Mechanisms of oxygen demand/supply balance in the right ventricle

Few studies have investigated factors responsible for the O2 demand/supply balance in the right ventricle. Resting right coronary blood flow is lower than left coronary blood flow, which is consistent with the lesser work of the right ventricle. Because right and left coronary artery perfusion pressures are identical, right coronary conductance is less than left coronary conductance, but the signal relating this conductance to the lower right ventricular O2 demand has not been defined. At rest, the left ventricle extracts approximately 75% of the O2 delivered by coronary blood flow, whereas right ventricular O2 extraction is only ~50%. As a result, resting right coronary venous PO2 is approximately 30 mm Hg, whereas left coronary venous PO2 is approximately 20 mm Hg. Right coronary conductance does not sufficiently restrict flow to force the right ventricle to extract the same percentage of O2 as the left ventricle. Endogenous nitric oxide impacts the right ventricular O2 demand/supply balance by increasing the right coronary blood flow at rest and during acute pulmonary hypertension, systemic hypoxia, norepinephrine infusion, and coronary hypoperfusion. The substantial right ventricular O2 extraction reserve is used preferentially during exercise-induced increases in right ventricular myocardial O2 consumption. An augmented, sympathetic-mediated vasoconstrictor tone blunts metabolically mediated dilator mechanisms during exercise and forces the right ventricle to mobilize its O2 extraction reserve, but this tone does not limit resting right coronary flow. During exercise, right coronary vasodilation does not occur until right coronary venous PO2 decreases to approximately 20 mm Hg. The mechanism responsible for right coronary vasodilation at low PO2 has not been delineated. In the poorly autoregulating right coronary circulation, reduced coronary pressure unloads the coronary hydraulic skeleton and reduces right ventricular systolic stiffness. Thus, normal right ventricular external work and O2 demand/supply balance can be maintained during moderate coronary hypoperfusion.     

Role of beta 2-adrenergic receptors on coronary resistance during exercise

The effects of regional alpha- and specific beta 2-adrenergic receptor blockade on measurements of late diastolic coronary resistance (LDCR) and mean coronary blood flow velocity (CBFV) during exercise were examined in 14 conscious adult mongrel dogs. Specific beta 2-adrenergic receptor blockade (ICI 118.551) significantly decreased CBFV and increased LDCR by blockade of beta 2-vasodilator tone independent of alpha-adrenergic receptor-mediated tone and independent of altering myocardial metabolism. alpha-Adrenergic receptor blockade (phentolamine, 1 mg) significantly increased CBFV and decreased LDCR by blocking sympathetically mediated vasoconstrictor tone. There was no significant difference in the magnitude of response between alpha- and beta 2-adrenergic receptor blockade. These results demonstrate that alpha- and beta 2-adrenergic receptors have a significant and evidently equal influence on CBFV and LDCR during exercise. Four weeks of daily exercise and left stellate ganglionectomy (LSGx) prevented phentolamine-induced vasodilation but not ICI 118.551-induced vasoconstriction. This suggests that daily exercise and LSGx significantly decreased the alpha-adrenergic receptor-mediated vasoconstrictor tone on the coronary circulation, resulting in an apparently greater role for the coronary vascular beta 2-adrenergic receptor on the control of CBFV and LDCR during exercise.     

Nitric oxide contributes to right coronary vasodilation during systemic hypoxia

As arterial partial pressure of O(2) (Pa(O(2))) is reduced during systemic hypoxia, right ventricular (RV) work and myocardial O(2) consumption (MVo(2)) increase. Mechanisms responsible for maintaining RV O(2) demand/supply balance during hypoxia have not been delineated. To address this problem, right coronary (RC) blood flow and RV O(2) extraction were measured in nine conscious, instrumented dogs exposed to normobaric hypoxia. Catheters were implanted in the right ventricle for measuring pressure, in the ascending aorta for measuring arterial pressure and for sampling arterial blood, and in an RC vein. A flow transducer was placed around the RC artery. After recovery from surgery, dogs were exposed to hypoxia in a chamber ventilated with N(2), and blood samples and hemodynamic data were collected as chamber O(2) was reduced progressively to approximately 8%. After control measurements were made, the chamber was opened and the dog was allowed to recover. N(omega)-nitro-L-arginine (L-NNA) was then administered (35 mg/kg, via RV catheter) to inhibit nitric oxide (NO) production, and the hypoxia protocol was repeated. RC blood flow increased during hypoxia due to coronary vasodilation, because RC conductance increased from 0.65 +/- 0.05 to 1.32 +/- 0.12 ml x min(-1) x 100 g(-1) x L-NNA blunted the hypoxia-induced increase in RC conductance. RV O(2) extraction remained constant at 64 +/- 4% as Pa(O(2)) was decreased, but after L-NNA, extraction increased to 70 +/- 3% during normoxia and then to 78 +/- 3% during hypoxia. RV MVo(2) increased during hypoxia, but after L-NNA, MVo(2) was lower at any respective Pa(O(2)). The relationship between heart rate times RV systolic pressure (rate-pressure product) and RV MVo(2) was not altered by l-NNA. To account for L-NNA-mediated decreases in RV MVo(2), O(2) demand/supply variables were plotted as functions of MVo(2). Slope of the conductance-MVo(2) relationship was depressed by L-NNA (P = 0.03), whereas the slope of the extraction-MVo(2) relationship increased (P = 0.003). In summary, increases in RV MVo(2) during hypoxia are met normally by increasing RC blood flow. When NO synthesis is blocked, the large RV O(2) extraction reserve is mobilized to maintain RV O(2) demand/supply balance. We conclude that NO contributes to RC vasodilation during systemic hypoxia.     

