The effect of central amino acid neurotransmitters on the antihypertensive response to angiotensin blockade in spontaneous hypertension

Objective : To investigate the effects of central amino acid neurons on the antihypertensive action of a newly developed angiotensin II type 1 receptor (AT1) antagonist, CV 11974. Materials and methods : We measured the release of various amino acids in the rostral ventrolateral medulla using the brain microdialysis technique. A microdialysis probe was inserted into the exposed rostral ventrolateral medulla in male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats anaesthetized with urethane. Mean arterial pressure and the release of amino acids (glutamate, glycine, glutamine, taurine and y-aminobutyric acid) were monitored before and after intravenous administration of CV 11974 (5 mg/kg), nitroglycerin (5 μg/kg per min) or vehicle. Results : In SHR, CV11974 decreased mean arterial pressure (-40 ± 6 mmHg) accompanied by significant increases in the release of inhibitory amino acids, glycine (411 ± 83%) and γ-aminobutyric acid (363 ± 71%) in the rostral ventrolateral medulla, whereas intravenous nitroglycerin produced a decrease in mean arterial pressure (-35 ± 4 mmHg) without changes in amino acid release. In WKY rats, both intravenous CV 11974 and intravenous nitroglycerin produced smaller but significant decreases in mean arterial pressure (CV 11974, -18 ± 5 mm Hg ; nitroglycerin, -20 ± 7 mmHg) without change in the release of amino acids in the rostral ventrolateral medulla. Selective perfusion of glycine or γ-aminobutyric acid into the rostral ventrolateral medulla caused a larger mean arterial pressure reduction in SHR than in WKY rats. Furthermore, the use of a specific antagonist of glycine or of the γ-aminobutyric acid receptor in the rostral ventrolateral medulla attenuated the antihypertensive response induced by the intravenous AT 1 antagonist in SHR. Conclusion : The present results suggest that the release of the inhibitory amino acids glycine and γ-aminobutyric acid in the rostral ventrolateral medulla contributes to the depressor action of this AT 1 receptor antagonist in the genetic hypertensive rat model.