Role of potassium channels in coronary vasodilation

Abstract

K⁺ channels in coronary arterial smooth muscle cells (CASMC) determine the resting membrane potential (E _m) and serve as targets of endogenous and therapeutic vasodilators. E _m in CASMC is in the voltage range for activation of L-type Ca²⁺ channels; therefore, when K⁺ channel activity changes, Ca²⁺ influx and arterial tone change. This is why both Ca²⁺ channel blockers and K⁺ channel openers have such profound effects on coronary blood flow; the former directly inhibits Ca²⁺ influx through L-type Ca²⁺ channels, while the latter indirectly inhibits Ca²⁺ influx by hyperpolarizing E _m and reducing Ca²⁺ channel activity. K⁺ channels in CASMC play important roles in vasodilation to endothelial, ischemic and metabolic stimuli. The purpose of this article is to review the types of K⁺ channels expressed in CASMC, discuss the regulation of their activity by physiological mechanisms and examine impairments related to cardiovascular disease.

Keywords

coronary blood flow coronary vascular smooth muscle

Ca²⁺ channels, K⁺ channels and coronary blood flow

K⁺ channels dominate the membrane conductance of coronary arterial smooth muscle cells (CASMC) at rest and thus determine E _m (Figure 1). That is, E _m is closer to the Nernst equilibrium potential for K⁺ (E _K) than for other ions. E _K in arterial smooth muscle is estimated to be −83 mV.¹ An asymmetric distribution of K⁺ across the cell membrane is maintained by the Na⁺/K⁺-ATPase and provides a large chemical driving force for K⁺ efflux by diffusion through open channels. If K⁺-selective channels were the only type of channels open in CASMC at rest, K⁺ would diffuse out of the cell until an electrical potential of −83 mV is developed. E _m in CASMC, however, is not as negative as E _K; generally, values around −50 mV are observed.^2–7 This less negative value of E _m, compared with E _K, in CASMC is because other ion channels are open at rest (e.g. those permeable to ions with more positive reversal potentials, such as Na⁺ and Ca²⁺).

Figure 1

Electromechanical coupling in CASMC. The Na⁺/K⁺-ATPase accumulates intracellular K⁺, providing a large chemical gradient for diffusion of K⁺ through open channels. Efflux of K⁺ largely determines E _m, which regulates the open probability of L-type Ca²⁺ channels. The level of free intracellular Ca²⁺ determines the contractile state of coronary vascular smooth muscle. CASMC, coronary arterial smooth muscle cells

Balancing the hyperpolarizing influence of K⁺ channels with the depolarizing influence of other channels produces a stable E _m in CASMC typically between −60 and −40 mV. The voltage threshold for L-type Ca²⁺ current activation, and thus contraction, is in this range.^3,6,8,9 CASMC are generally electrically quiescent, respond to stimuli with graded potentials and do not normally display action potentials. However, if K⁺ channels are inhibited with tetraethylammonium (TEA; a non-selective blocker of K⁺ channels), Ca²⁺-dependent action potentials can be observed.^10–12 L-type Ca²⁺ channel inhibitors and K⁺ channel openers inhibit phasic contractions induced by TEA and 4-aminopyridine (4-AP; an inhibitor of voltage-dependent K⁺, K_V channels^5,12–16). Such findings have led to the hypothesis that coronary vasospasm may be related to reduced K⁺ conductance in CASMC.¹⁷

Multiple types of K⁺ channels are expressed in CASMC, but it seems that some have more important roles in determining E _m and the state of contraction under resting conditions. For example, 4-AP strongly contracts conduit coronary arteries,^15,18 whereas charybdotoxin, iberiotoxin, apamin and glibenclamide cause little or no contraction.¹⁵ Charybdotoxin and iberiotoxin inhibit large conductance Ca²⁺-activated K⁺ (BK_Ca) channels, apamin inhibits some small conductance Ca²⁺-activated K⁺ channels and glibenclamide inhibits ATP-dependent K⁺ (K_ATP) channels. There may be complex heterogeneity in ion channel expression and function throughout the coronary tree; while glibenclamide does not contract conduit coronary arteries, it does tend to diminish the balance between coronary blood flow and myocardial metabolism, indicating increased microvascular resistance.^19–22 BK_Ca, K_V and K_ATP channels have important roles in certain facets of coronary vascular regulation; therefore, the properties of these channels and the modulation of their activity are discussed in the next section.

