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D J Duncker

Publications and source records attributed to D J Duncker.

At least 37 records · Page 2Linked to original sources
PubMed2000

Time course and mechanism of myocardial catecholamine release during transient ischemia in vivo.

BACKGROUND: Elevated concentrations of norepinephrine (NE) have been observed in ischemic myocardium. We investigated the magnitude and mechanism of catecholamine release in the myocardial interstitial fluid (MIF) during ischemia and reperfusion in vivo through the use of microdialysis. METHODS AND RESULTS: In 9 anesthetized pigs, interstitial catecholamine concentrations were measured in the perfusion areas of the left anterior descending coronary artery (LAD) and the left circumflex coronary artery. After stabilization, the LAD was occluded for 60 minutes and reperfused for 150 minutes. During the final 30 minutes, tyramine (154 nmol. kg(-1). min(-1)) was infused into the LAD. During LAD occlusion, MIF NE concentrations in the ischemic region increased progressively from 1. 0+/-0.1 to 524+/-125 nmol/L. MIF concentrations of dopamine and epinephrine rose from 0.4+/-0.1 to 43.9+/-9.5 nmol/L and from <0.2 (detection limit) to 4.7+/-0.7 nmol/L, respectively. Local uptake-1 blockade attenuated release of all 3 catecholamines by >50%. During reperfusion, MIF catecholamine concentrations returned to baseline within 120 minutes. At that time, the tyramine-induced NE release was similar to that seen in nonischemic control animals despite massive infarction. Arterial and MIF catecholamine concentrations in the left circumflex coronary artery region remained unchanged. CONCLUSIONS: Myocardial ischemia is associated with a pronounced increase of MIF catecholamines, which is at least in part mediated by a reversed neuronal reuptake mechanism. The increase of MIF epinephrine implies a (probably neuronal) cardiac source, whereas the preserved catecholamine response to tyramine in postischemic necrotic myocardium indicates functional integrity of sympathetic nerve terminals.

Animals↗
PubMed2000

Nitric oxide contributes to the regulation of vasomotor tone but does not modulate O(2)-consumption in exercising swine.

OBJECTIVE: The role of nitric oxide (NO) in the regulation of vasomotor tone and tissue O(2)-consumption is incompletely understood. We therefore determined the contribution of endogenous NO to regulation of systemic, pulmonary and coronary vasomotor tone and myocardial (MV(O(2))) and whole body (BV(O(2))) O(2)-consumption in exercising swine. METHODS AND RESULTS: Exercise (1-5 km/h) up to 85% of maximum heart rate in 11 swine produced a 4-fold increase in BV(O(2)), which was accommodated for by 2-fold increases in both cardiac output (CO) and body O(2)-extraction. The NO synthase inhibitor N(omega)-nitro-L-arginine (NLA, 20 mg/kg, i.v.) increased mean aortic pressure by 30 mmHg both at rest and during exercise, due to a decrease in systemic vascular conductance from 37+/-2 to 22+/-1 ml/min mmHg(-1) at rest and from 88+/-3 to 60+/-3 ml/min mmHg(-1) at 5 km/h (all P< or =0.05 versus control). NLA produced vasoconstriction at rest and at 5 km/h in virtually all regional beds but did not affect the exercise-induced redistribution of CO. NLA increased mean pulmonary artery pressure from 15+/-1 to 21+/-1 mmHg at rest and from 30+/-2 to 40+/-2 mmHg at 5 km/h, due to a decrease in pulmonary vascular conductance (all P< or =0.05). BV(O(2)) remained unchanged and consequently the decrease in CO resulted in a compensatory increase in O(2)-extraction. NLA in a dose of 40 mg/kg produced similar responses. NLA had no significant effect on myocardial O(2)-demand or MV(O(2)) either at rest or during exercise, but decreased coronary vascular conductance which resulted in a decrease in coronary venous PO(2) from 24.5+/-1.1 to 21.9+/-0.8 mmHg at rest and from 23.5+/-0.5 to 21.0+/-0.6 mmHg at 5 km/h (all P< or =0. 05). CONCLUSIONS: Endogenous NO dilates the systemic, pulmonary and coronary vascular bed, but does not modify MV(O(2)) or BV(O(2)) in swine at rest and during exercise.

Animals↗
PubMed2000

Regulation of coronary vasomotor tone under normal conditions and during acute myocardial hypoperfusion.

