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(Hypertension. 2007;49:528.)
© 2007 American Heart Association, Inc.

Original Articles

Lack of Macrophage Migration Inhibitory Factor Regulation Is Linked to the Increased Chronotropic Action of Angiotensin II in SHR Neurons

Chengwen Sun; Hongwei Li; Yongxin Gao; Tomokazu Matsuura; Patrick A. Upchurch; Mohan K. Raizada; Colin Sumners

From the Department of Physiology and Functional Genomics and McKnight Brain Institute, University of Florida, Gainesville.

Correspondence to Colin Sumners, Department of Physiology and Functional Genomics, College of Medicine, Box 100274, 1600 SW Archer Rd, University of Florida, Gainesville, FL 32610-0274. E-mail csumners{at}phys.med.ufl.edu

Macrophage migration inhibitory factor acts via its intrinsic thiol–protein oxidoreductase activity to negatively regulate the neuronal chronotropic actions of angiotensin II in normotensive rat neurons. Because the chronotropic action of angiotensin II is potentiated in spontaneously hypertensive rat neurons, we investigated whether this negative regulatory mechanism is absent in these rats. Angiotensin II (100 nM) elicited an 89% increase in neuronal firing in Wistar–Kyoto rat hypothalamus and brain stem cultured neurons and an increase in intracellular macrophage migration inhibitory factor levels in the same cells. The chronotropic action of angiotensin II was significantly greater (212% increase) in spontaneously hypertensive rat neurons, but angiotensin II failed to alter macrophage migration inhibitory factor expression in these cells. Intracellular application of recombinant macrophage migration inhibitory factor (0.8 nM) or its specific neuronal overexpression via Ad5-SYN-MIF (1x10⁷ infectious units) significantly attenuated the chronotropic action of angiotensin II in spontaneously hypertensive rat neurons, similar to results from Wistar–Kyoto rat neurons. In contrast, C60S-macrophage migration inhibitory factor (0.8 nM), which lacks thiol–protein oxidoreductase activity, failed to alter the chronotropic action of angiotensin II in neurons from either rat strain. Thus, whereas macrophage migration inhibitory factor has the potential to depress the chronotropic action of angiotensin II in spontaneously hypertensive rat neurons, it is unlikely that this regulatory mechanism occurs, because angiotensin II does not increase the expression of this protein. The lack of this regulatory mechanism may contribute to the increased chronotropic action of angiotensin II in spontaneously hypertensive rat neurons.

Key Words: hypothalamus • neuronal activity • hypertension • thiol–protein oxidoreductase • reactive oxygen species

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