Stubenitsky, R.

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

2001-01-01T00:00:00Z

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

2001-01-01T00:00:00Z

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.

Cardiac remodeling and contractile function in acid alpha-glucosidase knockout mice (Article)

2001-01-01T00:00:00Z

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.

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

2000-01-01T00:00:00Z

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.

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

1998-01-01T00:00:00Z

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.

Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise (Article)

1998-01-01T00:00:00Z

A pivotal role for adenosine in the regulation of coronary blood flow is still controversial. Consequently, we investigated its role in the regulation of coronary vasomotor tone in swine at rest and during graded treadmill exercise. During exercise, myocardial O2 consumption increased from 167 +/- 18 micromol/min at rest to 399 +/- 27 micromol/min at 5 km/h (P

Contribution of asynchrony and nonuniformity to mechanical interaction in normal and stunned myocardium (Article)

1997-01-01T00:00:00Z

In anesthetized pigs, we investigated whether asynchrony (delta T) and nonuniformity (regional differences) in contractility (delta E) could describe the interaction between normal and stunned myocardium. Mechanical interaction was evaluated by regional postsystolic work (PSW) before and after production of stunning by a 5-min occlusion of the left circumflex coronary artery [LCX (LCX stunning)] and a subsequent 10-min occlusion of the left anterior descending coronary artery [LAD (LAD stunning)]. delta T and delta E were intensified by intracoronary (LAD) infusions of dobutamine. From regional end-systolic pressure-segment length relationships, systolic segment shortening (SS), end-systolic elastance (E), external work (EW), and PSW were determined. LCX stunning decreased SSLCX from 14 +/- 2 (mean +/- SE, n = 9) to 10 +/- 2% and ELCX from 103 +/- 25 to 52 +/- 7 mmHg/mm, whereas the LAD region was unaffected. EWLCX decreased from 165 +/- 16 to 138 +/- 20 mmHg.mm, whereas PSWLCX increased from -4 +/- 6 to 8 +/- 3 mmHg.mm. Additional LAD stunning reduced SSLAD from 16 +/- 2 to 9 +/- 3% and ELAD from 79 +/- 10 to 31 +/- 6 mmHg/mm, without affecting SSLCX and ELCX. In the normal myocardium, PSWLAD increased and PSWLCX decreased, but, during local LAD dobutamine infusions after stunning, both PSWLCX and PSWLAD increased. In normal myocardium, the changes in PSWLCX could be described by delta T (65 +/- 11%) and delta E (37 +/- 15%). After stunning of the LAD area, the contribution of delta E increased to 55 +/- 14% at the expense of delta T (37 +/- 15%). Similar contributions of delta E (54 +/- 13%) and delta T (57 +/- 13%) were found when both the LCX and LAD distribution areas were stunned. In normal myocardium, both delta T and delta E modulate mechanical interaction, with the contribution of delta T exceeding that of delta E. In stunned myocardium, both factors contribute, but the contribution shifts in favor of delta E.