Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans

Abstract

In isolated organs, or when given in low dose intra-arterially, tricyclic antidepressant drugs are known to block reuptake of norepinephrine into sympathetic nerve varicosities, with a resultant increased norepinephrine washout. On the other hand, systemic administration of such drugs in humans reduces norepinephrine spillover to plasma. To clarify these seemingly contradictory findings, we have measured concurrently muscle sympathetic activity in the peroneal nerve (microneurography) and rates of norepinephrine spillover to plasma for the body as a whole and for the heart, the kidneys, and the forearm (radiotracer technique), both before and after intravenous infusion of desipramine, 0.5 mg/kg. Desipramine lowered the overflow of norepinephrine to plasma for the body as a whole and from the forearm and the kidneys (by 30-50%) but increased cardiac norepinephrine spillover by 25%. Both the number of sympathetic bursts per min in the peroneal nerve and their mean voltage amplitudes were markedly reduced after desipramine; total activity (bursts/min x mean burst amplitude) fell by approximately 90%. The effects of desipramine on norepinephrine spillover are explicable in terms of inhibition of central sympathetic outflow, balanced against the local blockade of transmitter reuptake. In most sites, the predominant effect is a reduction of norepinephrine overflow. For the heart, where reuptake is so important in transmitter disposition, the net effect is increased overflow.

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.…”

“…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. Yet, the drug profoundly attenuates the pressor response to sympathetic stimuli through a 'clonidine-like' sympatholytic effect.…”

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation

“…In animals, NET inhibition in the brain decreases sympathetic activity through ␣ 2 -adrenoreceptor stimulation (9). In human subjects, systemic NET inhibition decreases muscle sympathetic nerve activity and resets the sympathetic baroreflex to higher blood pressure values (7,12,22). Central sympathetic inhibition is opposed by sympathetic stimulation through NET inhibition in peripheral tissues (7).…”

“…In human subjects, systemic NET inhibition decreases muscle sympathetic nerve activity and resets the sympathetic baroreflex to higher blood pressure values (7,12,22). Central sympathetic inhibition is opposed by sympathetic stimulation through NET inhibition in peripheral tissues (7). Thus the net result of NET inhibition on regional hemodynamics differs between tissues.…”

“…NET, norepinephrine transporter; NS, not significant. (7,13). Predominant cardiac sympathetic stimulation with NET inhibition may be explained by ultrastructural or functional differences in cardiac adrenergic nerve terminals (6).…”