Biomedical subjects

D J Duncker

Publications and source records attributed to D J Duncker.

At least 73 records · Page 4Linked to original sources

PubMed1996

Role of K+ ATP channels and adenosine in the regulation of coronary blood flow during exercise with normal and restricted coronary blood flow.

Regulation of coronary vasomotor tone during exercise is incompletely understood. We investigated the contributions of K+ ATP channels and adenosine to the coronary vasodilation that occurs during exercise in the normal heart and in the presence of a coronary artery stenosis. Dogs that were chronically instrumented with a Doppler flow probe, hydraulic occluder, and indwelling catheter on the left anterior descending coronary artery were exercised on a treadmill to produce heart rates of approximately 200 beats/min. By graded inflation of the occluder to produce a wide range of coronary stenosis severities, we determined the coronary pressure-flow relation. K+ atp channel blockade with intracoronary glibenclamide (10-50 microgram/kg per min) decreased coronary blood flow during exercise at coronary pressures within and below the autoregulatory range, indicating that coronary K+ ATP channel activation is critical for producing coronary vasodilation with either normal arterial inflow or when flow is restricted by a coronary artery stenosis. Adenosine receptor blockade with intravenous 8-phenyltheophylline (5 mg/kg) had no effect on coronary flow at pressures within the autoregulatory range but decreased flow at pressures < 55 mmHg. In contrast, in the presence of K+ ATP channel blockade, the addition of adenosine receptor blockade further decreased coronary flow even at coronary pressures in the autoregulatory range, indicating increased importance of the vasodilator influence of endogenous adenosine during exercise when K+ atp channels are blocked. Intracoronary adenosine (50 microgram/kg per min) increased coronary flow at perfusion pressures both within and below the autoregulatory range. In contrast, selective K+ ATP channel activation with intracoronary pinacidil (0.2-5.0 microgram/kg per min) increased flow at normal but not at lower coronary pressures (< 55 mmHg). This finding demonstrates that not all K+ ATP channels are activated during exercise at pressures in the autoregulatory range, but that most K+ ATP channels are recruited as pressures approach the lower end of the autoregulatory plateau. Thus, K+ ATP channels and endogenous adenosine play a synergistic role in maintaining vasodilation during exercise in normal hearts and distal to a coronary artery stenosis that results in myocardial hypoperfusion during exercise.

Adenosine↗

PubMed1996

Rapid ventricular pacing produces myocardial protection by nonischemic activation of KATP+ channels.

BACKGROUND: Rapid ventricular pacing reduces the incidence of ventricular arrhythmias during a subsequent sustained period of ischemia and reperfusion. We investigated whether rapid ventricular pacing also limits myocardial infarction and determined the role of KATP+ channels in the protection afforded by ventricular pacing. METHODS AND RESULTS: Myocardial infarction was produced by a 60-minute coronary artery occlusion in open chest pigs. Infarct size of pigs subjected to 10 minutes of ventricular pacing at 200 beats per minute followed by 15 minutes of normal sinus rhythm before the occlusion (79 +/- 3% of the area at risk, mean +/- SEM) was not different from control infarct size (84 +/- 2%). Thirty-minute pacing followed by 15-minute sinus rhythm resulted in modest reductions in infarct size (71 +/- 2%, P<.05 versus control). Thirty minutes of pacing immediately preceding the occlusion without intervening sinus rhythm resulted in considerable limitation of infarct size (63 +/- 4%, P<.05), which was abolished by pretreatment with the KATP+ channel blocker glibenclamide (78 +/- 4%, P=NS). KATP+ channel activation did not appear to involve ischemia: (1) myocardial endocardial/epicardial blood flow ratio was 1.07 +/- 0.08, (2) phosphocreatine and ATP levels and arterial-coronary venous differences in pH and PCO2 were unchanged, (3) end-systolic segment length did not increase and postsystolic shortening was not observed during pacing, and (4) systolic shortening recovered immediately to baseline levels and coronary reactive hyperemia was absent after cessation of pacing. Administration of glibenclamide after 30 minutes of pacing at the onset of 15 minutes of normal sinus rhythm did not attenuate the protection (73 +/- 3%, P<.05 versus control), suggesting the KATP+ channels did not contribute to the moderate degree of protection that was still present 15 minutes after cessation of pacing. CONCLUSIONS: Rapid ventricular pacing protects the myocardium against infarction via nonischemic KATP+ channel activation. Continued activation of KATP+ channels does not appear mandatory for the protection that is still present 15 minutes after cessation of pacing.

Animals↗

PubMed1996

Effect of temperature on myocardial infarction in swine.

