Role of K<sub>ATP</sub> <sup>+</sup> channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine

Duncker, Dirk J.; Oei, H H; Hu, Frank B.; Stubenitsky, René; Verdouw, Pieter D.

doi:10.1152/ajpheart.2001.280.1.h22

Cited by 71 publications

(72 citation statements)

References 32 publications

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“…Excellent reproducibility of consecutive exercise trials has been reported previously (10,14,16,44). Four exercise protocols were performed on four different days and in random order.…”

Section: Exercise Protocolssupporting

confidence: 52%

Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction

Beer

Taverne

Kuster

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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de Beer VJ, Taverne YJ, Kuster DW, Najafi A, Duncker DJ, Merkus D. Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction. Am J Physiol Heart Circ Physiol 301: H1080 -H1089, 2011. First published June 17, 2011 doi:10.1152/ajpheart.01307.2010 is associated with endothelial dysfunction resulting in an imbalance in endothelium-derived vasodilators and vasoconstrictors. We have previously shown that despite increased endothelin (ET) plasma levels, the coronary vasoconstrictor effect of endogenous ET is abolished after MI. In normal swine, nitric oxide (NO) and prostanoids modulate the vasoconstrictor effect of ET. In light of the interaction among NO, prostanoids, and ET combined with endothelial dysfunction present after MI, we investigated this interaction in control of coronary vasomotor tone in the remote noninfarcted myocardium after MI. Studies were performed in chronically instrumented swine (18 normal swine; 13 swine with MI) at rest and during treadmill exercise. Furthermore, endothelial nitric oxide synthase (eNOS) and cyclooxygenase protein levels were measured in the anterior (noninfarcted) wall of six normal and six swine with MI. eNOS inhibition with N -nitro-L-arginine (L-NNA) and cyclooxygenase inhibition with indomethacin each resulted in coronary vasoconstriction at rest and during exercise, as evidenced by a decrease in coronary venous oxygen levels. The effect of L-NNA was slightly decreased in swine with MI, although eNOS expression was not altered. Conversely, in accordance with the unaltered expression of cyclooxygenase-1 after MI, the effect of indomethacin was similar in normal and MI swine. L-NNA enhanced the vasodilator effect of the ETA/B receptor blocker tezosentan but exclusively during exercise in both normal and MI swine. Interestingly, this effect of L-NNA was blunted in MI compared with normal swine. In contrast, whereas indomethacin increased the vasodilator effect of tezosentan only during exercise in normal swine, indomethacin unmasked a coronary vasodilator effect of tezosentan in MI swine both at rest and during exercise. In conclusion, the present study shows that endothelial control of the coronary vasculature is altered in post-MI remodeled myocardium. Thus the overall vasodilator influences of NO as well as its inhibition of the vasoconstrictor influence of ET on the coronary resistance vessels were reduced after MI. In contrast, while the overall prostanoid vasodilator influence was maintained, its inhibition of ET vasoconstrictor influences was enhanced in post-MI remote myocardium. endothelin; nitric oxide; prostacyclin CONGESTIVE HEART FAILURE IS the only major cardiovascular disorder of which the incidence has increased over the past decade, which is principally due to a reduction in mortality associated with acute myocardial infarction (MI). Consequently, MI has become an increasingly important risk factor for the development of congestive heart failure (5). The loss of viable myocardial tissue and the consequent left ve...

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“…Excellent reproducibility of consecutive exercise trials has been reported previously (10,14,16,44). Four exercise protocols were performed on four different days and in random order.…”

Section: Exercise Protocolssupporting

confidence: 52%

Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction

Beer

Taverne

Kuster

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…The contribution of 4-AP-sensitive K V channels to baseline coronary vascular resistance appears to be greater than that of other K ϩ channels investigated previously. Specifically, earlier studies found a ϳ10 -25% reduction in coronary blood flow following blockade of K ATP channels with glibenclamide (13,15,19,42) and little or no change in coronary flow following inhibition of BK Ca channels with iberiotoxin or charybdotoxin (30,36,40). We interpret these findings to indicate that vasodilator substances released by cardiac myocytes and endothelium under basal conditions regulate coronary microvascular resistance via pathways that converge largely upon K V channels.…”

