D. Duncker - Academia.edu (original) (raw)

Papers by D. Duncker

Research paper thumbnail of Contribution of KATP+ channels to coronary vasomotor tone regulation is enhanced in exercising swine with a recent myocardial infarction

American Journal of Physiology-Heart and Circulatory Physiology, 2004

Previous studies demonstrated a decreased flow reserve in the hypertrophied myocardium early afte... more Previous studies demonstrated a decreased flow reserve in the hypertrophied myocardium early after myocardial infarction (MI). Previously, we reported that exacerbation of hemodynamic abnormalities and neurohumoral activation during exercise caused slight impairment of myocardial O2 supply in swine with a recent MI. We hypothesized that increased metabolic coronary vasodilation [via ATP-sensitive K+ (KATP+) channels and adenosine] may have partially compensated for the increased extravascular compressive forces and increased vasoconstrictor neurohormones, thereby preventing a more severe impairment of myocardial O2 balance. Chronically instrumented swine were exercised on a treadmill up to 85% of maximum heart rate. Under resting conditions, adenosine receptor blockade [8-phenyltheophylline (8-PT), 5 mg/kg iv] and KATP+ channel blockade (glibenclamide, 3 mg/kg iv) produced similar decreases in myocardial O2 supply in normal and MI swine. However, while glibenclamide's effect wan...

Research paper thumbnail of Adrenal Angiotensin: Origin and Site of Generation

American Journal of Hypertension, 2005

Research paper thumbnail of Nuclear protein extraction from frozen porcine myocardium

Journal of Physiology and Biochemistry, 2010

Research paper thumbnail of Early Exercise Training Normalizes Myofilament Function and Attenuates Left Ventricular Pump Dysfunction in Mice With a Large Myocardial Infarction

Circulation Research, 2007

The extent and mechanism of the cardiac benefit of early exercise training following myocardial i... more The extent and mechanism of the cardiac benefit of early exercise training following myocardial infarction (MI) is incompletely understood, but may involve blunting of abnormalities in Ca 2+ -handling and myofilament function. Consequently, we investigated the effects of 8-weeks of voluntary exercise, started early after a large MI, on left ventricular (LV) remodeling and dysfunction in the mouse. Exercise had no effect on survival, MI size or LV dimensions, but improved LV fractional shortening from 8±1 to 12±1%, and LVdP/dt P30 from 5295±207 to 5794±207 mm Hg/s (both P <0.05), and reduced pulmonary congestion. These global effects of exercise were associated with normalization of the MI-induced increase in myofilament Ca 2+ -sensitivity (ΔpCa 50 =0.037). This effect of exercise was PKA-mediated and likely because of improved β 1 -adrenergic signaling, as suggested by the increased β 1 -adrenoceptor protein (48%) and cAMP levels (36%; all P <0.05). Exercise prevented the MI-i...

Research paper thumbnail of Nucleotide Excision DNA Repair Is Associated With Age-Related Vascular Dysfunction

Circulation, 2012

Background Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the agin... more Background Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction. Methods and Results In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD ( Ercc1 d/− and Xpd TTD mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1 d/− mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1 d/− mice, age-related endothelium-dependent vasodilator dysfunction in Xpd TTD animals ...

Research paper thumbnail of Role of adenosine in ischemic preconditioning in rats depends critically on the duration of the stimulus and involves both A1 and A3 receptors

Cardiovascular Research, 2001

Research paper thumbnail of Animal models in the study of myocardial ischaemia and ischaemic syndromes

Cardiovascular Research, 1998

Research paper thumbnail of Exercise unmasks autonomic dysfunction in swine with a recent myocardial infarction

Cardiovascular Research, 2005

Research paper thumbnail of Large variations in absolute wall shear stress levels within one species and between species

Research paper thumbnail of Cardiac effects of postconditioning depend critically on the duration of index ischemia

AJP: Heart and Circulatory Physiology, 2006

Postconditioning (POC) is known as the phenomenon whereby brief intermittent ischemia applied at ... more Postconditioning (POC) is known as the phenomenon whereby brief intermittent ischemia applied at the onset of reperfusion following index ischemia limits myocardial infarct size. Whereas there is evidence that the algorithm of the POC stimulus is an important determinant of the protective efficacy, the importance of the duration of index ischemia on the outcome of the effects of POC has received little attention. Pentobarbital sodium-anesthetized Wistar rats were therefore subjected to index ischemia produced by coronary artery occlusions (CAO) of varying duration (15–120 min) followed by reperfusion, without or with postconditioning produced by three cycles of 30-s reperfusion and reocclusion (3POC30). 3POC30 limited infarct size produced by 45-min CAO (CAO45) from 45 ± 3% to 31 ± 5%, and CAO60 from 60 ± 3% to 47 ± 6% (both P ≤ 0.05). In contrast, 3POC30 increased infarct size produced by CAO15 from 3 ± 1% to 19 ± 6% and CAO30 from 36 ± 6 to 48 ± 4% (both P ≤ 0.05). This deleteriou...