Body core temperature in the normothermic range alters infarct size in rabbits. Moreover, temperature may modulate the protection by adenosine during a coronary artery occlusion. We investigated the effect of core temperature within the normothermic range (35-39 degrees C) on myocardial infarct size produced by a 45-min coronary occlusion in open-chest swine (n = 10), and we determined whether adenosine blockade with 8-phenyltheophylline and adenosine deaminase increased infarct size in the normothermic range (n = 9). After 4 h of reperfusion the area at risk and infarct size were determined with Evans blue dye and triphenyltetrazolium chloride. Infarct size strongly correlated with temperature (r2 = 0.71, P = 0.0001) so that at 35 degrees C no infarction occurred and with each 1 degree C increase in temperature 20% of the area at risk became infarcted. In contrast, neither the low levels of collateral flow (0.03 +/- 0.01 ml.min-1.g-1) nor the rate-pressure product correlated with infarct size. In the normothermic range, adenosine blockade had no effect on infarct size. The data demonstrate that temperature can exert a profound effect on infarct size but fail to demonstrate a protective effect on endogenous adenosine at normothermic temperatures. Our findings emphasize the need for stringent control of core temperature during investigation of interventions aimed at reducing infarct size.

Adenosine↗

PubMed1996

Coronary hyperperfusion augments myocardial oxygen consumption.

This study was performed to test the hypothesis that increases in myocardial oxygen consumption (MVo2) and myocardial contractile function during exercise are flow limited. Studies were performed in 15 chronically instrumented normal dogs. MVo2 and regional percent systolic wall thickening were measured during control conditions and during maximal vasodilation produced by infusion of adenosine (20-75 micrograms.kg-1.min-1) or adenosine combined with nitroglycerin (0.4 micrograms.kg-1.min-1; TNG) into the left anterior descending coronary artery during a three-stage graded treadmill exercise protocol. Adenosine and adenosine plus TNG significantly increased coronary blood flow by 298 +/- 26 and 306 +/- 24%, respectively, at rest and by 134 +/- 7 and 145 +/- 9%, respectively, during the heaviest level of exercise (each P < 0.01). Adenosine and adenosine plus TNG increased MVo2 at rest, but this was associated with a parallel increase in heart rate, so that MVo2 per beat was not significantly changed. Systolic wall thickening was also not changed by hyperperfusion during resting conditions. However, MVo2 per beat was increased by 12 +/- 4% with adenosine and by 13 +/- 5% with adenosine plus TNG during moderate exercise and by 23 +/- 5% with adenosine and by 27 +/- 4% with adenosine plus TNG during the heaviest level of exercise (each P < 0.05). Systolic thickening of the full left ventricular wall did not change during hyperperfusion, but thickening in the subepicardial layer was increased by 14 +/- 3% with adenosine and 18 +/- 3% with adenosine plus TNG during the heaviest level of exercise (each P < 0.05). There was no difference in wall thickening between adenosine and adenosine plus TNG. These findings imply that the increases in MVo2 which occur during exercise are limited by coronary blood flow.

Animals↗

PubMed1995

Effect of left ventricular hypertrophy secondary to chronic pressure overload on transmural myocardial 2-deoxyglucose uptake. A 31P NMR spectroscopic study.

BACKGROUND: This study tested the hypothesis that 31P nuclear magnetic resonance (NMR)-detectable 2-deoxyglucose (2DG) uptake is increased in chronically pressure-overloaded hypertrophied left ventricular myocardium. METHODS AND RESULTS: 31P NMR spectroscopy was used to determine the transmural distribution of high-energy phosphate levels and 2-deoxyglucose-6-phosphate (2DGP) accumulation during intracoronary infusion of 2DG (15 mumol.kg body wt-1.min-1) in eight normal dogs and in eight dogs with severe left ventricular hypertrophy (LVH) produced by ascending aortic banding. The ratio of LV weight to body weight was 8.25 +/- 0.65 g/kg in the LVH group compared with 4.35 +/- 0.11 g/kg in the normal group (P < .01). Myocardial ATP content was decreased by approximately 40% and phosphocreatine (PCr) by approximately 60% in LVH hearts. ATP values were transmurally uniform in LVH and normal hearts, whereas PCr was lower in the subendocardium (Endo) than the subepicardium (Epi) of both groups. The PCr/ATP ratio was lower in LVH hearts (1.72 +/- 0.05, 1.64 +/- 0.07, and 1.53 +/- 0.10 in Epi, midwall, and Endo, respectively) compared with normal hearts (2.36 +/- 0.05, 2.09 +/- 0.06, and 1.96 +/- 0.06; each P < .01 normal versus LVH). Arterial blood levels of glucose, insulin, and free fatty acids were comparable between groups, whereas arterial lactate and norepinephrine levels were significantly higher in the LVH group. 2DG infusion did not affect systemic hemodynamics or myocardial high-energy phosphate or inorganic phosphate levels in either group. At the end of 60 minutes of 2DG infusion, there was no detectable accumulation of 2DGP in the normal hearts. However, seven of the eight LVH hearts showed time-dependent accumulation of 2DGP, which was linearly related to the severity of hypertrophy (r = .90 for subendocardial 2DGP versus LV weight/body weight). A transmural gradient of 2DGP was present, with greatest accumulation in the subendocardium (3.3 +/- 1.6, 5.8 +/- 2.3, and 7.9 +/- 2.2 mumol/g in Epi, midwall, and Endo of the LVH hearts, respectively; P < .05 Epi versus Endo). CONCLUSIONS: The pressure-overloaded hypertrophied left ventricle demonstrated increased accumulation of 2DGP detected with 31P NMR spectroscopy. Accumulation of 2DGP was positively correlated with the degree of hypertrophy and was most marked in the subendocardium.