Antagonists of L-type Ca²⁺ channels such as nifedipine, verapamil and diltiazem increase coronary blood flow,^23–26 as these drugs relax coronary arteries and arterioles.^27–30 Conversely, Bay K 8644, a dihydropyridine with agonist rather than antagonist properties, elicits coronary vasoconstriction.³¹ The coronary vasodilator effects of L-type Ca²⁺ channel blockers are rather simple to understand; these drugs directly inhibit a major Ca²⁺ entry pathway in CASMC and thus reduce the intracellular Ca²⁺ required to maintain contraction. The vasodilatory effects of K⁺ channel openers are similar; however, their mechanism involves an additional step to hyperpolarize E _m. Pinacidil and cromakalim, two K⁺ channel openers, increase coronary blood flow.^32–34 These agents relax coronary smooth muscle by activating K_ATP channels.^35–38 In doing so, these drugs render E _m more negative and reduce the open probability of L-type Ca²⁺ channels in CASMC,^8,9 thus limiting Ca²⁺ influx and promoting vasodilation. This interplay between K⁺ channels and voltage-dependent Ca²⁺ channels in CASMC represents a reasonably straightforward example of electromechanical coupling (Figure 2).

Figure 2

K⁺ channel openers and Ca²⁺ channel blockers. (a) Drugs that modulate L-type Ca²⁺ channel activity affect coronary vascular tone. Nifedipine, diltiazem and verapamil reduce intracellular Ca²⁺ and lead to vasodilation. In contrast, Bay K 8644 increases intracellular Ca²⁺ and leads to vasoconstriction. (b) K⁺ channel openers, e.g. K_ATP channel agonists pinacidil and cromakalim, hyperpolarize E _m. This reduces the open probability of L-type Ca²⁺ channels, lowers the free intracellular Ca²⁺ concentration and produces vasodilation. The K_ATP channel antagonist glibenclamide has an opposite effect

CASMC, of course, express a wide variety of cation and anion channels with important functions that extend far beyond electromechanical coupling (e.g. references^39–44); however, this review focuses on just a few of the types of K⁺ channels involved in coronary vasodilation. While only BK_Ca, K_V and K_ATP channels are discussed, it is clear that other K⁺ channels are expressed in CASMC and play important roles (e.g. additional types of Ca²⁺-activated K⁺ channels and inwardly rectifying K⁺ channels^45–47). Additionally, it is clear that the ion channels of other cells in the coronary vascular wall function to regulate microcirculatory tone (e.g. K_ATP channels in endothelial cells regulate NO release;^48,49); however, our discussion will be limited to K⁺ channels in CASMC.

Types of K⁺ channels expressed in CASMC

The K⁺ currents and the electrophysiological properties of CASMC have been demonstrated using patch clamp techniques (e.g. by Wilde and Lee⁵⁰ in dog coronary artery). CASMC E _m was −51 mV and the current was TEA-sensitive, K⁺-selective and abolished by intracellular Cs⁺. Input resistance was very high (>10⁸ Ohms); therefore, small changes in current produce large changes in E _m. K⁺ current increased with elevations in extracellular or intracellular Ca²⁺, indicating the functional expression of K_Ca channels. Total whole-cell K⁺ current consisted of at least two components based on amplitude, time dependence, sensitivity to Ca²⁺ and pharmacology. Specifically, there was a fast activating current followed by a larger and slower current; the fast component was more sensitive to block by extracellular Cs⁺, whereas the slow component was more sensitive to block by TEA. The slower component was increased by elevations in intracellular or extracellular Ca²⁺, but the fast component was little affected. Other patch clamp studies of rabbit and human CASMC elaborated on these two major types of K⁺ currents (established to be BK_Ca and K_V) and demonstrated a predominance of K_V current in the physiological range of E _m.^51–54 BK_Ca channels activate at more depolarized potentials than K_V channels in CASMC⁵² but increases in intracellular Ca²⁺ open BK_Ca channels at physiologically relevant voltages.^55,56 Activating Ca²⁺ for BK_Ca channels in CASMC comes from spontaneous release from intracellular stores,⁵⁶ L-type Ca²⁺ channels⁵⁷ and receptor stimulation.^58,59

The first patch clamp studies of CASMC K⁺ channels did not reveal notable K_ATP channel activity, but this is largely due to the use of conventional dialyzed patch techniques that included mmol/L concentrations of intracellular ATP and effectively inhibited K_ATP channels. Dart and Standen,^60,61 however, used nystatin- and amphotericin-perforated patch techniques (where the intracellular ATP concentration was not artificially manipulated) to demonstrate adenosine- and hypoxia-activated K_ATP current in CASMC. Pinacidil activates K_ATP currents in human CASMC regardless of the intracellular ATP concentration.^38,52 The discussion below concerns the molecular composition and regulation of BK_Ca, K_ATP and K_V in CASMC (Figure 3).

