Functional and Molecular Characterization of Receptor Subtypes Mediating Coronary Microvascular Dilation to Adenosine

Hein, Travis W.; Wang, Wei; Zoghi, Behyar; Muthuchamy, Mariappan; Li, Kuo

doi:10.1006/jmcc.2000.1298

Cited by 77 publications

(100 citation statements)

References 34 publications

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“…We also ascertained whether K V 7 channels contribute to relaxations produced by adenosine, which is released rapidly after myocardial ischemia in vivo and acts as a local metabolic regulator of coronary flow. 12,13 This study demonstrates that K V 7 channels are key regulators of coronary flow at rest, and they also contribute to adenosine-mediated dilatations and the active response to ischemia. …”

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confidence: 69%

Contribution of K _v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

et al. 2013

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F ailure of the coronary circulation to meet the constant demands of the cardiomyocytes results in ischemic heart disease or infarction. Determining the factors that regulate coronary blood flow is, therefore, crucial for understanding pathophysiological manifestations and for the development of new therapeutic strategies. Voltage-gated potassium channels (K V ) have been implicated in the control of the coronary circulation and reactive hyperemia, 1,2 but little is known about the specific molecular components. Kv channels encoded by KCNQ1-5 (K V 7.1-K V 7.5) are important regulators of the smooth muscle resting membrane potential and contractility in several different rodent and human arteries, [3][4][5][6][7][8][9][10][11] which are known to be compromised in animal models of primary and secondary hypertension. 3,6 These channels, in particular K V 7.4, are also functional end points in β-adrenoceptor-mediated relaxations.3 These combined observations provide a mechanism by which arteries become relatively resistant to endogenous vasorelaxants. However, little is known about K V 7 expression levels or the functional importance of these channels in coronary arteries.Consequently, we determined the expression profiles of KCNQ genes and the functional impact of K V 7 channel modulators in left anterior descending (LAD) coronary arteries. We also ascertained whether K V 7 channels contribute to relaxations produced by adenosine, which is released rapidly after myocardial ischemia in vivo and acts as a local metabolic regulator of coronary flow. 12,13 This study demonstrates that K V 7 channels are key regulators of coronary flow at rest, and they also contribute to adenosine-mediated dilatations and the active response to ischemia. MethodsFor more complete descriptions, see the online-only Data Supplement. AnimalsThe study complies with the European Community Guidelines for the Care and Use of Experimental Animals and was approved by the Animal Ethics Screening Committee in Denmark (license number: 2010/561-1799) and by the UK Animal (Scientific Procedures) Act 1986. Male, normotensive Wistar Hannover rats and spontaneously hypertensive rats (SHRs), aged 11 to 16 weeks, were purchased from Abstract-The goal of the present study was to determine the role of KCNQ-encoded K V channels (K V 7 channels) in the passive and active regulation of coronary flow in normotensive and hypertensive rats. In left anterior descending coronary arteries from normotensive rats, structurally different K V 7.2 to 7.5 activators produced relaxations, which were considerably less in arteries from hypertensive rats and were not mimicked by the K V 7.1-specific activator R-L3. In isolated, perfused heart preparations, coronary flow rate increased in response to the K V 7.2 to 7.5 activator (S)-1 and was diminished in the presence of a K V 7 inhibitor. The expression levels of KCNQ1-5 and their known accessory KCNE1-5 subunits in coronary arteries were similar in normotensive and hypertensive rats as measured by quantitative polymerase cha...

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confidence: 69%

Contribution of K _v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

et al. 2013

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“…Activation of cAMP results in a reduction in volume flux in intact, perfused frog mesenteric microvessels (1,20,21,47) and a decrease in solute flux in isolated perfused porcine coronary arterioles (33). Conversely, direct and indirect activation of the cGMP signaling pathways in intact isolated (57)(58)(59)(60) and in situ microvessels elicits loss of barrier function to solutes and volume (27,28,42,(50)(51)(52).…”

Section: Ado-sensitive Mechanismsmentioning

confidence: 99%

Sexual dimorphism in the permeability response of coronary microvessels to adenosine

Huxley

Wang

Whitt

2005

American Journal of Physiology-Heart and Circulatory Physiology

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Gender influences volume regulation via several mechanisms; whether these include microvascular exchange, especially in the heart, is not known. In response to adenosine (Ado), permeability (P s )to protein of coronary arterioles of female pigs decreases acutely. Whether Ado induces similar P s changes in arterioles from males or whether equivalent responses occur in coronary venules of either sex has not been determined. Hypotheses that 1) basal P s properties and 2) P s responses to vasoactive stimuli are sex independent were evaluated from measures of P s to two hydrophilic proteins, α-lactalbumin and porcine serum albumin (PSA), in arterioles and venules isolated from hearts of adult male and female pigs. Consistent with hypothesis 1, basal P s values of both microvessel types were independent of sex. Contrary to hypothesis 2, P s responses to Ado varied with sex, protein, and vessel type. Confirming earlier studies, Ado induced a ~20% decrease in P s to both proteins in coronary arterioles from females. In arterioles from males, Ado did not change P s for α-lactalbumin ( , 3 ± 13%) whereas P s for PSA ( ) decreased by 27 ± 8% (P < 0.005). In venules from females, Ado elevated by 44 ± 20% (P < 0.05), whereas in those from males, Ado reduced by 24 ± 5% (P < 0.05). The variety of outcomes is consistent with transvascular protein and protein-carried solute flux being regulated by multiple sex-dependent mechanisms in the heart and provides evidence of differences in exchange homeostasis of males and females in health and, likely, disease.