Adenosine Triphosphate↗

PubMed1995

Effect of beta-adrenergic receptor blockade on blood flow to collateral-dependent myocardium during exercise.

BACKGROUND: beta-Adrenergic receptors have been identified in isolated coronary collateral blood vessels, but their functional significance in the intact heart has not been demonstrated. METHODS AND RESULTS: We measured myocardial blood flow with radioactive microspheres in normal and collateral-dependent myocardium in eight dogs trained to run on a treadmill before and after beta-adrenergic blockade with propranolol, 200 micrograms/kg, a dose that effectively inhibited the increase in coronary blood flow produced by selective beta 1- and beta 2-adrenergic agonists. Collateral vessel growth was stimulated with 2-minute intermittent occlusions of the left anterior descending artery followed by permanent occlusion. During control exercise, blood flow in the collateral zone was 38 +/- 5% less than in the normal zone. At identical levels of exercise, with heart rate maintained constant by atrial pacing, propranolol decreased mean blood flow in the collateralized myocardium from 1.93 +/- 0.17 to 1.50 +/- 0.14 mL.min-1.g-1 (P < .01), while increasing the subendocardial to subepicardial blood flow ratio from 0.78 +/- 0.11 to 0.91 +/- 0.10 (P < .05). The decrease in collateral zone blood flow in response to propranolol resulted from an increase in both transcollateral resistance from 25.9 +/- 2.3 to 35.2 +/- 4.3 mm Hg.mL-1.min.g (P < .05) and small-vessel resistance in the collateral-dependent myocardium from 30.9 +/- 4.7 to 44.0 +/- 8.8 mm Hg.mL-1.min.g (P < .07). Blood flow to the normal zone was also significantly reduced from 3.14 +/- 0.21 to 2.23 +/- 0.12 mL.min-1.g-1 (P < .01) after propranolol. CONCLUSIONS: beta-Adrenergic blockade decreased blood flow to collateral-dependent myocardium during exercise. These results indicate that beta-adrenergic receptor activation contributes to vasodilation of coronary collateral vessels during exercise.

Animals↗

PubMed1995

Ischaemic preconditioning: is it clinically relevant?

Direct clinical evidence for the classical preconditioning phenomenon, with infarct size limitation as an endpoint, cannot be obtained. However, a number of patient groups have been identified in which adaptation to ischaemia has been demonstrated by enhanced recovery of function or preservation of high energy phosphates in models of repeated ischaemia, such as atrial pacing stress tests, percutaneous transluminal coronary angioplasty and aortic cross-clamping during cardiac surgery. Evidence is accumulating that mechanisms which are operative in experimental ischaemic preconditioning (infarct size limitation) are also operative in these clinical models of repeated reversible ischaemia. Insight into the mechanisms responsible for ischaemic preconditioning could potentially help to develop pharmacological agents which mimic preconditioning. This is especially attractive as several of the ischaemic episodes maybe too short or insufficiently severe to trigger preconditioning. By a synergistic or additive action, the combination of such a stimulus with a low dose of pharmacological agent might result in protective action. If these agents were also to be used for treating cardiovascular conditions, such as the K+ATP channel activator nicorandil for the treatment of angina pectoris, the cardioprotective effect could be a beneficial side effect. The currently available protein kinase C activators are oncogenic, but with the recognition and better understanding of the different subtypes possibly involved in preconditioning, new protein kinase C activators may become available without these side-effects. On the other hand, hearts of patients who regularly experience episodes of ischaemia may be in a more or less permanent state of preconditioning afforded by one of these stimuli or have developed tolerance. In this situation it is likely that (additional) protection by a pharmacological agent cannot be accomplished at that time. It is reassuring, however, that in the animal, preconditioning can be reinstated immediately after the cardioprotection is lost and that it can also be demonstrated in hearts with pathological conditions such as hypertrophy. Finally, in view of the observations that cardioprotection may also be produced by transient ischaemia in other organs, and even by some forms of stress which do not lead to myocardial ischaemia, it could be envisioned that ischaemic preconditioning is only one component of a general form of adaptation.

