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EDITORIAL FOCUS
RENAL HEMODYNAMICS AND CARDIORENAL INTEGRATION
University of Calgary Smooth Muscle Research Group, Calgary, Alberta, Canada
THE HETEROGENEITY OF THE VASCULATURE in regard to regional variations in the properties of vascular smooth muscle is an area of major interest and is of primary importance in understanding circulatory regulation. The renal microcirculation represents a rather remarkable example of such heterogeneity. In cortical nephrons, the activating mechanisms of the smooth muscle myocytes comprising preglomerular afferent and postglomerular efferent arterioles are strikingly different. Membrane potential and voltage-gated Ca entry play a prominent role in the afferent arteriole but have no apparent influence on the vasoconstrictor responses of the cortical efferent arteriole (13). Major differences also exist between the ion channel expression patterns and properties of cortical versus juxtamedullary efferent arterioles (11). The heterogeneity of renal microvascular mechanism extends beyond the juxtamedullary efferent arterioles to the vascular pericytes regulating the conductance of the descending vasa recta capillaries and medullary blood flow. Unlike the rest of the "postglomerular" circulation, this segment exhibits features similar to the afferent arteriole, and tone is regulated by voltage-gated Ca entry and modulated by factors influencing membrane potential (18). In the present issue, Cao and coworkers (2) report on their continuing investigations of the ionic channels and biophysical properties of the descending vasa recta pericytes, and they present evidence that these smooth muscle-like cells express an inward rectifier potassium conductance.
Potassium channels play an essential role in controlling membrane potential and in regulating cellular functions that are triggered by electrical signaling. This, of course, includes vasoconstrictor responses that are dependent on the activation of voltage-gated calcium channels. Four classes of potassium channels are recognized to be of primary importance in vascular myocytes, voltage-gated (KV), calcium activated (KCa), ATP-sensitive (KATP), and inward rectifier (KIR) K channels. These differing K channel types have unique biophysical characteristics, differing patterns of distribution within the circulation, and play distinct roles in regulating vascular function (5, 6, 10, 14, 19). For example, KV is activated when the myocyte is depolarized to membrane potentials more positive than that of relaxed perfused arterioles [–45 mV (6)]. The activity of KCa is similarly increased by positive shifts in membrane potential, but the activation range is additionally modulated by intracellular Ca2+ (14). Thus a physiological role of both KV and KCa is thought to involve a modulation of the agonist- and or pressure-induced membrane depolarization. The activity of KATP is not affected by voltage but is altered by intracellular metabolic events, suggesting a role in vascular responses to physiological signals, such as hypoxia (10, 19). The activities of some members of the KV, KCa, and KATP families are stimulated by cyclic nucleotide-dependent kinases and inhibited by protein kinase C, contributing to the actions of vasodilator and vasoconstrictor agonists (6, 14, 19). Accordingly, an understanding of physiological regulation of blood vessel function requires knowledge of the individual contributions of diverse K channel types to the membrane potential and information on the regulation of these channels by cell signaling pathways.
In this regard, the study by Cao and coworkers in the present issue (2) represents a significant advance to our understanding of this important region of the renal microcirculation. Previous work from this innovative group has established that membrane depolarization and the activation of voltage-gated Ca channels play major roles in the contractile responses of descending vasa recta pericytes (17, 20, 25), underscoring the importance of the present report. For example, ANG II, which constricts this segment, inhibits pericyte K currents (16), in addition to stimulating a chloride current (24). As discussed in the present article, this group had previously demonstrated that KATP exerts a basal influence on the pericyte membrane potential (3), and in the present study, they show an additional significant contribution of KIR. The bulk of this work is important, not only to our understanding of the renal medullary circulation but, in more general terms, to our understanding of the properties of contractile vascular pericytes. Pericytes are a heterogeneous cell type, exhibiting diverse properties and roles in regard to capillary development and function. We have only begun to appreciate the role of the contractile smooth muscle-like pericytes in blood flow regulation. However, a physiological function of pericytes in regulating renal medullary blood flow is clearly indicated (18), and a similar role is suggested in the retinal circulation (1). To my knowledge, the report by Cao et al. (2) is the first to demonstrate that vascular pericytes express KIR.
