Minimal impairment of myocardial blood flow responses to exercise in the remodeled left ventricle early after myocardial infarction, despite significant hemodynamic and neurohumoral alterations.

OBJECTIVES: Previous studies have demonstrated a decreased flow reserve in the surviving hypertrophied left ventricle (LV) early after myocardial infarction. We hypothesized that exacerbation of hemodynamic abnormalities and neurohumoral activation during exercise could exhaust coronary flow reserve and thereby impair myocardial O(2) supply. Consequently, we studied hemodynamic, neurohumoral and regional myocardial perfusion and metabolic responses to exercise in pigs with LV hypertrophic remodeling 3 weeks after a myocardial infarction produced by permanent left circumflex coronary artery ligation. METHODS: Chronically instrumented pigs were exercised on a treadmill up to 85% of maximum heart rate. Pigs with a myocardial infarction (MI) had a lower cardiac output (21%), stroke volume (28%), LVdP/dt(max) (18%), systemic (22%) and pulmonary (20%) vascular conductance, and increased left atrial (225%) and pulmonary artery (75%) pressures, compared to normal pigs. In MI, the exercise-induced increases in cardiac pump function, and systemic and pulmonary vasodilation were blunted compared to normals. Consequently, perfusion of visceral organs became impaired during strenuous exercise, but cerebral and skeletal muscle blood flows were maintained. Exercise-induced increases in norepinephrine and endothelin levels were exacerbated and, while relative sympathetic drive was maintained, cardiac responsiveness to norepinephrine was blunted. Despite lower capillary densities in the hypertrophied non-infarcted LV and relative subendocardial hypoperfusion during strenuous exercise, which necessitated a slight increase in O(2) extraction, there was no metabolic evidence of overt myocardial ischemia during strenuous exercise as indicated by the arterio-coronary venous pH difference. CONCLUSIONS: LV dysfunction and neurohumoral activation were present in pigs with a 3-week-old infarction, particularly during exercise. However, although myocardial perfusion and O(2) supply were slightly impaired, myocardial ischemia did not occur even during exercise up to 85% of maximum heart rate, suggesting that perfusion abnormalities do not contribute to LV dysfunction early after infarction.

Intrarenal angiotensin II: interstitial and cellular levels and site of production.

BACKGROUND: Both local production and angiotensin II subtype 1 (AT1) receptor-mediated uptake from the circulation contribute to the high levels of angiotensin (Ang) II in the kidney. It is largely unknown where Ang II is produced in the kidney and how much of it originates from the circulation. METHODS: The concentrations of endogenous and 125I-labeled Ang I and II were measured in renal tissue and in blood from pigs receiving systemic infusions of 125I-Ang I. Pigs were either untreated or treated with the angiotensin converting enzyme (ACE) inhibitor captopril or the AT1 receptor antagonist eprosartan. RESULTS: 125I-Ang I was undetectable in renal tissue but the steady-state concentrations of 125I-Ang II in cortical and medullary tissue were four and two times the concentration in arterial blood plasma, respectively. The tissue concentrations of endogenous Ang II were 100 and 60 times higher than in arterial plasma. Eprosartan reduced 125I-Ang II accumulation by 90%, but did not lower tissue Ang II. Captopril did not alter either 125I-Ang II accumulation or tissue Ang II. CONCLUSIONS: The bulk of Ang II in the kidney is cell-associated. The high tissue/blood concentration ratio of endogenous Ang II may depend on the same mechanism as demonstrated for 125I-Ang II, that is, AT1 receptor-mediated binding to cells and endocytosis. If so, the results indicate that most renal AT1 receptors are exposed to locally generated Ang II rather than Ang II from the circulation. We propose the existence of a low-Ang II vascular system-related interstitial compartment that is separate from tubular fluid, where, according to micropuncture studies, Ang II levels might be high.

"Edge Effect" of (32)p radioactive stents is caused by the combination of chronic stent injury and radioactive dose falloff.

