Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation Research. 2003;92:127-129
doi: 10.1161/01.RES.0000056965.71699.02
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Weintraub, N. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Weintraub, N. L.
Related Collections
Right arrow Coronary circulation
Right arrow Other diabetes
Right arrow Other Vascular biology
(Circulation Research. 2003;92:127.)
© 2003 American Heart Association, Inc.

Editorials

Impaired Hypoxic Coronary Vasodilation and ATP-Sensitive Potassium Channel Function

A Manifestation of Diabetic Microangiopathy in Humans?

Neal L. Weintraub

From the Department of Internal Medicine, Cardiovascular Division, University of Iowa College of Medicine, and VA Medical Center, Iowa City, Iowa.

Correspondence to Neal L. Weintraub, MD, Dept of Internal Medicine, Cardiovascular Division, University of Iowa College of Medicine, 200 Hawkins Dr, E329 GH, Iowa City, IA 52242. E-mail neal-weintraub{at}uiowa.edu


Key Words: coronary microcirculation • potassium channels • smooth muscle cells • diabetes • glibenclamide

Hypoxic coronary vasodilation contributes to the maintenance of oxygen supply to the working heart during increased metabolic demand. Mechanisms of hypoxic coronary dilation have been studied extensively and differ considerably depending upon the species and experimental model. In isolated coronary vessels, several mechanisms have been implicated either alone or in combination, including release of vasodilatory factors (ie, nitric oxide, prostaglandins, and adenosine), activation of ATP-sensitive potassium (KATP) channels and Ca2+-activated K+ channels, and inhibition of voltage-gated Ca2+ channels.1–5 To date, however, relatively few studies have been conducted in human blood vessels. Furthermore, whereas most prior studies have examined hypoxic dilation in conduit coronary arteries, coronary microvessels (<150 µm in diameter) are considered to be the principal regulators of coronary blood flow in response to metabolic stress.6 Thus, despite extensive studies conducted over the past several decades, surprisingly little is known about mechanisms of hypoxic coronary microvascular dilation in humans, and how it might be altered in disease states.

In this issue of Circulation Research, Miura and colleagues7 provide evidence that hypoxic dilation of human coronary microvessels is mediated primarily by activation of KATP channels in vascular smooth muscle cells (SMCs), independent of the endothelium. Moreover, they report that both hypoxic dilation and vasodilation induced by the KATP opener aprikalim are attenuated in microvessels from patients with diabetes mellitus, suggesting impaired KATP function. These findings provide new insight into mechanisms of coronary vasoregulation in humans, and they suggest that impaired microvascular KATPchannel function might contribute to increased cardiovascular morbidity and mortality in patients with diabetes.

KATP channels are distributed in a variety of tissues, including cardiomyocytes, SMCs, skeletal muscle, and pancreatic ß-cells.8 These octameric channels are composed of four inwardly rectifying potassium channel subunits (Kir) and four regulatory sulfonylurea receptor subunits (SUR). Channel complexes composed of less than 8 subunits are retained in the endoplasmic reticulum and thus cannot be targeted to the cell membrane.9 Two different KIR (KIR6.1 and KIR6.2) and SUR (SUR1 and SUR2) gene products have been identified to make up KATP channels. Splice variants of SUR2 (SUR2A and SUR2B) further add to the structural diversity of KATP channels. The molecular structure of KATP channels varies depending upon the species and tissue and is an important determinant of channel function, including sensitivity to ATP, nucleotide diphosphates, and potassium channel openers (KCO). Channel activity may also be regulated by posttranslational modification (ie, glycosylation, phosphorylation, and inositol phosphate metabolism). A characteristic feature of KATP channels is inhibition by sulfonylurea compounds such as glibenclamide.8

Recently, Farouque et al10 demonstrated that intracoronary infusion of glibenclamide reduced resting coronary blood flow in humans, suggesting that KATP channels contribute to basal regulation of the coronary circulation. In coronary arterioles from the right atrial appendages of humans (the same vessels used in the present study), nicorandil, a nonselective KCO compound, was demonstrated to induce vasodilation that was unaffected by methylene blue but markedly attenuated by glibenclamide, consistent with activation of KATP channels.11 The study by Miura et al7 confirms and extend these findings by demonstrating that dilation to aprikalim, a selective KCO, is markedly attenuated by glibenclamide, but unaffected by removal of the endothelium or by inhibitors of nitric oxide synthase or cyclooxygenase. These findings confirm that KATP channels are functionally expressed in human coronary microvessels and indicate that aprikalim acts directly on these channels to produce microvascular dilation.