Ischemia generally has been assumed to cause maximal vasodilation of the coronary resistance vessels. However, recent observations have demonstrated that during ischemia, the coronary microvessels can retain some degree of vasodilator reserve and remain responsive to vasoconstrictor stimuli. Traditional understanding of coronary blood flow regulation envisioned an array of resistance vessels that respond homogeneously to local myocardial metabolic needs. Although coronary arterioles (<100 microm) do respond to myocardial metabolic activity, recent studies have demonstrated that up to 40% of total coronary resistance resides in small arteries 100-400 microm in diameter. Vasoconstriction of these small arteries is capable of decreasing blood flow, but they are minimally responsive to the metabolic effects of the resultant flow reduction. The lack of metabolic vasoregulation of the resistance arteries explains, at least in part, the observation that myocardial ischemia does not predictably cause maximal resistance vessel dilation. In addition, vasoconstrictor influences can compete with metabolic vasodilator activity in coronary arterioles. These findings suggest that pharmacologic vasodilators acting at the microvascular level might be therapeutically useful in patients with ischemic heart disease. Unfortunately, when myocardial ischemia results from a flow-limiting coronary stenosis, nonselective pharmacologic vasodilation of the resistance vessels can worsen subendocardial ischemia by decreasing intravascular pressure to produce coronary steal and by worsening of stenosis severity. Selective dilation of small arteries in ischemic regions might have potential for enhancing blood flow. A critical property of an effective agent is that it not interfere with metabolic vasoregulation at the arteriole level, so that dilation of small arteries in adequately perfused regions would be countered by compensatory vasoconstriction of the arterioles to prevent coronary steal.

Arterioles↗
PubMed2000

Role of K+ATP channels in ischemic preconditioning and cardioprotection.

Since the phenomenon of ischemic preconditioning was first described some 15 years ago, interest in strategies aimed at reducing infarct size has increased. During the past 10 years, investigations into the mechanism of ischemic preconditioning have clearly demonstrated the cardioprotective effect of K+ATP channel opening. Thus, K+ATP channel activation has been shown to be involved in cardioprotection by a variety of stimuli, including a brief period of complete ischemia (classical ischemic preconditioning) or a partial coronary artery occlusion. In addition, ischemia in remote organs and nonischemic stimuli in the heart such as ventricular pacing, stretch, and heat stress also confer protection via K+ATP channel activation. Pharmacological agents that open K+ATP channels reduce infarct size, but K+ATP channel opening must occur prior to or early during the sustained infarct-producing coronary artery occlusion, while the degree and memory of cardioprotection are less than those produced by classical ischemic preconditioning. Although the exact mechanism by which K+ATP channel activation protects is still incompletely understood, recent studies indicate a role for the mitochondrial K+ATP channels. Before K+ATP channel opening can be employed in patients at increased risk of developing myocardial infarction (e.g., unstable angina), it is mandatory to determine whether tolerance (tachyphylaxia) occurs with repeated administration of K+ATP channel openers in a fashion similar to what occurs with ischemic preconditioning.

ATP-Binding Cassette Transporters↗
PubMed2000

Cardiovascular profile of the calcium sensitizer EMD 57033 in open-chest anaesthetized pigs with regionally stunned myocardium.

1. Ca(2+) sensitizers enhance systolic function, but may impair relaxation in vitro; these effects may differ in stunned and normal myocardium. We therefore studied the effect of EMD 57033 on systolic and diastolic function of normal and stunned porcine myocardium in vivo. 2. Myocardial stunning by 15 min coronary occlusion and 30 min reperfusion abolished systolic shortening (SS) (baseline 13+/-1%) and decreased end-systolic elastance (E(es)) from 67+/-7 to 47+/-5 mmHg mm(-1) (both P<0.05). Maximum rate of fall of myocardial elastance (dE/dt(min)) decreased from -850+/-100 to -320+/-30 mmHg mm(-1) s(-1), while the time constant tau(e) of the decay of elastance increased from 58+/-3 to 68+/-6 ms (both P<0.05). End-diastolic elastance (E(ed)) was unchanged although the zero pressure intercept (L(0,ed)) had increased. 3. In the stunned region, EMD 57033 (0.2 mg kg(-1) min(-1) for 60 min, i.v., n=7) increased SS to 19+/-2%, E(es) to 287+/-40 mmHg mm(-1), dE/dt(min) to -3630+/-640 mmHg mm(-1) s(-1) and decreased tau(e) to 50+/-3 ms, while E(ed) remained unchanged. In the normal region, 4. EMD 57033 increased SS from 14+/-2 to 18+/-3%, E(es) from 59+/-4 to 263+/-23 mmHg mm(-1), dE/dt(min) from -480+/-70 to -2280+/-700 mmHg mm(-1) s(-1) and decreased tau(e) from 91+/-12 to 61+/-3 ms (all P<0.05), while E(ed) remained unchanged. These responses were minimally affected by adrenoceptor blockade (n=7). Vehicle (n=7) had no effect on either region. EMD 57033 increased cardiac output (up to 27+/-8%) and LVdP/dt(max) (86+/-19%). Mean aortic pressure decreased (19+/-7%) due to systemic vasodilation that was not amenable to blockade of adrenoceptors or NO synthesis. 5. In conclusion, EMD 57033 restored systolic and diastolic function of stunned myocardium, and produced similar improvements in systolic and diastolic function in normal myocardium.

