AJP - Heart Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 280: H22-H33, 2001;
0363-6135/01 $5.00
This Article
Right arrow Abstract Freely available
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 Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (21)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Duncker, D. J.
Right arrow Articles by Verdouw, P. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Duncker, D. J.
Right arrow Articles by Verdouw, P. D.
Vol. 280, Issue 1, H22-H33, January 2001

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

D. J. Duncker, H. H. Oei, F. Hu, R. Stubenitsky, and P. D. Verdouw

Experimental Cardiology, Thoraxcenter, Cardiovascular Research Institute COEUR, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The role of ATP-sensitive K+ (KATP+) channels in vasomotor tone regulation during metabolic stimulation is incompletely understood. Consequently, we studied the contribution of KATP+ channels to vasomotor tone regulation in the systemic, pulmonary, and coronary vascular bed in nine treadmill-exercising swine. Exercise up to 85% of maximum heart rate increased body O2 consumption fourfold, accommodated by a doubling of both cardiac output and body O2 extraction. Mean aortic pressure was unchanged, implying that systemic vascular conductance (SVC) also doubled, whereas pulmonary artery pressure increased almost in parallel with cardiac output, so that pulmonary vascular conductance (PVC) increased only 25 ± 9% (both P < 0.05). Myocardial O2 consumption tripled during exercise, which was paralleled by an equivalent increase in O2 supply so that coronary venous PO2 was maintained. Selective KATP+ channel blockade with glibenclamide (3 mg/kg iv), decreased SVC by 29 ± 4% at rest and by 10 ± 2% at 5 km/h (both P < 0.05), whereas PVC was unchanged. Glibenclamide decreased coronary vascular conductance and hence myocardial O2 delivery, necessitating an increase in O2 extraction from 76 ± 2% to 86 ± 2% at rest and from 79 ± 2% to 83 ± 1% at 5 km/h. Consequently, coronary venous PO2 decreased from 25 ± 1 to 17 ± 1 mmHg at rest and from 23 ± 1 to 20 ± 1 mmHg at 5 km/h (all values are P < 0.05). In conclusion, KATP+ channels dilate the systemic and coronary, but not the pulmonary, resistance vessels at rest and during exercise in swine. However, opening of KATP+ channels is not mandatory for the exercise-induced systemic and coronary vasodilation.

exercise; coronary circulation; pulmonary circulation; systemic circulation


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

OVER A DECADE AGO, hyperpolarization of the vascular smooth muscle cell membrane caused by opening of ATP-sensitive K+ (KATP+) channels was discovered as a novel mechanism of vasodilation. Subsequently, the pharmacological openers of these KATP+ channels have been shown to dilate resistance vessels in the systemic (20, 27), pulmonary (13, 20, 24, 28), and coronary (9, 27) vascular beds. Additionally, blockade of KATP+ channels increases basal tone in the systemic (5, 11, 17, 21, 23, 33), pulmonary (20, 24), and coronary circulations (9, 15), indicating that these channels contribute significantly to the regulation of basal vasomotor tone in these vascular beds. In contrast, information on the role of KATP+ channels in the adaptation of vasomotor tone during increased metabolic demands produced by exercise is limited. Thus only two studies (9, 10) on dogs reported the role of KATP+ channels in exercise-induced coronary vasodilation, whereas no study investigated the role of KATP+ channels in the adaptation of vasomotor tone in the pulmonary and regional systemic vascular beds during exercise. Consequently, in the present study we investigated the role of KATP+ channels in the regulation of systemic, pulmonary, and coronary vasomotor tone in awake pigs under basal resting conditions and during treadmill exercise, resulting in heart rates up to 85% of the maximum heart rate.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Crossbred Landrace × Yorkshire pigs were used in the present study. All of the experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals as approved by the Council of the American Physiological Society and the regulations of the Animal Care Committee of the Erasmus University Rotterdam (The Netherlands). Adaptation of animals to the laboratory conditions started 1 wk before the day of surgery and continued until 10 days postoperatively. Full details of the experimental procedures have been published previously (7, 8, 27, 30).

Surgical Procedures

After an overnight fast, 11 pigs (6 male and 5 female, weighing 24 ± 1 kg at the time of surgery and 29 ± 1 kg at the time of study) were sedated with ketamine (20 mg/kg im; Ketalin, Apharmo, Arnhem, The Netherlands), anesthetized with 10 mg/kg iv thiopental sodium (Rhone-Rorer-Poulenc, Amstelveen, The Netherlands), and intubated and mechanically ventilated with a mixture of O2 and nitrous oxide (1:2), to which 0.2-1.0% vol/vol isoflurane (Forene, Abbott, Amstelveen, The Netherlands) was added. Anesthesia was further maintained with midazolam (2 mg/kg + 1 mg · kg-1 · h-1 iv; Dormicum, Roche, Mijdrecht, The Netherlands) and fentanyl (10 µg · kg-1 · h-1 iv; Janssen-Cilag, Tilburg, The Netherlands). Under sterile conditions, the chest was opened via the fourth left intercostal space and an 8-Fr fluid-filled polyvinyl chloride catheter was inserted into the aortic arch for the measurement of central aortic blood pressure and collection of arterial blood samples and secured with a purse-string suture. After the pericardium was opened, an electromagnetic flow probe (14-15 mm inner diameter) was positioned around the ascending aorta for the measurement of ascending aortic blood flow (Transflow 601 Systems, Skalar, Delft, The Netherlands). A high-fidelity pressure transducer (model P4.5, Konigsberg Instruments, Pasadena, CA) was inserted into the left ventricle via the apical dimple for recording of left ventricular (LV) pressure and the maximum of its first derivative (LV dP/dtmax). An 8-Fr catheter was inserted into the left ventricle for calibration of the Konigsberg transducer signal. An 8-Fr catheter was also inserted into the pulmonary artery for measurement of pulmonary artery pressure, withdrawal of mixed venous blood samples, and administration of drugs, and another 8-Fr catheter was inserted into the left atrial appendage for measurement of left atrial pressure and injection of radioactive microspheres to determine regional organ and tissue blood flows (27). For the measurement of coronary blood flow, a Doppler flow probe of 2.0-3.0 mm inner diameter, emitting frequency (F0) = 10 MHz, was placed around the proximal part of the left anterior descending (LAD) coronary artery (model HVPD-10, Crystal Biotech, Northboro, MA) for measurement of coronary blood flow (7, 8, 16). A small angiocatheter (0.8/1.1 mm, inner/outer diameter) connected to a larger Tygon catheter (0.8/2.4 mm, inner/outer diameter) was inserted directly into the anterior interventricular vein to allow sampling of coronary venous blood. Electrical wires and catheters were tunneled subcutaneously to the back, the chest was closed, and the animals were allowed to recover. All of the electrical wires and catheters were protected with a vest.

