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

Abstract

High blood pressure is a major risk factor of cerebro-cardiovascular outcomes. Blood pressure is partly regulated by the autonomic nervous system and its reflex functions; therefore, we hypothesized that pharmacological intervention in the brainstem that can regulate blood pressure could be a novel therapeutic strategy to control hypertension. We infused a group II metabotropic glutamate receptor (mGluR) antagonist (LY341495, 0.40 μg/day), using a mini-osmotic pump, into the dorsal medulla oblongata in young spontaneously hypertensive rats (SHRs), as this area is adjacent to the nucleus tractus solitarius (NTS), of which the neurons are involved in baroreflex pathways with glutamatergic transmission. Blood pressure was recorded for conscious rats with the tail cuff method. A 6-week antagonist treatment from 6 to 12 weeks of age slightly but significantly increased systolic blood pressure by >30 mmHg, compared to that in SHRs without treatment. Moreover, the effect continued even 3 weeks after the treatment ended, and concurred with an increase in blood catecholamine concentration. However, heart rate variability analysis revealed that LY341495 treatment had little effect on autonomic activity. Meanwhile, mRNA expression level of mGluR subtype 2, but not subtype 3 in the brainstem was significantly enhanced by the antagonist treatment in SHRs, possibly compensating the lack of mGluR signaling. In conclusion, mGluR2 signaling in the dorsal brainstem is crucial for preventing the worsening of hypertension over a relatively long period in SHRs, through a mechanism of catecholamine secretion. This may be a specific drug target for hypertension therapy.

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.…”