Anesthesia↗
PubMed1999

Ca(2+) sensitization and diastolic function of normal and stunned porcine myocardium.

Ca(2+) sensitizers prolong myofibrillar force development in vitro and might therefore aggravate relaxation abnormalities of stunned myocardium. This is the first in vivo study of the effects of the thiadiazinone derivative EMD 60263 ((+)-5-(l-(alpha-ethylimino-3, 4-dimethoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-yl)-6-methyl-3, 6-dihydro-2H-1,3,4-thiadiazine-2-on), a Ca(2+)-sensitizing agent with negligible phosphodiesterase III inhibitory activity, on diastolic function of regionally stunned myocardium. After producing stunning by two sequences of 10-min coronary artery occlusion and 30 min of reperfusion, anaesthetised pigs received either saline (n=7) or 1.5 and 3.0 mg/kg of EMD 60263 (n=8) or its enantiomer EMD 60264 (n=6), which lacks the Ca(2+)-sensitizing properties but shares the bradycardiac action via inhibition of the delayed inward rectifier K(+) current. In stunned myocardium, systolic shortening was reduced to 46+/-4% of baseline (P<0.05) and mean rate of half end-diastolic segment lengthening, an index for diastolic function, to 35+/-4%; systolic shortening and mean rate of half end-diastolic lengthening of remote normal myocardium remained unchanged. Saline did not affect these parameters in stunned or normal myocardium. EMD 60264 did not affect systolic shortening but decreased mean rate of half end-diastolic lengthening in normal myocardium to 61+/-8% and in stunned myocardium to 16+/-5% of baseline. During saline and EMD 60264, normal and stunned segments started to lengthen immediately after minimal segment length was reached (DeltaT=0). Low dose EMD 60263 restored systolic shortening of the stunned region with no effect on DeltaT. The high dose increased systolic shortening above baseline and DeltaT to 210+/-30 ms in both regions. Consequently, mean rate of half end-diastolic lengthening increased to 66+/-11% in stunned, while decreasing to 55+/-3% in normal myocardium. After elimination of bradycardia, DeltaT and hence mean rate of half end-diastolic lengthening recovered in stunned myocardium, but in normal myocardium the latter remained depressed because DeltaT persisted. In conclusion, both doses of EMD 60263 improved systolic as well as diastolic function of stunned myocardium. The high dose delayed relaxation of normal myocardium without adversely affecting systolic function.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

New insights into cardioprotection by ischemic preconditioning and other forms of stress.

Ischemic preconditioning has not only received wide attention in heart research, but has also been a topic of extensive studies involving other organs. In several of these studies, it has been shown that in spite of differences in the endpoints used to assess protection, the same mediators as in myocardial ischemic preconditioning may be involved. However, several of the putative mediators do not require ischemia to become activated. This has guided us and others to investigate whether the myocardium can also be protected by brief ischemia in other organs and whether other non-pharmacological forms of stress, which do not produce ischemia but are capable of activating these potential mediators, are also cardioprotective.

Animals↗
PubMed1999

Cardiac interstitial fluid levels of angiotensin I and II in the pig.

