The Hypotensive Action of Rilmenidine is Dependent on FunctionalN-Methyl-d-aspartate Receptor in the Rostral Ventrolateral Medulla of Conscious Spontaneously Hypertensive Rats

Abstract

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 (Ϫ24 Ϯ 1 versus 17 Ϯ 7 mm Hg; P Ͻ 0.05) and significantly attenuated the bradycardic response (Ϫ72 Ϯ 18 versus Ϫ24 Ϯ 20 bpm; P Ͻ 0.05). The blood pressure response to intra-RVLM N-methyl-D-aspartate (NMDA) depended on the dose applied. Whereas intra-RVLM NMDA (Ͼ20 pmol) produced the expected pressor response, a lower dose (10 pmol) reduced mean arterial pressure (MAP) (Ϫ14 Ϯ 3 mm Hg) and heart rate (Ϫ21 Ϯ 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.

Actions of rilmenidine on neurogenic hypertension in BPH/2J genetically hypertensive mice

“…The main evidence for this comes from studies in conscious rabbits indicating that small doses of antagonists into the RVLM block the hypotensive actions of systemic rilmenidine [19]. Additionally, there is also evidence from the marked hypotensive effect of intra-RVLM injections of low-dose rilmenidine in rats [21,22]. To our knowledge, there has been limited assessment of the specific actions of rilmenidine in the RVLM of mice.…”

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

“…All surgical and experimental procedures are detailed in the Supplemental Materials and Methods and were conducted in accordance with and approved by the East Carolina University Institutional Animal Care and Use Committee and in accordance with the Guide for the Care and Use of Laboratory Animals (Institute for Laboratory Animal Research, 2011). These surgeries were performed as reported in our previous studies (Zhang and Abdel-Rahman, 2002;Penumarti and Abdel-Rahman, 2014). On the day of the experiment, the arterial catheter was flushed with heparin in saline (200 U/ml), connected to a Gould-Statham (Oxnard, CA) pressure transducer, and the BP of unrestrained rats was measured as mentioned in our previous studies (Nassar et al, 2011;Ibrahim and Abdel-Rahman, 2012a).…”

The Novel Endocannabinoid Receptor GPR18 Is Expressed in the Rostral Ventrolateral Medulla and Exerts Tonic Restraining Influence on Blood Pressure

“…All surgical, postoperative care, and experimental procedures were performed in accordance with, and approved by, the Institutional Animal Care and Use Committee and in accordance with the Guide for the Care and Use of Laboratory Animals (Institute for Laboratory Animal Research, 2011). Arterial catheterization, intra-RVLM cannulation and BP measurements were performed as reported in our previous studies (Mao and Abdel-Rahman, 1995;Zhang and Abdel-Rahman, 2002) and as detailed in the Supplemental Material.…”