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“…It is well known that myocytes in the heart produce ATP, which is rapidly degraded to ADP, AMP, and adenosine by ectoenzymes. The myocyte-derived adenosine is a key substance in autoregulation of the coronary arterial system (11,12,19,43). Adenosine may play similar crucial roles in the autoregulatory function of the aortic (5), cerebral (14), and renal vasculature (17).…”

Section: ϫ7mentioning

confidence: 99%

ATP inhibits pump activity of lymph vessels via adenosine A₁ receptor-mediated involvement of NO- and ATP-sensitive K⁺ channels

Kousai¹,

Mizuno²,

Ikomi³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Kousai, Akira, Risuke Mizuno, Fumitaka Ikomi, and Toshio Ohhashi. ATP inhibits pump activity of lymph vessels via adenosine A 1 receptor-mediated involvement of NO-and ATP-sensitive K ϩ channels. Am J Physiol Heart Circ Physiol 287: H2585-H2597, 2004. First published August 12, 2004 doi:10.1152/ajpheart.01080. 2003.-We examined the effects of ATP on intrinsic pump activity in lymph vessels isolated from the rat. ATP caused significant dilation with a cessation of lymphatic pump activity. Removal of the endothelium or pretreatment with N -nitro-L-arginine methyl ester (L-NAME) significantly reduced ATP-induced inhibitory responses of lymphatic pump activity, whereas reduction was not suppressed completely by 10 Ϫ6 M ATP. L-Arginine significantly restored ATPinduced inhibitory responses in the presence of L-NAME. ATPinduced inhibitory responses in lymph vessels with endothelium were also significantly, but not completely, suppressed by pretreatment with glibenclamide. 8-Cyclopentyl-1,3-dipropylxanthine (a selective adenosine A 1 receptor antagonist), but not suramine (a P2X and P2Y receptor antagonist) or 3,7-dimethyl-1-proparglyxanthine (a selective adenosine A 2 receptor antagonist), significantly decreased ATP-induced inhibitory responses. ␣,␤-Methylene ATP (a selective P2X and P2Y receptor agonist) had no significant effect on lymphatic pump activity. In some lymph vessels with endothelium (24 of 30 preparations), adenosine also caused dose-dependent dilation with a cessation of lymphatic pump activity. L-NAME significantly reduced the inhibitory responses induced by the lower (3 ϫ 10 Ϫ8 -3 ϫ 10 Ϫ7 M) concentrations of adenosine. Glibenclamide or 8-cyclopentyl-1,3-dipropylxanthine also significantly suppressed adenosine-induced inhibitory responses. These findings suggest that ATP-induced dilation and inhibition of pump activity of isolated rat lymph vessels are endothelium-dependent and -independent responses. ATP-mediated inhibitory responses may be, in part, related to production of endogenous nitric oxide, involvement of ATP-sensitive K ϩ channels, or activation of adenosine A 1 receptors in lymphatic smooth muscle and endothelium.rat; endothelium; smooth muscle; nitric oxide THE TRANSPORT OF LYMPH depends on passive and active driving forces as well as the rate of lymph production in organs and tissues. The active driving forces, resulting from intrinsic pump activity of lymph vessels, play a pivotal role in the centripetal propulsion of lymph (1,31,39). Neural (21), humoral (30), and mechanical factors (8,22,23) modify the rhythm and amplitude of lymphatic intrinsic pump activity. Recently, it has become clear that lymphatic endothelium-derived nitric oxide (NO) strongly contributes to regulation of lymphatic intrinsic pump activity. Thus NO causes relaxation of lymphatic smooth muscles and reduces lymphatic intrinsic pump activity (24,26,27,35,40,45,48). ATP-sensitive K ϩ (K ATP ) channels have been found in the plasma membrane of cells, including vascular and nonvascular smooth muscles, and then beca...

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Functional and Molecular Characterization of Receptor Subtypes Mediating Coronary Microvascular Dilation to Adenosine

Cited by 77 publications

References 34 publications

Contribution of K _v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

Contribution of K _v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

Sexual dimorphism in the permeability response of coronary microvessels to adenosine

ATP inhibits pump activity of lymph vessels via adenosine A₁ receptor-mediated involvement of NO- and ATP-sensitive K⁺ channels

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Functional and Molecular Characterization of Receptor Subtypes Mediating Coronary Microvascular Dilation to Adenosine

Cited by 77 publications

References 34 publications

Contribution of K v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

Contribution of K v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

Sexual dimorphism in the permeability response of coronary microvessels to adenosine

ATP inhibits pump activity of lymph vessels via adenosine A1 receptor-mediated involvement of NO- and ATP-sensitive K+ channels

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Contribution of K _v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

Contribution of K _v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

ATP inhibits pump activity of lymph vessels via adenosine A₁ receptor-mediated involvement of NO- and ATP-sensitive K⁺ channels