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(Circulation. 2008;117:773-780.)
© 2008 American Heart Association, Inc.

Hypertension

Adenosine Modulates Cardiovascular Functions Through Activation of Extracellular Signal-Regulated Kinases 1 and 2 and Endothelial Nitric Oxide Synthase in the Nucleus Tractus Solitarii of Rats

Wen-Yu Ho, MD; Pei-Jung Lu, PhD; Michael Hsiao, DVM, PhD; Hwong-Ru Hwang, MD; Yu-Chou Tseng, BS; Mao-Hsiung Yen, PhD; Ching-Jiunn Tseng, MD, PhD

From the Graduate Institute of Medical Sciences (W.-Y.H.) and Department of Pharmacology (M.-H.Y., C.-J.T.), National Defense Medical Center, Taipei, Taiwan; Genomics Research Center (M.H.), Academia Sinica, Taipei, Taiwan; Graduate Institute of Clinical Medicine (P.-J.L.) and Department of Pharmacology (Y.-C.T.), National Cheng Kung University, Tainan, Taiwan; Institute of Biomedical Sciences (C.-J.T.), National Sun Yat-sun University, Kaohsiung, Taiwan; Institute of Clinical Medicine (C.-J.T.), National Yang-Ming University, Taipei, Taiwan; Department of Internal Medicine (H.-R.H.) and Department of Medical Education and Research (C.-J.T.), Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Correspondence to Ching-Jiunn Tseng, MD, PhD, Department of Medical Education and Research, Kaohsiung Veterans General Hospital, 386, Ta-Chung 1st Rd, Kaohsiung, Taiwan 813, Taiwan, Republic of China. E-mail cjtseng{at}vghks.gov.tw

Received April 18, 2007; accepted November 21, 2007.

Background— The nucleus tractus solitarius (NTS) is the primary integrative center for baroreflex. Adenosine has been shown to play an important modulatory role in blood pressure control in the NTS. Our previous results demonstrated that adenosine decreases blood pressure, heart rate, and renal sympathetic nerve activity and modulates baroreflex responses in the NTS. We also demonstrated that a nitric oxide synthase (NOS) inhibitor may block the cardiovascular effects of adenosine in the NTS, which suggests interaction between the adenosine receptor and NOS. However, the signaling mechanisms of adenosine that induce nitric oxide release in the NTS remain uncertain. The aim of the present study was to investigate the possible signal pathways involved in the cardiovascular regulation of adenosine in the NTS.

Methods and Results— Adenosine was microinjected into the NTS of urethane-anesthetized male Sprague-Dawley rats. Blood pressure and heart rate decreased significantly after microinjection. The cardiovascular effects of adenosine were attenuated by prior administration of the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor PD98059 (6 nmol/60 nL) or an endothelial NOS–selective inhibitor, L-NIO (6 nmol/60 nL); however, the neuronal NOS–specific inhibitor vinyl-L-NIO (600 pmol/60 nL) did not attenuate the cardiovascular effects of adenosine. Western blot and immunohistochemistry studies demonstrated that adenosine induced extracellular signal-regulated kinases 1 and 2 and endothelial NOS phosphorylation in the NTS. Pretreatment with PD98059 diminished the endothelial NOS phosphorylation evoked by adenosine.

Conclusions— These results represent a novel finding that extracellular signal-regulated kinases 1 and 2 is involved in cardiovascular regulation in the NTS. They also indicate that the cardiovascular modulatory effects of adenosine in the NTS are accomplished by activation of mitogen-activated protein kinase/extracellular signal-regulated kinases 1 and 2 and then endothelial NOS.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 117: 711-713. [Full Text]