Postsurgical period. After surgery, the animals received analgesia by daily intramuscular injections of 0.3 mg buprenorphine (Temgesic; Schering-Plough, Amstelveen, The Netherlands) during the first 48 h and intravenous injections of 25 mg/kg amoxicillin (Clamoxyl, Beecham Farma, Amstelveen, The Netherlands) and 5 mg/kg gentamycin (AUV, Cuijk, The Netherlands) on a daily basis during the first week to prevent infections. The catheters were flushed daily with physiological saline containing 2,000 U/ml heparin sodium (Leo Pharmaceutical Products, Weesp, The Netherlands).

Experimental Protocols

Studies were performed 10-20 days after surgery with animals either resting in a cage or exercising on a motor-driven treadmill.

Degree, duration, and selectivity of KATP+ channel blockade produced by glibenclamide. To determine the degree and duration of KATP+ channel blockade produced by glibenclamide, studies were performed in five awake resting pigs. After animals had been lying quietly for 15 min, baseline measurements were collected and the effects of four consecutive intravenous infusions (37.5, 75, 150, and 225 µg · kg-1 · min-1) of the KATP+ channel opener bimakalim (27) on heart rate, mean aortic blood pressure, cardiac output, and coronary blood flow were studied.

On a different day, baseline hemodynamic measurements were recorded and blood samples were collected, after which animals received an intravenous infusion of glibenclamide (3 mg/kg in 20 ml, administered over 5 min). Five minutes after administration was completed, measurements were made at 3-min intervals over a 12-min period corresponding to the total exercise protocol period (see Experimental Protocols). After we completed these measurements, four consecutive infusions of bimakalim (37.5, 75, 150, and 225 µg · kg-1 · min-1) were administered.

To confirm the reported (9, 10) specificity of glibenclamide, six consecutive, 5-min infusions of sodium nitroprusside (0.5, 1, 2, 3, 4, and 5 µg · kg-1 · min-1) were administered intravenously before and 5 min after glibenclamide (3 mg/kg iv) in two awake but resting pigs.

Exercise Protocols

Two exercise protocols were performed on different days and in random order. The aim of the first protocol was to study the effect of KATP+ channel blockade during exercise. In the second protocol we confirmed the reproducibility of two consecutive exercise tests performed at a 90-min interval (7, 8, 30).

KATP+ channel blockade. With the pigs resting quietly on the treadmill, resting hemodynamic measurements were obtained, and arterial, mixed venous, and coronary venous blood samples were collected (7, 8). After all of the hemodynamic measurements were repeated and rectal temperature was measured with animals standing on the treadmill, a five-stage treadmill exercise protocol was started (1-5 km/h). Each exercise stage lasted 2-3 min. Hemodynamic variables were continuously recorded and blood samples collected during the last 45 s of each exercise stage, at a time when hemodynamics had reached a steady state. After completing the exercise protocol, the animals were allowed to rest on the treadmill. Ninety minutes later, the animals received an intravenous infusion of glibenclamide (3 mg/kg in 20 ml, administered over 5 min) to produce KATP+ channel blockade. Five minutes after completion of the glibenclamide infusion, resting measurements were obtained, and the exercise protocol was repeated. To prevent glibenclamide-induced decreases in blood glucose levels, the animals received intravenous 10-ml 10% glucose injections at rest and after collection of measurements at 2 and 4 km/h.

On a different day, the effects of KATP+ channel blockade on regional organ and tissue blood flows were studied in five pigs. For this purpose, radioactive microspheres were injected in pigs when resting quietly on the treadmill and when exercising at 5 km/h before and after 90 min of rest, in the presence of glibenclamide (3 mg/kg iv).

Reproducibility of responses to exercise. Ninety minutes after the pigs had undergone a control exercise period, the animals received 20 ml of physiological saline, after which resting measurements were obtained and the five-stage exercise protocol was repeated.

Blood Gas and Glucose Measurements

Blood samples were maintained in ice-cold syringes until the conclusion of each exercise trial. Measurements of PO2 (mmHg), PCO2 (mmHg), pH, and standard base excess (SBE) were then immediately performed with a blood gas analyzer (Acid-Base Laboratory model 505, Radiometer, Copenhagen, Denmark). O2 saturation (SO2) and hemoglobin (Hb, 100 ml/g) were measured with a hemoximeter (OSM2, Radiometer). Arterial glucose measurements were performed with the use of Glucostix (Bayer Diagnostics, Mijdrecht, The Netherlands) and a glucometer (model 5626, Miles).

Data Acquisition and Analysis

All hemodynamic data were recorded and digitized on-line by using an eight-channel data-acquisition program ATCODAS (Dataq Instruments, Akron, OH) and stored on a computer for off-line analysis with a program written in MatLab (Mathworks, Natick, MA). A minimum of 15 consecutive beats were selected for analysis of the digitized hemodynamic signals.