Influence of dual ET(A)/ET(B)-receptor blockade on coronary responses to treadmill exercise in dogs.

We hypothesized that endothelin (ET) release during exercise may be triggered by alpha-adrenergic-receptor activation and thereby influence coronary hemodynamics and O(2) metabolism in dogs. Exercise resulted in coronary blood flow increases (to 1.88+/-0.26 from 1.10+/- 0.12 ml x min(-1) x g(-1)) and in a fall (P<0.01) in coronary sinus O(2) saturation (17.4+/-1.5 to 9.6+/-0.7 vol%), whereas myocardial O(2) consumption (MVO(2)) increased (109+/-13% from 145+/-16 microl O(2) min(-1) x g(-1)). Tezosentan, a dual ET(A)/ET(B)-receptor blocker, slightly reduced mean arterial pressure (MAP) and increased heart rate throughout exercise. The relationship between coronary sinus O(2) saturation and MVO(2) was shifted upward (P<0.05) after tezosentan administration; i.e., as MVO(2) increased during exercise, coronary sinus O(2) saturation was disproportionately higher after ET-receptor blockade. After propranolol, tezosentan resulted in significant decreases (P<0.05) in left ventricular pressure, the first derivative of left ventricular pressure over time, and MAP during exercise. As MVO(2) increased during exercise, coronary sinus O(2) saturation levels after tezosentan became superimposable over those observed before ET-receptor blockade. Thus dual blockade of ET(A)/ET(B) receptors alters coronary hemodynamics and O(2) metabolism during exercise, but ET activity failed to increase beyond baseline levels.     

Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure

Coronary blood flow (CBF) and myocardial oxygen consumption (MVO(2)) are reduced in dogs with pacing-induced congestive heart failure (CHF), which suggests that energy metabolism is downregulated. Because nitric oxide (NO) can inhibit mitochondrial respiration, we examined the effects of NO inhibition on CBF and MVO(2) in dogs with CHF. CBF and MVO(2) were measured at rest and during treadmill exercise in 10 dogs with CHF produced by rapid ventricular pacing before and after inhibition of NO production with N(G)-nitro-L-arginine (L-NNA, 10 mg/kg iv). The development of CHF was accompanied by decreases in aortic and left ventricular (LV) systolic pressure and an increase in LV end-diastolic pressure (25 +/- 2 mmHg). L-NNA increased MVO(2) at rest (from 3.07 +/- 0.61 to 4.15 +/- 0.80 ml/min) and during exercise; this was accompanied by an increase in CBF at rest (from 31 +/- 2 to 40 +/- 4 ml/min) and during exercise (both P < 0.05). Although L-NNA significantly increased LV systolic pressure, similar increases in pressure produced by phenylephrine did not increase MVO(2). The findings suggest that NO exerts tonic inhibition on respiration in the failing heart.     

Function of mature coronary collateral vessels and cardiac performance in the exercising dog

Formation of extensive collateral vessels after chronic constriction of a coronary artery in dogs can provide for similar increases in blood flow to native and collateralized regions of myocardium during exertion. Previous investigations have not compared myocardial blood flow and cardiac functional responses during exercise in constricted and nonconstricted (sham) animals. Thus we evaluated left ventricular performance and myocardial blood flow at rest and during mild, moderate, and severe exertion in sham-operated dogs and in dogs 2-3 mo after placement of an Ameroid occluder around the proximal left circumflex artery. Changes in double product, maximal left ventricular dP/dt, and pressure-work index were similar in both groups for each level of exertion. Despite similar increases in estimated myocardial O2 demand and similar diastolic perfusion pressures, average transmural myocardial blood flow increased less in the constrictor animals, particularly during severe exercise (2.74 +/- 0.22 vs. 1.45 +/- 0.29 ml X min-1 X g-1). The smaller increases in blood flow occurred equally in native and collateralized regions as well as in the papillary muscles and boundary areas between the native and collateralized regions. The differences in flow in the native and collateralized regions were uniform across the wall of the myocardium. We also observed smaller increases in stroke volume and cardiac output in the constrictor group, disparities which increased with increasing exertion (stroke volume, severe exercise = 0.92 +/- 0.13 vs. 0.53 +/- 0.09 ml/kg). We postulate that myocardial active hyperemia is limited either because the coronary vessels remaining after chronic circumflex occlusion cannot dilate sufficiently or that there is inappropriate active vasoconstriction during severe exertion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alpha-adrenergic tone in the coronary circulation of the conscious dog