The authors also provide evidence that Kir6.1 and SUR2B are expressed in human coronary microvessels. Deletion of Kir6.1 in mice was recently shown to induce coronary vasospasm and to block vasodilatory responses to KCO in vivo and in vitro, implying that this subunit is a constituent of coronary vascular SMC KATP channels.12 Also, deletion of SUR2 resulted in increased blood pressure in mice.13 Among the SUR2 variants, SUR2B is thought to be the most prevalent in vascular SMCs.14 Interestingly, coexpression of Kir6.1 and SUR2B formed a channel that was not sensitive to inhibition by ATP, although the channel was robustly activated by nucleotide diphosphates and KCO, and it was inhibited by glibenclamide.15 Thus, the channel is perhaps better classified as a nucleotide diphosphate-dependent K+ channel, rather than a KATP channel. It remains to be determined whether the K+ channels described in this study in human coronary microvessels exhibit the same functional characteristics as Kir6.1/SUR2B.

Diabetes in humans is associated with a substantial increase in risk of development of cardiovascular disease.16,17 Moreover, diabetics that suffer myocardial infarction have increased morbidity and mortality as compared with nondiabetics.18,19 Many factors likely contribute to the increased cardiovascular risk and adverse outcomes associated with diabetes, including concurrent dyslipidemia and hypertension, altered myocardial metabolism, etc.20 The use of older sulfonylurea drugs such as glibenclamide has also been associated with adverse cardiovascular outcomes in some studies,21,22 perhaps due to inhibition of mitochondrial KATP channels that mediate ischemic preconditioning in the myocardium.23

In the present study, impairment of vascular KATP channel function was observed in coronary microvessels from patients with diabetes. The findings are consistent with recent reports showing impaired relaxation responses to KCO in human saphenous veins and corporeal tissue strips from diabetic patients.24,25 In the study by Miura et al,7 KATP dysfunction in human coronary microvessels cannot be ascribed to sulfonylurea drugs, because impaired dilation to aprikalim was observed in microvessels from type I as well as type II diabetics (patients with type I diabetes are not treated with sulfonylurea drugs). Also, because the inhibitory effects of glibenclamide were reversible, rinsing the microvessels should have removed the drug even if it were taken before surgery. Endothelial dysfunction is commonly observed in diabetes, and impaired KCO-dependent dilation of cerebral arteries from diabetic rats was attributed to endothelial dysfunction.26 In the present study, dilation to aprikalim was unaffected by removal of the endothelium, and endothelium-dependent responses to bradykinin were similar in microvessels from diabetics versus nondiabetics. Consequently, the impaired dilatory responses observed in diabetic microvessels were not due to endothelial dysfunction. Finally, hypertension and hyperlipidemia are present in many diabetics and have been associated with impaired KATP channel–dependent relaxation27; however, data analysis suggests that these conditions did not account for the findings of the present study. The presence of coronary artery disease was likewise not correlated with microvascular KATP channel dysfunction. Thus, taken together, these findings suggest that impaired coronary microvascular KATP function is intrinsic to diabetes in humans. A number of issues remain to be resolved; for example, the patients in this study were predominately elderly, and most had atherosclerosis severe enough to warrant bypass surgery. Therefore, it is possible that microvascular KATP dysfunction is specific to this subset of patients with diabetes. Also, the relationship between microvascular KATP function and metabolic control can not be ascertained from available data. Finally, the potential modulating influence of medications such as insulin, insulin-sensitizing agents, and inhibitors of the renin-angiotensin system on microvascular KATP function in these patients is unknown.

What might account for impaired coronary microvascular KATP function in diabetes? The cellular and metabolic abnormalities linked to diabetic microvascular disease in the kidneys, eyes, and peripheral nerves are likely suspects (Figure).28 Elevated blood glucose per se, which is strongly associated with diabetic microvascular disease, could be the major instigator.28 Admission blood glucose and hemoglobin A1C were identified to be independent predictors of mortality in diabetics with acute myocardial infarction, and improved metabolic control after infarction was associated with reduced long-term mortality.29 Elevated glucose was demonstrated to acutely impair voltage-gated K+ channel function in rat coronary arteries through generation of reactive oxygen species.30 Whether acute hyperglycemia also impairs coronary microvascular KATP channel function, and the mechanisms by which this might occur, remain to be determined.



View larger version (29K):
[in this window]
[in a new window]
  		Potential mechanisms and consequences of microvascular KATP channel dysfunction in diabetes. PKC indicates protein kinase C; AGE, advanced glycation end-products.