Cardiac output was computed as the sum of ascending aortic blood flow (measured with an electromagnetic flow probe) and total coronary blood flow. Because the LAD coronary artery supplies ~40% of the left ventricle, total coronary blood flow was taken as 2.5× flow in the LAD coronary artery. Systemic and coronary vascular conductance were calculated as the ratio of cardiac output and mean aortic pressure and coronary blood flow and mean aortic pressure, respectively. Blood O2 content (µmol/ml) was computed as [0.621 · Hb (g%) · O2 saturation (%)] + [0.00131 · PO2 (mmHg)]. Myocardial O2 delivery (MDO2) in the LAD coronary artery perfused area was computed as the product of arterial O2 content and LAD coronary blood flow; whole body O2 delivery (BDO2) was calculated as the product of arterial O2 content and cardiac output. MVO2 in the region perfused by the LAD coronary artery was calculated as the product of coronary blood flow and the difference in O2 content between arterial and coronary venous blood; whole body O2 consumption (BVO2) was calculated as the product of cardiac output and difference in O2 content between arterial and mixed venous blood. Myocardial O2 extraction was computed as the ratio of arteriocoronary venous O2 content difference and the arterial O2 content; whole body O2 extraction was calculated as the ratio of the difference in the arterial and mixed venous O2 contents and the arterial O2 content.

Statistical analysis of the exercise and treatment data was performed by using a two-way ANOVA for repeated measures. When a significant effect of exercise was observed, post hoc testing was done by using Dunnett's test. When a significant effect of treatment was observed, post hoc testing was done with the use of either a paired Student's t-test or Wilcoxon signed rank test. A two-tailed P value of <0.05 was considered statistically significant. All data are presented as means ± SE.

Drugs

Glibenclamide (Sigma-Aldrich, Bornem, Belgium) was dissolved in 20-ml distilled water (30°C, pH 8-9), whereas bimakalim (courtesy of P. Schelling; Merck, Darmstadt, Germany) was dissolved in 30°C saline to produce a concentration of 100 µg · kg-1 · ml-1. Sodium nitroprusside (25 mg/ml) (Department of Pharmacy, Academic Hospital Dijkzigt, Rotterdam, The Netherlands) was diluted in 37°C saline to produce a concentration of 1 µg · kg-1 · ml-1. Fresh drug solutions were prepared daily.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Degree, Stability, and Selectivity of KATP+ Channel Blockade Produced by Glibenclamide

Bimakalim produced a dose-dependent increase in systemic and coronary vascular conductance (Fig. 1) and a small increase in pulmonary vascular conductance from 0.29 ± 0.04 l · min-1 · mmHg-1 at baseline up to 0.33 ± 0.06 l · min-1 · mmHg-1 (P < 0.05) during the highest dose of bimakalin (225 µg · kg-1 · min-1). Twenty minutes after administration of glibenclamide (3 mg/kg iv), the bimakalim-induced vasodilation was blunted by 60-70%, whereas the vasodilation produced by sodium nitroprusside remained unmitigated (Fig. 1). Glibenclamide resulted in stable decreases in mixed venous and coronary venous SO2 saturation over the 12-min period (Fig. 2). These data indicate that glibenclamide produced a good and stable degree of selective blockade of KATP+ channels over a time period corresponding with the total exercise trial period (12 ± 1 min).


View larger version (27K):
[in this window]
[in a new window]
  		Fig. 1.   Effect of glibenclamide (Glib, 3 mg/kg iv, n = 5 pigs) on bimakalim-induced (left) and sodium nitroprusside (right)-induced increases in systemic vascular conductance (SVC, top) and coronary vascular conductance (CVC, bottom). Note that the increase in conductance by bimakalim was significantly (P < 0.01) attenuated by Glib, whereas the increase in conductance by nitroprusside was unaffected. Data are means ± SE.



View larger version (19K):
[in this window]
[in a new window]
  		Fig. 2.   Stability of Glib-induced (3 mg/kg iv) decreases in mixed venous and coronary venous O2 saturations. Data are means ± SE; n = 3 pigs.

Effects of KATP+ Channel Blockade During Exercise

Systemic circulation. Exercise produced an increase in cardiac output from 4.0 ± 0.2 l/min at rest (lying down) to 8.3 ± 0.3 l/min at 5 km/h (P < 0.01), which was principally due to an increase in heart rate from 121 ± 5 to 245 ± 8 beats/min (P < 0.01, ~85% of maximum heart rate) as stroke volume increased <10% (Table 1). Because LV systolic pressure increased from 110 ± 2 mmHg at rest to 136 ± 3 mmHg at 5 km/h, P < 0.01, the maintained stroke volume was the result of an increase in left atrial pressure from 4 ± 1 to 14 ± 3 mmHg (P < 0.01) and an increase in LV dP/dtmax from 2,940 ± 120 to 5,890 ± 180 mmHg/s (P < 0.01). Mean aortic pressure decreased slightly when the animals went from a lying position to a standing position but did not change during exercise. The maintained mean aortic blood pressure in the presence of a doubling of cardiac output implies a doubling of systemic vascular conductance.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Effect of KATP+ channel blockade on hemodynamic responses to graded treadmill exercise

Exercise resulted in a decrease in arterial PCO2 from 44 ± 1 mmHg at rest to 39 ± 1 mmHg at 5 km/h and an increase in arterial pH from 7.44 ± 0.01 to 7.47 ± 0.01 (both P < 0.05) (Table 2). Arterial PO2 and SO2 (97 ± 1% at rest and 96 ± 1% at 5 km/h) did not change from their baseline values, but Hb and O2 content increased by 15 ± 4% and 14 ± 4% at the highest level of exercise compared with resting conditions (both P < 0.05). Mixed venous PO2 (Table 2), SO2, and O2 content (not shown) decreased progressively during exercise, whereas mixed venous PCO2 and pH were minimally affected. Because both cardiac output and the difference in the arterial and mixed venous O2 contents nearly doubled, BVO2 increased fourfold from 7.5 ± 0.3 to 30.1 ± 0.8 mmol/min, respectively (P < 0.01, Fig. 3).