Figure 3

Macroscopic K⁺ currents in CASMC and molecular composition of the channels responsible. K_V and BK_Ca channels mediate the two most prominent currents, although K_ATP channels are also expressed. Functional BK_Ca channels can be formed by the assembly of four pore-forming α subunits, which contain regulatory regions responding to voltage and Ca²⁺. In CASMC, most BK_Ca channels are complimented by four accessory β1 subunits, which increase Ca²⁺/voltage sensitivity and alter biophysical and pharmacological properties. K_ATP channels are an octameric complex of four pore-forming α subunits and four regulatory sulfonylurea receptors (SUR). The likely K_ATP subunits in CASMC are Kir6.1 and SUR2B. Functional K_V channels are formed by the assembly of four pore-forming α subunits, which are sensitive to voltage. The addition of auxiliary or modifying subunits can change channel properties. The identity of K_V channel subunits in CASMC remains an active area of investigation; however, a major portion of the current is sensitive to correolide, indicative of K_V1 expression. CASMC, coronary arterial smooth muscle cells

BK_Ca channels in CASMC

BK_Ca channels are large conductance (>200 pS), voltage-sensitive K⁺ channels regulated by Ca²⁺ in an allosteric fashion.⁶² The assembly of four pore-forming α subunits, products of single alternatively spliced gene (KCNMA1), can form functional BK_Ca channels. Studies have identified four types of modulatory β subunits. The accessory β1 subunit (KCNMB1) increases sensitivity to Ca²⁺, slows activation and deactivation, and reduces sensitivity to iberiotoxin.⁶³ In human CASMC, the majority of BK_Ca channels contain this β1 subunit.⁶⁴ Multiple stimuli regulate BK_Ca channel activity. As can be surmised from the previous section, those coupling to coronary vasoconstriction typically inhibit BK_Ca channels, while those coupling to coronary vasodilation typically activate BK_Ca channels.

BK_Ca channels are involved in CASMC responses to endothelial stimulation. The coronary vascular endothelium produces a number of relaxing factors such as nitric oxide (NO), prostacyclin (PGI₂) and epoxyeicosatrienoic acids (EETs). While the term endothelium-derived hyperpolarizing factor (EDHF) is typically reserved for the mediator(s) of dilations remaining after inhibition of NO synthase and cyclooxygenase, the term EDHF should be applied to any endothelium-derived factor that activates K⁺ channels. That is, one can consider NO an EDHF, as it activates BK_Ca channels in CASMC.^65–68 S-nitrosothiols have similar effects on BK_Ca channels in CASMC, and the actions of both NO and S-nitrosothiols appear to involve cyclic guanosine monophosphate (cGMP) signaling.^68–70 Some metabolites of arachidonic acid produced by cyclooxygenase, such as PGE₂, activate BK_Ca channels through cAMP and cross-activation of the cGMP-signaling pathway.^71,72 Various metabolites of arachidonic acid produced by other enzyme systems, such as EETs from cytochrome P450 metabolism, activate BK_Ca channels in CASMC.^73–77

The mediators of ischemic and metabolic vasodilation in the coronary circulation have not been identified conclusively;^78,79 however, K⁺ channels appear to be end-effectors and several putative dilator mechanisms have been examined. Sympathetic stimulation plays an important role in coronary metabolic vasodilation^80,81 and the β-adrenergic agonist isoproterenol activates BK_Ca channels in CASMC.^72,82 This appears to be mediated by G_s α and cross-activation of cGMP-dependent protein kinase; dopamine has similar effects.^72,83 Adenosine is proposed as a mediator of ischemic and metabolic vasodilation; however, no patch clamp data show a stimulatory effect of adenosine on BK_Ca channels in CASMC (such data are available in mesenteric smooth muscle⁸⁴). H₂O₂, a putative metabolic vasodilator, activates BK_Ca channels in CASMC;⁸⁵ this may be mediated by activation of phospholipase A₂ and production of lipoxygenase metabolites.⁸⁶

A variety of substances that constrict coronary vessels inhibit BK_Ca channels. Angiotensin II,^87,88 endothelin-1^87,89 and thromboxane A₂ ⁹⁰ inhibit BK_Ca channels in CASMC. Common underlying mechanisms for inhibition of BK_Ca by these G protein-coupled receptors may include activation of protein kinase C⁹¹ or c-Src, a tyrosine kinase.⁹²

K_ATP channels in CASMC

Functional K_ATP channels are composed of eight subunits: four pore-forming subunits (either Kir6.1 or Kir6.2) and four sulfonylurea receptors (SUR1, SUR2A or SUR2B; the 2A and 2B isoforms are splice variants of the same gene, ABCC9). In situ hybridization and RT-PCR show Kir6.1 and SUR2B mRNA in coronary arteries and arterioles^93,94 and immunohistochemistry indicates Kir6.1 and SUR2 proteins in coronary arterioles <100 μm.^94,95 Kir6.1-null mice demonstrate coronary vasospasm,⁹⁶ but Kir6.2-null mice do not.⁹⁷ Genetic ablation of ABCC9 (encoding both SUR2A and SUR2B) also produces coronary vasospasm.⁹⁸ These studies support the idea that CASMC K_ATP channels are composed of Kir6.1 and SUR2A/B subunits, as knockout of these subunits produce coronary vasospasm. The mechanism may be much more complex, however, as smooth muscle-specific restoration of SUR2 expression in knockout mice does not correct coronary vasospasm.⁹⁹ Thus, coronary vasospasm in Kir6.1 and SUR2A/B mice may be secondary to some other change and unrelated to channels in CASMC.

