The effect of dopamine type-2 receptor blockade on autonomic modulation

Abstract.

Dopamine2 (D2)-like receptor antagonists are widely used for the treatment of gastroparesis and vomiting. Metoclopramide (MCP), a peripheral and central D2-like receptor antagonist, stimulates the sympathetic nervous system and may alter autonomic modulation, but the net effect of MCP to the heart is not known. The aim of our study was to investigate the effects of MCP on cardiac autonomic modulation, using power spectral analysis of heart rate variability.

We evaluated the effect of MCP on cardiac autonomic modulation during prolonged supine and standing positions in 9 healthy men. We intravenously administered 10 mg MCP and placebo in a double blind and crossover manner to all participants during continuous electrocardiography recording. Placebo or MCP was administered after 15 minutes in supine position (REST phase), where participants remained for an additional 50 minutes (PSUP phase) and then stood up for 10 minutes (STA phase). Five-minute intervals were selected for power spectral analysis, and average values were calculated for low frequency (LF), normalized unit of LF (LFnu), high frequency (HF), normalized unit of HF (HFnu) components of the power spectrum, and for LF/HF ratio.

Heart rate alterations were statistically significant during placebo administration (Friedman’s p < 0.0001). These changes were related to the decrease in PSUP phase and increase in STA phase in post hoc analyses. There was a trend toward lower LFnu in PSUP phase (Friedman’s p = 0.050), but LF/HF ratio changes did not reach a statistically significant level during placebo administration. MCP administration prevented the decrease in heart rate and LFnu component was seen with placebo in PSUP phase. Heart rate alterations also reached a significant level during MCP administration (Friedman’s p = 0.002), and post hoc analyses showed that these changes were mainly related to the increase in STA phase. In contrast to placebo, MCP administration resulted in significant alterations in LFnu and LF/HF ratio (Friedman’s p = 0.004 and p = 0.003, respectively). Two-way ANOVA model for LF/HF ratio changes showed that MCP induced a significant upward shift in LF/HF ratio than placebo during each phase of the study (F = 5.570; p = 0.031).

We concluded that the net effect of MCP on sympathovagal balance is an increased sympathetic drive to the heart. MCP prevented the decrease in sympathetic drive to the heart during prolonged supine position and augmented sympathetic drive to the heart during mild sympathetic stimulation such as induced by standing up.