Vascular action of glycine in hypertensive rat models

Description

<p>Glycine, a lipophilic non-essential amino acid biosynthesized from L-serine, L-alanine and L-threonine, plays a role in the biosynthesis of proteins, nucleotides, and glutathione. It is a neurotransmitter in the central nervous system and acts as a co-agonist at the N-methyl-D aspartate (NMDA) receptor. Oral administration of glycine is helpful in the management of schizophrenia. While long-term oral treatment with glycine is considered to exert a cardio-vascular protective role by overcoming endothelial dysfunction and oxidative stress, there are no systematic studies examining the cardiovascular effects of glycine. Recently, we showed that the precursor/metabolite of glycine, L-serine, evoked endothelium-dependent vasodilatation in rat mesenteric arterioles. Acute intravenous administration of L-serine produced a rapid, dose-dependent fall in blood pressure (BP) in both normotensive and hypertensive rats. These responses were abolished in the combined presence of the Ca²⁺ activated small and intermediate conductance K⁺ channel inhibitors, apamin and Tram-34/charybdotoxin. In contrast, intravenous administration of glycine evoked a fall in BP in normotensive Wistar-Kyoto (WKY) rats and an elevation of BP in spontaneously hypertensive rats (SHR), and in WKY rats subjected to chronic nitric oxide (NO) synthase (NOS) inhibition by oral treatment with NOS inhibitor, L-NAME (N^G-nitro-L-arginine-methylester). Therefore, <i>in vivo</i> and <i>in vitro</i> studies were designed to address the mechanisms that contribute to the opposite effects of glycine in normotensive <i>vs</i>. hypertensive rats.</p>
<p>Experiments were performed using 14 weeks old male WKY, chronic L-NAME treated WKY and SHR strains. <i>In vivo</i> studies involved examination of changes in systemic hemodynamic parameters such as mean arterial pressure (MAP), heart rate (HR), total peripheral resistance (TPR) and cardiac output (CO) as well as regional hemodynamic parameters of changes in blood flow and vascular resistance in major organs/tissues following acute intravenous administration of glycine using fluorescent microsphere distribution technique. Parallel complementary <i>in vitro</i> studies were conducted to examine the effects of glycine on changes in basal tone and phenylephrine (PE) constricted tone in aortic rings with endothelium-intact and endothelium-denuded states after isolation from WKY and SHR strains. All these studies were conducted in the presence and absence of two NMDA antagonists, MK-801 and memantine.</p>
<p>In normotensive WKY rats, glycine (1 mmol/L) administration decreased MAP (P<0.01), TPR (P<0.05) while it increased CO (P<0.01) and blood flow to brain (215%), kidney (190%) and heart (160%). In SHR and L-NAME treated WKY rats, glycine administration elevated MAP and TPR but reduced CO (P<0.01) and blood flow to brain, kidney and heart. These effects were abolished in animals pretreated with either MK-801 or memantine. These data are consistent with the likely expression of vascular NMDA receptors activated by glycine in brain and kidney. Glycine (0.5-3.0 mmol/L) <i>per se</i> increased basal tone (E_max1.4g) in aortic rings from all rats and it was absent following incubation with NMDA antagonist(s). The concentration-dependent vasodilatation (I_max43%) evoked by glycine in PE-constricted rings with intact endothelium of WKY rats was attenuated by either MK-801 or L-NAME. Such vasodilator responses to glycine could be abolished by pretreatment with either NMDA antagonist or L-NAME. In contrast, in PE-constricted rings of SHR strain, addition of glycine enhanced the tone and this was abolished in the presence of NMDA antagonist, MK-801.</p>
<p>Taken together, these data suggest that NMDA receptors, likely present on both endothelium and vascular smooth muscle cells, predominantly in brain, kidney and coronary vascular beds as well as the conduit vessel, aorta, could contribute to the systemic and regional hemodynmic effects of glycine. In normotensive WKY rats, addition of glycine promotes endothelium/NO-dependent vasodilatation subsequent to Ca2+ mobilization evoked following endothelial NMDA receptor activation by glycine. Thus, glycine-induced dose-dependent, reversible fall in MAP and TPR in normotensive WKY rats is likely associated with NO-dependent/endothelium-mediated vasodilatation. However, in hypertensive rat models such as in the SHR model with endothelial dysfunction and reduced NO bioavailability or in chronic L-NAME treated rats, glycine administration promotes vascular NMDA receptor activation leading to enhanced vascular tone resulting in increased TPR and MAP.</p>
<p>These observations are important and critical in terms of considering glycine as a possible antihypertensive agent as this was proposed by several earlier reports that did not explore the direct vascular effects of glycine in hypertensive animal models.</p>

Tags

Glycine

Hypertension

Additional Fields

Identifer	oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:SSU.etd-01132011-195940
Date	24 January 2011
Creators	Tripathy, Saswati
Contributors	Weber, Lynn, Gopalakrishnan, Venkat, Desai, Kaushik, Sawicki, Greg, Yu, Peter, Richardson, J Steven
Publisher	University of Saskatchewan
Source Sets	Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada
Language	English
Detected Language	English
Type	text
Format	application/pdf
Source	http://library.usask.ca/theses/available/etd-01132011-195940/
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