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Effect of KATP+ channel blockade on blood gas responses to graded treadmill exercise



View larger version (21K):
[in this window]
[in a new window]
  		Fig. 3.   Effect of ATP-sensitive K+ (KATP+) channel blockade with Glib (3 mg/kg iv, top) or an equivalent volume of saline (bottom) on the relations between whole body O2 consumption (BVO2) and SVC, between BVO2 and body O2 delivery (BDO2; dashed line represents line of identity), between BVO2 and body O2 extraction, and between BVO2 and mixed venous PO2. Data points were obtained at rest (lying) and during 5 levels of treadmill exercise (1-5 km/h). Data are means ± SE; n = 9 pigs; *P < 0.05 vs. Control.

Glibenclamide increased mean aortic blood pressure that was the result of a decrease in systemic vascular conductance as cardiac output decreased at rest and lower levels of exercise or remained unchanged at 4 and 5 km/h (Table 1) due to a possibly baroreceptor reflex-mediated decrease in heart rate. The decrease in systemic vascular conductance was compensated by an increase in O2 extraction, so that body O2 consumption was maintained. Consequently, mixed venous PO2 and O2 content were decreased at rest and during each level of exercise (Table 2). The glibenclamide-induced decrease in systemic vascular conductance and mixed venous PO2 were similar at rest and all levels of exercise, indicating that KATP+ channel blockade did not affect the exercise-induced systemic vasodilation (Fig. 3). The increased systemic vasomotor tone resulted in an increased arterio-mixed venous pH difference, which was principally due to an increase in arterio-mixed venous PCO2 difference (not shown), suggesting that the glibenclamide-induced vasoconstriction did not result in anaerobic metabolism.

Regional blood flows. During exercise at 5 km/h, flow to the various skeletal muscle groups increased (Fig. 4), varying from 5-fold in predominantly white fiber muscle to 20-fold in predominantly red fiber muscle (1). Brain flow increased by ~20% (P <=  0.05), flow to the adrenals and bone did not change, and flow to most visceral organs decreased (Table 3). Arteriovenous anastomotic (AVA) flow, represented by lung flow (27) and cutaneous flow increased by 300% and 25%, respectively.


View larger version (28K):
[in this window]
[in a new window]
  		Fig. 4.   Effect of KATP+ channel blockade with Glib (3 mg/kg iv) on blood flow to various skeletal muscle groups of the trunk (A), hind legs (B), and front legs (C). Data points were obtained at rest (lying) and during treadmill exercise at 5 km/h. Glib had no significant effect on blood flow in any of the skeletal muscle groups either at rest or during exercise. Data are means ± SE; n = 5 pigs.


                              
View this table:
[in this window]
[in a new window]
  		Table 3.   Effect of KATP+ channel blockade on regional blood flows and regional vascular conductances

Glibenclamide had no effect on skeletal muscle blood flow, in any of various skeletal muscle groups independent of fiber-type composition, either at rest or during exercise (Fig. 4). In contrast, glibenclamide decreased flow to most visceral organs at rest and/or during exercise at 5 km/h (Table 3), whereas bone flow was not affected. Glibenclamide also reduced skin flow but had no effect on AVA flow. Vascular conductance in all visceral organs, bone, and skin decreased at rest and/or during exercise, but AVA conductance was not significantly altered (Table 3). Glibenclamide had no effect on the exercise-induced increases in vascular conductance in skeletal muscle (not shown).

Pulmonary circulation. Exercise resulted in an increase of mean pulmonary artery pressure from 16 ± 1 to 34 ± 2 mmHg (P < 0.01; Table 1). The driving pressure across the pulmonary vascular bed (mean pulmonary artery pressure-mean left atrial pressure) increased slightly less than the increase in cardiac output so that pulmonary vascular conductance increased by 25 ± 9% (P < 0.05) (Table 1 and Fig. 5). Glibenclamide had no effect on pulmonary artery pressure or pulmonary vascular conductance, either at rest or during exercise.


View larger version (13K):
[in this window]
[in a new window]
  		Fig. 5.   Effect of KATP+ channel blockade with Glib (3 mg/kg iv; left) or an equivalent volume of saline (right) on the relation between BVO2 and pulmonary vascular conductance (PVC). Data points were obtained at rest (lying) and during 5 levels of treadmill exercise (1-5 km/h). Data are means ± SE; n = 7 pigs; neither saline nor Glib had a significant effect on the relation between BVO2 and PVC.

Coronary circulation. Blood flow in the LAD coronary artery increased from 50 ± 4 ml/min at rest to 118 ± 13 ml/min during the highest level of exercise (P < 0.01). Exercise had no effect on coronary venous PCO2, pH, PO2 (Table 2, Fig. 6), SO2, or O2 content (not shown). MVO2 increased from 162 ± 18 to 465 ± 44 µmol/min, whereas MDO2 increased from 212 ± 20 to 585 ± 53 µmol/min, respectively (both P < 0.01). Consequently, myocardial O2 extraction and coronary venous PO2 were minimally affected during exercise. KATP+ channel blockade with glibenclamide decreased coronary blood flow and coronary vascular conductance, which resulted in a decrease in O2 delivery at each level of MVO2 (P < 0.05), necessitating an increase in O2 extraction, which led to a decrease in coronary venous PO2 (Fig. 6). Similar to the systemic circulation, the effect of glibenclamide on coronary vascular conductance was also similar at rest and at each level of exercise, indicating that KATP+ channel blockade did not modify the exercise-induced coronary vasodilation. The increased coronary vasomotor tone resulted in an increased arteriocoronary venous pH difference, due to the widening of arteriocoronary venous PCO2 gradient as the arteriocoronary venous SBE difference was unchanged (not shown), indicating that the glibenclamide-induced flow reduction did not result in myocardial ischemia.