Aged↗

PubMed1995

Nitrovasodilators ITF 296 and isosorbide dinitrate exert antiischemic activity by dilating coronary penetrating arteries.

We examined the effect of the novel nitrovasodilator ITF 296 and isosorbide dinitrate (ISDN) on myocardial blood flow (BF) distal to a coronary artery stenosis. Eleven dogs with a Doppler velocity probe, hydraulic occluder, and indwelling microcatheter in the left anterior descending coronary artery (LAD) were studied during treadmill exercise in the presence of a coronary artery stenosis. On separate days, the effects of ITF 296 in doses of 4 and 20 micrograms/kg/min i.v. or ISDN 20 micrograms/kg/min i.v. were compared. Coronary pressure distal to the stenosis was maintained constant during the control period and after administration of either nitrovasodilator. Neither ITF 296 nor ISDN significantly altered heart rate (HR), arterial blood pressure (BP), or left ventricular end-diastolic pressure (LVEDP). In the presence of a stenosis that decreased distal coronary pressure to 58 +/- 4 mm Hg, mean myocardial BF measured with microspheres was 0.91 +/- 0.08 ml/min/g in the LAD-dependent region and 2.36 +/- 0.11 ml/min/g in the posterior control region, respectively. With no change in distal coronary pressure, ITF 296 increased mean BF in the LAD region to 1.25 +/- 0.05 ml/min/g (4 micrograms/kg/min i.v.) and 1.40 +/- 0.10 ml/min/g (20 micrograms/kg/min i.v.), whereas ISDN (20 micrograms/kg/min i.v.) increased flow to 1.28 +/- 0.18 ml/min/g (each p < 0.05). The increase in BF occurred exclusively in the deeper layers, with no change in subepicardial BF. Consequently, the endocardial/epicardial (endo/epi) BF ratio increased from 0.33 +/- 0.04 during control stenosis to 0.70 +/- 0.10 after ITF 296 (20 micrograms/kg/min), and to 0.56 +/- 0.08 after ISDN (each p < 0.05). Neither ITF 296 nor ISDN had an effect on myocardial BF in the normally perfused control region. Therefore, both ITF 296 and ISDN improved BF to the deeper myocardial layers distal to a coronary artery stenosis. This effect occurred without alterations in stenosis severity or diastolic intraventricular pressure, suggesting that these agents act by dilating the penetrating arteries which deliver BF to the subendocardium.

Analysis of Variance↗

PubMed1995

Transmural bioenergetic responses of normal myocardium to high workstates.

The response of myocardial high-energy and inorganic phosphates (HEP and Pi, respectively) and associated changes in myocardial blood flow, lactate uptake, and O2 consumption (MVo2) rates were examined in an open-chest canine model during progressively increasing workloads achieved by catecholamine infusion. HEP and Pi levels (measured with transmurally localized 31P-nuclear magnetic resonance spectroscopy) were unaffected by moderate increases in the level of energy expenditure but were significantly altered by high workloads, especially in the subepicardium. The MVo2 and HEP data from three different protocols that utilized pharmacological augmentation of blood flow demonstrated that the maximal rate of myocardial energy production during inotropic stimulation was dictated by perfusion limitation. This limitation was more severe in the subepicardial layer at the high workloads despite equivalent or even higher increases in blood flow to this layer, reflecting a preferential enhancement of demand in the outer layer by catecholamines. In contrast, under basal conditions, existence of a marginal perfusion limitation was evident in the inner but not in the outer layer.

Adenosine Triphosphate↗

PubMed1995

Effect of exercise on coronary pressure-flow relationship in hypertrophied left ventricle.