Of the four types of K channel mentioned above, KIR is unique in that its expression is generally restricted to resistance vessels, and this channel is rarely seen in larger conduit arteries or other smooth muscle types (10, 19). This pattern of distribution suggests a primary importance in regard to physiological responses governing tissue perfusion and blood flow regulation. In this regard the report by Cao et al. (2) is consistent with the role that pericytes are suggested to play in regulating the medullary circulation. Of the vascular K channel types, KIR is the least characterized, in part, because of its limited distribution and the difficulties of investigating ion channel regulation in microvessels. For example, although protein kinase C is known to inhibit the activities of other smooth muscle K-channel types, the potential role of this signaling pathway in the regulation of microvascular KIR channels is not fully resolved (5). However, the unique biophysical characteristics of KIR suggest mechanisms contributing to some of its proposed physiological roles. As the name implies, the outward or hyperpolarizing current through this channel is impeded by its rectification properties. Elevations in extracellular K+ at the outer vestibule of the channel alter this property, reducing a polyamine block of K+ efflux and increasing the outward current passed by the channel (15). The resultant effect is that modest elevations in interstitial K+ concentrations are capable of evoking a K-induced hyperpolarization and vasodilation through this mechanism in vessels expressing KIR (19).
A physiological importance of this phenomenon relates to local regulatory mechanisms. For example in the cerebral microcirculation, increased neural activity can result in modest elevations in extracellular K+, eliciting hyperpolarization and vasodilation in the microvasculature feeding this region (19). Whether such a function underlies the role of KIR in the renal circulation is unexplored. Another potential role for this phenomenon concerns the suggestion that extracellular K+ might be the long-sought endothelium-derived hyperpolarizing factor (EDHF). EDHF responses are more prominent in small resistance vessels than in larger conduit vessels, and a major component of this response is dependent on charybdotoxin- and apamin-sensitive endothelial KCa channels (12). It has been suggested that endothelial K+ efflux via these channels sufficiently elevates K+ in the vicinity of KIR and the electrogenic Na+-K+-ATPase of the underlying vascular myocytes to trigger a K+-induced hyperpolarization and vasodilation (7). For a number of reasons, this postulate, however, remains controversial. For example, many vessels exhibiting EDHF responses do not express KIR or exhibit K+-induced vasodilation (12). Moreover, the EDHF responses seen in vessels exhibiting a strong dependence on KIR are often not affected by barium. A prime example is the renal afferent arteriole. Barium blockade of KIR fully prevents K+-induced vasodilation (4) but does not affect the charybdotoxin and apamin-sensitive EDHF response of this vessel (23). Whether KIR contributes to endothelium-dependent responses of the vasa recta is, however, a very interesting question that is prompted by the report by Cao et al. (2).
Another important characteristic of small resistance vessels expressing KIR is that electrical responses originating at one location can be transmitted along the vessel to evoke vasomotor responses at remote sites. These conducted responses occur over relatively large distances and are generally thought to be mediated by a passive electrotonic current spread through gap junction communications in both the endothelium and underlying myocytes (22). However, the excessive length constants that are often observed also suggest the possibility that a regenerative process may be involved. In this regard, recent studies implicating an essential role of KIR in conducted hyperpolarization and vasodilation are of considerable interest. As first shown by Rivers et al. (21), the ability of a local application of hyperpolarizing stimuli to elicit remote vasodilatory responses in coronary arterioles is prevented by micromolar concentrations of barium but not other K-channel blocking agents. Horiuchi et al. (9) and Goto et al. (8) demonstrated similar effects of barium in cerebral-penetrating arterioles and small mesenteric arteries, respectively. In each case, KIR blockade prevented or impaired conducted vasodilation or hyperpolarization, and evidence was presented suggesting a role of KIR in the underlying myocytes. Of interest, Goto et al. (8) further reported that the effects of barium were not seen in hypertensive animals, and this group exhibited impaired conductance. The mechanisms underlying this apparent dependence of conducted responses on KIR are not fully understood, but if this represents a general phenomenon, it would be of major importance in regard to our understanding of the specific roles of KIR in the microcirculation. It is interesting to speculate that if conducted responses are seen in the descending vasa recta and play a physiological role in regulating the medullary circulation, the recent finding by Cao and coworkers (2) that KIR is a prominent outward current in vasa recta pericytes may have further significance.
FOOTNOTES
Address for reprint requests and other correspondence: R. Loutzenhiser, Dept. of Pharmacology and Therapeutics, Univ. of Calgary Faculty of Medicine, Calgary, Alberta T2N 4N1 Canada (E-mail: rloutzen{at}ucalgary.ca)
REFERENCES
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