BACKGROUND: Radioactive stents have been reported to reduce in-stent neointimal thickening. An unexpected increase in neointimal response was observed, however, at the stent-to-artery transitions, the so-called "edge effect." To investigate the factors involved in this edge effect, we studied stents with 1 radioactive half and 1 regular nonradioactive half, thereby creating a midstent radioactive dose-falloff zone next to a nonradioactive stent-artery transition at one side and a radioactive stent-artery transition at the other side. METHODS AND RESULTS: Half-radioactive stents (n=20) and nonradioactive control stents (n=10) were implanted in the coronary arteries of Yucatan micropigs. Animals received aspirin and clopidogrel as antithrombotics. After 4 weeks, a significant midstent stenosis was observed by angiography in the half-radioactive stents. Two animals died suddenly because of coronary occlusion at this mid zone at 8 and 10 weeks. At 12-week follow-up angiography, intravascular ultrasound and histomorphometry showed a significant neointimal thickening at the midstent dose-falloff zone of the half-radioactive stents, but not at the stent-to-artery transitions at both extremities. Such a midstent response (mean angiographic late loss 1.0 mm) was not observed in the nonradioactive stents (mean loss 0.4 to 0.6 mm; P< 0.01). CONCLUSIONS: The edge effect of high-dose radioactive stents in porcine coronary arteries is associated with the combination of stent injury and radioactive dose falloff.

Beneficial effects of the Ca2+ sensitizer EMD 57033 in exercising pigs with infarction-induced chronic left ventricular dysfunction.

1. It is unknown how cardiac stimulation by Ca(2+) sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the effects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca(2+)-sensitizer/phosphodiesterase-III inhibitor pimobendan. 2. Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n=12). Studies in MI were performed in the awake state, 2 - 3 weeks after infarction. 3. MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/dt(max) (18%), and a doubling of LV end-diastolic pressure, compared to normal pigs (N, n=13). 4. In 11 resting MI, intravenous EMD 57033 (0.2 - 0.8 mg kg(-1) min(-1)) increased LVdP/dt(max) (57+/-5%) and stroke volume (26+/-6%) with no effect on heart rate, LV filling pressure, and myocardial O(2)-consumption, similar to N. 5. In MI, the effects of EMD 57033 (0.4 mg kg(-1) min(-1), IV) on stroke volume and LVdP/dt(max) were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P<0.05). In contrast, the effects of EMD57033 gradually waned in N at increasing intensity of exercise. 6. Compared to N, the cardiostimulatory effects of pimobendan (20 microg kg(-1) min(-1), IV) were blunted in MI both at rest and during exercise compared to N. 7. In conclusion, the positive inotropic actions of the Ca(2+) sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca(2+)-sensitizer/phosphodiesterase-III inhibitor pimobendan are blunted.

Role of adenosine in ischemic preconditioning in rats depends critically on the duration of the stimulus and involves both A(1) and A(3) receptors.

OBJECTIVES: There is currently general agreement that adenosine is not involved in ischemic preconditioning (IP) in rat hearts. We hypothesized that the failure to show a role for adenosine is due to the use of brief preconditioning stimuli, and therefore investigated whether adenosine is involved when longer stimuli are employed and which receptor subtypes are involved. METHODS AND RESULTS: Infarct size (IS) was determined in anesthetized rats after 180 min of reperfusion (REP) following a 60-min coronary artery occlusion (CAO). IS was 69+/-2% (n=15) of the risk area in control rats and 45+/-2% (n=19; P<0.05) following IP by a single 15-min CAO. The non-selective adenosine receptor antagonist SPT, which itself had no effect on IS (74+/-1%), blunted the protection by IP (IS=57+/-2%, P<0.05) in a dose of 2 x 5 mg/kg i.v., and abolished the protection (IS=70+/-1%) at 2 x 25 mg/kg i.v. Following IP by three cycles of 3-min CAO and 3-min REP, IS was 24+/-6% (P<0.05), which was not affected by SPT in doses of 2 x 10 and 2 x 25 mg/kg i.v. The A(3) antagonist MRS-1191 (3.3 mg/kg, i.p.), which itself did not affect IS (70+/-2%), blunted the protection by IP with a 15-min CAO (IS=54+/-2%, P<0.05). When 2 x 5 mg/kg SPT (a dose selective for A(1)-receptors, as it did not affect the protection by the A(3) selective agonist IB-MECA, 51+/-3%) and MRS 1191 were combined the protection by IP was abolished (IS=67+/-2%). CONCLUSIONS: Involvement of adenosine in IP in rats depends critically on the duration of the stimulus. Thus, whereas adenosine was not involved when stimuli of 3-min duration were employed, activation of both A(1) and A(3) receptors contributed when a stimulus of 15 min was used.