OBJECTIVE: To study whether cardiac interstitial fluid levels of angiotensin I and II (Ang I and II) can be monitored in vivo, using the microdialysis technique, and to assess the contribution of plasma-derived angiotensins to the interstitial fluid levels of these peptides. DESIGN AND METHODS: Microdialysis probes were placed in the left ventricular (LV) myocardium of eight anaesthetized pigs, three of which were untreated and five treated with the angiotensin II type 1 (AT1) receptor antagonist L-158,809 (10 mg intracoronary). All pigs were given a 1 h intracoronary infusion of 125I-Ang II. Aortic and coronary venous blood samples were taken under steady-state conditions, and interstitial dialysate was collected during the entire infusion period. Immediately after stopping the infusion, LV tissue pieces were obtained at various time points. RESULTS: L-158,809 did not affect the levels of endogenous Ang I and II or the levels of plasma 125I-Ang II. Aortic Ang I and II levels (22 and 16 fmol/ml; geometric mean of eight pigs) were comparable to coronary venous Ang I and II levels, whereas the coronary venous 125I-Ang II levels (6650 c.p.m./ml) were approximately 30 times higher than those in the aorta. Tissue Ang I and II levels were 5 and 17 fmol/g, respectively. In untreated animals, the 125I-Ang II levels per g LV tissue were similar to the levels per ml coronary venous plasma, and the ex vivo half-life of tissue 1251-Ang II was > 30 min. In treated animals, tissue 125I-Ang II was < 5% of coronary venous 125I-Ang II and became undetectable within 15 min. 125I-Ang II, Ang I and Ang II levels in the interstitial fluid were close to or below the detection limit (200 c.p.m., 60 fmol and 20 fmol per ml, respectively) in all animals. CONCLUSIONS: Plasma and myocardial interstitial fluid angiotensin levels are of the same order of magnitude. Plasma Ang II does not contribute to the interstitial fluid level of Ang II, most likely because of its rapid metabolism in the vascular wall. Binding to AT1 receptors protects Ang II against metabolism.

Angiotensin I↗
PubMed1999

Cardiovascular aspects of experimental meningococcal sepsis in young and older awake piglets: age-related differences.

Severe meningococcal disease is characterized by: a high load of specific endotoxin, capillary leakage and coagulation disorders. We studied the possible age-related differences in global hemodynamic and regional blood flow responses to different dosages (1 and 10 microg/kg body weight) of rough meningococcal endotoxin in young (8 kg) and older piglets (40 kg). Animals were chronically instrumented and studied in the awake state. The response to plasma infusion (30 mL/kg in 30 min) was evaluated after placebo and endotoxin infusion. The clinical picture was similar in all groups. The mortality was 0/8, 3/8,1/8, 4/9 in young-low, young-high, old-low, and old-high dose respectively. Most important findings were that cardiac index (CI) decreased in the young animals after endotoxin infusion, while it was well preserved in the older animals; in the older animals the systemic vascular resistance dropped 20%, while in the younger ones there was no change in resistance. Conductance to the kidneys, intestines, and spleen decreased significantly more in the young animals, while the increase in conductance and flow to the liver was higher in the old animals; subsequent volume loading resulted only partly in a recovery of the hemodynamic parameters, but failed to improve oxygen delivery.

Age Factors↗
PubMed1999

Effect of NO on transmural distribution of blood flow in hypertrophied left ventricle during exercise.

When exercise in the presence of a coronary artery stenosis results in subendocardial ischemia, administration of a nitric oxide (NO) donor increases subendocardial blood flow, whereas NO synthesis blockade worsens subendocardial hypoperfusion. Because left ventricular hypertrophy (LVH) is also associated with subendocardial hypoperfusion during exercise, this study tested the hypothesis that alterations of NO availability can similarly influence subendocardial blood flow in the hypertrophied heart. Studies were performed in seven dogs in which ascending aortic banding resulted in an 80% increase in LV weight. Myocardial blood flow was measured with microspheres during treadmill exercise that increased heart rates to 216 +/- 8 beats/min. During control exercise, mean myocardial blood flow in animals with LVH was similar to that in historic controls, but the ratio of subendocardial to subepicardial blood flow was lower in animals with hypertrophy (0.88 +/- 0.07) than in controls (1.36 +/- 0.08; P < 0.05). Blockade of NO synthesis with NG-nitro-L-arginine (L-NNA; 1.5 mg/kg ic) caused no change in heart rate or LV systolic pressure during exercise. Furthermore, L-NNA did not worsen subendocardial hypoperfusion during exercise. Intracoronary infusion of nitroglycerin (0.4 microgram. kg-1. min-1) did not significantly alter either mean blood flow or the transmural distribution of perfusion during exercise in the hypertrophied hearts. Thus, unlike the subendocardial underperfusion that occurs when a stenosis limits coronary blood flow, alterations of NO availability did not alter subendocardial hypoperfusion in the hypertrophied hearts.