Left ventricular (LV) hypertrophy (LVH) secondary to chronic pressure overload is associated with increased susceptibility to myocardial hypoperfusion and ischemia during exercise. The present study was performed to determine whether exercise causes alterations in minimum coronary resistance or effective back pressure [coronary pressure at zero flow (Pzf)] that limit maximum myocardial perfusion in the hypertrophied heart. Ascending aortic banding in 7 dogs increased the LV weight-to-body weight ratio to 7.7 +/- 0.3 g/kg compared with 4.6 +/- 0.2 g/kg in 11 normal dogs (P < 0.01). Maximum coronary vasodilation was produced by intracoronary infusion of adenosine. Under resting conditions, the slope of the pressure-flow relationship (conductance) was significantly lower in the LVH animals than in the normal dogs (7.2 +/- 0.8 vs. 11.9 +/- 0.8 x 10(-2) ml.min-1.g-1.mmHg-1; P < 0.01); the slope correlated with the degree of hypertrophy r = 0.74; P < 0.001). The Pzf measured during total coronary artery occlusion (Pzf,measured) was significantly elevated in LVH compared with normal dogs (25.6 +/- 2.2 vs. 13.0 +/- 1.2 mmHg; P < 0.01); Pzf,measured was positively correlated (r = 0.78, P < 0.0005) with LV end-diastolic pressure measured during total coronary artery occlusion (9.0 +/- 1.1 mmHg in normal dogs and 22.2 +/- 3.2 mmHg in LVH dogs; P < 0.01). Graded treadmill exercise to maximum heart rates of 210 +/- 9 and 201 +/- 8 beats/min in normal and LVH animals, respectively, caused similar decreases in the slope of the pressure-flow relationship in LVH (from 7.7 +/- 0.9 to 6.1 +/- 0.8 x 10(-2) ml.min-1.g-1.mmHg-1; P < 0.01) and normal dogs (from 11.9 +/- 0.8 to 10.0 +/- 0.7 x 10(-2) ml.min-1.g-1.mmHg-1; P < 0.01). However, exercise-induced increases in Pzf,measured were significantly greater in the LVH animals (from 25.6 +/- 2.2 to 40.8 +/- 2.1 mmHg; P < 0.01) than in normal animals (from 13.0 +/- 1.2 to 24 +/- 2.1 mmHg; P < 0.01) (P < 0.01 LVH vs. normal). The greater increase in Pzf paralleled a more pronounced increase in LV end-diastolic pressure in the LVH dogs from 22.2 +/- 3.2 to 39.1 +/- 2.7 mmHg) than in normal dogs from 9.0 +/- 1.1 to 14.2 +/- 2.0 mmHg). The results suggest that exaggerated increases in filling pressure during exercise in the hypertrophied left ventricles contributed to impairment of myocardial perfusion during exercise by augmenting the back pressure, which opposes coronary flow.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗

PubMed1995

Endogenous adenosine mediates coronary vasodilation during exercise after K(ATP)+ channel blockade.

The mechanism of coronary vasodilation produced by exercise is not understood completely. Recently, we reported that blockade of vascular smooth muscle K(ATP)+ channels decreased coronary blood flow at rest, but did not attenuate the increments in coronary flow produced by exercise. Adenosine is not mandatory for maintaining basal coronary flow, or the increase in flow produced by exercise during normal arterial inflow, but does contribute to coronary vasodilation in hypoperfused myocardium. Therefore, we investigated whether adenosine opposed the hypoperfusion produced by K(ATP)+ channel blockade, thereby contributing to coronary vasodilation during exercise. 11 dogs were studied at rest and during exercise under control conditions, during intracoronary infusion of the K(ATP)+ channel blocker glibenclamide (50 micrograms/kg per min), and during intracoronary glibenclamide in the presence of adenosine receptor blockade. Glibenclamide decreased resting coronary blood flow from 45 +/- 5 to 35 +/- 4 ml/min (P < 0.05), but did not prevent exercise-induced increases of coronary flow. Glibenclamide caused an increase in myocardial oxygen extraction at the highest level of exercise with a decrease in coronary venous oxygen tension from 15.5 +/- 0.7 to 13.6 +/- 0.8 mmHg (P < 0.05). The addition of the adenosine receptor antagonist 8-phenyltheophylline (5 mg/kg intravenous) to K(ATP)+ channel blockade did not further decrease resting coronary blood flow but did attenuate the increase in coronary flow produced by exercise. This was accompanied by a further decrease of coronary venous oxygen tension to 10.1 +/- 0.7 mmHg (P < 0.05), indicating aggravation of the mismatch between oxygen demand and supply. These findings are compatible with the hypothesis that K+ATP channels modulate coronary vasomotor tone both under resting conditions and during exercise. However, when K(ATP)+ channels are blocked, adenosine released from the hypoperfused myocardium provides an alternate mechanism to mediate coronary vasodilation in response to increases in oxygen demand produced by exercise.

Adenosine↗

PubMed1995

Endocardial and epicardial infarct size after preconditioning by a partial coronary artery occlusion without intervening reperfusion. Importance of the degree and duration of flow reduction.

