The Journal of Neurophysiology Vol. 85 No. 5 May 2001, pp. 2177-2183
Copyright ©2001 by the American Physiological Society

Chronotropic Effect of Angiotensin II via Type 2 Receptors in Rat Brain Neurons

 ¹Department of Physiology, College of Medicine and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610; and  ²Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama 36849-5519

Zhu, Mingyan, Colin Sumners, Craig H. Gelband, and Philip Posner. Chronotropic Effect of Angiotensin II via Type 2 Receptors in Rat Brain Neurons. J. Neurophysiol. 85: 2177-2183, 2001. Previously, we determined that angiotensin II (Ang II) elicits an Ang II type 2 (AT₂) receptor-mediated increase of neuronal delayed rectifier K⁺ (I_KV) current in neuronal cultures from newborn rat hypothalamus and brain stem. This requires generation of lipoxygenase (LO) metabolites of arachidonic acid (AA) and activation of serine/threonine phosphatase type 2A (PP-2A). Enhancement of I_KV results in a decrease in net inward current during the action potential (AP) upstroke as well as shortening of the refractory period, which may lead to alterations in neuronal firing rate. Thus, in the present study, we used whole-cell current clamp recording methods to investigate the AT₂ receptor-mediated effects of Ang II on the firing rate of cultured neurons from the hypothalamus and brain stem. At room temperature, these neurons exhibited spontaneous APs with an amplitude of 77.72 ± 2.7 mV (n = 20) and they fired at a frequency of 0.8 ± 0.1 Hz (n = 11). Most cells had a prolonged early after-depolarization that followed an initial fully developed AP. Superfusion of Ang II (100 nM) plus losartan (LOS, 1 µM) to block Ang II type 1 receptors elicited a significant chronotropic effect that was reversed by the AT₂ receptor inhibitor PD 123,319 (1 µM). LOS alone had no effect on any of the parameters measured. The chronotropic effect of Ang II was reversed by the general LO inhibitor 5,8,11,14-eicosatetraynoic acid (10 µM) or by the selective PP-2A inhibitor okadaic acid (1 nM) and was mimicked by the 12-LO metabolite of AA 12-(S)-hydroxy-(5Z, 8Z, 10E, 14Z)-eicosatetraynoic acid. These data indicate that Ang II elicits an AT₂ receptor-mediated increase in neuronal firing rate, an effect that involves generation of LO metabolites of AA and activation of PP-2A.