Animals↗
PubMed1999

Role of K(+)(ATP) channels and adenosine in regulation of coronary blood flow in the hypertrophied left ventricle.

In the hypertrophied heart, increased extravascular forces acting to compress the intramural coronary vessels might require augmentation of metabolic vasodilator mechanisms to maintain adequate coronary blood flow. Vascular smooth muscle ATP-sensitive potassium (K(+)(ATP)) channel activity is important in metabolic coronary vasodilation, and adenosine contributes to resistance vessel dilation in the hypoperfused heart. Consequently, this study was performed to determine whether K(+)(ATP) channels and adenosine have increased importance in exercise-induced coronary vasodilation in the hypertrophied left ventricle. Studies were performed in dogs in which banding of the ascending aorta had resulted in a 66% increase in left ventricular mass in comparison with historic normal animals. Treadmill exercise resulted in increases of coronary blood flow that were linearly related to the increase of heart rate or rate-pressure product. During resting conditions, K(+)(ATP) channel blockade with glibenclamide caused a 17 +/- 5% decrease in coronary blood flow, similar to that previously observed in normal hearts. Unlike normal hearts, however, glibenclamide blunted the increase in coronary flow that occurred during exercise, causing a significant decrease in the slope of the relationship between coronary flow and the rate-pressure product. Adenosine receptor blockade with 8-phenyltheophylline did not alter coronary blood flow at rest or during exercise. Furthermore, even after K(+)(ATP) channel blockade with glibenclamide, the addition of 8-phenyltheophylline had no effect on coronary blood flow. This finding was different from normal hearts, in which the addition of adenosine receptor blockade after glibenclamide impaired exercise-induced coronary vasodilation. The data suggest that, in comparison with normal hearts, hypertrophied hearts have increased reliance on opening of K(+)(ATP) channels to augment coronary flow during exercise. Contrary to the initial hypothesis, however, adenosine was not mandatory for exercise-induced coronary vasodilation in the hypertrophied hearts either during control conditions or when K(+)(ATP) channel activity was blocked with glibenclamide.

Adenosine↗
PubMed1999

Catecholamine handling in the porcine heart: a microdialysis approach.

Experimental findings suggest a pronounced concentration gradient of norepinephrine (NE) between the intravascular and interstitial compartments of the heart, compatible with an active neuronal reuptake (U1) and/or an endothelial barrier. Using the microdialysis technique in eight anesthetized pigs, we investigated this NE gradient, both under baseline conditions and during increments in either systemic or myocardial interstitial fluid (MIF) NE concentration. At steady state, baseline MIF NE (0.9 +/- 0.1 nmol/l) was higher than arterial NE (0.3 +/- 0.1 nmol/l) but was not different from coronary venous NE (1.5 +/- 0.3 nmol/l). Local U1 inhibition raised MIF NE concentration to 6.5 +/- 0.9 nmol/l. During intravenous NE infusions (0.6 and 1.8 nmol. kg(-1). min(-1)), the fractional removal of NE by the myocardium was 79 +/- 4% to 69 +/- 3%, depending on the infusion rate. Despite this extensive removal, the quotient of changes in MIF and arterial concentration (DeltaMIF/DeltaA ratio) for NE were only 0.10 +/- 0.02 for the lower infusion rate and 0.11 +/- 0.01 for the higher infusion rate, whereas U1 blockade caused the DeltaMIF/DeltaA ratio to rise to 0.21 +/- 0.03 and 0.36 +/- 0.05, respectively. From the differences in DeltaMIF/DeltaA ratios with and without U1 inhibition, we calculated that 67 +/- 5% of MIF NE is removed by U1. Intracoronary infusion of tyramine (154 nmol. kg(-1). min(-1)) caused a 15-fold increase in MIF NE concentration. This pronounced increase was paralleled by a comparable increase of NE in the coronary vein. We conclude that U1 and extraneuronal uptake, and not an endothelial barrier, are the principal mechanisms underlying the concentration gradient of NE between the interstitial and intravascular compartments in the porcine heart.

