Evidence for clonidine presynaptically modulating amino acid release in the rostral ventral medulla: role in hypertension.
Reports suggested that the predominant site of action for the antihypertensive effects of clonidine is the rostral ventrolateral medulla (RVL), the presumed tonic vasomotor center. This study examined whether clonidine directly interacts with nerve terminal alpha 2-adrenergic receptors in the RVL to inhibit the release of sympathoexcitatory transmitters like glutamate (Glu) and aspartate (Asp), and/or facilitate the release of sympathoinhibitory transmitters like gamma-aminobutyric acid (GABA). Release of GABA and Glu was measured from synaptosomes prepared from the rostral ventral medulla of spontaneously hypertensive rats (SHR), a genetic model of hypertension, and normotensive Wistar-Kyoto rats (WKY). Quantification of neurotransmitter release was performed by high-performance liquid chromatography. Depolarization with 35 mM K+ significantly increased by 58-110% the release of GABA, Glu and Asp; however, no strain differences were observed. In contrast, spontaneous release of GABA and Asp was significantly lower in SHR than that of WKY (-36 and -41%, respectively); this effect was not observed for Glu. Clonidine (1 and 10 microM) enhanced the spontaneous release of GABA (+44%), Asp (+50%) and Glu (+70%) in SHR, but not WKY; this effect was prevented by yohimbine (1 microM). These data, together with previous findings, support the presence of facilitory alpha 2-adrenergic receptors on nerve terminals of GABAergic, glutamatergic and aspartatergic neurons in the rostral ventral medulla. These findings also suggest the existence of another inhibitory transmitter that may mediate the actions of clonidine to decrease sympathetic outflow from the RVL.
Tingley
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FD
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield 62702.
Arnerić
S P
SP
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology*; D005260:Female; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D006973:Hypertension / Q000378:metabolism*; D066298:In Vitro Techniques; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D015016:Yohimbine / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000596:Amino Acids; D005971:Glutamates; D018377:Neurotransmitter Agents; D015016:Yohimbine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D003000:Clonidine