Section: Discussionmentioning

confidence: 53%

Voltage-dependent K⁺ channels regulate the duration of reactive hyperemia in the canine coronary circulation

Dick¹,

Bratz²,

Borbouse³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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ϩ (KV) channels in coronary vasodilation elicited by myocardial metabolism and exogenous H2O2, as responses were attenuated by the KV channel blocker 4-aminopyridine (4-AP). Here we tested the hypothesis that KV channels participate in coronary reactive hyperemia and examined the role of KV channels in responses to nitric oxide (NO) and adenosine, two putative mediators. Reactive hyperemia (30-s occlusion) was measured in open-chest dogs before and during 4-AP treatment [intracoronary (ic), plasma concentration 0.3 mM]. 4-AP reduced baseline flow 34 Ϯ 5% and inhibited hyperemic volume 32 Ϯ 5%. Administration of 8-phenyltheophylline (8-PT; 0.3 mM ic or 5 mg/kg iv) or N G -nitro-L-arginine methyl ester (L-NAME; 1 mg/min ic) inhibited early and late portions of hyperemic flow, supporting roles for adenosine and NO. 4-AP further inhibited hyperemia in the presence of 8-PT or L-NAME. Adenosine-induced blood flow responses were attenuated by 4-AP (52 Ϯ 6% block at 9 g/min). Dilation of arterioles to adenosine was attenuated by 0.3 mM 4-AP and 1 M correolide, a selective KV1 antagonist (76 Ϯ 7% and 47 Ϯ 2% block, respectively, at 1 M). Dilation in response to sodium nitroprusside, an NO donor, was attenuated by 4-AP in vivo (41 Ϯ 6% block at 10 g/min) and by correolide in vitro (29 Ϯ 4% block at 1 M). KV current in smooth muscle cells was inhibited by 4-AP (IC50 1.1 Ϯ 0.1 mM) and virtually eliminated by correolide. Expression of mRNA for KV1 family members was detected in coronary arteries. Our data indicate that KV channels play an important role in regulating resting coronary blood flow, determining duration of reactive hyperemia, and mediating adenosine-and NO-induced vasodilation. ischemic vasodilation; adenosine; 4-aminopyridine; delayed rectifier potassium channel; vascular smooth muscle IN THE CORONARY CIRCULATION, a brief period of ischemia is normally followed by a large and transient compensatory increase in blood flow. This phenomenon of reactive hyperemia, different from active (also known as functional or metabolic) hyperemia, is thought to represent a repayment of blood flow debt and is attributed to the accumulation of ischemic vasodilator metabolites. Evidence supports both adenosine and nitric oxide (NO) as mediators of reactive hyperemia (2, 4, 12, 52). Importantly, however, neither block of adenosine nor NO signaling can completely abolish reactive hyperemia (56). Thus the mechanisms of reactive hyperemia remain incompletely understood. Moreover, other mediators have been suggested, and it is likely that future studies will identify additional candidates. Rather than focus on putative metabolites underlying reactive hyperemia, we have turned our attention to possible end-effectors in vascular smooth muscle. K ϩ channels are likely targets of vasodilator metabolites, because K ϩ channels determine membrane potential and thus vascular tone (27,35). Previous studies have focused on Ca 2ϩ /voltage-sensitive (BK Ca ) and ATP-dependent (K ATP ) K ϩ channels. To date, only one study suggests a role for BK C...