Oxygen wastage of stunned myocardium in vivo is due to an increased oxygen cost of contractility and a decreased myofibrillar efficiency.

OBJECTIVE: We investigated whether an increased oxygen cost of contractility and/or a decreased myofibrillar efficiency contribute to oxygen wastage of stunned myocardium. Because Ca(2+)-sensitizers may increase myofibrillar Ca(2+)-sensitivity without increasing cross-bridge cycling, we also investigated whether EMD 60263 restores myofibrillar efficiency and/or the oxygen cost of contractility. METHODS: Regional fiber stress and strain were calculated from mesomyocardially implanted ultrasound crystals and left ventricular pressure in anesthetized pigs (n=18). Regional myocardial oxygen consumption (MVO(2)) was measured before contractility (end-systolic elastance, E(es)) and total myofibrillar work (stress-strain area, SSA) were determined from stress-strain relationships. Atrial pacing at three heart rates and two doses of dobutamine were used to vary SSA and E(es), respectively. After stunning (two times 10-min ischemia followed by 30-min reperfusion), measurements were repeated following infusion of saline (n=8) or EMD 60263 (1.5 mg.kg(-1) i.v., n=10). Linear regression was performed using: MVO(2)=alpha.SSA+beta.E(es)+gamma.HR(-1) (alpha(-1), myofibrillar efficiency; beta, oxygen cost of contractility; and gamma, basal metabolism/min). RESULTS: Stunning decreased SSA by 57% and E(es) by 64%, without affecting MVO(2), while increasing alpha by 71% and beta by 134%, without affecting gamma. From the wasted oxygen, 72% was used for myofibrillar work and 18% for excitation-contraction coupling. EMD 60263 restored both alpha and beta. CONCLUSIONS: Oxygen wastage in stunning is predominantly caused by a decreased myofibrillar efficiency and to a lesser extent by an increased oxygen cost of contractility. Considering that EMD 60263 reversed both causes of oxygen wastage, it is most likely that this drug increases myofibrillar Ca(2+)-sensitivity without increasing myofibrillar cross-bridge cycling.

Cardiac remodeling and contractile function in acid alpha-glucosidase knockout mice.

Pompe's disease is an autosomal recessive and often fatal condition, caused by mutations in the acid alpha-glucosidase gene, leading to lysosomal glycogen storage in heart and skeletal muscle. We investigated the cardiac phenotype of an acid alpha-glucosidase knockout (KO) mouse model. Left ventricular weight-to-body weight ratios were increased 6.3 +/- 0.8 mg/g in seven KO compared with 3.2 +/- 0.2 mg/g in eight wild-type (WT) mice (P < 0.05). Echocardiography under ketamine-xylazine anesthesia revealed an increased left ventricular (LV) wall thickness (2.17 +/- 0.16 in KO vs. 1.18 +/- 0.10 mm in WT mice, P < 0.05) and a decreased LV lumen diameter (2.50 +/- 0.32 in KO vs. 3.21 +/- 0.14 mm in WT mice, P < 0.05), but LV diameter shortening was not different between KO and WT mice. The maximum rate of rise of left ventricular pressure (LV dP/dt(max)) was lower in KO than in WT mice under basal conditions (2,720 +/- 580 vs. 4,440 +/- 440 mmHg/s) and during dobutamine infusion (6,220 +/- 800 vs. 8,730 +/- 790 mmHg/s, both P < 0.05). Similarly, during isoflurane anesthesia LV dP/dt(max) was lower in KO than in WT mice under basal conditions (5,400 +/- 670 vs. 8,250 +/- 710 mmHg/s) and during norepinephrine infusion (10,010 +/- 1,320 vs. 14,710 +/- 220 mmHg/s, both P < 0.05). In conclusion, the markedly increased LV weight and wall thickness, the encroachment of the LV lumen, and LV dysfunction reflect cardiac abnormalities, although not as overt as in humans, of human infantile Pompe's disease and make these mice a suitable model for further investigation of pathophysiology and of novel therapies of Pompe's disease.