K_ATP channels in CASMC may be the targets of endothelium-dependent relaxing factors, but there are few patch clamp studies to provide direct evidence. For example, no patch clamp study has demonstrated the activation of K_ATP channels by NO in CASMC (such data are available in bladder smooth muscle¹⁰⁰). With regard to ischemic vasodilation, it has been demonstrated that adenosine and hypoxia activate K_ATP channels in CASMC.^60,61 In the context of metabolic vasodilation, dopamine, an endogenous catecholamine, has been shown to activate K_ATP in CASMC.¹⁰¹ In contrast, coronary vasoconstrictors including endothelin-1, vasopressin and angiotensin II inhibit K_ATP channels.^102–104

K_V channels in CASMC

More than 40 K_V channel subunits have been identified; because of this diversity, the molecular identity of K_V channels in CASMC remains unclear. Complexity arises not only from the sheer number of genes involved, but is compounded by the alternative splicing of mRNA encoding individual subunits, assembly of different subunits into heteromultimeric channels and a variety of post-translational modifications. Functional K_V channels are a tetrameric assembly of pore-forming α subunits, but multiple types of accessory subunits modify K_V channel properties. The K_V current in CASMC is a delayed rectifier with little or no time-dependent inactivation. Its biophysical behaviors share many properties with some channels cloned from the K_V1 (Shaker; KCNA), K_V2 (Shab; KCNB) and K_V3 (Shal; KCNC) gene families. Sections of the human heart demonstrate K_V1.5 immunoreactivity in CASMC.¹⁰⁵ Further, K_V1 family genes, multiple K_V1 proteins and current sensitive to correolide (a blocker of Shaker-type K_V1 channels) are expressed in canine and rat coronary artery.^106,107 K_V3 gene transcripts and a highly TEA-sensitive K_V current are expressed in pig coronary arteries.¹⁰⁸ More studies will be required to determine the molecular composition of delayed rectifier channels in CASMC, as well as differences that may be due to species, vessel caliber and other factors (e.g. side of the heart from which the vessels originate¹⁰⁷).

NO and iloprost (a PGI₂ mimetic), but not 11,12-EET (an EDHF from the cytochrome P450 pathway), activate K_V channels in CASMC.⁶⁷ No patch clamp study demonstrates effects of adenosine or β-adrenergic agonists on K_V current in CASMC; however, a common signaling pathway may be cAMP-dependent protein kinase, which has been shown to activate K_V channels in portal vein smooth muscle.^109,110 H₂O₂, a putative metabolic vasodilator, activates K_V channels in CASMC through unknown signaling mechanisms.¹¹¹ No patch clamp studies demonstrate inhibition of K_V channels by vasoconstrictors in CASMC; however, data are available from other vascular beds. Endothelin-1, angiotensin II and thromboxane A₂ inhibit K_V current in the mesenteric artery, pulmonary artery and portal vein smooth muscle and a common mechanism appears to be activation of protein kinase C.^112–115 In cerebral arterial smooth muscle, Rho kinase and tyrosine kinases, involved in CASMC Ca²⁺ regulation and contraction, inhibit K_V current.^116,117

Regulation of CASMC K⁺ channels by endogenous vasodilators

Many mechanisms regulate coronary vascular resistance,^79,118,119 several of which were introduced in the above section. Factors from the endothelium influence coronary vascular tone, ischemia is an important pathophysiological stimulus and metabolism is the key regulator of coronary blood flow on a beat-to-beat basis. Importantly, K⁺ channels play a central role in producing vasodilation to all of these stimuli and their endogenous mediators. At present, the study of K⁺ channels in coronary blood flow depends almost entirely upon pharmacological blockers (e.g. iberiotoxin, glibenclamide and 4-AP) and very few investigators have been able to take advantage of newer, and perhaps more specific, molecular tools. Hopefully, models that incorporate knockout, transgenic and RNA interference approaches will receive more attention in the future. The following section summarizes studies of K⁺ channels in coronary vascular relaxation (in vitro studies of arteries and arterioles) and the regulation of coronary blood flow (in vivo). For simplicity, the role of K⁺ channels in various coronary vascular responses are discussed one at a time; however, it is important to recognize that key vasoregulatory factors modulate coronary microvascular tone via multiple K⁺ channels subtypes. For example, coronary endothelial-dependent dilation to bradykinin is mediated, to varying degrees, by BK_Ca, K_ATP and K_v channels (Figure 4a). Another example is how ischemic coronary vasodilation involves both K_ATP and K_v channels (Figure 4b). Dilators appear to regulate coronary blood flow through mechanisms involving multiple types of K⁺ channels; therefore, if one K⁺ channel type is inhibited/impaired, another may compensate. Such redundancy may act to preserve myocardial perfusion.¹²⁰ The precise roles of redundant K⁺ channel pathways and signaling cross-talk in the overall control of coronary blood flow merit further investigation.

