Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K_ATP channels

K_ATP channels couple the intracellular energy state to membrane excitability and regulate a wide array of biologic activities. K_ATP channels contain a pore-forming inwardly rectifying potassium channel and a sulfonylurea receptor regulatory subunit (SUR1 or SUR2). To clarify the role of K_ATP channels in vascular smooth muscle, we studied Sur2 gene-targeted mice (Sur2^–/–) and found significantly elevated resting blood pressures and sudden death. Using in vivo monitoring, we detected transient, repeated episodes of coronary artery vasospasm in Sur2^–/– mice. Focal narrowings in the coronary arteries were present in Sur2^–/– mice consistent with vascular spasm. We treated Sur2^–/– mice with a calcium channel antagonist and successfully reduced vasospastic episodes.

K_ATP channels respond to changes in the intracellular ATP content by altering a cell’s membrane potential (1, 2). K_ATP channels are widely expressed in neural, endocrine, and muscle tissues where they are inhibited by ATP and stimulated by ADP. K_ATP channels are an octameric complex consisting of four potassium channel subunits, either Kir6.1 or Kir6.2, and four sulfonylurea receptor subunits, SUR1 or SUR2 (3–9). SURs, named for their ability to bind with high affinity the hypoglycemic sulfonylurea agents, are members of the ATP-binding cassette (ABC) transporter family of transmembrane proteins. SUR1 and SUR2 are 70% identical proteins encoded by different genes. SUR2 undergoes differential splicing altering its carboxy-terminal 42 amino acids, yielding channels with unique pharmacologic properties.

In cardiomyocytes, where K_ATP channels modulate protection from ischemia, SUR1 and SUR2 are coexpressed (10, 11). In smooth muscle and voluntary striated muscle, only SUR2 is expressed (11). The physiology and pharmacology of K_ATP channels have been most extensively studied in the pancreatic β cell. Here, sulfonylurea agents such as glibenclamide inhibit K_ATP channels by binding to SUR1, which results in the closure of the channel and the stimulation of insulin release (3). In vascular smooth muscle, potassium channel openers, such as nicorandil, implicate K_ATP channels in the regulation of tonic vasomotor activity. These agents, useful in the treatment of hypertension and angina, open K_ATP channels leading to potassium efflux, membrane hyperpolarization, and vasodilation (12–14). Potassium channel openers alter membrane potential through K_ATP channels and thereby activate voltage-dependent calcium channels producing changes in vascular smooth muscle contractility (15). In skeletal muscle, K_ATP channels affect glucose metabolism. Using mice with a targeted disruption of the Sur2 gene (16), we demonstrated that the loss of K_ATP channels increased insulin responsiveness mediated by striated muscle.

The diversity of responses to individual pharmacologic agents that act through K_ATP channels derives in part from the tissue-specific expression of K_ATP subunits and the composition of K_ATP channels within a cell. Since pharmacologic agents act through the SUR subunit, the significant homology between SUR isoforms and their overlapping expression pattern complicates the interpretation of pharmacologic studies in vivo. To better understand the potential role of K_ATP channels in the vascular smooth muscle physiology, we studied mice with a targeted disruption of the Sur2 gene (Sur2^–/–) (16). We observed elevated resting blood pressure in Sur2^–/– mice and found that Sur2^–/– displayed sudden death from ST segment elevation and coronary artery vasospasm. Furthermore, we inhibited ST segment elevation with nifedipine, a calcium channel antagonist. These data highlight the importance of the vascular smooth muscle K_ATP channel in the tonic and episodic regulation of vasomotor tone.

Hypertension and sudden death in Sur2^–/– mice. In the course of our previous studies on the insulin responsiveness of Sur2^–/– mice, we noted sudden, unanticipated death, despite a normal outward appearance and normal basal glucose and serum electrolyte concentrations. By 30 weeks of age, 65% of the male Sur2^–/– mice died, as did 35% of Sur2^–/– females (Figure 1a). Because potassium channel openers have a role in lowering blood pressure, we evaluated vascular tone in Sur2^–/– mice with continuous, telemetrically recorded blood pressure monitoring of conscious 12- to 18-week-old Sur2^+/+ and Sur2^–/– mice (Figure 1, b and c). Sur2^–/– mice exhibited significantly elevated systolic and diastolic blood pressures of 161/122 mmHg when compared with normal control littermates, which had blood pressures of 135/100 mmHg (n = 4 and 6, respectively; P < 0.04). Mean arterial blood pressure (MAP) was similarly elevated, 140 ± 6.4 mmHg for Sur2^–/– compared with 115 ± 5.2 mmHg for normal Sur2^+/+ mice. Anesthetized blood pressure recordings were taken during intravenous application of K_ATP-activating and -inhibiting compounds (Figure 1d, n = 3). Pinacidil elicited a significant blood pressure drop in normal littermate control mice, while the coadministration of the sulfonyl-urea glyburide inhibited the pinacidil response to restore baseline blood pressures. Sur2^–/– mutant mice did not experience a drop in blood pressure with the application of pinacidil, nor did they demonstrate any response to glyburide, consistent with the loss of smooth muscle SUR2 K_ATP channel activity. Despite elevated systemic blood pressures, histologic analysis of Sur2^–/– hearts (age 12–16 weeks) showed no obvious differences from normal mice (data not shown).