Research paper thumbnail of A novel approach to assess hemorrhagic shock severity using the arterially determined left ventricular isovolumic contraction period

AJP: Heart and Circulatory Physiology, 2013

Recently, the ventilatory variation in pre-ejection period (ΔPEP) was found to be useful in the p... more Recently, the ventilatory variation in pre-ejection period (ΔPEP) was found to be useful in the prediction of fluid-responsiveness of patients in shock. In the present study we investigated the behavior of the ventilation-induced variations in the systolic timing intervals in response to a graded hemorrhage protocol. The timing intervals studied included the ventilatory variation in ventricular electromechanical delay (ΔEMD), isovolumic contraction period (determined from the arterial pressure waveform, ΔAIC), pulse travel time (ΔPTT), and ΔPEP. ΔAIC and ΔPEP were evaluated in the aorta and carotid artery (annotated by subscripts Ao and CA) and were compared with the responses of pulse pressure variation (ΔPPAo) and stroke volume variation (ΔSV). The graded hemorrhage protocol, followed by resuscitation using norepinephrine and autologous blood transfusion, was performed in eight anesthetized Yorkshire X Landrace swine. ΔAICAo, ΔAICCA, ΔPEPAo, ΔPEPCA, ΔPPAo, ΔPPCA, and ΔSV showed si...

Research paper thumbnail of Functional Expression of Endothelial Nitric Oxide Synthase Fused to Green Fluorescent Protein in Transgenic Mice

The American Journal of Pathology, 2003

The activity of endothelial nitric oxide synthase (eNOS) is subject to complex transcriptional an... more The activity of endothelial nitric oxide synthase (eNOS) is subject to complex transcriptional and posttranslational regulation including the association with several proteins and variations in subcellular distribution. In the present study we describe a transgenic mouse model expressing eNOS fused to green fluorescent protein (GFP), which allows the study of localization and regulation of eNOS expression. We tested the functionality of eNOS in the eNOS-GFP mice. Expression of eNOS was restricted to the endothelial lining of blood vessels in various tissues tested, without appreciable expression in non-endothelial cells. Activity of the enzyme was confirmed by assaying the conversion of L-arginine to L-citrulline. NO production in isolated vessels was increased in transgenic mice when compared to non-transgenic control animals (4.88 ؎ 0.59 and 2.48 ؎ 0.47 mol/L NO, respectively, P < 0.005). Both the mean aortic pressure and the pulmonary artery pressure were reduced in eNOS-GFP mice (both ϳ30%, P < 0.05). Plasma cholesterol levels were also slightly reduced (ϳ20%, P < 0.05). In conclusion, eNOS-GFP mice express functional eNOS and provide a unique model to study regulation of eNOS activity or eNOS-mediated vascular events, including response to ischemia, response to differences in shear stress, angiogenesis and vasculogenesis, and to study the subcellular distribution in relation with functional responses to these events.

Research paper thumbnail of Integrative Physiology 2.0': integration of systems biology into physiology and its application to cardiovascular homeostasis

The Journal of physiology, 2011

Since the completion of the Human Genome Project and the advent of the large scaled unbiased &#39... more Since the completion of the Human Genome Project and the advent of the large scaled unbiased '-omics' techniques, the field of systems biology has emerged. Systems biology aims to move away from the traditional reductionist molecular approach, which focused on understanding the role of single genes or proteins, towards a more holistic approach by studying networks and interactions between individual components of networks. From a conceptual standpoint, systems biology elicits a 'back to the future' experience for any integrative physiologist. However, many of the new techniques and modalities employed by systems biologists yield tremendous potential for integrative physiologists to expand their tool arsenal to (quantitatively) study complex biological processes, such as cardiac remodelling and heart failure, in a truly holistic fashion. We therefore advocate that systems biology should not become/stay a separate discipline with '-omics' as its playing field, ...

