The hypotensive action of rilmenidine is dependent on functional N-methyl-D-aspartate receptor in the rostral ventrolateral medulla of conscious spontaneously hypertensive rats.
Rilmenidine is a second-generation centrally acting antihypertensive drug that acts mainly through the activation of the imidazoline (I(1)) receptor in the rostral ventrolateral medulla (RVLM). To investigate the contribution of the N-methyl-D-aspartate receptor (NMDAR) to the hypotensive action of rilmenidine, experiments were undertaken in conscious male spontaneously hypertensive rats (SHRs). Microinjection of cumulative doses of rilmenidine (10, 20, and 40 nmol) at 10- to 15-min intervals, into the RVLM elicited dose-dependent hypotensive and bradycardic response. Pretreatment with intra-RVLM 2-amino-5-phosphonopentanoic acid (AP5) (2 nmol), a selective NMDAR antagonist, not only abolished the hypotensive response elicited by intra-RVLM rilmenidine (40 nmol) but also converted it to a pressor response (-24 +/- 1 versus 17 +/- 7 mm Hg; P < 0.05) and significantly attenuated the bradycardic response (-72 +/- 18 versus -24 +/- 20 bpm; P < 0.05). The blood pressure response to intra-RVLM N-methyl-D-aspartate (NMDA) depended on the dose applied. Whereas intra-RVLM NMDA (>20 pmol) produced the expected pressor response, a lower dose (10 pmol) reduced mean arterial pressure (MAP) (-14 +/- 3 mm Hg) and heart rate (-21 +/- 12 bpm). The divergent MAP responses were attenuated by intra-RVLM AP5 (2 nmol), which implicates the NMDAR in the pressor as well as the depressor response. The present findings suggest that the NMDAR in the RVLM of the SHR 1) exerts dual effects on blood pressure, with the response type depending on the level of NMDAR activation, and 2) plays a pivotal role in the hypotension mediated by I(1) receptor activation in the RVLM.
Zhang
Jian
J
Department of Pharmacology, The Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858, USA.
Abdel-Rahman
Abdel A
AA
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D008845:Microinjections; D016202:N-Methylaspartate / Q000494:pharmacology; D010080:Oxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D000077769:Rilmenidine
D000959:Antihypertensive Agents; D010080:Oxazoles; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D000077769:Rilmenidine