Animals↗
PubMed1998

Autonomic control of vasomotion in the porcine coronary circulation during treadmill exercise: evidence for feed-forward beta-adrenergic control.

To date, no studies have investigated coronary vasomotor control of myocardial O2 delivery (MDO2) and its modulation by the autonomic nervous system in the porcine heart during treadmill exercise. We studied 8 chronically instrumented swine under resting conditions and during graded treadmill exercise. Exercise up to 85% to 90% of maximum heart rate produced an increase in myocardial O2 consumption (MVO2) from 163+/-16 micromol/min (mean+/-SE) at rest to 423+/-75 micromol/min (P< or =0.05), which was paralleled by an increase in MDO2, so that myocardial O2 extraction (79+/-1% at rest) and coronary venous O2 tension (cvPO2, 23.7+/-1.0 mm Hg at rest) were maintained. Beta-adrenoceptor blockade blunted the exercise-induced increase of MDO2 out of proportion compared with the attenuation of the exercise-induced increase in MVO2, so that O2 extraction rose from 78+/-1% at rest to 83+/-1% during exercise and cvPO2 fell from 23.5+/-0.9 to 19.6+/-1.1 mm Hg (both P< or =0.05). In contrast, alpha-adrenoceptor blockade, either in the absence or presence of beta-adrenoceptor blockade, had no effect on myocardial O2 extraction or cvPO2 at rest or during exercise. Muscarinic receptor blockade resulted in a decreased O2 extraction and an increase in cvPO2 at rest, an effect that waned during exercise. The vasodilation produced by muscarinic receptor blockade was likely due to an increased beta-adrenoceptor activity, since combined muscarinic and beta-adrenoceptor blockade produced similar changes in O2 extraction and cvPO2, as did beta-adrenoceptor blockade alone. In conclusion, in swine myocardium, MVO2 and MDO2 are matched during exercise, which is the result of feed-forward beta-adrenergic vasodilation in conjunction with minimal a-adrenergic vasoconstriction. Beta-adrenergic vasodilation is due to an increase in sympathetic activity but may also be supported by withdrawal of muscarinic receptor-mediated inhibition of beta-adrenergic coronary vasodilation. The observation that cvPO2 levels are maintained even during heavy exercise suggests that a decrease in cvPO2 is not essential for coronary vasodilation during exercise.

Animals↗
PubMed1998

ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during exercise.

We previously reported that combined blockade of adenosine receptors and ATP-sensitive K+ channels (K+(ATP) channels) blunted but did not abolish the response of coronary blood flow to exercise. This study tested the hypothesis that the residual increase in coronary flow in response to exercise after adenosine receptor and K+(ATP) channel blockade is dependent on endogenous NO. Dogs were studied at rest and during a four-stage treadmill exercise protocol under control conditions, during K+(ATP) channel blockade with glibenclamide (50 microg x kg(-1) x min(-1) i.c.) in the presence of adenosine receptor blockade with 8-phenyltheophylline (8-PT, 5 mg/kg i.v.), and after the addition of the NO synthase inhibitor N(G)-nitro-L-arginine (LNNA, 1.5 mg/kg i.c.). During control conditions, coronary blood flow was 49 +/- 3 mL/min at rest and increased to 92 +/- 8 mL/min at peak exercise. LNNA alone or in combination with 8-PT did not alter resting coronary flow and did not impair the normal increase in flow during exercise, indicating that when K+(ATP) channels are intact, neither NO nor adenosine-dependent mechanisms are obligatory for maintaining coronary blood flow. Combined K+(ATP) channel and adenosine blockade decreased resting coronary flow to 27 +/- 3 mL/min (P<.05), but exercise still increased flow to 45 +/- 5 mL/min (P<.05). The subsequent addition of LNNA further decreased resting coronary flow to 20 +/- 2 mL/min and markedly blunted exercise-induced coronary vasodilation (coronary vascular conductance, 0.20 +/- 0.03 mL x min(-1) x mm Hg(-1) at rest versus 0.24 +/- 0.04 mL x min(-1) x mm Hg(-1) during the heaviest level of exercise; P=.22), so that coronary flow both at rest and during exercise was below the control resting level. The findings suggest that K+(ATP) channels are critical for maintaining coronary vasodilation at rest and during exercise but that when K+(ATP) channels are blocked, both adenosine and NO act to increase coronary blood flow during exercise. In the presence of combined K+(ATP) channel blockade and adenosine receptor blockade, NO was able to produce approximately one quarter of the coronary vasodilation that occurred in response to exercise when all vasodilator systems were intact.