Research paper thumbnail of Gene reprogramming in exercise-induced cardiac hypertrophy in swine: A transcriptional genomics approach

Journal of molecular and cellular cardiology, 2014

Cardiac hypertrophy of the left ventricle (LV) in response to dynamic exercise-training (EX) is a... more Cardiac hypertrophy of the left ventricle (LV) in response to dynamic exercise-training (EX) is a beneficial adaptation to increased workload, and is thought to result from genetic reprogramming. We aimed to determine which transcription factors (TFs) are involved in this genetic reprogramming of the LV in swine induced by exercise-training. Swine underwent 3-6 weeks of dynamic EX, resulting in a 16% increase of LV weight/body weight ratio compared to sedentary animals (P=0.03). Hemodynamic analysis showed an increased stroke volume index (stroke volume/body weight +35%; P=0.02). Microarray-analysis of LV tissue identified 339 upregulated and 408 downregulated genes (false discovery rate<0.05). Of the human homologues of the differentially expressed genes, promoter regions were searched for TF consensus binding sites (TFBSs). For upregulated and downregulated genes, 17 and 24 TFBSs were overrepresented by >1.5-fold (P<0.01), respectively. In DNA-binding assays, using LV nuc...

Research paper thumbnail of Pressure-maximal coronary flow relationship in regionally stunned porcine myocardium

The American journal of physiology, 1992

In view of variable results on maximal coronary blood flow in stunned myocardium, we studied the ... more In view of variable results on maximal coronary blood flow in stunned myocardium, we studied the pressure-maximal coronary flow (PMCF) relationship in stunned myocardium in 12 anesthetized swine by using intracoronary adenosine (20 micrograms/kg). Subendocardial systolic segment shortening (SS) measured with sonomicrometry was 19 +/- 5% (means +/- SD) at baseline and 7 +/- 6% (P less than 0.01) at 30 min of reperfusion after 15 min of low-flow ischemia, at which time postsystolic shortening was present. Myocardial stunning increased the slope of the PMCF regression line (alpha PMCF) from 3.34 +/- 1.03 to 3.89 +/- 1.33 ml.min-1.mmHg-1 (P less than 0.01). Atrial pacing at 40 beats/min above spontaneous heart rate (n = 6) further reduced subendocardial SS to 6 +/- 6% (P less than 0.05). Dobutamine (4 micrograms.kg-1.min-1; n = 6) increased subendocardial SS to 13 +/- 5% (P less than 0.05) and abolished postsystolic shortening. Both interventions left alpha PMCF unchanged. In conclusion...

Research paper thumbnail of Recruitment of Regional External Work and Oxygen-Consumption in Stunned Porcine Myocardium

Research paper thumbnail of Pressure-maximal coronary flow relationship in regionally stunned porcine myocardium

In view of variable results on maximal coronary blood flow in stunned myocardium, we studied the ... more In view of variable results on maximal coronary blood flow in stunned myocardium, we studied the pressure-maximal coronary flow (PMCF) relationship in stunned myocardium in 12 anesthetized swine by using intracoronary adenosine (20 micrograms/kg). Subendocardial systolic segment shortening (SS) measured with sonomicrometry was 19 +/- 5% (means +/- SD) at baseline and 7 +/- 6% (P less than 0.01) at 30 min of reperfusion after 15 min of low-flow ischemia, at which time postsystolic shortening was present. Myocardial stunning increased the slope of the PMCF regression line (alpha PMCF) from 3.34 +/- 1.03 to 3.89 +/- 1.33 ml.min-1.mmHg-1 (P less than 0.01). Atrial pacing at 40 beats/min above spontaneous heart rate (n = 6) further reduced subendocardial SS to 6 +/- 6% (P less than 0.05). Dobutamine (4 micrograms.kg-1.min-1; n = 6) increased subendocardial SS to 13 +/- 5% (P less than 0.05) and abolished postsystolic shortening. Both interventions left alpha PMCF unchanged. In conclusion, myocardial stunning was associated with an increase in alpha PMCF that most likely resulted from the decreased contractile function. The absence of an effect of dobutamine may be due to its predominant action on diastolic function.

Research paper thumbnail of Coronary–aortic interaction during ventricular isovolumic contraction

Medical & Biological Engineering & Computing, 2011

In earlier work, we suggested that the start of the isovolumic contraction period could be detect... more In earlier work, we suggested that the start of the isovolumic contraction period could be detected in arterial pressure waveforms as the start of a temporary presystolic pressure perturbation (AIC start , start of the Arterially detected Isovolumic Contraction), and proposed the retrograde coronary blood volume flow in combination with a backwards traveling pressure wave as its most likely origin. In this study, we tested this hypothesis by means of a coronary artery occlusion protocol. In six Yorkshire 9 Landrace swine, we simultaneously occluded the left anterior descending (LAD) and left circumflex (LCx) artery for 5 s followed by a 20-s reperfusion period and repeated this sequence at least two more times. A similar procedure was used to occlude only the right coronary artery (RCA) and finally all three main coronary arteries simultaneously. None of the occlusion protocols caused a decrease in the arterial pressure perturbation in the aorta during occlusion (P [ 0.20) nor an increase during reactive hyperemia (P [ 0.22), despite a higher deceleration of coronary blood volume flow (P = 0.03) or increased coronary conductance (P = 0.04) during hyperemia. These results show that the pre-systolic aortic pressure perturbation does not originate from the coronary arteries.