View larger version (25K):
[in this window]
[in a new window]
  		Fig. 6.   Effect of KATP+ channel blockade with Glib (3 mg/kg iv, top) or an equivalent volume of saline (bottom) on the relations between myocardial VO2 consumption (MVO2) and CVC; between MVO2 and myocardial O2 delivery (MDO2) (dashed line represents line of identity); between MVO2 and myocardial O2 extraction; and between MVO2 and coronary venous PO2. Data points were obtained at rest and during 5 levels of treadmill exercise. Data are means ± SE; n = 8 pigs; *P < 0.05 vs. control.

Blood glucose. Blood glucose did not change during control exercise (6.8 ± 0.8 mmol/l at rest and 5.9 ± 0.6 mmol/l at 5 km/h). With the glucose-supplementation regimen, glucose levels after glibenclamide were similar to levels during control conditions (7.1 ± 0.6 mmol/l at rest and 6.0 ± 0.6 mmol/l at 5 km/h).

Reproducibility of Responses to Exercise

Ninety minutes after the control exercise period, at a time when all hemodynamic variables had returned to baseline resting values, the second period of exercise resulted in almost identical responses to exercise (Tables 4 and 5, and Figs. 3, 5, and 6), with the exception of heart rate and LV dP/dtmax, which were slightly (<10%) lower during exercise at 2-5 km/h compared with the first run (Table 4).

                              
View this table:
[in this window]
[in a new window]
  		Table 4.   Reproducibility of hemodynamic responses to graded treadmill exercise


                              
View this table:
[in this window]
[in a new window]
  		Table 5.   Reproducibility of blood gas responses to graded treadmill exercise


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The present study describes the role of KATP+ channels in the regulation of coronary, pulmonary, and systemic vasomotor tone in awake pigs at rest and during treadmill exercise. There are three major findings in the present study. First, KATP+ channel blockade resulted in a decrease in systemic vascular conductance and regional vascular conductances within the systemic bed at rest and during exercise, which was associated with an increase in body O2 extraction and decreased mixed venous PO2. However, the exercise-induced increase in systemic vascular conductance, which occurred principally in skeletal muscle, was not affected. Second, KATP+ channel blockade had no effect on pulmonary vascular conductance either at rest or during exercise. Third, KATP+ channel blockade resulted in an increased myocardial O2 extraction and a decreased coronary venous PO2 under resting conditions and during exercise indicating that KATP+ channels exerted a vasodilator influence that contributed to maintaining MDO2 commensurate with O2 demands. However, KATP+ channels were not mandatory for the exercise-induced coronary vasodilation. The implications of these findings will be discussed in detail.

Methodological Considerations

Glibenclamide has been reported to be a selective KATP+ channel blocker at concentrations up to 5 µM (2, 26). In the present study we used a dose of 3 mg/kg iv. In 30-kg pigs, this dose corresponds to 90 mg in ~2 liters of circulating blood volume, i.e., 90 µmol/l (Mw = 494). However, 98-99% of glibenclamide is bound to plasma proteins (12), so that the concentration of free glibenclamide is in the range of 1-2 µM. These concentrations are well within the range where glibenclamide is selective for KATP+ channels (2, 26). Moreover, we observed that glibenclamide attenuated the bimakalim-mediated vasodilation without blunting the sodium nitroprusside-mediated vasodilation, indicating that glibenclamide in a dose of 3 mg/kg iv selectively inhibited KATP+ channels without nonspecifically blunting vascular smooth muscle relaxation.

Systemic Circulation

KATP+ channels have been implicated in the regulation of vasomotor tone under basal resting conditions in a variety of regional vascular beds within the systemic circulation including the mesenteric (11, 21), renal (11, 23), and skeletal muscle bed (5, 11, 17, 33), although the latter is not a ubiquitous finding (6, 19, 20, 31, 32). In the present study, we observed that in awake resting pigs, KATP+ channel activity exerts a vasodilator influence in the brain, a variety of visceral organs as well as bone and skin. In contrast, KATP+ channel blockade had no effect on blood flow and vascular conductance of various skeletal muscle groups, indicating a minimal contribution of KATP+ channels to the regulation of basal vasomotor tone in resistance vessels of skeletal muscle.

KATP+ channel blockade also decreased systemic vascular conductance during treadmill exercise but did not blunt the exercise-induced doubling of systemic vascular conductance. The latter is principally due to an increase in vascular conductance in active skeletal muscle groups and to a lesser extent to increases in cerebral, AVA, and cutaneous vascular conductance (1, 18, and present study). Recent studies in anesthetized animal models suggest that KATP+ channels can contribute to metabolic vasodilation in skeletal muscle produced by electrical muscle stimulation (3, 5, 31, 33). Although the vasoconstrictor effect of KATP+ channel blockade in the present study persisted during treadmill exercise, indicating that KATP+ channels exert a vasodilator influence at rest and during exercise, KATP+ channel blockade had no effect on the increase in vascular conductance in the brain, skeletal muscle, skin, and of AVA. These findings demonstrate that the opening of KATP+ channels is not mandatory for the exercise-induced vasodilation in these regional beds. It is possible that under normal conditions opening of these channels does contribute but that after KATP+ channel blockade other vasodilator mechanisms are recruited during exercise, which compensate for the loss of KATP+ channel activity (10).

The decrease in systemic vascular conductance produced by glibenclamide impeded O2 delivery within the systemic bed necessitating an increase in whole body O2 extraction to maintain BVO2, reflected in the decrease in mixed venous PO2. The impediment of O2 delivery was associated with a widening of the arterio-mixed venous pH gap, which could be interpreted to suggest anaerobic metabolism. However, the increased pH difference was principally due to a widening of the arterio-mixed venous PCO2 difference. The latter probably resulted from a maintained whole body CO2 production in the face of a reduced cardiac output.

