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.


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 gamma-aminobutyric acid) were monitored before and after intravenous administration of CV 11974 (5 mg/kg), nitroglycerin (5 mu g/kg per min) or vehicle.


RESULTS
In SHR, CV 11974 decreased mean arterial pressure (-40 +/- 6 mmHg) accompanied by significant increases in the release of inhibitory amino acids, glycine (411 +/- 83%) and gamma-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 mmHg; nitroglycerin, -20 +/- 7 mmHg) without change in the release of amino acids in the rostral ventrolateral medulla. Selective perfusion of glycine or gamma-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 gamma-aminobutyric acid receptor in the rostral ventrolateral medulla attenuated the antihypertensive response induced by the intravenous AT1 antagonist in SHR.


CONCLUSIONS
The present results suggest that the release of the inhibitory amino acids glycine and gamma-aminobutyric acid in the rostral ventrolateral medulla contributes to the depressor action of this AT1 receptor antagonist in the genetic hypertensive rat model.
Department of Geriatric Medicine, Osaka University Medical School, Japan.
K
K
Yamada
A
A
Moriguchi
H
H
Mikami
N
N
Okuda
J
J
Higaki
T
T
Ogihara
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000503:physiopathology; D018377:Neurotransmitter Agents / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013777:Tetrazoles / Q000627:therapeutic use*
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018377:Neurotransmitter Agents; D013777:Tetrazoles; C081643:candesartan