Research paper thumbnail of L-Propionylcarnitine Does Not Affect Myocardial Metabolic or Functional Response to Chronotropic and Inotropic Stimulation After Repetitive Ischemia in Anesthetized Pigs

Journal of Cardiovascular Pharmacology, 1993

In postischemic myocardium, fatty acid oxidation may be deficient owing to depletion of carnitine... more In postischemic myocardium, fatty acid oxidation may be deficient owing to depletion of carnitine and citric acid cycle intermediates and fatty acylCoA-induced inhibition of adenine nucleotide translocase. During postischemic stress, the impairment of the fatty acid oxidation may become more apparent. We therefore investigated in open-chest anesthetized pigs the effect of L-propionylcarnitine [100 mg/kg per day orally (p.o.) for 3 days and 50 mg/kg intravenously (i.v.) 2 h before the first occlusion; n = 13] on myocardial function and metabolism of postischemic (two cycles of 10-min occlusion each followed by 30-min reperfusion) myocardium under resting conditions and during chronotropic and inotropic stimulation with dobutamine. Myocardial levels of free carnitine were higher after pretreatment (5.7 +/- 1.4 vs. 4.0 +/- 1.3 mumol/g protein, p &lt; 0.05). The ischemia-reperfusion-induced decreases in free carnitine were similar for both the untreated and treated animals, but in the latter free carnitine was not different from the baseline levels in the control animals. In untreated animals (n = 15), regional systolic segment shortening (SS) was 18.5 +/- 5.5% (means +/- SD) at baseline, but was reduced to 5.1 +/- 5.5% (p &lt; 0.05) at the end of the second reperfusion period. Myocardial ATP levels had decreased by 30% (p &lt; 0.05) in the presence of a maintained energy charge, while myocardial oxygen and lactate consumption had decreased to 61% and 9% of baseline, respectively. During subsequent i.v. infusion of dobutamine (2 micrograms/kg/min), SS and myocardial oxygen consumption per beat increased to 75 and 65% of baseline, respectively, whereas lactate consumption per beat increased to only 25% of baseline. Decreases in myocardial ATP and oxygen and lactate consumption were not different between treated and untreated animals. L-Propionylcarnitine-treated animals displayed slightly better postischemic recovery of systolic SS than did control animals; to 39 and 28% (p = 0.056) of baseline, respectively, probably owing to a reduction in arterial blood pressure (BP), because L-propionylcarnitine prevented the increase in systemic vascular resistance produced by ischemia-reperfusion. L-Propionylcarnitine did not affect myocardial metabolic and contractile functional responses to chronotropic and inotropic stimulation. In a model of repetitive myocardial ischemia, L-propionylcarnitine prevents systemic vasoconstriction in response to ischemia and reperfusion and, probably as a result of the lower afterload, slightly ameliorates postischemic hypofunction, but loss of carnitine apparently does not play a role in myocardial hypofunction after brief repetitive ischemia and reperfusion in pigs.

Research paper thumbnail of Coronary–aortic interaction during ventricular isovolumic contraction

Medical and Biological …, 2011

In earlier work, we suggested that the start of the isovolumic contraction period could be detect... more In earlier work, we suggested that the start of the isovolumic contraction period could be detected in arterial pressure waveforms as the start of a temporary pre-systolic pressure perturbation (AICstart, start of the Arterially detected Isovolumic Contraction), and proposed the retrograde coronary blood volume flow in combination with a backwards traveling pressure wave as its most likely origin. In this study, we tested this hypothesis by means of a coronary artery occlusion protocol. In six Yorkshire × Landrace swine, we simultaneously occluded the left anterior descending (LAD) and left circumflex (LCx) artery for 5 s followed by a 20-s reperfusion period and repeated this sequence at least two more times. A similar procedure was used to occlude only the right coronary artery (RCA) and finally all three main coronary arteries simultaneously. None of the occlusion protocols caused a decrease in the arterial pressure perturbation in the aorta during occlusion (P > 0.20) nor an increase during reactive hyperemia (P > 0.22), despite a higher deceleration of coronary blood volume flow (P = 0.03) or increased coronary conductance (P = 0.04) during hyperemia. These results show that the pre-systolic aortic pressure perturbation does not originate from the coronary arteries.

