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 (AT(1)) antagonist, CV 11974. Materials and methods: We mea sured 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 s pontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats anaes thetized with urethane. Mean arterial pressure and the release of amin o acids (glutamate, glycine, glutamine, taurine and gamma-aminobutyric acid) were monitored before and after intravenous administration of C V 11974 (5 mg/kg), nitroglycerin (5 mu g/kg per min) or vehicle. Resul ts: In SHR, CV11974 decreased mean arterial pressure (-40 +/- 6 mmHg) accompanied by significant increases in the release of inhibitory amin o acids, glycine (411 +/- 83%) and gamma-aminobutyric acid (363 +/- 71 %) in the rostral ventrolateral medulla, whereas intravenous nitroglyc erin produced a decrease in mean arterial pressure (-35 +/- 4 mmHg) wi thout changes in amino acid release. In WKY rats, both intravenous CV 11974 and intravenous nitroglycerin produced smaller but significant d ecreases in mean arterial pressure (CV11974, -18 +/- 5 mmHg; nitroglyc erin, -20 +/- 7 mmHg) without change in the release of amino acids in the rostral ventrolateral medulla. Selective perfusion of glycine or g amma-aminobutyric acid into the rostral ventrolateral medulla caused a larger mean arterial pressure reduction in SHR than in WKY rats. Furt hermore, the use of a specific antagonist of glycine or of the gamma-a minobutyric acid receptor in the rostral ventrolateral medulla attenua ted the antihypertensive response induced by the intravenous AT(1) ant agonist in SHR. Conclusion: The present results suggest that the relea se of the inhibitory amino acids glycine and gamma-aminobutyric acid i n the rostral ventrolateral medulla contributes to the depressor actio n of this AT(1) receptor antagonist in the genetic hypertensive rat mo del.