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Endogenous substance P modulates human cardiovascular regulation at rest and during orthostatic load

¹Department of Pediatrics, Division of Pediatric Cardiology, ²Department of Medicine, Division of Clinical Pharmacology, Autonomic Dysfunction Center, ³Department of Biostatistics, Vanderbilt University School of Medicine, and ⁴Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee

Submitted 2 September 2006 ; accepted in final form 4 January 2007

Substance P (SP) is a peptide neurotransmitter identified in many central and peripheral neural pathways. Its precise role in human physiology has been difficult to elucidate. We used the selective neurokinin 1 (NK₁) antagonist aprepitant as a pharmacological probe to determine the role of endogenous SP in human cardiovascular regulation. We performed a randomized, double-blind, placebo-controlled, crossover trial in healthy subjects. Blockade of endogenous NK₁ receptors reduced resting muscle sympathetic activity 38% (P = 0.002), reduced systemic vascular resistance by 25% (P = 0.021), and increased cardiac index by 47% (P = 0.006). This constellation of changes did not, however, alter either blood pressure or heart rate in the supine position. NK₁ antagonism also raised orthostatic heart rate change by 38% (P = 0.023), although during the incremental postural adjustment on the tilt table neither heart rate nor blood pressure was altered significantly. Despite a mildly attenuated vagal baroreflex with SP blockade, the depressor and pressor responses to nitroprusside and phenylephrine did not differ compared with placebo, suggesting other compensatory mechanisms. NK₁ blockade manifests as a decrease in muscle sympathetic nerve activity and systemic vascular resistance. Our study suggests SP exerts a tonic enhancement of sympathetic outflow to some cardiovascular structures via its modulation of the NK₁ receptor. Most likely, this ubiquitous neurotransmitter exerts effects at multiple sites that, in the aggregate, are relatively well compensated under many circumstances but may emerge with perturbations. This study is consistent with a role for SP afferents in supporting peripheral vascular resistance.

neurokinin 1; tachykinin; blood pressure; syncope; hypertension