Research paper thumbnail of Contribution of KATP+ channels to coronary vasomotor tone regulation is enhanced in exercising swine with a recent myocardial infarction

American Journal of Physiology-Heart and Circulatory Physiology, 2004

Previous studies demonstrated a decreased flow reserve in the hypertrophied myocardium early afte... more Previous studies demonstrated a decreased flow reserve in the hypertrophied myocardium early after myocardial infarction (MI). Previously, we reported that exacerbation of hemodynamic abnormalities and neurohumoral activation during exercise caused slight impairment of myocardial O2 supply in swine with a recent MI. We hypothesized that increased metabolic coronary vasodilation [via ATP-sensitive K+ (KATP+) channels and adenosine] may have partially compensated for the increased extravascular compressive forces and increased vasoconstrictor neurohormones, thereby preventing a more severe impairment of myocardial O2 balance. Chronically instrumented swine were exercised on a treadmill up to 85% of maximum heart rate. Under resting conditions, adenosine receptor blockade [8-phenyltheophylline (8-PT), 5 mg/kg iv] and KATP+ channel blockade (glibenclamide, 3 mg/kg iv) produced similar decreases in myocardial O2 supply in normal and MI swine. However, while glibenclamide's effect wan...

Research paper thumbnail of Adrenal Angiotensin: Origin and Site of Generation

American Journal of Hypertension, 2005

Research paper thumbnail of Nuclear protein extraction from frozen porcine myocardium

Journal of Physiology and Biochemistry, 2010

Research paper thumbnail of Early Exercise Training Normalizes Myofilament Function and Attenuates Left Ventricular Pump Dysfunction in Mice With a Large Myocardial Infarction

Circulation Research, 2007

The extent and mechanism of the cardiac benefit of early exercise training following myocardial i... more The extent and mechanism of the cardiac benefit of early exercise training following myocardial infarction (MI) is incompletely understood, but may involve blunting of abnormalities in Ca 2+ -handling and myofilament function. Consequently, we investigated the effects of 8-weeks of voluntary exercise, started early after a large MI, on left ventricular (LV) remodeling and dysfunction in the mouse. Exercise had no effect on survival, MI size or LV dimensions, but improved LV fractional shortening from 8±1 to 12±1%, and LVdP/dt P30 from 5295±207 to 5794±207 mm Hg/s (both P <0.05), and reduced pulmonary congestion. These global effects of exercise were associated with normalization of the MI-induced increase in myofilament Ca 2+ -sensitivity (ΔpCa 50 =0.037). This effect of exercise was PKA-mediated and likely because of improved β 1 -adrenergic signaling, as suggested by the increased β 1 -adrenoceptor protein (48%) and cAMP levels (36%; all P <0.05). Exercise prevented the MI-i...

Research paper thumbnail of Nucleotide Excision DNA Repair Is Associated With Age-Related Vascular Dysfunction

Circulation, 2012

Background Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the agin... more Background Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction. Methods and Results In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD ( Ercc1 d/− and Xpd TTD mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1 d/− mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1 d/− mice, age-related endothelium-dependent vasodilator dysfunction in Xpd TTD animals ...

Research paper thumbnail of Role of adenosine in ischemic preconditioning in rats depends critically on the duration of the stimulus and involves both A1 and A3 receptors

Cardiovascular Research, 2001

Research paper thumbnail of Animal models in the study of myocardial ischaemia and ischaemic syndromes

Cardiovascular Research, 1998

Research paper thumbnail of Exercise unmasks autonomic dysfunction in swine with a recent myocardial infarction

Cardiovascular Research, 2005

Research paper thumbnail of Large variations in absolute wall shear stress levels within one species and between species

Research paper thumbnail of Cardiac effects of postconditioning depend critically on the duration of index ischemia

AJP: Heart and Circulatory Physiology, 2006

Postconditioning (POC) is known as the phenomenon whereby brief intermittent ischemia applied at ... more Postconditioning (POC) is known as the phenomenon whereby brief intermittent ischemia applied at the onset of reperfusion following index ischemia limits myocardial infarct size. Whereas there is evidence that the algorithm of the POC stimulus is an important determinant of the protective efficacy, the importance of the duration of index ischemia on the outcome of the effects of POC has received little attention. Pentobarbital sodium-anesthetized Wistar rats were therefore subjected to index ischemia produced by coronary artery occlusions (CAO) of varying duration (15–120 min) followed by reperfusion, without or with postconditioning produced by three cycles of 30-s reperfusion and reocclusion (3POC30). 3POC30 limited infarct size produced by 45-min CAO (CAO45) from 45 ± 3% to 31 ± 5%, and CAO60 from 60 ± 3% to 47 ± 6% (both P ≤ 0.05). In contrast, 3POC30 increased infarct size produced by CAO15 from 3 ± 1% to 19 ± 6% and CAO30 from 36 ± 6 to 48 ± 4% (both P ≤ 0.05). This deleteriou...

