Reduced Cardiac Contractile Force Due to Sympathovagal Dysfunction Mediates the Additive Hypotensive Effects of Limited-Access Regimens of Ethanol and Clonidine in Spontaneously Hypertensive Rats

Abstract

Our previous attempts to investigate the long-term hemodynamic interaction between ethanol and clonidine in telemetered spontaneously hypertensive rats (SHRs) were hampered by the lack of a sustained hypotensive response to continuous clonidine exposure. This limitation was circumvented when we adopted a limited-access clonidine (8:30 AM-4:30 PM) paradigm in a recent study. The latter paradigm was employed here to evaluate the ethanol-clonidine interaction and possible roles of myocardial function and autonomic control in this interaction. Changes in blood pressure (BP), heart rate, maximum rate of rise in BP wave (ϩdP/dt max ), and spectral cardiovascular autonomic profiles were measured by radiotelemetry in pair-fed SHRs receiving clonidine (150 g/kg/day), ethanol [2.5% (w/v)], or their combination during the day for 12 weeks. Ethanol or clonidine elicited long-term decreases in BP, and their combination caused additive hypotensive response. Significant reductions in ϩdP/dt max were observed upon concurrent treatment with ethanol and clonidine, in contrast to no effect for individual treatment. In addition, the combined treatment increased the high-frequency (HF) spectral band of interbeat interval (IBI-HF nu , 0.75-3 Hz) and decreased low-frequency (IBI-LF nu , 0.2-0.75 Hz) bands and IBI LF/HF ratios. Clonidineevoked reductions in plasma and urine norepinephrine and BP-LF spectral power (measure of vasomotor sympathetic tone) were not affected by ethanol. In conclusion, concurrent treatment with ethanol and clonidine shifts the sympathovagal balance toward parasympathetic dominance and elicits exaggerated hypotension as a result of a reduction in cardiac contractile force.

Reduced Renal Mass, Salt-Sensitive Hypertension Is Resistant to Renal Denervation

“…This shows that in the absence of sympathoexcitation, global reductions in sympathetic activity to regions exclusive of the kidneys do not chronically lower BP. However, although we used doses of clonidine reported to reduce BP under conditions of sympathetic activation ( Abdel-Rahman, 1994 ; Thomas et al, 2003 ; El-Mas and Abdel-Rahman, 2010 ) it should be noted that the central actions of clonidine to lower BP in the present study, in the absence of increased sympathetic activity, may have been masked by direct stimulation of vasoconstrictor peripheral alpha-2 adrenoreceptors ( Francis, 1988 ; Lohmeier et al, 2009 ). These observations are especially relevant to clinical practice, as the BP response to clonidine has been proposed to determine the dependency of hypertension on elevated central sympathetic activity and predict the response to RDNx in RHT patients ( Katholi et al, 2010 ).…”

“…We therefore considered whether sympathetic activation to non-renal territories contributes to the hypertension in the absence of the renal nerves. Since we considered the possibility that the spectral analytical methods used may have been insufficiently sensitive to detect increases in global sympathetic activity after RDNx, we determined the sympathetic and hemodynamic responses to central sympathoinhibition by clonidine, administered chronically in doses that previously have been shown to lower BP and sympathetic activity in several experimental models of sympathetically mediated hypertension ( Abdel-Rahman, 1994 ; Thomas et al, 2003 ; El-Mas and Abdel-Rahman, 2010 ).…”

“…While on HS and after RRM and RDNx, global sympathetic activity was assessed from the hemodynamic and BP power spectral responses during administration of the centrally acting sympatholytic drug, clonidine. Clonidine (300–150 μg/kg/day; Sintofarm S.A., Bucharest, Romania) was administered in the drinking water for 6 and 3 days, respectively, in doses reported to reduce BP under conditions of sympathetic activation ( Abdel-Rahman, 1994 ; Thomas et al, 2003 ; El-Mas and Abdel-Rahman, 2010 ). The lower dose was administered to avoid the potentially deleterious rebound effect from clonidine withdrawal.…”

The effect of constant darkness and circadian resynchronization on the recovery of alcohol hangover

“…In fact, it is known that the normal circadian patterns of a variety of behavioral and physiological parameters are disrupted by alcohol administration, ingestion, and/or withdrawal syndrome [16]. For instance, in laboratory rats and mice as in human subjects, alcohol administration alters the circadian response related to locomotor activity, body temperature [17], sleep [18], food intake [19] and the secretion of the stress related hormones [20,21]. A low blood alcohol content of 0.1% reached after the consumption of several alcoholic drinks (about 6-8 beverages) could lead to impaired clock synchronization [22].…”