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

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 </= 0.05), which was paralleled by an increase in O2 delivery, so that myocardial O2 extraction (76 +/- 1 and 78 +/- 1% at rest and 5 km/h, respectively) and coronary venous PO2 (24.5 +/- 1.0 and 22.8 +/- 0.3 mmHg at rest and 5 km/h, respectively) remained unchanged. After adenosine receptor blockade with 8-phenyltheophylline (5 mg/kg iv), the relation between myocardial O2 consumption and coronary vascular resistance was shifted toward higher resistance, whereas myocardial O2 extraction rose to 81 +/- 1 and 83 +/- 1% at rest and 5 km/h and coronary venous PO2 fell to 19.2 +/- 0.8 and 18.9 +/- 0.8 mmHg at rest and 5 km/h, respectively (all P </= 0.05). Thus, although adenosine is not mandatory for the exercise-induced coronary vasodilation, it exerts a vasodilator influence on the coronary resistance vessels in swine at rest and during exercise

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 rat

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

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

Cardiovascular effects of the novel Ca2+-sensitiser EMD 57033 in pigs at rest and during treadmill exercise.

1. To date no study has described the cardiovascular effects of increased myofilament Ca(2+) responsiveness in awake animals both under resting conditions and during treadmill exercise. In the present study we therefore investigated the systemic, pulmonary and coronary haemodynamic actions of the Ca(2+) sensitizer EMD 57033 in 16 chronically instrumented awake pigs at rest and during treadmill exercise, and compared these to the haemodynamic actions of the Ca(2+) sensitizer/phosphodiesterase inhibitor pimobendan. 2. Under resting conditions EMD 57033 (0.2, 0.4 and 0.8 mg kg(−1) min(−1), i.v.) produced dose-dependent increases in LVdP/dt(max) (up to 65±17% (mean ±s.e.mean), P⩽0.05) and stroke volume (up to 20±3%, P⩽0.05), with an increase in heart rate only after the highest dose (22±5%, P⩽0.05), while mean aortic blood pressure and LVdP/dt(min) were not altered. EMD 57033 had also no effect on pulmonary vascular resistance, but produced dose-dependent decreases in systemic vascular resistance (32±4%, P⩽0.05), and coronary vascular resistance (44±2%, P⩽0.05). These effects were essentially unchanged when animals were pretreated with non-selective β-adrenoceptor blockade, indicating that phosphodiesterase inhibition did not contribute to the positive inotropic actions of EMD 57033. 3. During exercise at 2, 3, and 4 km h(−1), the positive inotropic actions of EMD 57033 gradually waned at higher levels of exercise. This may have been caused by the exercise-induced increase in β-adrenergic activity, because after pretreatment with propranolol the positive inotropic actions of EMD 57033 were preserved at all levels of exercise. In contrast, the positive inotropic and chronotropic effects of pimobendan were amplified during exercise, but were abolished (at rest) or markedly attenuated (during exercise) after pretreatment with propranolol. 4. The responses to EMD 57033 during exercise after combined α- and β-adrenergic receptor blockade were not different from those after β-adrenergic receptor blockade alone, indicating that the positive inotropic actions of EMD 57033 were not mediated via or did not depend on intact α-adrenergic receptor activity. 5. In conclusion, EMD 57033 increases left ventricular myocardial contractility in awake pigs. During exercise this effect is partially offset by the increased β-adrenergic activity, with no effect of α-adrenergic activity, suggesting that EMD 57033 may be most effective in patients with severe loss of β-adrenergic responsiveness