Research paper thumbnail of A novel approach to assess hemorrhagic shock severity using the arterially determined left ventricular isovolumic contraction period

AJP: Heart and Circulatory Physiology, 2013

Recently, the ventilatory variation in pre-ejection period (ΔPEP) was found to be useful in the p... more Recently, the ventilatory variation in pre-ejection period (ΔPEP) was found to be useful in the prediction of fluid-responsiveness of patients in shock. In the present study we investigated the behavior of the ventilation-induced variations in the systolic timing intervals in response to a graded hemorrhage protocol. The timing intervals studied included the ventilatory variation in ventricular electromechanical delay (ΔEMD), isovolumic contraction period (determined from the arterial pressure waveform, ΔAIC), pulse travel time (ΔPTT), and ΔPEP. ΔAIC and ΔPEP were evaluated in the aorta and carotid artery (annotated by subscripts Ao and CA) and were compared with the responses of pulse pressure variation (ΔPPAo) and stroke volume variation (ΔSV). The graded hemorrhage protocol, followed by resuscitation using norepinephrine and autologous blood transfusion, was performed in eight anesthetized Yorkshire X Landrace swine. ΔAICAo, ΔAICCA, ΔPEPAo, ΔPEPCA, ΔPPAo, ΔPPCA, and ΔSV showed si...

Research paper thumbnail of Functional Expression of Endothelial Nitric Oxide Synthase Fused to Green Fluorescent Protein in Transgenic Mice

The American Journal of Pathology, 2003

The activity of endothelial nitric oxide synthase (eNOS) is subject to complex transcriptional an... more The activity of endothelial nitric oxide synthase (eNOS) is subject to complex transcriptional and posttranslational regulation including the association with several proteins and variations in subcellular distribution. In the present study we describe a transgenic mouse model expressing eNOS fused to green fluorescent protein (GFP), which allows the study of localization and regulation of eNOS expression. We tested the functionality of eNOS in the eNOS-GFP mice. Expression of eNOS was restricted to the endothelial lining of blood vessels in various tissues tested, without appreciable expression in non-endothelial cells. Activity of the enzyme was confirmed by assaying the conversion of L-arginine to L-citrulline. NO production in isolated vessels was increased in transgenic mice when compared to non-transgenic control animals (4.88 ؎ 0.59 and 2.48 ؎ 0.47 mol/L NO, respectively, P < 0.005). Both the mean aortic pressure and the pulmonary artery pressure were reduced in eNOS-GFP mice (both ϳ30%, P < 0.05). Plasma cholesterol levels were also slightly reduced (ϳ20%, P < 0.05). In conclusion, eNOS-GFP mice express functional eNOS and provide a unique model to study regulation of eNOS activity or eNOS-mediated vascular events, including response to ischemia, response to differences in shear stress, angiogenesis and vasculogenesis, and to study the subcellular distribution in relation with functional responses to these events.

Research paper thumbnail of Integrative Physiology 2.0': integration of systems biology into physiology and its application to cardiovascular homeostasis

The Journal of physiology, 2011

Since the completion of the Human Genome Project and the advent of the large scaled unbiased &#39... more Since the completion of the Human Genome Project and the advent of the large scaled unbiased '-omics' techniques, the field of systems biology has emerged. Systems biology aims to move away from the traditional reductionist molecular approach, which focused on understanding the role of single genes or proteins, towards a more holistic approach by studying networks and interactions between individual components of networks. From a conceptual standpoint, systems biology elicits a 'back to the future' experience for any integrative physiologist. However, many of the new techniques and modalities employed by systems biologists yield tremendous potential for integrative physiologists to expand their tool arsenal to (quantitatively) study complex biological processes, such as cardiac remodelling and heart failure, in a truly holistic fashion. We therefore advocate that systems biology should not become/stay a separate discipline with '-omics' as its playing field, ...