Figure 4

K⁺ channels in the regulation of coronary blood flow. (a) Effects of iberiotoxin (i), glibenclamide (ii) and 4-AP (iii) on endothelium-dependent coronary vasodilation. (b) Roles of BK_Ca (i), K_ATP (ii) and K_V (iii) channels in coronary reactive hyperemia. (c) Coronary metabolic vasodilation does not involve BK_Ca (i) or K_ATP (ii) channels, but does depend upon the opening of K_V channels (iii). 4-AP, 4-aminopyridine

Endothelium-dependent vasodilation

Agonists such as acetylcholine and bradykinin couple to NO, PGI₂ and EDHF production and thus coronary vasodilation. Many other endothelium-dependent agonists have been tested and adenosine-induced coronary dilation also has an endothelial component.^48,49 The contribution of specific K⁺ channel types to endothelium-dependent coronary vasodilation has been studied in numerous species. Iberiotoxin, a selective BK_Ca channel antagonist, inhibits bradykinin-induced coronary vasodilation in dogs in vivo.¹²¹ Similarly, charybdotoxin, a BK_Ca channel antagonist, inhibits bradykinin-induced vasodilation of human coronary arterioles.¹²² Iberiotoxin attenuates NO- and cGMP-induced relaxation of human⁶⁶ and animal^123–125 coronary arteries, indicating a role for BK_Ca channels in endothelium-dependent NO-induced hyperpolarization.¹²⁶ The role of BK_Ca channels in PGI₂-induced coronary artery relaxation may depend on species, as iberiotoxin inhibits hyperpolarization induced by iloprost, a stable PGI₂ mimetic, in porcine CASMC,¹²⁷ but iloprost has no effect on BK_Ca channels in bovine CASMC.⁶⁷ No in vivo study has addressed the role of BK_Ca channels in iloprost-induced coronary vasodilation. When NO and PGI₂ production are blocked, the remaining relaxation is attributed to EDHF (which may be a cytochrome P450 metabolite). Iberiotoxin inhibits EDHF-induced coronary relaxation in vitro in pigs¹²⁸ and EDHF-induced coronary vasodilation in vivo in dogs.¹²⁹ Some investigators present data indicating no significant role for BK_Ca channels in endothelium-dependent relaxation of the coronary arteries of guinea pigs,¹³⁰ dogs and monkeys,¹³¹ as well as humans.¹³² However, the general consensus seems to be that BK_Ca channels play at least some role in endothelium-dependent coronary vasodilation (Figure 4ai).

It is generally reported that there is no effect of glibenclamide on endothelium-dependent vasodilation to bradykinin or acetylcholine in the coronary circulation, suggesting no role for K_ATP channels in this response. Negative findings for glibenclamide in endothelium-dependent vasodilation have been found for coronary blood flow in vivo ^19,133–135 and for isolated hearts and arterioles in vitro.^122,136 Also, glibenclamide does not affect the coronary vascular smooth muscle response to NO donors.²⁰ However, K_ATP channels have been reported as mediators of bradykinin- and PGI₂-, but not NO- induced vasodilation in rabbit hearts.¹³⁷ Glibenclamide has no effect on EDHF responses in pig¹³⁸ or human¹³⁹ coronary arteries. Thus, the general consensus is that K_ATP channels play little, if any, role in endothelium-dependent coronary vasodilation (Figure 4aii).

There has been some conflicting evidence regarding the role of K_V channels in endothelium-dependent vasodilation; however, most studies have demonstrated that these channels contribute significantly. Using pig coronary arteries, Cowan and Cohen¹⁴⁰ demonstrated no effect of 4-AP on bradykinin-induced relaxation; however, Thollon et al. ¹⁴¹ showed that 4-AP inhibits NO-induced hyperpolarization. The latter is compatible with the effect of NO and iloprost to activate K_V channels in bovine coronary smooth muscle.⁶⁷ While Illiano et al. ¹⁴² have shown that 4-AP has no effect on EDFH-induced relaxation in canine coronary arteries, Nakashima et al. ¹⁴³ have observed an inhibitory effect of 4-AP in the same tissue. Three studies agree that 4-AP inhibits EDHF-induced relaxation in guinea pig coronary arteries.^130,144,145 Our group has demonstrated the role of 4-AP-sensitive K_V channels in regulating basal coronary flow^106,111,146 and our preliminary studies indicate that K_V channels play a large role in endothelium-dependent coronary vasodilation in vivo in dogs. These data do not necessarily suggest that K_V channels have a more prominent role in the microcirculation, as 4-AP-induced vasospasm is observed throughout the coronary tree from conduit arteries to resistance arterioles.¹⁴⁷ The overall consensus for K_V channels in endothelium-dependent coronary vasodilation is shown in Figure 4aiii.

