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Cardiovascular Research 1999 43(1):219-227; doi:10.1016/S0008-6363(99)00060-7
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Congestive heart failure induces downregulation of P2X1-receptors in resistance arteries

Malin Malmsjöa, Anders Bergdahla, Sebastian Möllera, Xiao-He Zhaob, Xiang-Ying Sunb, Thomas Hednerb, Lars Edvinssona and David Erlinge1,a,*

aDivision of Experimental Vascular Research, Department of Internal Medicine, Lund University Hospital, Lund, Sweden
bDepartment of Clinical Pharmacology, Gothenburg University, Gothenburg, Sweden

* Corresponding author. Tel.: +46-46-173-545; fax: +46-46-328-242 david.erlinge{at}med.lu.se

Objective: Congestive heart failure (CHF) is accompanied by enhanced peripheral sympathetic nerve activity, increased vascular resistance and impaired peripheral blood flow. Besides noradrenaline and neuropeptide Y, the sympathetic nervous system also releases ATP, which has contractile effects mediated by different subtypes of P2-receptors on the vascular smooth muscle cells. The present study was designed to examine postsynaptic changes of the contractile responses to ATP and other extracellular nucleotides in CHF. Methods: CHF was induced by left coronary artery ligation resulting in a reproducible myocardial infarction in Sprague–Dawley rats. Contractile responses were examined in cylindrical segments of aorta and the mesenteric artery after endothelium removal. To determine if an altered response was regulated on the transcriptional level, competitive reverse transcription polymerase chain reaction (RT-PCR) was used to estimate the amount of P2X1-receptor mRNA. Results: ATP, which is both a P2X1- and a P2Y-receptor agonist, induced a weaker contraction in the mesenteric artery from CHF as compared to sham operated rats. A decrease in both potency and maximum contraction was shown for the selective P2X1-receptor agonist, {alpha}β-MeATP, in the mesenteric artery (pEC50=6.04 vs. 5.76, Cmax=57% vs. 33%, sham vs. CHF operated rats), but not in the aorta. Competitive RT-PCR also revealed decreased P2X1-receptor mRNA levels in CHF operated rats in the mesenteric artery (9106·103 vs. 714·103 molecules/µg, sham vs. CHF operated rats), while it remained unaltered in the aorta. To study the P2Y-receptor induced contractile effects, the P2X1-receptors were first desensitised with {alpha}β-MeATP (10–5 M for 8 min). After P2X1-receptors desensitisation, UTP and UDP induced strong contractions in both the mesenteric artery and in the aorta, while ATP and ADP were much less effective. These contractions were not altered by CHF, indicating that vascular contraction mediated by P2Y-receptors are unaffected by CHF. Conclusion: CHF induces downregulation of P2X1-receptor stimulated contraction in the mesenteric artery depending on decreased mRNA synthesis for the receptor, while the P2Y-receptor activity remains unchanged. Downregulation of P2X1-receptors appears to be specific for peripheral resistance arteries. This may represent a compensatory response to enhanced peripheral sympathetic nerve activity and increased vascular resistance in CHF.

KEYWORDS Adenosine triphosphate; autonomous nervous system; heart failure; gene expression; receptors

1 Dept. of Biological Cell Research 1, EB-blocket, Lund University Hospital, S-221 85 Lund, Sweden.


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