ATP-Dependent K+ Channels Contribute to Local Metabolic Coronary Vasodilation in Experimental Diabetes

Abstract

This study tested whether ATP-dependent K ؉ channels (K ATP channels) are an important mechanism of functional coronary hyperemia in conscious, instrumentimplanted diabetic dogs. Data were collected at rest and during exercise before and after induction of diabetes with alloxan monohydrate (40 -60 mg/kg intravenously). K ATP channels were inhibited with glibenclamide (1 mg/kg intravenously). In nondiabetic dogs, arterial plasma glucose concentration increased from 4.8 ؎ 0.3 to 21.5 ؎ 2.2 mmol/l 1 week after alloxan injection. In nondiabetic dogs, exercise increased myocardial oxygen consumption (MVO 2 ) 3.4-fold, myocardial O 2 delivery 3.0-fold, and heart rate 2. N umerous investigations have focused on the role of ATP-dependent K ϩ (K ATP ) channels in coronary blood flow regulation (1-14). These studies indicate that K ATP channels are important in regulating coronary vascular resistance under baseline conditions (3-10), during hypoxic coronary vasodilation (11,12), and during reactive coronary hyperemia (1,4,13). However, it does not appear that K ATP channels are required to increase coronary blood flow when myocardial metabolism is increased (3)(4)(5)7,8).Recently, Kersten et al. (14) found that diabetes enhanced K ATP channel-mediated coronary vasodilation of coronary arterioles, suggesting that K ATP channels are important in local metabolic coronary vasodilation in diabetes. Supporting this notion are the results of Shimoni et al. (15) showing that the half-maximal inhibitory concentration (IC 50 ) for ATP-dependent inhibition of K ATP channels was approximately twofold higher for channels from diabetic rat hearts. If there is an increase of K ATP channel activity in diabetes, then oral hypoglycemic agents such as glibenclamide (Glyburide or Diabeta), which are K ATP channel antagonists, could seriously impair control of coronary blood flow, especially when myocardial oxygen demand is elevated. Despite this fact, no study has examined whether K ATP channels contribute to metabolic coronary vasodilation in an intact diabetic model. Furthermore, characterizing mechanisms that regulate coronary vascular tone is particularly important since coronary flow reserve (16 -19), functional coronary hyperemia (18), and the balance between coronary blood flow and myocardial metabolism (20) are impaired in diabetic subjects. Accordingly, this study was designed to determine whether K ATP channels contribute to local metabolic coronary vasodilation in diabetic subjects. Experiments were conducted at rest and during graded treadmill exercise, with and without K ATP channel blockade (glibenclamide, 1 mg/kg i.v.) (7,8), in chronically instrument-implanted dogs before and after induction of diabetes with alloxan monohydrate (40 -60 mg/kg i.v.) (21). RESEARCH DESIGN AND METHODSSurgical preparation. This investigation was approved by the Institutional Animal Care and Use Committee and was conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publ. no. 85-23, revise...

Contribution of BKCa channels to local metabolic coronary vasodilation: effects of metabolic syndrome

“…BK Ca channels and local metabolic control of coronary blood flow. Given the abundant expression of BK Ca channels in coronary vascular smooth muscle cells (4,22,23,38,39) and the importance of K ϩ channels to the regulation of coronary vascular resistance (15,17,53), we hypothesized that decreases in BK Ca channel function would likely contribute to diminished local metabolic coronary vasodilation in MetS. Our hypothesis is supported by a recent study from Merkus et al (34) who found that administration of the BK Ca channel inhibitor tetraethylammonium (TEA) significantly decreased the relationship between coronary venous PO 2 and MV O 2 in normal, lean swine both at rest and during exercise.…”

Altered Mechanism of Adenosine-Induced Coronary Arteriolar Dilation in Early-Stage Metabolic Syndrome

“…In addition, pilot results from our lab demonstrate a trend toward reduced coronary arteriolar dilation to the K ATP channel opener levcromakalim in early-stage MetS (unpublished observations). Conversely, two studies have noted enhanced K ATP -mediated vasodilation in vivo in coronary arterioles of acutely diabetic and hyperglycemic dogs (42, 43). The reason for this discrepancy is unclear but may be due to differences in species, length of disease, combination of risk factors or method of disease induction.…”

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

“…Alloxan-induced diabetes in dogs or hyperglycemia increases aprikalim-induced dilation of coronary arterioles, although ischemia-induced dilation, which is mediated by K ATP channels, is depressed (742). Also, in contrast to normal dogs, K ATP channels contributed significantly to the local regulation of coronary blood flow during exercise (1440), suggesting increased, rather than decreased K ATP channel function in this model of diabetes. An explanation for these results is not apparent, but could relate to the degree or duration of diabetes.…”