Chronic stimulation of group II metabotropic glutamate receptors in the medulla oblongata attenuates hypertension development in spontaneously hypertensive rats

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.

Loss of Group II Metabotropic Glutamate Receptor Signaling Exacerbates Hypertension in Spontaneously Hypertensive Rats

“…Thus, we initially suspected that mGluR2/3 antagonists could have a therapeutic potential for hypertension treatment. Although this idea was negated, our results were consistent with our previous study, which showed mGluR2/3 “agonists” could suppress hypertension development in young SHRs [ 22 ]. Thus, mGluR2/3 could be important for hypertension development in SHRs and these receptors, and/or neurons expressing these receptors, may have memory functions in blood pressure regulation.…”

“…For mGluRs intervention, we chronically applied a selective mGluR2/3 antagonist, LY341495, into the dorsal medulla oblongata with the aid of an osmotic pump to block endogenous glutamate in rats during 6–12 weeks of age. In our previous study, we found that mGluR2/3 agonist treatment into the dorsal medulla oblongata could suppress the development of hypertension [ 22 ]. However, as NTS microinjection of the mGluR2/3 antagonist could also decrease mean blood pressure by approximately 18 mmHg in normotensive rats [ 18 ], the current study was considered very important for understanding pathophysiological mechanisms of blood pressure regulation.…”

Literature-Based Discovery to Elucidate the Biological Links between Resistant Hypertension and COVID-19

“…More recent work showed that uridine has a hypoglycemic effect that protects against diabetes-mediated functional and structural damage to cardiac mitochondria and disruption of mitochondrial quality-control systems in the diabetic heart [ 48 ]. metabotropic glutamate receptors —Chronic stimulation of group II metabotropic glutamate receptors in the medulla oblongata attenuates hypertension development in spontaneously hypertensive rats [ 49 ]. Group III metabotropic glutamate receptors regulate hypothalamic pre-sympathetic neurons through opposing presynaptic and postsynaptic actions in hypertension [ 50 ].…”

“…metabotropic glutamate receptors —Chronic stimulation of group II metabotropic glutamate receptors in the medulla oblongata attenuates hypertension development in spontaneously hypertensive rats [ 49 ]. Group III metabotropic glutamate receptors regulate hypothalamic pre-sympathetic neurons through opposing presynaptic and postsynaptic actions in hypertension [ 50 ].…”

The balance within

“…In addition, mGluR2/3 are also involved in the functional connection between NTS neurons and parasympathetic preganglionic neurons of the DMV, as well as to other areas, and modulate vagal sensory input and gastric motor responses [96]. For example, blocking mGluR2 signaling in the dorsal brainstem, an area including NTS (which is involved in baroreflex pathways through glutamatergic transmission), has been shown to lead to higher blood pressure in animal research [97], while mGluR2/3 stimulation in the same area can decrease blood pressure and sympathetic nervous activity [98]. Our findings, thus, suggest favorable effects of mGluR2/3 agonism on stress-related autonomic responses in accordance with animal data [95,99] and are relevant to individual stress responsiveness and anxiety and stress-related disorders susceptibility.…”