Subcellular localization of angiotensin II in kidney and adrenal.

OBJECTIVES: To investigate whether tissue angiotensin II generation occurs intra- or extracellularly, we studied the subcellular localization of angiotensin II in kidney and adrenal, two organs with high endogenous angiotensin II concentrations. DESIGN AND METHODS: Tissues were obtained, following a 1 h infusion of 125I-angiotensin I or 125I-angiotensin II to simultaneously determine the localization of plasma-derived angiotensin II, from five control pigs and four pigs that had been pretreated with the AT1 receptor antagonist eprosartan. Subcellular organelles, prepared by differential centrifugation from homogenized tissue, were characterized using organelle-specific markers. RESULTS: 125I-angiotensin II and angiotensin II were present in all organelles, with identical distribution profiles. In mitochondria-enriched fractions the relative specific activities [RSAs = (concentration per mg protein in fraction)/(concentration per mg protein in homogenate)] of the two peptides were similar to those in homogenate, whereas in cytosol-enriched fractions their RSAs were five- to 10-fold lower (P< 0.05 versus homogenate). In microsome- as well as in lysosome-enriched fractions the RSAs of 125I-angiotensin II and angiotensin II were two- to four-fold higher than in homogenate (P < 0.05), and their RSAs were also higher in renal nuclei-enriched fractions (P< 0.05). Eprosartan increased plasma angiotensin II to a larger degree than tissue angiotensin II and greatly reduced tissue 125I-angiotensin II. This led to similar decreases in the tissue/plasma concentration ratios of 125I-angiotensin II and angiotensin II. The subcellular distribution of both angiotensin II peptides was not affected by eprosartan. CONCLUSIONS: Local angiotensin II synthesis in adrenal and kidney occurs predominantly extracellularly, and is followed by rapid AT1 receptor-mediated endocytosis, thereby leading to high intracellular angiotensin II levels.

Cardioprotection in pigs by exogenous norepinephrine but not by cerebral ischemia-induced release of endogenous norepinephrine.

BACKGROUND AND PURPOSE: Endogenous norepinephrine release induced by cerebral ischemia may lead to small areas of necrosis in normal hearts. Conversely, norepinephrine may be one of the mediators that limit myocardial infarct size by ischemic preconditioning. Because brief ischemia in kidneys or skeletal muscle limits infarct size produced by coronary artery occlusion, we investigated whether cardiac norepinephrine release during transient cerebral ischemia also elicits remote myocardial preconditioning. METHODS: Forty-one crossbred pigs of either sex were assigned to 1 of 7 experimental groups, of which in 6 groups myocardial infarct size was determined after a 60-minute coronary occlusion and 120 minutes of reperfusion. One group served as control (no pretreatment), while the other groups were pretreated with either cerebral ischemia or an intracoronary infusion of norepinephrine. RESULTS: In 10 anesthetized control pigs, infarct size was 84+/-3% (mean+/-SEM) of the area at risk after a 60-minute coronary occlusion and 120 minutes of reperfusion. Intracoronary infusion of 0.03 nmol/kg. min(-)(1) norepinephrine for 10 minutes before coronary occlusion did not affect infarct size (80+/-3%; n=6), whereas infusion of 0.12 nmol/kg. min(-)(1) limited infarct size (65+/-2%; n=7; P:<0.05). Neither 10-minute (n=5) nor 30-minute (n=6) cerebral ischemia produced by elevation of intracranial pressure before coronary occlusion affected infarct size (83+/-4% and 82+/-3%, respectively). Myocardial interstitial norepinephrine levels tripled during cerebral ischemia and during low-dose norepinephrine but increased 10-fold during high-dose norepinephrine. Norepinephrine levels increased progressively up to 500-fold in the area at risk during the 60-minute coronary occlusion, independent of the pretreatment, while norepinephrine levels remained unchanged in adjacent nonischemic myocardium and arterial plasma. CONCLUSIONS: Cerebral ischemia preceding a coronary occlusion did not modify infarct size, which is likely related to the modest increase in myocardial norepinephrine levels during cerebral ischemia. The infarct size limitation by high-dose exogenous norepinephrine is not associated with blunting of the ischemia-induced increase in myocardial interstitial norepinephrine levels.