OBJECTIVE: Recently, we reported that a partial coronary artery occlusion immediately preceding a sustained coronary artery occlusion limited infarct size. We now investigated whether the protection by partial coronary artery occlusions (i) depends on the severity and(or) duration of the flow reduction and (ii) varies in the different myocardial layers. METHODS: In 71 open-chest pigs (eight groups) left ventricular area at risk (AR) and infarct area (IA) were determined for the endocardial (IAendo and ARendo) and epicardial halves (IAepi and ARepi). RESULTS: In control animals (60 min total coronary artery occlusion (TCO) followed by 120 min reperfusion (Rep)) there were highly linear relations between IA and AR in the endocardium (r = 0.98, P < 0.01) and epicardium (r = 0.97, P < 0.01), which could be described by IAendo = 1.01 ARendo - 4.5 and by IAepi = 0.88ARepi - 3.6, respectively. In animals that underwent a 10 min TCO + 15 min Rep prior to the 60 min TCO + 120 min Rep, IA in both myocardial layers were again highly linearly related with AR, with less steep slopes for both the endocardium (0.63) and epicardium (0.57) (both P < 0.01). Two groups of pigs were subjected to either a 30 or 90 min 70% reduction in coronary blood flow (FR) immediately preceding the 60 min TCO + 120 min Rep, without intervening reperfusion. A 30 min 70% FR decreased IA to the same degree in the endo- and epicardial half. A 90 min 70% FR resulted in protection in the epicardium (P < 0.01) but not in the endocardium, most likely because 90 min 70% FR without 60 min TCO already caused infarction which was more severe in the endo- than in the epicardium (P < 0.01). Endocardial and epicardial IA after either a 30 or 90 min 30% FR prior to the 60 min TCO was not different from that in the control group, indicating that this mild flow reduction failed to limit irreversible damage. CONCLUSIONS: Thirty or ninety min of severe (70%) but not mild (30%) coronary flow reductions protected against myocardial infarction. The protection by a 70% FR was influenced by the duration of FR as a 30 min 70% FR similarly decreased IA in the endocardial and epicardial halves, while 90 min 70% FR preferentially limited IA in the epicardial half. These findings suggest that perfusion abnormalities immediately preceding an infarction could be an important source of infarct size variability in patients.

Animals↗

PubMed1994

Effect of inhibition of nitric oxide formation on coronary blood flow during exercise in the dog.

OBJECTIVE: The aim was to test the hypothesis that nitric oxide (or a related compound) contributes to the coronary vasodilatation during physiological increases of myocardial O2 consumption that occur with exercise. METHODS: Active hyperaemia associated with graded treadmill exercise and coronary reactive hyperaemia were examined in chronically instrumented awake dogs during control conditions and after administration of the nitric oxide synthase inhibitor, N-nitro-L-arginine (LNNA). RESULTS: LNNA blunted the response to intracoronary acetylcholine, with an 80(SEM 6)% decrease in the maximum acetylcholine induced coronary vasodilatation, but did not alter the response to sodium nitroprusside. Increases of myocardial oxygen requirements during treadmill exercise were associated with progressive increases of coronary blood flow. LNNA caused a significant increase in arterial pressure at rest and during exercise, and this was associated with slightly but significantly higher myocardial oxygen consumption. Coronary blood flow-during exercise was also slightly higher after LNNA, while coronary vascular resistance was unchanged. Coronary sinus PO2 was slightly but significantly lower during exercise after LNNA, indicating that coronary vasodilatation in response to the increased myocardial oxygen demands during exercise was slightly blunted by LNNA. LNNA did not alter the peak increase in blood flow during reactive hyperaemia following a 15 s coronary occlusion, but decreased the duration of the response and decreased reactive hyperaemia debt repayment from 300(56)% during control conditions to 182(36)% after LNNA (p < 0.01). CONCLUSIONS: LNNA antagonised coronary vasodilatation in response to acetylcholine and blunted coronary reactive hyperaemia, but did not substantially impair the coronary vasodilatation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support an essential role for nitric oxide in coronary resistance vessel dilatation during exercise in the dog.

Acetylcholine↗

PubMed1994

Coronary pressure-flow relationship and exercise: contributions of heart rate, contractility, and alpha 1-adrenergic tone.