What are the potential clinical implications of coronary microvascular KATP channel dysfunction in diabetes? Assuming that responses in atrial microvessels can be extrapolated to coronary resistance vessels in general, the findings by Miura et al7 suggest that KATP channel dysfunction could contribute significantly to myocardial ischemia in patients with diabetes. Interestingly, some patients with diabetes suffer from microvascular angina (chest pain due to myocardial ischemia in the absence of obstructive epicardial coronary artery disease). Although this disorder has been associated with endothelial dysfunction and insulin resistance.31 perhaps microvascular KATP channel dysfunction is a contributing factor. In addition, impaired metabolic coronary arteriolar vasodilation due to KATP channel dysfunction could potentially increase the extent of myonecrosis and contribute to worsened prognosis in diabetic patients who suffer myocardial infarction. Finally, if KATP channel dysfunction affects resistance vessels in general, it could contribute to systemic hypertension. Potential consequences of microvascular KATP channel dysfunction in diabetes are summarized in the Figure.

In summary, the study by Miura and colleagues establishes a role for KATP channels in mediating hypoxic coronary microvascular dilation in humans, and it suggests that dysfunction of KATP channels represents a manifestation of diabetic microangiopathy that could help to explain the increased incidence of cardiovascular disease in diabetic patients.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. Daut J, Maier-Rudolph W, von Beckerath N, Mehrke G, Gunther K, Goedel-Meinen L. Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels. Science. 1990; 247: 1341–1344.[Abstract/Free Full Text]
  2. Park KH, Rubin LE, Gross SS, Levi R. Nitric oxide is a mediator of hypoxic coronary vasodilatation. Relation to adenosine and cyclooxygenase-derived metabolites. Circ Res. 1992; 71: 992–1001.[Abstract/Free Full Text]
  3. Liu Q, Flavahan NA. Hypoxic dilatation of porcine small coronary arteries: role of endothelium and KATP-channels. Br J Pharmacol. 1997: 120: 728–734.[CrossRef][Medline] [Order article via Infotrieve]
  4. Kamekura I, Okumura K, Matsui H, Murase K, Mokuno S, Toki Y, Nakashima Y, Ito T. Mechanisms of hypoxic coronary vasodilatation in isolated perfused rat hearts. J Cardiovasc Pharmacol. 1999; 33: 836–842.[CrossRef][Medline] [Order article via Infotrieve]
  5. Smani T, Hernandez A, Urena J, Castellano AG, Franco-Obregon A, Ordonez A, Lopez-Barneo J. Reduction of Ca2+ channel activity by hypoxia in human and porcine coronary myocytes. Cardiovasc Res. 2002; 53: 97–104.[Abstract/Free Full Text]
  6. Embrey RP, Brooks LA, Dellsperger KC. Mechanism of coronary microvascular responses to metabolic stimulation. Cardiovasc Res. 1997; 35: 148–157.[Abstract/Free Full Text]
  7. Miura H, Wachtel RE, Loberiza FR Jr, Saito T, Miura M, Nicolosi AC, Gutterman DD. Diabetes mellitus impairs vasodilation to hypoxia in human coronary arterioles: reduced activity of ATP-sensitive potassium channels. Circ Res. 2003; 92: 151–158.[Abstract/Free Full Text]
  8. Fujita A, Kurachi Y. Molecular aspects of ATP-sensitive K+ channels in the cardiovascular system and K+ channel openers. Pharmacol Ther. 2000; 85: 39–53.[CrossRef][Medline] [Order article via Infotrieve]
  9. Zerangue N, Schwappach B, Jan YN, Jan LY. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane KATP channels. Neuron. 1999; 22: 537–548.[CrossRef][Medline] [Order article via Infotrieve]
  10. Farouque HM, Worthley SG, Meredith IT, Skyrme-Jones RA, Zhang MJ. Effect of ATP-sensitive potassium channel inhibition on resting coronary vascular responses in humans. Circ Res. 2002; 90: 231–236.[Abstract/Free Full Text]
  11. Takahashi K, Ohyanagi M, Kobayashi S, Miyamoto T. Effect of angiotensin-converting enzyme inhibitors and nitroxy groups on human coronary resistance vessels in vitro. J Cardiovasc Pharmacol. 2000; 36: 417–422.[CrossRef][Medline] [Order article via Infotrieve]
  12. Miki T, Suzuki M, Shibasaki T, Uemura H, Sato T, Yamaguchi K, Koseki H, Iwanaga T, Nakaya H, Seino S. Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat Med. 2002; 8: 466–472.[CrossRef][Medline] [Order article via Infotrieve]
