Intermittent clonidine regimen abolishes tolerance to its antihypertensive effect: a spectral study

The development of tolerance to the antihypertensive effect of clonidine and related imidazolines is clinically recognized. Here, we employed a restricted daytime (8:30 AM until 4:30 PM) clonidine regimen to establish a model of sustained hypotension in spontaneously hypertensive rats (SHRs). Blood pressure (BP), heart rate (HR), and myocardial contractility (dP/dt(max)) were measured by radiotelemetry in pair-fed SHRs receiving liquid diets with or without clonidine (150 microg/kg per day) for 12 weeks. The cardiovascular autonomic control was assessed by power spectral analysis [fast Fourier transformations (FFT)] of hemodynamic variability. Clonidine had no effect on dP/dt(max) and significantly decreased BP and HR during the 8 hour exposure periods throughout the study duration. BP returned to control levels during overnight periods, with no signs of rebound hypertension. FFT analysis of interbeat intervals (IBI) showed pronounced decreases and increases of spectral powers in low-frequency (IBI-LF, 0.20-0.75 Hz) and high-frequency (IBI-HF, 0.75-3 Hz) bands, respectively, in clonidine-treated rats. The IBI(LF/HF) ratio was significantly reduced by clonidine, suggesting cardiac parasympathetic dominance. Clonidine also decreased the vasomotor sympathetic tone, as reflected by the reduced BP-LF spectral density. The sympathoinhibitory effect of clonidine is further confirmed by the significant reductions in urinary norepinephrine levels. Clonidine increased urine output during the 8 hour treatment period but not during the 24 hour period. Plasma and urine osmolality and electrolytes were not altered by clonidine. It is concluded that by adopting the limited-access paradigm, tolerance to the hypotensive and sympathoinhibitory actions of clonidine and, possibly, its side effects, could be minimized.