Role of K(ATP)(+) channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine.

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

Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent cardiac remodeling in pigs after myocardial infarction: role of tissue angiotensin II.

BACKGROUND: The mechanisms behind the beneficial effects of renin-angiotensin system blockade after myocardial infarction (MI) are not fully elucidated but may include interference with tissue angiotensin II (Ang II). METHODS AND RESULTS: Forty-nine pigs underwent coronary artery ligation or sham operation and were studied up to 6 weeks. To determine coronary angiotensin I (Ang I) to Ang II conversion and to distinguish plasma-derived Ang II from locally synthesized Ang II, (125)I-labeled and endogenous Ang I and II were measured in plasma and in infarcted and noninfarcted left ventricle (LV) during (125)I-Ang I infusion. Ang II type 1 (AT(1)) receptor-mediated uptake of circulating (125)I-Ang II was increased at 1 and 3 weeks in noninfarcted LV, and this uptake was the main cause of the transient elevation in Ang II levels in the noninfarcted LV at 1 week. Ang II levels and AT(1) receptor-mediated uptake of circulating Ang II were reduced in the infarct area at all time points. Coronary Ang I to Ang II conversion was unaffected by MI. Captopril and the AT(1) receptor antagonist eprosartan attenuated postinfarct remodeling, although both drugs increased cardiac Ang II production. Captopril blocked coronary conversion by >80% and normalized Ang II uptake in the noninfarcted LV. Eprosartan did not affect coronary conversion and blocked cardiac Ang II uptake by >90%. CONCLUSIONS: Both circulating and locally generated Ang II contribute to remodeling after MI. The rise in tissue Ang II production during angiotensin-converting enzyme inhibition and AT(1) receptor blockade suggests that the antihypertrophic effects of these drugs result not only from diminished AT(1) receptor stimulation but also from increased stimulation of growth-inhibitory Ang II type 2 receptors.

In vivo evidence that EMD 57033 restores myocardial responsiveness to intracoronary Ca(2+) in stunned myocardium.