Ischemic vasodilation

Large and transient compensatory increases in coronary blood flow follow a brief period of ischemia. This reactive hyperemia represents a repayment of blood flow debt due to the accumulation and washout of ischemic vasodilators. Mediators of ischemic coronary vasodilation have not been identified conclusively. Regardless of what the signaling mechanism might be, it is clear that K⁺ channels in CASMC play a large role in reactive hyperemia. Node et al. demonstrate that BK_Ca channels regulate blood flow to ischemic myocardium in dogs;¹²¹ however, our preliminary studies show that penitrem A, another inhibitor of BK_Ca channels, has no effect on reactive hyperemia in pigs.¹⁴⁸ A modest role for BK_Ca channels in reactive hyperemia is shown in Figure 4bi. Most studies have focused on the contribution of K_ATP channels to ischemic vasodilation. In dogs and pigs, glibenclamide reduces the peak and duration of blood flow repayment following a brief coronary occlusion.^{19,20,149–152} No study has addressed whether K_ATP channels regulate reactive hyperemia in the human coronary circulation; however, tolbutamide-sensitive channels may regulate this response in the human forearm.¹⁵³ The contribution of K_ATP channels to reactive hyperemia is summarized in Figure 4bii. We have demonstrated that K_V channels regulate the duration of reactive hyperemia in the canine coronary circulation in vivo.¹⁰⁶ 4-AP (300 μmol/L) reduced resting coronary blood flow by approximately 33%. Higher doses of 4-AP reduced coronary flow to the point of causing S-T segment depression, a sign of myocardial ischemia. K_V channels regulate the duration of reactive hyperemia and reduce the repayment of flow debt. Additionally, 4-AP inhibited coronary vasodilation to NO and adenosine, two putative mediators of reactive hyperemia. The role of K_V channels in coronary reactive hyperemia is shown in Figure 4biii.

Metabolic vasodilation

Myocardial metabolism is the key regulator of coronary blood flow on a beat-to-beat basis, from rest to climbing a flight of stairs or to maximal exercise. Coronary blood flow increases in an almost linear fashion with myocardial oxygen consumption. This very tight coupling between oxygen supply and demand is necessary because the heart has very little capacity for anaerobic metabolism and the myocardium, even at the resting heart rate, consumes approximately 75% of the oxygen delivered to it. Thus, there is very little reserve for oxygen extraction from coronary arterial blood and increases in work done by the heart must be met with parallel increases in coronary blood flow. Unfortunately, at present, we know more about which mechanisms are not responsible for coronary metabolic vasodilation. Further, complexity is added by species-specific differences in responses to exercise and mechanisms underlying them.⁷⁹ Thus, much research remains to be done on this central question of coronary physiology. Studies in the last two decades have focused on what K⁺ channels may be responsible for this critical physiological phenomenon. BK_Ca channels appear to play little, if any, role in coronary metabolic vasodilation.¹⁵⁴ Merkus and colleagues measured coronary blood flow and myocardial oxygen consumption in pigs exercising on a treadmill before and after intravenous treatment with TEA.¹⁵⁴ When one examines the relationship between coronary flow and myocardial oxygen consumption, there is no difference; however, there was a significant reduction in coronary venous oxygen tension.¹⁵⁴ TEA, even at an estimated plasma concentration of 0.6 mmol/L, is not ideal as an inhibitor of BK_Ca in exercise hyperemia studies, as TEA is also a ganglionic blocker¹⁵⁵ and reduces heart rate and blood pressure (major determinants of myocardial oxygen consumption) as well as coronary blood flow. We have conducted preliminary experiments with penitrem A, a more selective inhibitor of BK_Ca channels, in exercising pigs. Penitrem A has no effect on exercise-induced coronary metabolic vasodilation.¹⁵⁶ The lack of effect of BK_Ca channel blockers on the coronary blood flow versus myocardial oxygen consumption is shown in Figure 4ci.

Most studies in this area have focused on the contribution of K_ATP channels to coronary metabolic vasodilation. The general consensus is that K_ATP channels are not responsible for exercise-induced coronary hyperemia (Figure 4cii). Glibenclamide decreases coronary blood flow at rest in dogs, but has no effect on exercise-induced coronary vasodilation.^19–21,157 In humans, however, glibenclamide attenuates pacing-induced hyperemia.¹⁵⁸ K_ATP channels also appear to play a role in pacing-induced hyperemia in dogs.¹⁵⁹ However, comparing pacing and exercise-induced hyperemia is tenuous, as there are fundamental differences in the nature of the vasodilator mechanisms activated (e.g. pacing does not include the sympathetic control mechanisms elicited by exercise¹⁶⁰). Examples of discrepancies between pacing- and exercise-induced hyperemia have included conclusions made about BK_Ca and K_ATP channels.^{20,156,159,161} If one considers exercise the most physiologically relevant stimulus, then the contribution of K_ATP channels to metabolic vasodilation is negligible. In humans performing handgrip exercise, glibenclamide has no effect on exercise-induced forearm blood flow,¹⁶² an observation identical to the lack of effect of glibenclamide on coronary blood flow in exercising animals.