Research paper thumbnail of Gene reprogramming in exercise-induced cardiac hypertrophy in swine: A transcriptional genomics approach

Journal of molecular and cellular cardiology, 2014

Cardiac hypertrophy of the left ventricle (LV) in response to dynamic exercise-training (EX) is a... more Cardiac hypertrophy of the left ventricle (LV) in response to dynamic exercise-training (EX) is a beneficial adaptation to increased workload, and is thought to result from genetic reprogramming. We aimed to determine which transcription factors (TFs) are involved in this genetic reprogramming of the LV in swine induced by exercise-training. Swine underwent 3-6 weeks of dynamic EX, resulting in a 16% increase of LV weight/body weight ratio compared to sedentary animals (P=0.03). Hemodynamic analysis showed an increased stroke volume index (stroke volume/body weight +35%; P=0.02). Microarray-analysis of LV tissue identified 339 upregulated and 408 downregulated genes (false discovery rate<0.05). Of the human homologues of the differentially expressed genes, promoter regions were searched for TF consensus binding sites (TFBSs). For upregulated and downregulated genes, 17 and 24 TFBSs were overrepresented by >1.5-fold (P<0.01), respectively. In DNA-binding assays, using LV nuc...

Research paper thumbnail of Pressure-maximal coronary flow relationship in regionally stunned porcine myocardium

The American journal of physiology, 1992

In view of variable results on maximal coronary blood flow in stunned myocardium, we studied the ... more In view of variable results on maximal coronary blood flow in stunned myocardium, we studied the pressure-maximal coronary flow (PMCF) relationship in stunned myocardium in 12 anesthetized swine by using intracoronary adenosine (20 micrograms/kg). Subendocardial systolic segment shortening (SS) measured with sonomicrometry was 19 +/- 5% (means +/- SD) at baseline and 7 +/- 6% (P less than 0.01) at 30 min of reperfusion after 15 min of low-flow ischemia, at which time postsystolic shortening was present. Myocardial stunning increased the slope of the PMCF regression line (alpha PMCF) from 3.34 +/- 1.03 to 3.89 +/- 1.33 ml.min-1.mmHg-1 (P less than 0.01). Atrial pacing at 40 beats/min above spontaneous heart rate (n = 6) further reduced subendocardial SS to 6 +/- 6% (P less than 0.05). Dobutamine (4 micrograms.kg-1.min-1; n = 6) increased subendocardial SS to 13 +/- 5% (P less than 0.05) and abolished postsystolic shortening. Both interventions left alpha PMCF unchanged. In conclusion...

Research paper thumbnail of Recruitment of Regional External Work and Oxygen-Consumption in Stunned Porcine Myocardium

Research paper thumbnail of Pressure-maximal coronary flow relationship in regionally stunned porcine myocardium

In view of variable results on maximal coronary blood flow in stunned myocardium, we studied the ... more In view of variable results on maximal coronary blood flow in stunned myocardium, we studied the pressure-maximal coronary flow (PMCF) relationship in stunned myocardium in 12 anesthetized swine by using intracoronary adenosine (20 micrograms/kg). Subendocardial systolic segment shortening (SS) measured with sonomicrometry was 19 +/- 5% (means +/- SD) at baseline and 7 +/- 6% (P less than 0.01) at 30 min of reperfusion after 15 min of low-flow ischemia, at which time postsystolic shortening was present. Myocardial stunning increased the slope of the PMCF regression line (alpha PMCF) from 3.34 +/- 1.03 to 3.89 +/- 1.33 ml.min-1.mmHg-1 (P less than 0.01). Atrial pacing at 40 beats/min above spontaneous heart rate (n = 6) further reduced subendocardial SS to 6 +/- 6% (P less than 0.05). Dobutamine (4 micrograms.kg-1.min-1; n = 6) increased subendocardial SS to 13 +/- 5% (P less than 0.05) and abolished postsystolic shortening. Both interventions left alpha PMCF unchanged. In conclusion, myocardial stunning was associated with an increase in alpha PMCF that most likely resulted from the decreased contractile function. The absence of an effect of dobutamine may be due to its predominant action on diastolic function.

Research paper thumbnail of Coronary–aortic interaction during ventricular isovolumic contraction

Medical & Biological Engineering & Computing, 2011

In earlier work, we suggested that the start of the isovolumic contraction period could be detect... more In earlier work, we suggested that the start of the isovolumic contraction period could be detected in arterial pressure waveforms as the start of a temporary presystolic pressure perturbation (AIC start , start of the Arterially detected Isovolumic Contraction), and proposed the retrograde coronary blood volume flow in combination with a backwards traveling pressure wave as its most likely origin. In this study, we tested this hypothesis by means of a coronary artery occlusion protocol. In six Yorkshire 9 Landrace swine, we simultaneously occluded the left anterior descending (LAD) and left circumflex (LCx) artery for 5 s followed by a 20-s reperfusion period and repeated this sequence at least two more times. A similar procedure was used to occlude only the right coronary artery (RCA) and finally all three main coronary arteries simultaneously. None of the occlusion protocols caused a decrease in the arterial pressure perturbation in the aorta during occlusion (P [ 0.20) nor an increase during reactive hyperemia (P [ 0.22), despite a higher deceleration of coronary blood volume flow (P = 0.03) or increased coronary conductance (P = 0.04) during hyperemia. These results show that the pre-systolic aortic pressure perturbation does not originate from the coronary arteries.