Pulmonary Circulation

Evidence for KATP+ channels in the pulmonary vascular bed has been obtained in a variety of species such as rats (13), cats (20), pigs (24, and present study), and dogs (28) by demonstrating pulmonary vasodilator responses to KATP+ channel agonists in vivo. However, under basal conditions, KATP+ channel activity appears to contribute minimally to regulation of vasomotor tone in the intact lung of anesthetized rats (13) and cats (6). Only in anesthetized newborn piglets was a decrease in pulmonary vascular conductance observed after exposure of a lung lobar arterial system to 10 µM of glibenclamide (24). However, glibenclamide at a dose higher than 5 µM may produce blockade of other K+ channels (14, 26), including Ca2+-sensitive channels, which are abundantly present in the pulmonary bed and active under basal conditions (13). This may also explain why Kadowitz and co-workers (6, 20) observed that glibenclamide, in a dose of 20 mg/kg but not at 5 mg/kg, produced a transient increase in pulmonary artery pressure in anesthetized cats. Thus 20 mg/kg in a 3-kg cat with an approximate blood volume of 300 ml corresponds to a concentration of free glibenclamide of 8 µM, whereas 5 mg/kg corresponds to 2 µM. Another concern is that in most previous in vivo studies anesthesia was employed, which can produce KATP+ channel blockade (28). However, because in awake dogs glibenclamide (3 mg/kg iv) had no effect on pulmonary vascular conductance (28), and in the present study, glibenclamide (3 mg/kg iv, a dose that produced a systemic vasoconstrictor response) had also no effect on pulmonary vascular conductance, the weight of evidence suggests that KATP+ channel activity is minimal under basal conditions in the pulmonary vascular bed.

The present study is the first to investigate the role of KATP+ channel activity in regulation of pulmonary vascular conductance during exercise. The rationale for this investigation was that we previously observed that beta -adrenoceptor activation contributes to exercise-induced pulmonary vasodilation in pigs (30). Because pharmacological beta -adrenoceptor stimulation produces vasodilation in pulmonary arteries (29), as well as other vascular beds (3, 22), that is in part mediated by KATP+ channel activation, we hypothesized that the exercise-induced pulmonary vasodilation could also be mediated via KATP+ channel opening. However, the results clearly demonstrate that KATP+ channels are not mandatory for maintaining pulmonary vascular conductance in awake pigs either at rest or during treadmill exercise.

Coronary Circulation

Coronary blood flow is tightly regulated to maintain a consistently high level of myocardial O2 extraction. Consequently, any increase in myocardial O2 demand must be met by an equivalent increase in coronary blood flow. In dogs the exercise-induced increase in coronary blood flow does not fully match the increased myocardial O2 demand, so that even during light exercise (<60% of maximum heart rate) myocardial O2 extraction increases and coronary venous PO2 decreases (18). In humans, myocardial O2 extraction changes minimally during light-to-moderate exercise, but myocardial O2 extraction increases and coronary venous PO2 decreases during strenuous exercise (>85% of maximum heart rate) (18). Up to moderate exercise, pigs resemble humans more closely than dogs but, in contrast to dogs and humans, pigs also maintain a constant level of myocardial O2 extraction and coronary venous PO2 during strenuous exercise, implying that the exercise-induced increases in O2 delivery match the increases in MVO2 (7, 18). A decrease in coronary venous PO2 could represent an error signal needed for negative feedback metabolic control (18), but data in pigs indicate that a decrease in coronary venous PO2 is not mandatory for the increase in coronary blood flow during heavy exercise due to increased importance of beta -adrenergic feedforward vasodilation (7). In awake dogs, glibenclamide decreased coronary blood flow at rest and during treadmill exercise but did not blunt the exercise-induced increase in coronary blood flow (9, 10). On the other hand, Narishige et al. (22) reported that coronary vasodilation in the dog heart that was produced by pharmacological beta -adrenoceptor stimulation was markedly blunted by KATP+ channel blockade. In view of the increased importance of beta -adrenergic feedforward vasodilation in the porcine coronary circulation during exercise (7), we hypothesized that beta -adrenoceptor-mediated KATP+ channel activation would have increased importance in the coronary circulation of exercising pigs. Although KATP+ channel activity exerted a vasodilator influence both at rest and during exercise, contrary to our hypothesis it was not mandatory for the exercise-induced vasodilation in the porcine heart. It is possible that under normal conditions opening of these channels does contribute but that after KATP+ channel blockade other vasodilator mechanisms are recruited during exercise, which compensate for the loss of KATP+ channel activity (10).

The decrease in coronary vascular conductance produced by glibenclamide restricted MDO2 at each level of MVO2, resulting in an increase in myocardial O2 extraction and hence a decrease in coronary venous PO2. The impediment of MDO2 was associated with a widening of the arteriocoronary venous pH gap, suggestive of anaerobic metabolism (i.e., ischemia). However, the increased pH difference was entirely the result of an increased arteriocoronary venous PCO2 difference; the latter likely resulted from a maintained CO2 production in the face of reduced coronary arterial inflow.

In conclusion, the opening of KATP+ channels contributes to a state of vasodilation in the systemic and coronary circulation of pigs at rest and during exercise, although KATP+ channels are not mandatory for the exercise-induced systemic and coronary vasodilation. In contrast, KATP+ channels are not mandatory for regulation of pulmonary vasomotor tone either at rest or during exercise.


    ACKNOWLEDGEMENTS

The authors thank Rob H. van Bremen for technical assistance.


    FOOTNOTES

D. Duncker's work was supported by a Research Fellowship from the Royal Netherlands Academy of Arts and Sciences.

Address for reprint requests and other correspondence: D. J. Duncker, Experimental Cardiology, Thoraxcenter, Erasmus Univ. Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands (E-mail: Duncker{at}tch.fgg.eur.nl).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12 June 2000; accepted in final form 23 August 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Armstrong, RB, Delp MD, Goljan EF, and Laughlin MH. Progressive elevations in muscle blood flow during prolonged exercise in swine. J Appl Physiol 63: 285-291, 1987[Abstract/Free Full Text].

2.   Beech, DJ, Zhang H, Nakao K, and Bolton TB. Single channel and whole-cell K-currents evoked by levcromakalim in smooth muscle cells from the rabbit portal vein. Br J Pharmacol 110: 583-590, 1993[Web of Science][Medline].

