Abstract-To date, no studies have investigated coronary vasomotor control of myocardial O 2 delivery (MDO 2 ) 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 O 2 consumption (MV O 2 ) from 163Ϯ16 mol/min (meanϮSE) at rest to 423Ϯ75 mol/min (PՅ0.05), which was paralleled by an increase in MDO 2 , so that myocardial O 2 extraction (79Ϯ1% at rest) and coronary venous O 2 tension (cvPO 2 , 23.7Ϯ1.0 mm Hg at rest) were maintained. ␤-Adrenoceptor blockade blunted the exercise-induced increase of MDO 2 out of proportion compared with the attenuation of the exercise-induced increase in MV O 2 , so that O 2 extraction rose from 78Ϯ1% at rest to 83Ϯ1% during exercise and cvPO 2 fell from 23.5Ϯ0.9 to 19.6Ϯ1.1 mm Hg (both PՅ0.05). In contrast, ␣-adrenoceptor blockade, either in the absence or presence of ␤-adrenoceptor blockade, had no effect on myocardial O 2 extraction or cvPO 2 at rest or during exercise. Muscarinic receptor blockade resulted in a decreased O 2 extraction and an increase in cvPO 2 at rest, an effect that waned during exercise. The vasodilation produced by muscarinic receptor blockade was likely due to an increased ␤-adrenoceptor activity, since combined muscarinic and ␤-adrenoceptor blockade produced similar changes in O 2 extraction and cvPO 2 , as did ␤-adrenoceptor blockade alone. In conclusion, in swine myocardium, MV O 2 and MDO 2 are matched during exercise, which is the result of feed-forward ␤-adrenergic vasodilation in conjunction with minimal ␣-adrenergic vasoconstriction. ␤-Adrenergic vasodilation is due to an increase in sympathetic activity but may also be supported by withdrawal of muscarinic receptor-mediated inhibition of ␤-adrenergic coronary vasodilation. The observation that cvPO 2 levels are maintained even during heavy exercise suggests that a decrease in cvPO 2 is not essential for coronary vasodilation during exercise. (Circ Res. 1998;82:1312-1322.)

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.

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.

.-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 O 2 consumption increased from 167 Ϯ 18 µmol/min at rest to 399 Ϯ 27 µmol/min at 5 km/h (P Յ 0.05), which was paralleled by an increase in O 2 delivery, so that myocardial O 2 extraction (76 Ϯ 1 and 78 Ϯ 1% at rest and 5 km/h, respectively) and coronary venous PO 2 (24.5 Ϯ 1.0 and 22.8 Ϯ 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 O 2 consumption and coronary vascular resistance was shifted toward higher resistance, whereas myocardial O 2 extraction rose to 81 Ϯ 1 and 83 Ϯ 1% at rest and 5 km/h and coronary venous PO 2 fell to 19.2 Ϯ 0.8 and 18.9 Ϯ 0.8 mmHg at rest and 5 km/h, respectively (all P Յ 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. coronary circulation; myocardial oxygen extraction; myocardial oxygen consumption; pulmonary circulation; systemic circulation THE NORMAL HEART IS characterized by a high myocardial O 2 extraction (MĖ O 2 ), requiring a tight coupling of coronary blood flow to changing metabolic needs (16,26). The close coupling of coronary blood flow and myocardial O 2 demand has been proposed to depend primarily on messengers released from the myocardium, such as adenosine (4, 30). Although adenosine has been shown to contribute to coronary vasodilation in isolated rodent hearts, a pivotal role for adenosine in the regulation of coronary blood flow in the large mammalian in situ heart is still controversial. Thus neither increased adenosine catabolism with adenosine deaminase nor adenosine receptor blockade with the adenosine A 1 /A 2 -receptor blocker 8-phenyltheophylline (8-PT) altered resting coronary blood flow in anesthetized or awake dogs (2,22,24,33). In addition, during treadmill exercise, coronary blood flow and resistance, as well as myocardial O 2 consumption (MV O 2 ) and MĖ O 2 , were not altered by adenosine receptor blockade or adenosine deaminase (2), suggesting that adenosine is not mandatory for the regulation of coronary blood flow in the dog heart at rest or during exercise. In contrast, several studies have reported that adenosine receptor blockade produced by theophylline increased coronary vascular resistance and MĖ O 2 and decreased coronary blood flow and coronary venous PO2 (Pcv O 2 ) in the human heart under basal conditions (11-13), whereas only one study reported no change in resting coronary blood flow after adenosine receptor blockade with aminophylline (32). Also, in closed-chest sedated swine, adenosine deaminase produced a small increase in coronary vasomotor tone under basal conditions (17) while markedly blunting the...

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.