We have investigated the role of K_V channels in coronary metabolic vasodilation.¹⁶³ Measuring coronary blood flow and myocardial oxygen consumption in dogs, we demonstrated that intracoronary infusion of 300 μmol/L 4-AP reduced blood flow at rest and attenuated pacing- and catecholamine-induced vasodilation.¹⁶³ The inhibitory effect of 4-AP on the relationship between myocardial metabolism and coronary blood flow is significantly more pronounced than has been observed with any other inhibitor of CASMC K⁺ channels such as glibenclamide, TEA or penitrem A. These data suggest that K_V channels may be the most important channel type linking myocardial metabolism to coronary blood flow. Unfortunately, however, no study has yet addressed the role of K_V channels in exercise-induced coronary vasodilation. We have suggested that H₂O₂ may be a signaling molecule linking myocardial metabolism to coronary blood flow,^163,164 and others support this idea.^161,165 H₂O₂ activates 4-AP-sensitive K_V channels in CASMC¹¹¹ and H₂O₂-induced coronary vasodilation is blocked by 4-AP.¹⁴⁶ The role of K_V channels in coronary metabolic vasodilation is shown in Figure 4ciii.

Dysfunction of CASMC K⁺ channels in disease

K⁺ channels in CASMC are involved in and affected by many processes related to the pathogeneses of cardiovascular diseases.

Diabetes, hyperglycemia and metabolic syndrome

A number of studies have demonstrated defects in CASMC BK_Ca channels in diabetes, hyperglycemia and metabolic syndrome. The activation of BK_Ca channels by arachidonic acid in CASMC of Zucker diabetic fatty rats is reduced compared with lean rats; this appears to be secondary to reduced activity of PGI₂ synthase.¹⁶⁶ BK_Ca channels in CASMC from Zucker diabetic fatty rats also have a lower Ca²⁺/voltage-sensitivity due to reduced expression of the regulatory β1 subunit.¹⁶⁷ Diabetes increases BK_Ca current in CASMC from conduit arteries of pigs,¹⁶⁸ while spontaneous transient outward currents mediated by BK_Ca channels are reduced in arteriolar CASMC from diabetic pigs.¹⁶⁹ We have shown that metabolic syndrome reduces whole-cell penitrem A-sensitive and NS1619-activated BK_Ca current in CASMC.¹⁷⁰ K_ATP channels in CASMC are also affected by diabetes, as vasodilation due to K_ATP channel activation is impaired in human coronary arterioles from patients with type 1 and type 2 diabetes.⁹⁴ K_V channel function is negatively impacted by high glucose concentrations in vitro. Elevated glucose impairs cAMP-mediated dilation by reducing K_V channel activity in rat CASMC;^171,172 one mechanism appears to be nitration of the channels.¹⁷³ Another mechanism by which diabetes may impair K⁺ channel function in CAMSC is through the activation of protein kinase C.¹⁷⁴

Atherosclerosis and ischemia

Hypercholesterolemia impairs coronary vasodilation mediated by K⁺ channels.¹⁷⁵ In pigs, high blood cholesterol has been reported to increase¹⁶⁸ and decrease¹⁷⁶ BK_Ca current in CASMC. The contribution of K_V channels to adenosine-mediated dilation of pig coronary arterioles is abolished by hypercholesterolemia.^108,176,177 Further, K_V currents in porcine CASMC are reduced by high blood cholesterol.^{108,176–178} Homocysteine, an independent risk factor for atherosclerosis, inhibits BK_Ca channels in pig CASMC.¹⁷⁹ BK_Ca channels in smooth muscle cells from coronary plaque have a higher activity than those in normal CASMC.¹⁸⁰ Further, compared with normal CASMC, the BK_Ca channels of CASMC from atherosclerotic plaques respond differently to growth factors.¹⁸¹ BK_Ca channels contribute significantly to endothelium-dependent vasodilation in the ischemic myocardium of dogs.^121,182 K_ATP and K_V channels compensate to preserve hypercapnic coronary flow when NO production is absent.¹⁸³ Acute hypoxia dilates guinea pig hearts¹⁸⁴ and pig coronary arteries and arterioles^185,186 through the activation of K_ATP channels; however, in rabbit coronary arteries, K_ATP channels are not involved.¹⁸⁷ Chronic hypoxia has opposite effects on K_V current magnitude in right and left CASMC from rats, suggesting differences in K_V channel isoforms or signaling mechanisms.¹⁸⁸ Acidosis increases K_V, but not BK_Ca or K_ATP, current in rat CASMC;¹⁸⁹ however, acidosis dilates pig coronary arterioles through a glibenclamide-sensitive mechanism.^190,191 Lactate, a metabolite produced during myocardial ischemia, activates BK_Ca channels in pig CASMC.¹⁹²