Adenosine↗
PubMed1998

Decreased coronary flow reserve in hypertrophic cardiomyopathy is related to remodeling of the coronary microcirculation.

BACKGROUND: Ischemia occurs frequently in hypertrophic cardiomyopathy (HCM) without evidence of epicardial stenosis. This study evaluates the hypothesis that the occurrence of ischemia in HCM is related to remodeling of the coronary microcirculation. METHODS AND RESULTS: End-diastolic septal wall thickness was significantly increased in patients with HCM (25.8+/-2.9 mm) in comparison with cardiac transplant recipients (control subjects: 11.4+/-3.0 mm; P<0.05). Although the diameter of the left anterior descending coronary artery was similar in both groups (3.0+/-0.8 versus 3.0+/-0.5 mm, P=NS), the coronary resistance reserve (CRR=CRRbasal/CRRhyperemic), corrected for extravascular compression (end-diastolic left ventricular pressure), was reduced to 1.5+/-0.6 in HCM (P<.05; control, 2.6+/-0.8). Arteriolar lumen (AL) divided by wall area was lower in HCM (21+/-5% versus 30+/-4%; P<.05), and capillary density tended to decrease (from 1824+/-424 to 1445+/-513 per mm2, P=.11) in HCM. CRR was linearly related to normalized AL according to the formula CRR=O.1 AL-0.45 (r=.57; P<.05). Further analysis revealed that CRR, AL, and capillary density were all linearly related to the degree of hypertrophy. CONCLUSIONS: Decrements in CRR were related to changes of the coronary microcirculation. Both the decrease in CRR and these changes in the coronary microcirculation were related to the degree of hypertrophy. All these factors might contribute to the well-known occurrence of ischemia in this patient group.

Adult↗
PubMed1998

Hypothermia extends the cardioprotection by ischaemic preconditioning to coronary artery occlusions of longer duration.

OBJECTIVE: To test the hypothesis that mild hypothermia potentiates the cardioprotection afforded by ischaemic preconditioning so that infarct size limitation can be obtained after coronary artery occlusion (CAO) durations which exceed the cardioprotective range (> 90 min) of either hypothermia or ischaemic preconditioning alone. METHODS: Four groups of anaesthetized rats were subjected to different durations of CAO: (i) normothermia (N, 36.5-37.5 degrees C, n = 29), (ii) normothermia + ischaemic preconditioning (N + IP, 15 min CAO followed by 10 min of reperfusion, n = 35), (iii) hypothermia (H, 30-31 degrees C, n = 31) and (iv) hypothermia + ischaemic preconditioning (H + IP, n = 24). Infarct size (IA/AR) was determined after 3 hours of reperfusion using trypan blue to delineate the area at risk (AR) from non-risk region and nitroblue tetrazolium to delineate infarcted area (IA) from viable myocardium. RESULTS: In N the CAO duration versus infarct size relation had a sigmoid shape with virtually no infarction occurring at 15 min CAO and 56 +/- 5% of the area at risk being infarcted at 30 min CAO reaching a plateau of 71 +/- 2% at 60 min CAO. Hypothermia produced a rightward shift of the relation resulting in an approximately 15 min delay in onset of infarction. Ischaemic preconditioning produced a similar reduction in infarct size (23 +/- 4%) at 30 min CAO compared to hypothermia (13 +/- 3%) but also limited infarct size at 45 min to 36 +/- 3% and at 60 min CAO to 50 +/- 3% suggesting a slowing of infarct progression. Neither intervention limited IA/AR produced by 120 min CAO. In H + IP, combined hypothermia and ischaemic preconditioning resulted in synergistic infarct size reduction so that at 45 min and 60 min CAO IA/AR was reduced to 17 +/- 3% and 23 +/- 3%, respectively, and even at 120 min CAO to 58 +/- 5%, which was significantly smaller than during normothermic control conditions (p < 0.05 vs. N). CONCLUSION: Mild hypothermia limited IA/AR modestly but markedly enhanced the cardioprotection afforded by ischaemic preconditioning in the in situ rat heart so that irreversible damage produced by even prolonged coronary artery occlusions was limited.

Analysis of Variance↗