Despite ample in vitro evidence that myofilament Ca(2+)-responsiveness of stunned myocardium is decreased, in vivo data are inconclusive. Conversely, while Ca(2+)-sensitizing agents increase myofilament Ca(2+)-responsiveness in vitro, it has been questioned whether this also occurs in vivo. We therefore tested in open-chest anesthetized pigs whether EMD 57033 (the (+) enantiomer of 5-[1-(3,4-dimethoxybenzoyl)-1,2,3, 4-tetrahydro-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3, 4-thiadiazin-2-one) increases responsiveness to Ca(2+) of non-stunned myocardium and restores function of stunned myocardium by normalizing the responsiveness to Ca(2+). Studies were performed under beta-adrenoceptor blockade to minimize the contribution of the phosphodiesterase-III inhibitory actions of EMD 57033. Consecutive intracoronary Ca(2+) infusions were used to evaluate the contractile response (assessed by the left ventricular end-systolic elastance, E(es)) to added Ca(2+) of non-stunned myocardium and myocardium stunned by 15 min coronary artery occlusion and 30 min reperfusion. In non-stunned propranolol-treated myocardium, the Ca(2+) infusions doubled E(es) (baseline 6.9+/-0.9 mmHg mm(-2), n=8). Following Ca(2+)-washout, subsequent EMD 57033 infusion (0.1 mg kg(-1) min(-1), i.v.) tripled E(es) (P<0.05) and potentiated the Ca(2+)-induced increase in E(es) to 55.7+/-10.0 mmHg mm(-2) (P<0.05). Stunning (n=7) decreased E(es) to 5.3+/-0.6 mmHg mm(-2) (P>0.10) and attenuated the Ca(2+)-induced increase in E(es) (P<0.05). Subsequent infusion of EMD 57033 increased E(es) to 6.8+/-1.8 mmHg mm(-2) (P<0. 05) and restored responsiveness to added Ca(2+). These in vivo findings are consistent with the in vitro observations that myofilament Ca(2+)-responsiveness of stunned myocardium is reduced and that EMD 57033 increases contractility by enhancing myofilament Ca(2+)-responsiveness.

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.

Efficiency of energy transfer, but not external work, is maximized in stunned myocardium.

There is no evidence regarding the effect of stunning on maximization of regional myocardial external work (EW) or efficiency of energy transfer (EET) in relation to regional afterload (end-systolic stress, sigma(es)). To that end, we studied these relationships in both the left anterior descending coronary artery (LADCA) and left circumflex coronary artery regions in anesthetized, open-chest pigs before and after LADCA stunning. In normal myocardium, EET vs. sigma(es) was maximal at 75.4 (69.7-81.0)%, whereas EW vs. sigma(es) was submaximal at 12.0 (6.61-17.3) x 10(2) J/m(3). Increasing sigma(es) increased EW by 18 (10-27)%. Regional myocardial stunning decreased EET (27%) and EW (36%) and caused the myocardium to operate both at maximal EW (EW(max)) and at maximal EET (EET(max)). EET and EW became also more sensitive to changes in sigma(es). In the nonstunned region the situation remained unchanged. Combining the data from before and after stunning, both EW(max) and EET(max) displayed a positive relationship with contractility. In conclusion, the normal regional myocardium operated at maximal EET rather than at maximal EW. Therefore, additional EW could be recruited by increasing regional afterload. After myocardial stunning, the myocardium operated at both maximal EW and maximal EET, at the cost of increased afterload sensitivity. Contractility was a major determinant of this shift.

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.

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.

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.

Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries.

OBJECTIVE: To improve the biocompatibility of stents using a phosphorylcholine coated stent as a form of biomimicry. INTERVENTIONS: Implantation of phosphorylcholine coated (n = 20) and non-coated (n = 21) stents was performed in the coronary arteries of 25 pigs. The animals were killed after five days (n = 6), four weeks (n = 7), and 12 weeks (n = 8), and the vessels harvested for histology, scanning electron microscopy, and morphometry. MAIN OUTCOME MEASURES: Stent performance was assessed by studying early endothelialization, neointima formation, and vessel wall reaction to the synthetic coating. RESULTS: Stent thrombosis did not occur in either group. Morphometry showed no significant differences between the two study groups at any time point. At five days both the coated and non-coated stents were equally well endothelialised (91% v 92%, respectively). At four and 12 weeks there was no difference in intimal thickness between the coated and non-coated stents. Up to 12 weeks postimplant the phosphorylcholine coating was still discernible in the stent strut voids, and did not appear to elicit an adverse inflammatory response. CONCLUSION: In this animal model the phosphorylcholine coating showed excellent blood and tissue compatibility, unlike a number of other polymers tested in a similar setting. Given that the coating was present up to 12 weeks postimplant with no adverse tissue reaction, it may be a potential candidate polymer for local drug delivery.