Research paper thumbnail of L-Propionylcarnitine Does Not Affect Myocardial Metabolic or Functional Response to Chronotropic and Inotropic Stimulation After Repetitive Ischemia in Anesthetized Pigs

Journal of Cardiovascular Pharmacology, 1993

In postischemic myocardium, fatty acid oxidation may be deficient owing to depletion of carnitine... more In postischemic myocardium, fatty acid oxidation may be deficient owing to depletion of carnitine and citric acid cycle intermediates and fatty acylCoA-induced inhibition of adenine nucleotide translocase. During postischemic stress, the impairment of the fatty acid oxidation may become more apparent. We therefore investigated in open-chest anesthetized pigs the effect of L-propionylcarnitine [100 mg/kg per day orally (p.o.) for 3 days and 50 mg/kg intravenously (i.v.) 2 h before the first occlusion; n = 13] on myocardial function and metabolism of postischemic (two cycles of 10-min occlusion each followed by 30-min reperfusion) myocardium under resting conditions and during chronotropic and inotropic stimulation with dobutamine. Myocardial levels of free carnitine were higher after pretreatment (5.7 +/- 1.4 vs. 4.0 +/- 1.3 mumol/g protein, p &lt; 0.05). The ischemia-reperfusion-induced decreases in free carnitine were similar for both the untreated and treated animals, but in the latter free carnitine was not different from the baseline levels in the control animals. In untreated animals (n = 15), regional systolic segment shortening (SS) was 18.5 +/- 5.5% (means +/- SD) at baseline, but was reduced to 5.1 +/- 5.5% (p &lt; 0.05) at the end of the second reperfusion period. Myocardial ATP levels had decreased by 30% (p &lt; 0.05) in the presence of a maintained energy charge, while myocardial oxygen and lactate consumption had decreased to 61% and 9% of baseline, respectively. During subsequent i.v. infusion of dobutamine (2 micrograms/kg/min), SS and myocardial oxygen consumption per beat increased to 75 and 65% of baseline, respectively, whereas lactate consumption per beat increased to only 25% of baseline. Decreases in myocardial ATP and oxygen and lactate consumption were not different between treated and untreated animals. L-Propionylcarnitine-treated animals displayed slightly better postischemic recovery of systolic SS than did control animals; to 39 and 28% (p = 0.056) of baseline, respectively, probably owing to a reduction in arterial blood pressure (BP), because L-propionylcarnitine prevented the increase in systemic vascular resistance produced by ischemia-reperfusion. L-Propionylcarnitine did not affect myocardial metabolic and contractile functional responses to chronotropic and inotropic stimulation. In a model of repetitive myocardial ischemia, L-propionylcarnitine prevents systemic vasoconstriction in response to ischemia and reperfusion and, probably as a result of the lower afterload, slightly ameliorates postischemic hypofunction, but loss of carnitine apparently does not play a role in myocardial hypofunction after brief repetitive ischemia and reperfusion in pigs.

Research paper thumbnail of Coronary–aortic interaction during ventricular isovolumic contraction

Medical and Biological …, 2011

In earlier work, we suggested that the start of the isovolumic contraction period could be detect... more In earlier work, we suggested that the start of the isovolumic contraction period could be detected in arterial pressure waveforms as the start of a temporary pre-systolic pressure perturbation (AICstart, start of the Arterially detected Isovolumic Contraction), and proposed the retrograde coronary blood volume flow in combination with a backwards traveling pressure wave as its most likely origin. In this study, we tested this hypothesis by means of a coronary artery occlusion protocol. In six Yorkshire × Landrace swine, we simultaneously occluded the left anterior descending (LAD) and left circumflex (LCx) artery for 5 s followed by a 20-s reperfusion period and repeated this sequence at least two more times. A similar procedure was used to occlude only the right coronary artery (RCA) and finally all three main coronary arteries simultaneously. None of the occlusion protocols caused a decrease in the arterial pressure perturbation in the aorta during occlusion (P > 0.20) nor an increase during reactive hyperemia (P > 0.22), despite a higher deceleration of coronary blood volume flow (P = 0.03) or increased coronary conductance (P = 0.04) during hyperemia. These results show that the pre-systolic aortic pressure perturbation does not originate from the coronary arteries.