Abstract
Impaired L-carnitine uptake correlates with higher blood pressure in adult men, and L-carnitine restores endothelial function in aortic rings from spontaneously hypertensive rat (SHR). Thus, endothelial dysfunction in hypertension could result from lower L-carnitine transport in this cell type. L-Carnitine transport is mainly mediated by novel organic cation transporters 1 (Octn1, Na+-independent) and 2 (Octn2, Na+-dependent); however, their kinetic properties and potential consequences in hypertension are unknown. We hypothesize that L-carnitine transport kinetic properties will be altered in aortic endothelium from spontaneously hypertensive rats (SHR). L-Carnitine transport was measured at different extracellular pH (pHo 5.5–8.5) in the absence or presence of sodium in rat aortic endothelial cells (RAECs) from non-hypertensive Wistar-Kyoto (WKY) rats and SHR. Octn1 and Octn2 mRNA relative expression was also determined. Dilation of endothelium-intact or denuded aortic rings in response to calcitonine gene related peptide (CGRP, 0.1–100 nmol/L) was measured (myography) in the absence or presence of L-carnitine. Total L-carnitine transport was lower in cells from SHR compared with WKY rats, an effect due to reduced Na+-dependent (Na+ dep) compared with Na+-independent (Na+ indep) transport components. Saturable L-carnitine transport kinetics show maximal velocity (V max), without changes in apparent K m for Na+ indep transport in SHR compared with WKY rats. Total and Na+ dep component of transport were increased, but Na+ indep transport was reduced by extracellular alkalization in WKY rats. However, alkalization reduced total and Na+ indep transport in cells from SHR. Octn2 mRNA was higher than Octn-1 mRNA expression in cells from both conditions. Dilation of artery rings in response to CGRP was reduced in vessels from SHR compared with WKY rats. CGRP effect was endothelium-dependent and restored by L-carnitine. All together these results suggest that reduced L-carnitine transport (likely via Na+-dependent Octn2) could limit this compound's potential beneficial effects in RAECs from SHR.
Highlights
Essential hypertension is characterized by high blood pressure without an identifiable primary cause [1,2]
We have characterized the kinetics of L-carnitine transport in primary cultures of rat aortic endothelial cells (RAECs) from nonhypertensive WKY rats and contrasted this information with cells from spontaneously hypertensive rats (SHR)
The kinetics assays for saturable overall transport of this amino acid (TSC) show that maximal transport capacity (Vmax/Km) for L-carnitine is lower in cells from SHR compared with WKY rats, a finding paralleled by reduced Vmax/ Km for the TSCNa+dep, but not the TSCNa+indep component
Summary
Essential hypertension is characterized by high blood pressure without an identifiable primary cause [1,2]. Other studies show that L-carnitine supplementation in healthy subjects improved postprandial flow-mediated dilation after a high-fat meal [11]. Taken together, all these findings suggest that the transport of L-carnitine into the endothelial cells could be an essential, limiting step of its potential beneficial biological effects in hypertension. Studies performed in spontaneously hypertensive rat (SHR) show that Lcarnitine restores endothelial function in preparations of aortic rings [24,25], and ameliorates the high-systolic arterial blood pressure exhibited by hypertensive animals [5,8,26]. We hypothesize that the activity of OCTNs-mediated membrane transport of Lcarnitine by the aortic endothelium is reduced in these hypertensive animals
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