Figure 1

Cardiovascular physiology in Sur2^–/– mice. (a) Sur2^–/– mice exhibit decreased survival. Survival of littermate control and heterozygous mice (Sur2^+/+n = 15, 5 males and 10 females, and Sur2^+/–, n = 41, 12 males and 29 females), homozygous mutant females (Sur2^–/–, n = 18), and homozygous mutant males (Sur2^–/–, n = 17) as a function of age. (b) Telemetric blood pressure recordings of Sur2^–/– and normal littermate control mice. Representative blood pressure tracings from conscious, untethered control (Sur2^+/+) and homozygous mutant (Sur2^–/–) mice. (c) Systolic (white bars), diastolic (gray bars), and MAP (black bars) for littermate control and mutant mice (n = 6 and 4, respectively), recorded between days 2 and 4 after implantation. *P < 0.04, **P < 0.03, ***P < 0.02 versus normal littermate controls by two-tailed, unpaired Student t test. (d) Sur2^–/– mice do not respond to K_ATP vasoactive agents. Representative MAP tracings from a littermate control mouse (dotted line) and a Sur2^–/– mouse (solid line) during infusions of the agents indicated. Pinacidil was administered at 5 μg/kg/min and glibenclamide at 100 μg/kg/min. The interrupted line for glyburide infusion indicates the beginning of infusion for the normal control mouse (Sur2^+/+), while the mutant mouse (Sur2^–/–) infusion begins with the solid line.

Absent smooth muscle K_ATP channels. Electrophysiologic patch clamp recordings on isolated aortic smooth muscle cells from Sur2^–/– and Sur2^+/+ mice (Figure 2) demonstrated the absence of SUR2 K_ATP channels. The average cell capacitance was 8.03 ± 0.73 pF for Sur2^+/+ mice and 7.74 ± 0.76 pF for Sur2^–/– mice (P < 0.05). Immediately after membrane rupture, an increase of whole cell current was seen in Sur2^+/+ cells, but was absent in Sur2^–/– cells (Figure 2a). Extracellular application of 20 μM glibenclamide partially blocked this increase of whole cell current in Sur2^+/+ smooth muscle cells, demonstrating that this current reflects SUR2 function (Figure 2a). At all voltages tested, typical voltage-dependent and glibenclamide-sensitive K_ATP current was seen in Sur2^+/+ cells, but was absent in Sur2^–/– cells. The current was outward under physiological potassium concentration (4_out/140_in) and reversed at –87 mV, near the theoretical value of –89 mV for K⁺ (Figure 2, b and c). The current density at a test pulse of –10 mV was 1.72 ± 0.64 pA/pF in Sur2^+/+ cells and only 0.04 ± 0.04 pA/pF in Sur2^–/– cells (P < 0.01). From these studies, we conclude that the glibenclamide-sensitive K_ATP current was indeed absent in the Sur2^–/– vascular smooth muscle.

Figure 2

Absence of K_ATP current in aortic smooth muscle cells isolated from Sur2^–/– mice. (a) Examples of original whole cell current traces recorded in a Sur2^+/+ and a Sur2^–/– aortic smooth muscle cell 2 minutes after cell rupture (maximal potassium channel current [I_K], left), after 20 μM of glibenclamide (GLB, middle), and the GLB-sensitive I_KATP obtained by subtraction (right). The glibenclamide-sensitive current was interpreted as K_ATP current and was normalized by cell capacitance to obtain the whole cell current density. The GLB-sensitive current was absent from the Sur2^–/– cell. (b) Whole cell current protocol. The cell was held at –70 mV, and 235 ms test pulses from –90 to 10 mV were delivered to induce a whole cell current. (c) Mean summary data of the current voltage plot for the GLB-sensitive I_KATP density at all voltages tested (n = 13 cells from five Sur2^+/+ mice vs. n = 14 cells from four Sur2^–/– mice, *P < 0.05).

