Abstract
Baroreflex dysfunction is partly implicated in hypertension and one responsible region is the dorsal medulla oblongata including the nucleus tractus solitarius (NTS). NTS neurons receive and project glutamatergic inputs to subsequently regulate blood pressure, while G-protein-coupled metabotropic glutamate receptors (mGluRs) play a modulatory role for glutamatergic transmission in baroreflex pathways. Stimulating group II mGluR subtype 2 and 3 (mGluR2/3) in the brainstem can decrease blood pressure and sympathetic nervous activity. Here, we hypothesized that the chronic stimulation of mGluR2/3 in the dorsal medulla oblongata can alleviate hypertensive development via the modulation of autonomic nervous activity in young, spontaneously hypertensive rats (SHRs). Compared with that in the sham control group, chronic LY379268 application (mGluR2/3 agonist; 0.40 μg/day) to the dorsal medulla oblongata for 6 weeks reduced the progression of hypertension in 6-week-old SHRs as indicated by the 40 mmHg reduction in systolic blood pressure and promoted their parasympathetic nervous activity as evidenced by the heart rate variability. No differences in blood catecholamine levels or any echocardiographic indices were found between the two groups. The improvement of reflex bradycardia, a baroreflex function, appeared after chronic LY379268 application. The mRNA expression level of mGluR2, but not mGluR3, in the dorsal medulla oblongata was substantially reduced in SHRs compared to that of the control strain. In conclusion, mGluR2/3 signaling might be responsible for hypertension development in SHRs, and modulating mGluR2/3 expression/stimulation in the dorsal brainstem could be a novel therapeutic strategy for hypertension via increasing the parasympathetic activity.
Highlights
Hypertension is a leading risk factor for cardiovascular diseases worldwide [1], and blood pressure (BP) control is important in reducing the risk of these illnesses [2]
HR and BP were measured by the tail-cuff method throughout the developmental stages of hypertension, and autonomic nervous activity was evaluated by the power spectral analysis of heart rate variability (HRV) using a radio-telemetry system
This study showed that the development of hypertension was weakened by chronic mGluR2/3 agonist treatment in juvenile spontaneously hypertensive rats (SHRs)
Summary
Hypertension is a leading risk factor for cardiovascular diseases worldwide [1], and blood pressure (BP) control is important in reducing the risk of these illnesses [2]. Microinjection of mGluR modulators into the dorsal area of medulla oblongata has been previously attempted with SpragueDawley or Wistar rats for short-term administration. Of these modulators, agonists for group II mGluR subtypes 2 and 3 (mGluR2/3) could acutely change HR, BP, and sympathetic nervous activity [7, 13,14,15,16], but these results show discrepancies. We hypothesized that the chronic stimulation of mGluR2/3 in the dorsal medulla oblongata, especially NTS, of juvenile SHRs might alleviate the development of hypertension by modulating the autonomic nervous activities. HR and BP were measured by the tail-cuff method throughout the developmental stages of hypertension, and autonomic nervous activity was evaluated by the power spectral analysis of heart rate variability (HRV) using a radio-telemetry system
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