We examined the impeding effects of exercise on coronary blood flow by analyzing exercise-induced changes in the pressure-flow relationship during maximal coronary vasodilation with adenosine in chronically instrumented dogs and assessed the individual contributions produced by heart rate, contractility, and alpha 1-adrenergic vasoconstriction. Treadmill exercise that increased heart rate from 118 +/- 6 beats/min at rest to 213 +/- 8 beats/min (P < 0.01) decreased maximum coronary blood flows by decreasing the slope of the linear part of the pressure-flow relationship for coronary pressures > or = 30 mmHg (slopeP > or = 30) from 12.3 +/- 0.9 to 10.9 +/- 0.9 ml.min-1 x g-1 x mmHg-1 (P < 0.01) and increasing the measured coronary pressure at zero flow (P zf,measured) from 12.6 +/- 1.2 to 23.3 +/- 2.0 mmHg (P < 0.01). Atrial pacing at 200 beats/min caused an increase of P zf,measured from 15.0 +/- 1.6 to 18.3 +/- 2.1 mmHg (P < 0.05) with no change in slopeP > or = 30. While pacing continued, infusion of dobutamine (20 micrograms.kg-1 x min-1 i.v.) increased contractility to levels similar to those during exercise but caused no significant change in coronary blood flow, as a decrease of the slopeP > or = 30 was compensated for by a slight decrease in P zf,measured. alpha 1-Adrenergic blockade with intracoronary prazosin (10 micrograms/kg) did not prevent the exercise-induced increase of P zf,measured but abolished the decrease of the slopeP > or = 30. When the increases in heart rate, contractility, and alpha 1-adrenergic vasoconstriction were prevented, exercise still increased P zf,measured from 15.8 +/- 2.1 to 21.8 +/- 2.6 mmHg (P < 0.05) but had no effect on the slopeP > or = 30. This residual increase in P zf,measured correlated with the concomitant increase in left ventricular filling pressure. In conclusion, exercise-induced decreases of maximum coronary blood flow were explained by increases in heart rate, alpha 1-adrenergic vasoconstriction, and left ventricular filling pressure, with a minimal contribution of contractility.

Animals↗

PubMed1994

Inhibition of nitric oxide production aggravates myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis.

Regulation of coronary vasomotor tone during myocardial hypoperfusion is incompletely understood. The present study was performed to test the hypothesis that endogenous production of nitric oxide contributes to resistance vessel dilation distal to a coronary artery stenosis that results in myocardial ischemia during exercise. Seven dogs instrumented with a Doppler velocity probe, hydraulic occluder, and indwelling microcatheter in the left anterior descending coronary artery (LAD) were studied during treadmill exercise in the presence of a coronary artery stenosis before and after intracoronary infusion of NG-nitro-L-arginine (LNNA, 20 mg/kg). This dose of LNNA inhibited the maximal increase in LAD flow produced by intracoronary acetylcholine by 82 +/- 5% but did not alter the response to intracoronary nitroprusside. Coronary pressure distal to the stenosis was maintained constant during the control period and after administration of LNNA. LNNA increased aortic and left ventricular systolic and end-diastolic pressures at rest and during exercise. During control in the absence of a stenosis, LNNA had no effect on coronary blood flow. In the presence of a stenosis that decreased distal coronary pressure to 55 +/- 2 mm Hg, mean myocardial blood flow measured with microspheres was 1.09 +/- 0.13 mL.min-1.g-1 in the LAD-dependent and 2.57 +/- 0.50 mL.min-1.g-1 in the posterior control region, respectively. With no change in distal coronary pressure, LNNA decreased mean myocardial blood flow in the LAD region to 0.68 +/- 0.11 mL.min-1.g-1 (P < .01). To avoid systemic hemodynamic effects, LNNA was administered in a dose of 1.5 mg/kg IC to four additional dogs. This low dose inhibited the coronary blood flow increases produced by acetylcholine by 61 +/- 5% but was devoid of systemic hemodynamic effects. During exercise in the presence of a coronary stenosis that decreased coronary pressure to 52 +/- 1 mm Hg, this dose of LNNA decreased mean myocardial blood flow from 0.89 +/- 0.23 to 0.66 +/- 0.21 mL.min-1.g-1 (P < .02). These data demonstrate that nitric oxide contributes to the maintenance of myocardial perfusion distal to a flow-limiting coronary artery stenosis during exercise.

Animals↗

PubMed1993

Enhanced gene expression of calcium regulatory proteins in stunned porcine myocardium.

OBJECTIVE: Increasing evidence points to a molecular disturbance of Ca2+ homeostasis in stunned myocardium. The aim of this study was therefore to investigate the expression of mRNAs for Ca2+ binding proteins related to the sarcoplasmic reticulum in a porcine model of myocardial stunning. METHODS: In 22 anaesthetised pigs, stunning was achieved by one or two cycles of 10 min left anterior descending coronary artery occlusion and reperfusion. Hearts were excised at various timepoints of the protocol. Total RNA was extracted from stunned (experimental) as well as normally perfused (control) myocardium. RESULTS: Northern blot analysis using radioactive cDNA probes revealed that the Ca(2+)-ATPase mRNA levels increased 1.6-fold compared to the control value at 90 min of the second reperfusion. The steady state level of phospholamban mRNA rose 2.5-fold at 180 min of reperfusion. A 2.3-fold increase in calsequestrin mRNAs was observed after 90 min of the second reperfusion. The calmodulin and alpha, beta myosin heavy chain mRNA levels were unchanged. A glyceraldehyde-3-phosphate dehydrogenase cDNA probe served as a reference system. Nuclear run-on assays showed increased transcription for Ca(2+)-ATPase and calsequestrin at 90 min of reperfusion, supporting the view that increased mRNA levels seen with northern hybridisation were due to increased transcription of the respective gene. CONCLUSIONS: The results suggest specific repair mechanisms of stunned myocardium and point to the involvement of calcium regulatory proteins related to the sarcoplasmic reticulum in the pathogenesis of myocardial stunning.