Coronary artery vasospasm. Early sudden death in Sur2^–/– mice suggested cardiac arrhythmias. We investigated this possibility in Sur2^–/– animals using continuous telemetric ECG recording. Baseline resting heart rates, PR intervals, and QRS morphology were similar between Sur2^–/– mice and normal littermate controls (Figure 3a.) However, both male and female Sur2^–/– mice exhibited repeated episodes of spontaneous ST segment elevation (Figure 3, b and c). Frequently, ST segment episodes were followed by slow heart rates, typically the consequence of atrioventricular heart block (Figure 3d). ST segment depression, a marker of global myocardial ischemia, was noted during the recovery phase of these transient ischemic events (Figure 3e). A number of recordings captured Sur2^–/– moribund events, and an example is shown in Figure 3g. Death occurred from a rapid sequence of ST segment elevation followed by prolonged atrioventricular heart block and asystole (Figure 3g). Only normal baseline ECG tracings were seen in littermate control mice, and no littermate control mice died during monitoring. The pattern of ST segment elevation ECG changes observed in the Sur2^–/– mice is identical to that seen in Prinzmetal or variant angina, a human disorder associated with chest pain and sudden death stemming from coronary artery vasospasm (23). While arrhythmias are commonly noted in Prinzmetal patients, in humans arrhythmias may be due to tachy-arrhythmias or bradyarrhythmias.

Figure 3

In vivo evidence of coronary artery vasospasm in Sur2^–/– mice. (a–f) Representative telemetric ECG recording of a 12-week-old male Sur2^–/– mouse. Each of the serial tracings reflects 1.5 seconds of the entire 160-second episode. The timing of each 1.5-second segment with respect to the duration of the entire episode is indicated in seconds below the tracing. (a) A baseline tracing at the beginning of the event. (b and c) Marked ST segment elevation that occurs within 30 seconds. ST segment elevation leads to atrioventricular heart block seen in d. Following the acute injury pattern of ST segment elevation, ST segment depression was present during recovery (e). (f) A return to baseline ECG readings. (g) Continuous ECG recording capturing sudden death. Upper tracing depicts heart rate and bradycardia events (downward spikes) over a 17-hour period. Individually, numbered regions are magnified in the lower three sets of ECG waveform tracings indicating: 1, normal rate and rhythm; 2, post-ST elevation atrioventricular heart block with bradycardia; 3, agonal rhythm with a widened QRS.

To demonstrate spontaneous vasospasm as an underlying cause of the episodic ECG changes and sudden death, we perfused the coronary arteries of mice with latex Microfil as described (20). The coronary arteries of littermate control male mice were normally distributed and smoothly tapered, with an occasional focal tapering (Figure 4, upper left). In contrast, every Sur2^–/– mouse studied showed evidence of arterial stenoses (Figure 4). Coronary vasculature constrictions seen in Sur2^–/– mice represent the anatomic correlate of ST segment changes and spontaneous vasospasm.

Figure 4

Coronary artery vasospasm. The coronary vasculature was perfused with Microfil, a liquid latex medium, as described previously (20). Microvascular perfusion was visualized by transillumination under low-power magnification. (upper left panel) Normal microvasculature of a littermate control male mouse. (upper right panel and lower panels) Examples of focal artery stenoses in three Sur2^–/– mice. Arrows indicate significant coronary artery stenoses.

Inhibition of coronary artery vasospasm with calcium channel antagonists. Resting membrane potential modulated by K_ATP channel activity directly alters calcium channel function. Because calcium channel antagonists suppress spontaneous vasospasm and subsequent myocardial ischemia, they are used to treat Prinzmetal variant angina (24). Telemetric ECG monitoring was repeated in Sur2^–/– male mice after a continuous infusion of the calcium channel antagonist nifedipine. Sur2^–/– mice receiving a 3 mg/kg/d nifedipine infusion had a marked reduction in the number of ST segment elevations in the first 48 hours of ECG recording (210 ± 11 events/d in sham-infused vs. 66 ± 12 events/d in nifedipine-infused mice; P < 0.0001) (Figure 5b). Furthermore, the nifedipine-treated group experienced a significant reduction in the number of heart block/bradycardia events over 48 hours compared with the sham-infused group (41.0 ± 9 vs. 2.6 ± 0.9; P < 0.002). These findings emphasize the downstream role of calcium channels with respect to K_ATP activity (23).