3.   Chang, HY. The involvement of ATP-sensitive potassium channels in beta 2-adrenoceptor agonist-induced vasodilatation on rat diaphragmatic microcirculation. Br J Pharmacol 121: 1024-1030, 1997[Web of Science][Medline].

4.   Clapp, LH, Davey R, and Gurney AM. ATP-sensitive K+ channels mediate vasodilation produced by lemakalim in rabbit pulmonary artery. Am J Physiol Heart Circ Physiol 264: H1907-H1915, 1993[Abstract/Free Full Text].

5.   Comtois, A, Sinderby C, Comtois N, Grassino A, and Renaud JM. An ATP-sensitive potassium channel blocker decreases diaphragmatic circulation in anesthetized dogs. J Appl Physiol 77: 127-134, 1994[Abstract/Free Full Text].

6.   DeWitt, BJ, Cheng DY, McMahon TJ, Marrone JR, Champion HC, and Kadowitz PJ. Effects of U-37883A, a vascular selective KATP+ channel antagonist, in the pulmonary and hindlimb circulation. Am J Physiol Lung Cell Mol Physiol 271: L924-L931, 1996[Abstract/Free Full Text].

7.   Duncker, DJ, Stubenitsky R, and Verdouw PD. Autonomic control of vasomotion in the porcine coronary circulation during treadmill exercise: evidence for feed-forward beta -adrenergic control. Circ Res 82: 1312-1322, 1998[Abstract/Free Full Text].

8.   Duncker, DJ, Stubenitsky R, and Verdouw PD. Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise. Am J Physiol Heart Circ Physiol 275: H1663-H1672, 1998[Abstract/Free Full Text].

9.   Duncker, DJ, Van Zon NS, Altman JD, Pavek TJ, and Bache RJ. Role of KATP+ channels in coronary vasodilation during exercise. Circulation 88: 1245-1253, 1993[Abstract/Free Full Text].

10.   Duncker, DJ, van Zon NS, Pavek TJ, Herrlinger SK, and Bache RJ. Endogenous adenosine mediates coronary vasodilation during exercise after KATP+ channel blockade. J Clin Invest 95: 285-295, 1995.

11.   Gardiner, SM, Kemp PA, March JE, Fallgren B, and Bennett T. Effects of glibenclamide on the regional haemodynamic actions of alpha -trinositol and its influence on responses to vasodilators in conscious rats. Br J Pharmacol 117: 507-515, 1996[Web of Science][Medline].

12.   George, S, McBurney A, and Cole A. Possible protein binding displacement interaction between glibenclamide and metolazone. Eur J Clin Pharmacol 38: 93-95, 1990[Web of Science][Medline].

13.   Hasunuma, K, Rodman DM, and McMurtry IF. Effects of K+ channel blockers on vascular tone in the perfused rat lung. Am Rev Respir Dis 144: 884-887, 1991[Web of Science][Medline].

14.   Hu, SL, Kim HS, Okolie P, and Weiss GB. Alterations by glyburide of effects of BRL 34915 and P 1060 on contraction, 86Rb efflux and the maxi-K+ channel in rat portal vein. J Pharmacol Exp Ther 253: 771-777, 1990[Abstract/Free Full Text].

15.   Imamura, Y, Tomoike H, Narishige T, Takahashi T, Kasuya H, and Takeshita A. Glibenclamide decreases basal coronary blood flow in anesthetized dogs. Am J Physiol Heart Circ Physiol 263: H399-H404, 1992[Abstract/Free Full Text].

16.   Ishida, T, Lewis RM, Hartley CJ, Entman ML, and Field JB. Comparison of hepatic extraction of insulin and glucagon in conscious and anesthetized dogs. Endocrinology 112: 1098-1109, 1983[Abstract/Free Full Text].

17.   Jackson, WF. Arteriolar tone is determined by activity of ATP-sensitive potassium channels. Am J Physiol Heart Circ Physiol 265: H1797-H1803, 1993[Abstract/Free Full Text].

18.  Laughlin MH, Korthuis R, Duncker DJ, and Bache RJ. Control of blood flow to cardiac and skeletal muscle during exercise. In: Handbook of Physiology. Exercise: Regulation and Integration of Multiple Systems. Bethesda, MD: Am. J. Physiol., 1996, sect. 12, chapt. 16, p. 705-769.

19.   Lippton, H, Choe E, Franklin E, Grivas T, Flint L, Hyman A, and Ferrara J. Femoral vasodilation to cromakalim is blocked by U37883A, a non-sulphonylurea that selectively inhibits KATP+ channels. J Pharm Pharmacol 47: 243-245, 1995[Web of Science][Medline].

20.   Minkes, RK, Kvamme P, Higuera TR, Nossaman BD, and Kadowitz PJ. Analysis of pulmonary and systemic vascular responses to cromakalim, an activator of KATP+ channels. Am J Physiol Heart Circ Physiol 260: H957-H966, 1991[Abstract/Free Full Text].

21.   Moreau, R, Komeichi H, Kirstetter P, Yang S, Aupetit-Faisant B, Cailmail S, and Lebrec D. Effects of glibenclamide on systemic and splanchnic haemodynamics in conscious rats. Br J Pharmacol 112: 649-653, 1994[Web of Science][Medline].

22.   Narishige, T, Egashira K, Akatsuka Y, Imamura Y, Takahashi T, Kasuya H, and Takeshita A. Glibenclamide prevents coronary vasodilation induced by beta 1-adrenoceptor stimulation in dogs. Am J Physiol Heart Circ Physiol 266: H84-H92, 1994[Abstract/Free Full Text].

23.   Parekh, N, and Zou AP. Role of prostaglandins in renal medullary circulation: response to different vasoconstrictors. Am J Physiol Renal Fluid Electrolyte Physiol 271: F653-F658, 1996[Abstract/Free Full Text].

24.   Pinheiro, JM, and Malik AB. KATP+-channel activation causes marked vasodilation in the hypertensive neonatal pig lung. Am J Physiol Heart Circ Physiol 263: H1532-H1536, 1992[Abstract/Free Full Text].

