Effects of Chronic Ethanol Feeding on Clonidine-Evoked Reductions in Blood Pressure, Heart Rate, and Their Variability: Time-Domain Analyses

Abstract

The effects of chronic ethanol administration on the acute hemodynamic effects of clonidine were investigated in conscious radiotelemetered spontaneously hypertensive rats (SHRs). Changes evoked by clonidine (30 g/kg i.p.) in blood pressure, heart rate, and their variability were evaluated in ethanol [2.5 or 5% (w/v), 12 weeks] and pair-fed control rats. The blood pressure variability was determined as the standard deviation of the mean arterial pressure (SDMAP). Two heart rate variability indices were used, the standard deviation of beat-tobeat intervals (SDRR) and the root mean square of successive beat-to-beat differences in R-R interval durations (rMSSD). Compared with control rats, ethanol (2.5 and 5%)-fed rats exhibited concentration-related reductions in mean arterial pressure (MAP) and SDMAP versus no change in heart rate variability. In control rats, clonidine caused a significant reduction in MAP that continued for at least 5 h and was associated with significant reductions in SDMAP, SDRR, and rMSSD, responses that are consistent with the inhibition of central sympathetic tone. The hypotensive effect of clonidine was attenuated by ethanol in a concentration-related manner. The maximum reductions in MAP elicited by clonidine in ethanol (2.5 and 5%)-fed rats amounted to Ϫ23.4 Ϯ 2.8 and Ϫ15.1 Ϯ 1.5 mm Hg, respectively, compared with Ϫ35.4 Ϯ 1.2 mm Hg in control rats. The clonidine-induced reductions in SDMAP, SDRR, and rMSSD were also significantly attenuated by ethanol. These findings suggest that the attenuation of MAP and heart rate variability responses elicited by clonidine in ethanolfed SHRs reflects alterations in the sympathovagal balance, which may be implicated in the antagonistic hemodynamic interaction between the two drugs.Clonidine is a centrally acting antihypertensive drug that decreases blood pressure predominantly via stimulation of ␣ 2 -adrenergic (Timmermans and van Zwieten, 1982) and imidazoline (Tibirica et al., 1991) receptors in the brainstem, resulting in suppression of central sympathetic outflow. Sympathoinhibition has also been implicated in the clonidine-induced reductions in blood pressure and heart rate variability as determined by frequency-and time-domain analyses (Grichois et al., 1990;Elghozi et al., 1991;Janssen et al., 1991;Tulen et al., 1993). The reduction in hemodynamic variability by clonidine is important at least in two clinical settings. First, the long-term reduction in blood pressure variability by clonidine may contribute to the regression of ventricular and vascular hypertrophy in hypertensive patients (Timio et al., 1987;Strauer, 1988). Second, by reducing blood pressure and heart rate variability, clonidine promotes hemodynamic stability in patients undergoing surgery and reduces anesthetic requirements (Nishikawa et al., 1991). It is noteworthy that 1) blood pressure and heart rate variability is an indirect measure of cardiovascular autonomic balance and 2) oscillation abnormalities in these hemodynamic variables are associated with life-threaten...

Time-Domain Evaluation of Cyclosporine Interaction with Hemodynamic Variability in Rats

“…In effect, the rMSSD differences between cyclosporine-treated rats and their control counterparts were virtually abolished after atropine administration. Notably, the rMSSD is believed to primarily reflect the vagal activity of the heart [3,31], a view which is supported by the present finding that rMSSD of control rats was reduced after vagal blockade but it was insensitive to β-adrenergic blockade. Together, the present findings implicate alterations in vagal cardiomotor activity, at least partly, in the deleterious effect of cyclosporine on heart rate variability.…”

“…The time-domain measurement of hemodynamic variability was employed in the present study to determine changes in the cardiovascular autonomic balance. Time-domain indices correlate with frequency-domain measurements and, therefore, provide a reliable evaluation of cardiovascular autonomic control [3,6,31,32]. The results showed that cyclosporine had no effect on blood pressure or its variability but caused remarkable increases in heart rate and decreases in heart rate variability.…”

“…The RR intervals were computed from the heart rate values (i.e. the reciprocal of heart rate in ms) [31,32]. Our previous studies and others have shown that the time-domain indices of hemodynamic variability correlate well with the frequency-domain measurements [3,6,33].…”

“…Three time-domain parameters were employed to measure hemodynamic variability as in previous studies including our own [3,6,31,32]. The standard deviation of the mean arterial pressure (SDMAP) was taken as a measure of blood pressure variability.…”

“…The SDRR is comparable to the total power of the spectrum of RR variability, which measures the overall autonomic balance of the heart. The rMSSD is largely validated as a measure of the parasympathetic input to the heart and, therefore, correlates with the high frequency power of the spectrum [3,6,31,32]. The short-term blood pressure variability and heart rate variability before (baseline) and after autonomic blockade were calculated by averaging the 5-min values (10 successive measurements at 30 sec intervals) of each variable at each time point.…”