Figure 5

Successful treatment of coronary artery vasospasm in Sur2^–/– mice with nifedipine. (a) Representative continuous ECG recordings obtained during subcutaneous infusion of a sham-infusate (saline or DMSO) versus nifedipine at 3 mg/kg/d. Tracings depict heart rate, with sharp downward deflections representing deceleration in the heart rate or episodic bradycardia. Graphic summary of quantitative decrease of (b) ST segment elevation events per 24-hour period, and (c) heart block episodes per 24-hour period (n = 5 each). White bars represent sham-infusate group. Black bars represent nifedipine group. *^,**P < 0.0001 by two-tailed, unpaired Student t test.

The presence of hypertension and vasospasm in Sur2^–/– mice reveals a pivotal role for smooth muscle K_ATP channels in the overall regulation of vascular tone. SUR2 K_ATP channel-deficient mice develop increased vascular tone consistent with essential hypertension. In addition to this tonic increase in vasomotor tone, the absence of K_ATP channels promotes episodic vasospasm. Episodic alterations in vascular tone result from a shift in the balance of vasodilatory and vasoconstrictive cues. A number of metabolic and humoral vasoactivators have been suggested to modulate K_ATP channels. Examples of vasodilating agents that act through K_ATP channels include nitric oxide, adenosine, calcitonin gene-related peptide, neuropeptide Y, prostacyclin, adrenergic stimuli, and metabolic changes associated with hypoxia (14, 15, 25–28). K_ATP-associated vasoconstrictors include thromboxane A2 and endothelin (29). Because of the absence of vascular K_ATP channels, factors that usually do not elicit vasoconstriction in the presence of normal K_ATP channel activity may now be unopposed in Sur2^–/– mice.

We showed previously an absence of myocardial SUR2 K_ATP channels in Sur2^–/– mice (16), and here we show that ST segment elevation occurs in the absence of SUR2. K_ATP channels have been implicated previously in the generation of ST segment elevation (30). Kir6.2 null mice have attenuated ST segment elevation after 5 minutes of ischemia. In Sur2^–/– mice, episodes of ST segment elevation are brief, 30–60 seconds. Thus, early ST segment elevation may be mediated by alternative channel activity or, in Sur2^–/– cardiomyocytes, Kir6.2 may couple with an alternative regulatory subunit capable of mediating ST segment elevation.

K_ATP channels have been identified as important mediators of ischemic preconditioning where intermittent exposure to hypoxic conditions limits ischemic damage (31). Potassium channel–opening agents stimulate ischemic preconditioning via their action on K_ATP channels. The precise mechanism by which ischemic preconditioning occurs is unknown, although it has been suggested to involve mitochondrial K_ATP channels. It may be expected that the repeated instances of vasospasm coupled with the loss of K_ATP channels in the myocardium would render Sur2^–/– mice more susceptible to ischemic damage. We did not observe histological evidence of myocardial ischemia or infarction in hearts from Sur2^–/– mice (not shown). The brevity of the coronary artery vasospastic episodes may be insufficient to generate a prolonged interval of ischemic damage necessary to cause histologic changes. Alternatively, the arrhythmic episodes that result from coronary artery vasospasm may lead to death before the development of myocardial infarction.

Our results demonstrate that SUR2-K_ATP channels serve as key modulators of vascular smooth muscle activity regulating blood pressure and episodic coronary artery tone. This work identifies an important pharmacologic target for the treatment of hypertension and vasospasm. Our findings suggest that SUR2 plays a critical role in clinically defined human illnesses, namely essential hypertension and Prinzmetal angina, as well as the vasospasm frequently associated with atherosclerotic coronary artery disease. Finally, because antihyperglycemic sulfonylurea agents close SUR2 K_ATP channels with low affinity, these data raise the possibility that their use may increase susceptibility to vasospasm. Some epidemiologic studies of sulfonylurea agents in diabetics have found an increase in cardiovascular events, while others have not (32). In light of the data now presented, further studies are warranted.

Note added in proof: T. Miki et al. recently reported similar findings in mice lacking Kir6.1, the partner protein of SUR2 (2002. Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat. Med.8:466–472).

This work was supported by a pilot project award from an NIH Diabetes Research and Training grant, the American Heart Association, and the Burroughs Wellcome Fund (to E.M. McNally), and by NIH grant HL-57414 (to J.C. Makielski).

See the related Commentary beginning on page 153.

Conflict of interest: No conflict of interest has been declared.

Nonstandard abbreviations used: ATP-binding cassette (ABC); sulfonylurea receptor subunit (SUR); electrocardiogram (ECG); mean arterial blood pressure (MAP).

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