25.   Quayle, JM, Nelson MT, and Standen NB. ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev 77: 1165-1232, 1997[Abstract/Free Full Text].

26.   Sadraei, H, and Beech DJ. Ionic currents and inhibitory effects of glibenclamide in seminal vesicle smooth muscle cells. Br J Pharmacol 115: 1447-1454, 1995[Web of Science][Medline].

27.   Sassen, LM, Duncker DJ, Gho BC, Diekmann HW, and Verdouw PD. Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs. Br J Pharmacol 101: 605-614, 1990[Web of Science][Medline].

28.   Seki, S, Sato K, Nakayama M, and Murray PA. Halothane and enflurane attenuate pulmonary vasodilation mediated by adenosine triphosphate-sensitive potassium channels compared with the conscious state. Anesthesiology 86: 923-935, 1997[Web of Science][Medline].

29.   Sheridan, BC, McIntyre RC, Jr, Meldrum DR, and Fullerton DA. KATP+ channels contribute to beta - and adenosine receptor-mediated pulmonary vasorelaxation. Am J Physiol Lung Cell Mol Physiol 273: L950-L956, 1997[Abstract/Free Full Text].

30.   Stubenitsky, R, Verdouw PD, and Duncker DJ. Autonomic control of cardiovascular performance and whole body O2 delivery and utilization in swine during treadmill exercise. Cardiovasc Res 39: 459-474, 1998[Abstract/Free Full Text].

31.   Thomas, GD, Hansen J, and Victor RG. ATP-sensitive potassium channels mediate contraction-induced attenuation of sympathetic vasoconstriction in rat skeletal muscle. J Clin Invest 99: 2602-2609, 1997[Web of Science][Medline].

32.   Vallet, B, Guery B, Mangalaboyi J, Menager P, Curtis SE, Cain SM, Chopin C, and Dupuis BA. Critical oxygen extraction in piglet hindlimb is impaired after inhibition of ATP-sensitive potassium channels. Adv Exp Med Biol 388: 311-317, 1996[Medline].

33.   Vanelli, G, Chang HY, Gatensby AG, and Hussain SN. Contribution of potassium channels to active hyperemia of the canine diaphragm. J Appl Physiol 76: 1098-1105, 1994[Abstract/Free Full Text].

Am J Physiol Heart Circ Physiol 280(1):H22-H33
0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society


This article has been cited by other articles:


Home page
 Exp Biol MedHome page
G. M Dick and J. D Tune
Role of potassium channels in coronary vasodilation
Exp Biol Med, January 1, 2010; 235(1): 10 - 22.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
G. I. Purves, T. Kamishima, L. M. Davies, J. M. Quayle, and C. Dart
Exchange protein activated by cAMP (Epac) mediates cAMP-dependent but protein kinase A-insensitive modulation of vascular ATP-sensitive potassium channels
J. Physiol., July 15, 2009; 587(14): 3639 - 3650.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
D. J. Duncker and R. J. Bache
Regulation of Coronary Blood Flow During Exercise
Physiol Rev, July 1, 2008; 88(3): 1009 - 1086.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. M. Dick, I. N. Bratz, L. Borbouse, G. A. Payne, U. D. Dincer, J. D. Knudson, P. A. Rogers, and J. D. Tune
Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation
Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2371 - H2381.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
L. J. Sampson, L. M. Davies, R. Barrett-Jolley, N. B. Standen, and C. Dart
Angiotensin II-activated protein kinase C targets caveolae to inhibit aortic ATP-sensitive potassium channels
Cardiovasc Res, October 1, 2007; 76(1): 61 - 70.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
D. J. Duncker and D. Merkus
Exercise hyperaemia in the heart: the search for the dilator mechanism
J. Physiol., September 15, 2007; 583(3): 847 - 854.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. J. Joyner and B. W. Wilkins
Exercise hyperaemia: is anything obligatory but the hyperaemia?
J. Physiol., September 15, 2007; 583(3): 855 - 860.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Merkus, O. Sorop, B. Houweling, B. A. Hoogteijling, and D. J. Duncker
KCa+ channels contribute to exercise-induced coronary vasodilation in swine
Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2090 - H2097.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
B. Houweling, D. Merkus, O. Sorop, F. Boomsma, and D. J. Duncker
Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction
J. Physiol., July 15, 2006; 574(2): 615 - 626.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
W. G. Schrage, N. M. Dietz, and M. J. Joyner
Effects of combined inhibition of ATP-sensitive potassium channels, nitric oxide, and prostaglandins on hyperemia during moderate exercise
J Appl Physiol, May 1, 2006; 100(5): 1506 - 1512.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
B. Houweling, D. Merkus, M. M. D Dekker, and D. J Duncker
Nitric oxide blunts the endothelin-mediated pulmonary vasoconstriction in exercising swine
J. Physiol., October 15, 2005; 568(2): 629 - 638.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Merkus, B. Houweling, M. van Vliet, and D. J. Duncker
Contribution of KATP+ channels to coronary vasomotor tone regulation is enhanced in exercising swine with a recent myocardial infarction
Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1306 - H1313.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. D. Tune, M. W. Gorman, and E. O. Feigl
Matching coronary blood flow to myocardial oxygen consumption
J Appl Physiol, July 1, 2004; 97(1): 404 - 415.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Merkus, D. B. Haitsma, T.-Y. Fung, Y. J. Assen, P. D. Verdouw, and D. J. Duncker
Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways
Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H424 - H433.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
Y Hayabuchi, C Dart, and N B Standen
Evidence for involvement of A-kinase anchoring protein in activation of rat arterial KATP channels by protein kinase A
J. Physiol., October 15, 2001; 536(2): 421 - 427.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
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 Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (21)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Duncker, D. J.
Right arrow Articles by Verdouw, P. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Duncker, D. J.
Right arrow Articles by Verdouw, P. D.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online