Hypertension, cardiac hypertrophy and cardiomyopathy

Aldosterone, a mineralocorticoid with relevance to hypertension, reduces BK_Ca channel expression and iberiotoxin-sensitive relaxations in murine coronary arteries.¹⁹³ BK_Ca channels compensate for a loss of endothelial function in coronary arteries of rats made hypertensive with ouabain.¹⁹⁴ Genetic ablation of K_ATP channels causes hypertension and coronary vasospasm in mice.^96,98 BK_Ca current is reduced in CASMC from rats and rabbits with left ventricular hypertrophy, attributable to a reduction in single channel amplitude and Ca²⁺/voltage sensitivity.¹⁹⁵ K_ATP channels are normally not involved in coronary metabolic vasodilation; however, K_ATP channels become important for exercise-induced hyperemia in dogs with left ventricular hypertrophy.¹⁹⁶ K_V current is increased in CASMC from rats with right ventricular hypertrophy due to pulmonary hypertension.¹⁸⁸ BK_Ca channels compensate for the loss of NO-dependent coronary artery relaxation in cardiomyopathic hamsters.¹⁹⁷ The role of K_ATP channels in coronary vascular regulation changes in the remodeled left ventricle of swine with a 2–3-week-old myocardial infarction.¹⁹⁸ Specifically, in normal pigs, K_ATP channels are not required for exercise-induced coronary vasodilation; however, following an infarction, K_ATP channels are responsible for a significant portion of exercise hyperemia.

Aging and reactive oxygen species

Aging is the main risk factor for coronary heart disease and spontaneous contractile activity is higher in coronary arteries of the aged, consistent with the idea that reduced K⁺ channel expression or activity is related to coronary vasospasm.¹⁷ Aging reduces BK_Ca channel current and pore-forming α subunit protein in CASMC from rats and humans.¹⁹⁹ Similarly, the expression of the regulatory β1 subunit of BK_Ca channels is reduced in CASMC from aged rats.²⁰⁰ Menopause, part of the aging process in women, reduces estrogen levels; this may also influence BK_Ca channel activity and coronary artery reactivity. Estrogen increases BK_Ca channel activity in human CASMC and iberiotoxin inhibits estrogen-induced coronary artery relaxation.^201,202 Reactive oxygen species are signaling molecules involved in normal coronary physiology as well as pathophysiology. H₂O₂ relaxes pig coronary arteries and arterioles via BK_Ca channels^85,203 and dilates the canine coronary circulation through the activation of K_V channels.^111,146 Peroxynitrite, the product of a reaction between NO and superoxide anion, inhibits BK_Ca channels in human CASMC; superoxide alone was without effect.²⁰⁴ Peroxynitrite also inhibits K_V current in rat CASMC,¹⁷³ as does superoxide, which inhibits cAMP-mediated dilation by reducing K_V channel function in the coronary arteries of diabetic rats.²⁰⁵

Summary of K⁺ channels in coronary blood flow

BK_Ca, K_ATP and K_V channels are important in various aspects of coronary vascular regulation. K_ATP and K_V channels are important in determining basal coronary microvascular tone, whereas BK_Ca channels do not appear to contribute to resting coronary flow. BK_Ca and K_V channels participate in endothelium-dependent coronary vasodilation, while K_ATP channels appear to play no role. All three channels seem to contribute in some way to ischemic coronary vasodilation. Only K_V channels are mediators of coronary metabolic vasodilation, as inhibitors of K_ATP and BK_Ca channels have no effect on coronary blood flow elicited by metabolic demands. Diabetic conditions impair the function of BK_Ca, K_ATP and K_V channels in CASMC. The expression and activity of CASMC BK_Ca, K_ATP and K_V are altered by hypercholesterolemia, ischemia, hypoxia, hypertension, myocardial hypertrophy and cardiomyopathy. Aging decreases the function and expression of BK_Ca channels, while reactive oxygen species have physiological and pathophysiological effects on the activity of BK_Ca and K_V channels. Overall, K_V channels may have the most central role in regulating coronary blood flow, as these channels are involved in resting vascular tone, as well as endothelium-dependent, ischemic and metabolic vasodilation.

Footnotes

Acknowledgements

This work was supported by NIH HL-67804 and Research Funds Development Grant from West Virginia University.

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Role of potassium channels in coronary vasodilation

Abstract

Keywords

Ca2+ channels, K+ channels and coronary blood flow

Types of K+ channels expressed in CASMC

BKCa channels in CASMC

KATP channels in CASMC

KV channels in CASMC

Regulation of CASMC K+ channels by endogenous vasodilators

Endothelium-dependent vasodilation

Ischemic vasodilation

Metabolic vasodilation

Dysfunction of CASMC K+ channels in disease

Diabetes, hyperglycemia and metabolic syndrome

Atherosclerosis and ischemia

Hypertension, cardiac hypertrophy and cardiomyopathy

Aging and reactive oxygen species

Summary of K+ channels in coronary blood flow

Footnotes

Acknowledgements

References

Ca²⁺ channels, K⁺ channels and coronary blood flow

Types of K⁺ channels expressed in CASMC

BK_Ca channels in CASMC

K_ATP channels in CASMC

K_V channels in CASMC

Regulation of CASMC K⁺ channels by endogenous vasodilators

Dysfunction of CASMC K⁺ channels in disease

Summary of K⁺ channels in coronary blood flow