  13. Chutkow WA, Samuel V, Hansen PA, Pu J, Valdivia CR, Makielski JC, Burant CF. Disruption of SUR2-containing KATP channels enhances insulin-stimulated glucose uptake in skeletal muscle. Proc Nat Acad Sci U S A. 2001; 98: 11760–11764.[Abstract/Free Full Text]
  14. Brayden JE. Functional roles of KATP channels in vascular smooth muscle. Clin Exp Pharmacol Physiol. 2002; 29: 312–316.[CrossRef][Medline] [Order article via Infotrieve]
  15. Yamada M, Isomoto S, Matsumoto S, Kondo C, Shindo T, Horio Y, Kurachi Y. Sulphonylurea receptor 2B and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K+ channel. J Physiol. 1997; 499: 715–720.[Medline] [Order article via Infotrieve]
  16. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Diabetes as a cardiovascular risk factor. Diabetes. 1974; 23: 105–112.[Medline] [Order article via Infotrieve]
  17. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA. 1979; 241: 2035–2038.[Abstract]
  18. Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner SM, Pyorala K, Tuomilehto J. Impact of diabetes on mortality after the first myocardial infarction: the FINMONICA Myocardial Infarction Register Study Group. Diabetes Care. 1998; 21: 69–75.[Abstract]
  19. Mak KH, Moliterno DJ, Granger CB, Miller DP, White HD, Wilcox RG, Califf RM, Topol EJ. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. J Am Coll Cardiol. 1997; 30: 171–179.[Abstract]
  20. Jacoby R, Nesto R. Acute myocardial infarction in the diabetic patient: pathophysiology, clinical course, and prognosis. J Am Coll Cardiol. 1992; 20: 736–744.[Abstract]
  21. Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol. 1999; 33: 119–124.[Abstract/Free Full Text]
  22. Caufield MT, O’Brien KD. Cardiovascular safety of oral antidiabetic agents: the insulin secretagogues. Clin Diabetes. 2002; 20: 81–84.[Abstract/Free Full Text]
  23. Cleveland JC Jr, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium: two paradoxes revisited. Circulation. 1997; 96: 29–32.[Abstract/Free Full Text]
  24. Yöntem Ö, Sahilli M, Karasu C, Özcelikay AT, Altan VM, Ari N. Troglitazone has no effect on KATP channel opener induced-relaxations in rat aorta and in human saphenous veins from patients with type 2 diabetics. Life Sci. 2000; 68: 557–568.[CrossRef][Medline] [Order article via Infotrieve]
  25. Venkateswarlu K, Giraldi A, Zhao W, Wang HZ, Melman A, Spektor M, Christ GJ. Potassium channels and human corporeal smooth muscle cell tone: diabetes and relaxation of human corpus cavernosum smooth muscle by adenosine triphosphate sensitive potassium channel openers. J Urology. 2002; 168: 355–361.[CrossRef][Medline] [Order article via Infotrieve]
  26. Zimmerman PA, Knot HJ, Stevenson AS, Nelson MT. Increased myogenic tone and diminished responsiveness to ATP-sensitive K+ channel openers in cerebral arteries from diabetic rats. Circ Res. 1997; 81: 996–1004.[Abstract/Free Full Text]
  27. Sobey CG. Potassium channel function in vascular disease. Arterioscler Thromb Vasc Biol. 2001; 21: 28–39.[Abstract/Free Full Text]
  28. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414: 813–820.[CrossRef][Medline] [Order article via Infotrieve]
  29. Malmberg K, Norhammar A, Wedel H, Ryden L. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction. Circulation. 1999; 99: 2626–2632.[Abstract/Free Full Text]
  30. Liu Y, Terata K, Rusch NJ, Gutterman DD. High glucose impairs voltage-gated K+ channel current in rat small coronary arteries. Circ Res. 2001; 89: 146–152.[Abstract/Free Full Text]
  31. Botker HE, Moller N, Ovesen P, Mengel A, Schmitz O, Orskov H, Bagger JP. Insulin resistance in microvascular angina (syndrome X). Lancet. 1993; 342: 136–140.[CrossRef][Medline] [Order article via Infotrieve]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
K. M. Gauthier
Hypoxia-induced vascular smooth muscle relaxation: increased ATP-sensitive K+ efflux or decreased voltage-sensitive Ca2+ influx?
Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H24 - H25.
[Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Weintraub, N. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Weintraub, N. L.
Related Collections
Right arrow Coronary circulation
Right arrow Other diabetes
Right arrow Other Vascular biology

Circulation Research Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2003 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.