Animals↗

PubMed1993

Increased activity of the sarcoplasmic reticular calcium pump in porcine stunned myocardium.

OBJECTIVE: The aim was to determine whether changes in sarcoplasmic reticular Ca2+ transport activity and the degree of phosphorylation of phospholamban of "stunned" myocardium are involved in the reversible depression of contractile function. METHODS: In anaesthetised open chest swine, stunning was induced by subjecting the myocardium perfused by the left anterior descending coronary artery to two cycles of 10 min of occlusion and 30 min of reperfusion. Before and after stunning, systemic haemodynamic variables and regional myocardial function and perfusion were determined, while biopsies were taken for determination of the content of high energy phosphate compounds. Sarcoplasmic reticular function (ATP dependent Ca2+ transport and phosphorylation of phospholamban) of the stunned and control myocardium was determined at the end of the stunning protocol. RESULTS: In the stunned myocardium the segment length shortening decreased from 17.4(SD 4.0)% to 3.5(4.4)%, while perfusion was 38% less than at baseline. ATP and total adenine nucleotide levels of the stunned myocardium were about 35% lower than in the control myocardium, but the energy charge was normal as creatine phosphate levels had increased by 66% over the content determined at baseline. Ca2+ uptake by the sarcoplasmic reticulum isolated from the stunned region was 17% (p < 0.05) higher than Ca2+ uptake from the control region [1240(303) and 1450(280) nmol.min-1.mg-1 protein, respectively]. In the presence of exogenous cyclic AMP dependent protein kinase the amount of 32P incorporated into phospholamban was similar for both myocardial regions. CONCLUSIONS: In this model of stunned porcine myocardium, the phosphorylation state of phospholamban was unchanged, but Ca2+ uptake by the sarcoplasmic reticulum was slightly increased. The results indicate that a change in active Ca2+ transport by the sarcoplasmic reticulum is most likely not to be the principal cause of contractile dysfunction of stunned myocardium.

Adenosine Diphosphate↗

PubMed1993

Dobutamine restores the reduced efficiency of energy transfer from total mechanical work to external mechanical work in stunned porcine myocardium.

OBJECTIVE: In order to determine whether the relatively high oxygen consumption of stunned myocardium is related to decreased mechanical efficiency, myocardial oxygen consumption (MVO2) and its major determinants were studied in 10 open chest anaesthetised pigs. METHODS: According to the time varying elastance concept, MVO2 is determined by contractility (Emax) and total mechanical work (PLA), which is the sum of the external work (EW) and potential energy (PE). Mechanical efficiency (EW/MVO2) equals the product of EW/PLA (= efficiency of energy transfer or EET) and PLA/MVO2. Emax is the slope of the end systolic pressure-segment length relationship, determined by gradually clamping the aorta. PLA is the area enclosed by the end systolic pressure-segment length relationship and the pressure-segment length trajectory. EW is the area of the pressure-segment length loop. Systemic haemodynamics, regional segment shortening, and MVO2 were determined at baseline, during stunning (two sequences of 10 min occlusion and 30 min of reperfusion), after a subsequent 50 beats.min-1 increase in heart rate by atrial pacing and additional infusion of 2 micrograms.kg-1.min-1 dobutamine. RESULTS: Stunning decreased segment shortening from 18.2(SEM 1.9)% to 10.2(1.5)%, MVO2 from 4.16(0.27) x 10(-2) to 2.84(0.25) x 10(-2) mumol.beat-1.g-1, and Emax from 47(9) to 23(3) mm Hg.mm-1 (all p < 0.05). PLA decreased by 13(4)%, as EW decreased by 42(6)%, and PE tended to increase. Although EET decreased from 0.58(0.04) to 0.40(0.03) (p < 0.05), there was no decrease in the mechanical efficiency, as an increase in PE caused an increase in PLA/MVO2 which compensated for the decrease in EET. Dobutamine infusion increased Emax and EW per beat to 120(23)% and 67(8)% of baseline, respectively, while MVO2 [4.12(0.53) mumol.beat-1.g-1] and EET [0.57(0.04)] returned to baseline. CONCLUSIONS: In stunned myocardium, mechanical efficiency is not decreased despite a decrease in EET. The increase in EET after dobutamine may explain the lack of the excessive increase in MVO2.

Animals↗