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“…Subsequently, animals were instrumented under sterile conditions as described previously. 17,18 Briefly, a thoracotomy was performed through the left fourth intercostal space. Subsequently, a polyvinylchloride catheter was inserted into the aortic arch, for the measurement of aortic pressure and blood sampling for the determination of PO 2 , PCO 2 , pH, O 2 saturation, and hemoglobin concentration (ABL800, Radiometer).…”

Section: Surgical Proceduresmentioning

confidence: 99%

“…Excellent reproducibility of exercise trials has been reported previously. 17,18 After obtaining hemodynamic measurements with swine lying quietly on a treadmill, a 5-stage (1-5 km/h) treadmill exercise protocol was started with each exercise stage lasting 2 to 3 minutes. Hemodynamic variables were continuously recorded, and both arterial and mixed venous blood samples were collected during the last 60 s of each exercise stage for the determination of body oxygen consumption.…”

Section: Sunitinibmentioning

confidence: 99%

Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress

et al. 2012

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Abstract-Angiogenesis inhibition with agents targeting tyrosine kinases of vascular endothelial growth factor receptors is an established anticancer treatment, but is, unfortunately, frequently accompanied by systemic hypertension and cardiac toxicity. Whether vascular endothelial growth factor receptor antagonism also has adverse effects on the pulmonary and coronary circulations is presently unknown. In chronically instrumented awake swine, the effects of the vascular endothelial growth factor receptor antagonist sunitinib on the systemic, pulmonary, and coronary circulation were studied. One week after sunitinib (50 mg PO daily), mean aortic blood pressure (MABP) had increased from 83Ϯ5 mm Hg at baseline to 97Ϯ6 mm Hg (PϽ0.05) because of a 57Ϯ20% increase in systemic vascular resistance as cardiac output decreased. In contrast, sunitinib had no discernible effects on pulmonary and coronary hemodynamics or cardiac function. We subsequently investigated the mechanisms underlying the sunitinib-induced systemic hypertension. Intravenous administration of NO synthase inhibitor N G -nitro-L-arginine increased MABP by 24Ϯ1 mm Hg under baseline conditions, whereas it increased MABP even further after sunitinib administration (32Ϯ3 mm Hg; PϽ0.05). Reactive oxygen species scavenging with a mixture of antioxidants lowered MABP by 13Ϯ2 mm Hg before but only by 5Ϯ2 mm Hg (PϽ0.05) after sunitinib administration. However, intravenous administration of the dual endothelin A/endothelin B receptor blocker tezosentan, which did not lower MABP at baseline, completely reversed MABP to presunitinib values. These findings indicate that sunitinib produces vasoconstriction selectively in the systemic vascular bed, without affecting pulmonary or coronary circulations. The sunitinib-mediated systemic hypertension is principally attributed to an increased vasoconstrictor influence of endothelin, with no apparent contributions of a loss of NO bioavailability or increased oxidative stress. (Hypertension. 2012;59:151-157.) Key Words: endothelin 1 Ⅲ hypertension Ⅲ oxidative stress Ⅲ pulmonary hypertension Ⅲ vascular endothelial growth factor A ngiogenesis inhibition, by targeting the tyrosine kinases of the vascular endothelial growth factor (VEGF) receptors (VEGFRs), has become an established treatment of several tumor types. This therapy is associated with adverse effects, including the development of hypertension and cardiac and renal toxicity. 1 Hypertension has been reported in Յ60% of patients treated with sunitinib, an orally active multitarget receptor tyrosine kinase inhibitor (RTKI), targeting, among others, the VEGFR-1 and -2, which is used as first-line treatment of metastatic renal cell carcinoma or imatinib-resistant gastrointestinal stromal tumors. 1 In addition, impaired cardiac function, as reflected by a decrease in left ventricular ejection fraction of 10% to 15%, has been observed in Յ28% of patients treated with sunitinib. 2 Angina pectoris and increased levels of biomarkers reflecting ischemic myocardial damage may als...

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Role of K_ATP ⁺ channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine

Cited by 71 publications

References 32 publications

Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction

Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction

Voltage-dependent K⁺ channels regulate the duration of reactive hyperemia in the canine coronary circulation

Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress

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Role of KATP + channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine

Cited by 71 publications

References 32 publications

Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction

Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction

Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation

Sunitinib-Induced Systemic Vasoconstriction in Swine Is Endothelin Mediated and Does Not Involve Nitric Oxide or Oxidative Stress

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Role of K_ATP ⁺ channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine

Voltage-dependent K⁺ channels regulate the duration of reactive hyperemia in the canine coronary circulation