Central sympathoinhibition and peripheral neuronal uptake blockade after desipramine in rabbits

Abstract

Peripheral- and central nervous system (CNS)-mediated effects of desipramine (Des) on sympathetic nerves and the contribution of alpha 2-adrenoceptors to these effects were studied in conscious rabbits. Blood pressure, renal sympathetic nerve activity (SNA), and norepinephrine (NE) reuptake and spillover into plasma were measured before and after intracisternal (ic) or intravenous (i.v.) administration of Des. In other animals, NE spillover responses to i.v. Des were examined before and after alpha 2-adrenoceptor blockade with i.v. idazoxan. Treatment with i.v. Des blocked neuronal reuptake and decreased renal SNA but did not alter blood pressure or NE spillover. Decreased NE release by sympathetic nerves after i.v. Des was reflected by a decrease in the combined rate of NE reuptake and spillover. Treatment with ic Des (at 1.7% of the i.v. dose) decreased blood pressure and renal SNA and produced equivalent falls in NE reuptake and spillover, indicating little peripheral effect of centrally administered Des on the efficiency of neuronal reuptake. Thus Des had two distinct actions: the drug blocked neuronal reuptake by direct actions on nerve endings and reduced SNA by actions within the CNS. After ic Des, decreased SNA produced parallel falls in NE reuptake, spillover, and blood pressure. After i.v. Des, blockade of neurotransmitter reuptake increased NE concentrations at sympathoeffector junctions offsetting the fall in SNA, so that there was little change in NE spillover or blood pressure. However, after alpha 2-adrenoceptor blockade with i.v. idazoxan, NE spillover increased in response to i.v. Des. Thus the Des-induced decrease in NE release was partly mediated by an action of raised intrasynaptic NE concentrations on inhibitory alpha 2-adrenoceptors.

Influence of Sibutramine on blood pressure: evidence from placebo-controlled trials

“…[12][13][14] The latter effect may be related to a 'clonidine-like' sympatholytic effect of norepinephrine transporter inhibition in the brain. [10][11][12]14 In contrast, in the present study, chronic sibutramine treatment in obese patients increased blood pressure slightly or not at all. Body weight reduction with chronic treatment is an obvious difference between acute and long-term sibutramine application.…”

“…In the central nervous system, norepinephrine transporter blockade attenuates sympathetic outflow through activation of alpha-2 adrenoreceptors. 10 Therefore, the systemic application of any norepinephrine uptake-inhibiting drug is associated with complex and opposing cardiovascular effects. [11][12][13][14] For example, in normal-weight and normotensive young subjects, sibutramine acutely increases resting blood pressure.…”

Paradoxical Effect of Sibutramine on Autonomic Cardiovascular Regulation

“…10 A similar reduction in systemic norepinephrine spillover was observed in rabbits when desipramine was applied locally to the brain. 9 Thus, selective and nonselective norepinephrine transporter blockade leads to a substantial inhibition of sympathetic outflow from the central nervous system. The sympatholytic effect of norepinephrine transporter inhibition is mediated at least in part by central nervous system ␣ 2 -adrenoreceptors.…”

“…The sympatholytic effect of norepinephrine transporter inhibition is mediated at least in part by central nervous system ␣ 2 -adrenoreceptors. 9,21 Baroreflex-mediated inhibition of sympathetic activity in response to the increase in blood pressure may also be contributory. Interestingly, a sympatholytic effect indicated by a marked reduction in 24-hour urinary norepinephrine excretion has also been described for ephedrine, which is sometimes used in the treatment of obesity.…”

“…However, when applied to the central nervous system, norepinephrine transporter blockade paradoxically attenuates sympathetic activity. 9 Thus, systemic changes in norepinephrine transporter function due to mutations in the norepinephrine transporter gene or pharmacological manipulation are associated with complex and opposing cardiovascular effects. 10 -12 We conducted a randomized, double-blind, crossover study in young, healthy, normotensive volunteers to characterize the cardiovascular effects of sibutramine both at rest and during sympathetic stimulation.…”