Proton magnetic resonance spectroscopy detection of neurotransmitters in dorsomedial medulla correlate with spontaneous baroreceptor reflex function

Abstract

Control of heart rate variability via modulation of sympathovagal balance is a key function of nucleus tractus solitarii and the dorsal motor nucleus of the vagus localized in the dorsomedial medulla oblongata. Normal blood pressure regulation involves precise balance of glutamate (Glu)-glutamine-gamma-aminobutyric acid transmitter systems, and angiotensin II modulates these transmitters to produce tonic suppression of reflex function. It is not known, however, whether other brain transmitters/metabolites are indicators of baroreflex function. This study establishes the concept that comprehensive baseline transmitter/metabolite profiles obtained using in vivo (1)H magnetic resonance spectroscopy in rats with well-characterized differences in resting blood pressure and baroreflex function can be used as indices of autonomic balance or baroreflex sensitivity. Transgenic rats with over-expression of renin [m(Ren2)27] or under-expression of glial-angiotensinogen (ASrAogen) were compared with Sprague-Dawley rats. Glu concentration in the dorsal medulla is significantly higher in ASrAogen rats compared with either Sprague-Dawley or (mRen2)27 rats. Glu levels and the ratio of Glu:glutamine correlated positively with indices of higher vagal tone consistent with the importance of these neurotransmitters in baroreflex function. Interestingly, the levels of choline-containing metabolites showed a significant positive correlation with spontaneous baroreflex sensitivity and a negative correlation with sympathetic tone. Thus, we demonstrate the concept that noninvasive assessment of neurochemical biomarkers may be used as an index of baroreflex sensitivity.

Figure 1

Representative in vivo ¹H MRS showing the metabolites of interest. From left to right N-Acetyl aspartate (NAA), N-acetyl aspartyl glutamate (NAAG), GABA, glutamine (Gln), glutamate (Glu), creatine (Cr), phosphocreatine (PCr), choline containing metabolites (tCho), myo-Inositol (mIno) and taurine (Tau). High resolution T₂ weighted coronal image illustrating the voxel located in the dorsal medulla used to obtain ¹H MRS (top right).

Figure 2

Spontaneous baroreflex sensitivity (BRS) determined by spectral analysis and sequence methods. Low Frequency alpha (LFα), High Frequency alpha (HFα), Sympatho-vagal balance (LF_RRI/HF_RRI) and by sequence method: Sequence up, down and all (Seq up, down and all). The data are expressed as mean ± SEM of 3 animals in each group.

Figure 3

Linear regression between Sequence all index (Seq all) and Glu/Gln ratio, Glu concentration and Choline-containing compounds concentration (GPC+PCh). Sprague-Dawley, (mRen2)27 and ASrAogen rats. R values shown in Table 2.

Figure 4

Correlate Summation Analysis (CSA) of neurotransmitters/metabolite concentration and metabolites ratios detected by ¹H MRS and indices of baroreflex sensitivity or sympathovagal balance determined by spectral analysis and sequence methods. CSA summary shows the significant linear correlations (positive relationships in solid shading; negative relationships in hatched shading) for the variables measured. From left to right and from top to bottom: PCr/Cr Phospohocreatine/Creatine ratio, LF_RRI/HF_RRI Low Frequency of beat to beat interval, Tau Taurine, Cr Creatine, NAAG/NAA N-Acetyl AspartylGlutamate/ N-Acetyl Aspartate ratio, HF alpha bsln High Frequency alpha index baseline, LF Low Frequency alpha index baseline, Seq up bsln Sequence up index baseline, Seq down blsn Sequence down baseline, Glu/Gln Glutamate/Glutamine ratio, Seq all bsln Sequence all baseline, GABA/Glu bsln GABA/Glutamate ratio baseline, NAA N-Acetyl Aspartate, GPC+PCh Glycerol Phosphorylcholine plus PhosphorylCholine, GABA, Gln Glutamine, SDMAP Standard deviation of beat to beat interval, SDRR Standard deviation of the beat-to-beat interval, HR Heart Rate, Glu Glutamate, Cr+PCr Creatine plus Phoshocreatine, rMSSD Root means square of successive beat-to-beat interval (SDRR), Ins Inositol, Glu+Gln Glutamate+Glutamine, MAP Mean arteria Pressure, NAA+NAAG N-Acetyl AspartylGlutamate/N-Acetyl Aspartate.