Knockout blow for channel identity crisis : vasodilation to potassium is mediated via Kir2.1.

The normal concentration of potassium ion (K ) in extracellular fluid is '3 to 5 mmol/L.1 In contrast to the depolarization and contraction of vascular muscle that are commonly produced by high concentrations of K, small to moderate increases in the concentration of extracellular K produce membrane hyperpolarization and relaxation in a variety of blood vessels in vitro.2–9 This vasodilator response is particularly prominent in cerebral arteries.2,3–5 Because K is released during normal neuronal and muscle activity, this mechanism may play a role in the coupling of cellular metabolism and local blood flow.10–12 Several mechanisms have been proposed to contribute to K-induced hyperpolarization of vascular muscle and vasodilatation. The two most studied have been (1) increased activation of Na/K-ATPase and (2) increased activity of inwardly rectifying K channels (Kir).2–4,8 These studies have relied almost exclusively on the use of pharmacological inhibition with ouabain and extracellular barium ion (Ba), respectively. Although a ouabain-sensitive vascular response may be present for very modest increases in extracellular K (,5 mmol/L), the major sustained component elicited by higher concentrations of K (7 to 20 mmol/L) is Basensitive.2–5,8 Because of these findings, recent interest has focused on Kir channels as the key signaling pathway that produces vasodilatation through physiological elevations in extracellular K. K channels are thought to play a major role in regulation of vascular tone by producing hyperpolarization of vascular muscle in response to diverse stimuli including receptormediated agonists, second messengers, and Ca sparks.13–15 Hyperpolarization of vascular muscle leads to vasorelaxation by a mechanism that is thought to involve closure of voltage-operated Ca channels and a lowering in the levels of intracellular Ca. As the name indicates, Kir channels display inward rectification, ie, they conduct inward current much more readily than outward current. Importantly, though, a small increase above the physiological extracellular K concentration leads to a shift in the channel gating properties and an increase in the resting outward K current through Kir channels. Hence, a modest increase in extracellular K can paradoxically lead to vascular hyperpolarization due to K efflux through Kir channels. The biology of K channels is extremely complex, given that there is enormous diversity at the molecular level in mammalian cells.16 Even if one focuses on vascular muscle, the array of K channels that have been reported to be expressed is intimidating for those interested in precisely defining mechanisms that regulate vascular tone. For example, at least five voltage-dependent K channels are expressed in pulmonary arteries.17 Overall, there are at least seven subfamilies of Kir channels.16 Within the brain, immunocytochemistry has suggested that three isoforms of Kir are present in cerebral arteries (Kir2.1, Kir2.2, and Kir2.3).18 In contrast, another study suggested that only the Kir2.1 channel was functionally expressed in cerebral vascular muscle.19 This conclusion was formed on the basis of several lines of evidence including the finding that the Kir currents in normal vascular muscle most closely resemble those observed in Xenopus oocytes expressing cloned Kir2.1 channels.19 Unfortunately, although pharmacological inhibitors such as Ba can be very useful in implicating the involvement of a particular family of K channels in a functional response, these inhibitors cannot distinguish which K channel protein is the key for carrying a specific K current. Gene targeting in mice is increasingly being used to establish the functional importance of a particular gene product and is now used widely in many disciplines. A major strength of the gene targeting approach is that it allows the use of a precise genetic alteration to study complex responses in cells or tissue or in intact animals. Gene targeting offers a level of specificity that traditional K channel pharmacology cannot achieve. In the study by Zaritsky et al,20 gene-targeted mice were produced that were deficient in expression of either of two channels, Kir2.1 or Kir2.2. After generation of the mice, electrophysiological studies of isolated cerebral myocytes revealed that Ba-sensitive inward K currents were present in wild-type mice but not in Kir2.1-deficient mice. Functional studies were also performed using isolated, but pressurized, cerebral arteries. In wild-type mice, raising extracellular K from 6 to 15 mmol/L produced marked Ba-sensitive vasodilation that is consistent with many previous studies.2–6 The key novel finding was that the dilator response to K was completely absent in Kir2.1-deficient mice. The absence of vasodilation in response to K in Kir2.1 mice represented a selective change, because both the myogenic contractile response to increased intravascular pressure and the vasodilator response to forskolin (an activator of adenylate cyclase) The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia; Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa. Correspondence to Frank M. Faraci, PhD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242-1081. E-mail [email protected] (Circ Res. 2000;87:83-84.) © 2000 American Heart Association, Inc.