion of clonidine, respectively. Clonidine-induced diuresis was not at least due to the inhibition of ADH release. The decrease in urine volume observed by continuous infusion of clonidine may be due to decrease in renal blood flow based on stimulation of peripheral adorenoceptors of clonidine. These findings suggest that the increases in ADH and PRA are due to the compensatory effects related to both diuresis and the long-lasting hypotensive effect induced by high plasma concentrations of clonidine. Thus, it can be expected that M-5041T at 1.5 mg/kg showing the minimum effective plasma concentration of clonidine will not result in tolerance to the hypotensive effect of clonidine associated with the retention of sodium in SHRs.
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