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The cardiovascular actions of fractalkine/CX3CL1 in the hypothalamic paraventricular nucleus are attenuated in rats with heart failure
Author(s) -
Ruchaya P. J.,
Antunes V. R.,
Paton J. F. R.,
Murphy D.,
Yao S. T.
Publication year - 2014
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/expphysiol.2013.075432
Subject(s) - microinjection , medicine , endocrinology , hypothalamus , heart failure , heart rate , autonomic nervous system , central nervous system , blood pressure
New Findings• What is the central question of this study? The chemokine fractalkine (FKN) and its cognate receptor, CX3CR1, are expressed in the brain, but their distribution and function within the paraventricular nucleus of the hypothalamus (PVN) have not been previously investigated. • What is the main finding and its importance? We show that both FKN and CX3CR1 receptor mRNA and protein are expressed in the PVN and that FKN elicits hypotension and tachycardia when exogeneously applied by microinjection, an effect that is attenuated in rats with heart failure. These findings are important because they demonstrate that FKN and its cognate receptor are expressed and play a role in controlling cardiovascular function within the PVN.The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the regulation of sympathetic nerve activity, which is significantly elevated in chronic heart failure (CHF). Fractalkine (FKN) and its cognate receptor, CX3CR1, are constitutively expressed in the central nervous system, but their role and physiological significance are not well known. The aims of the present study were to determine whether FKN plays a cardiovascular role within the PVN and to investigate how the actions of FKN might be altered in CHF. We show that both FKN and CX3CR1 are expressed on neurons in the PVN of rats, suggesting that they may have a physiological function in this brain nucleus. Unilateral microinjection of FKN directly into the PVN of anaesthetized rats elicited a significant dose‐related decrease in blood pressure (1.0 nmol, −5 ± 3 mmHg; 2.5 nmol, −13 ± 2 mmHg; 5.0 nmol, −22 ± 3 mmHg; and 7.5 nmol, −32 ± 3 mmHg) and a concomitant increase in heart rate (1.0 nmol, 6 ± 3 beats min −1 ; 2.5 nmol, 11 ± 3 beats min −1 ; 5 nmol, 18 ± 4 beats min −1 ; and 7.5 nmol, 27 ± 5 beats min −1 ) compared with control saline microinjections. In order to determine whether FKN signalling is altered in rats with CHF, we first performed quantitative RT‐PCR and Western blot analysis and followed these experiments with functional studies in rats with CHF and sham‐operated control rats. We found a significant increase in CX3CR1 mRNA and protein expression, as determined by quantitative RT‐PCR and Western blot analysis, respectively, in the PVN of rats with CHF compared with sham‐operated control rats. We also found that the blood pressure effects of FKN (2.5 nmol in 50 nl) were significantly attenuated in rats with CHF (change in mean arterial pressure, −6 ± 3 mmHg) compared with sham‐operated control rats (change in mean arterial pressure, −16 ± 6 mmHg). These data suggest that FKN and its receptor, CX3CR1, modulate cardiovascular function at the level of the PVN and that the actions of FKN within this nucleus are altered in heart failure.