To examine the role of neural factors in the control of coronary vasoactivity in conscious animals, dogs were supplied with miniature pressure gauges in the aorta and left ventricle (to measure aortic and left ventricular pressures, respectively and with a flow probe on the left circumflex coronary artery (to measure coronary blood flow). The experiments were conducted several weeks after recovery from operation. Stimulation of the carotid chemoreceptor and pulmonary inflation elicited a biphasic reflex response. Initially, coronary vasodilation was observed; coronary blood flow tripled even after changes in metabolic factors were minimized by pretreatment with propranolol. A similar response occurred after a spontaneous deep breath. The coronary vasodilation could be blocked by alpha-adrenergic receptor blockade. The second phase of the response involved an increase in coronary vascular resistance, associated with elevated arterial pressure and an absolute reduction in coronary blood flow and coronary sinus oxygen content. The secondary coronary vasoconstriction was also abolished by alpha-adrenergic blockade. Paradoxically, alpha-adrenergic receptor blockade with phentolamine (at constant heart rate and after beta-adrenergic receptor blockade) did not increase coronary blood flow and reduced coronary vascular resistance only slightly. Selective alpha 1-adrenergic receptor blockade with prazosin and trimazosin on different days induced progressively greater reductions in coronary vascular resistance. Trimazosin was the only alpha-adrenergic receptor blocker to elevate coronary blood flow significantly. It is conceivable, but speculative, that withdrawal of alpha-adrenergic tone may involve activation of an intermediate agent, which is a potent coronary vasodilator. Alternatively, withdrawal of alpha-adrenergic tone may be an important mechanism for immediate control of the coronary circulation, but under more chronic conditions it plays a lesser role as a result of suppression by metabolic factors.     

Evidence against significant resting alpha-adrenergic coronary vasoconstrictor tone

The importance of sympathetically mediated coronary vasoconstrictor tone as a determinant of resting coronary blood flow was assessed in the conscious dog by comparing blood flow and oxygen extraction in a normally innervated (I) and a previously sympathectomized (Sx) region of the same left ventricle. The regional ventricular sympathectomy was achieved by the topical application of phenol. The animals were well acclimated to the laboratory environment before regional myocardial blood flow was measured with microspheres or regional myocardial oxygen extraction was determined on blood sampled from chronically implanted coronary venous catheters. Results indicated that blood flow and oxygen extraction were not significantly different in I and Sx regions under these conditions. Regional blood flow data obtained after beta-adrenergic blockade or combined alpha- and beta-adrenergic blockade were not significantly different from control data. Thus we were unable to confirm previous evidence in the literature of significant resting sympathetic coronary vasoconstrictor tone in the conscious animal.     

Volumetric responses of right and left ventricles during upright exercise in normal subjects

We evaluated the volumetric responses of the right and left ventricles to upright exercise using two noninvasive methods, first-pass radionuclide angiocardiography and the CO2 rebreathing technique, in nine normal subjects. Right (RV) and left (LV) ventricular ejection fractions, heart rate, and cardiac index were determined at rest and during steady-state exercise on the bicycle ergometer at 50% of maximal O2 consumption. From these data, stroke volume index (SVI), end-diastolic volume index (EDVI), and end-systolic volume index (ESVI) were derived. SVI increased from 40 +/- 7 ml/m2 at rest to 59 +/- 13 ml/m2 with exercise (P less than 0.001). RVEDVI increased significantly from 82 +/- 16 ml/m2 at rest to 95 +/- 21 ml/m2 during exercise (P = 0.008), while there was no significant change in RVESVI with exercise. Changes in LVEDVI and LVESVI during upright exercise were similar to the right ventricle. The increase in systolic blood pressure during exercise, along with no change in LVESVI, indicated enhanced ventricular contractility. The normal augmentation in SVI during submaximal exercise was due to both the Frank-Starling mechanism and an increased contractile state. Application of these or similar techniques may be useful in evaluating ventricular performance in patients with cardiorespiratory dysfunction.     

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.     

Hemodynamic responses to heat stress in the resting and exercising human leg: insight into the effect of temperature on skeletal muscle blood flow

Heat stress increases limb blood flow and cardiac output (Q) in humans, presumably in sole response to an augmented thermoregulatory demand of the skin circulation. Here we tested the hypothesis that local hyperthermia also increases skeletal muscle blood flow at rest and during exercise. Hemodynamics, blood and tissue oxygenation, and muscle, skin, and core temperatures were measured at rest and during exercise in 11 males across four conditions of progressive whole body heat stress and at rest during isolated leg heat stress. During whole body heat stress, leg blood flow (LBF), Q, and leg (LVC) and systemic vascular conductance increased gradually with elevations in muscle temperature both at rest and during exercise (r(2) = 0.86-0.99; P < 0.05). Enhanced LBF and LVC were accompanied by reductions in leg arteriovenous oxygen (a-vO(2)) difference and increases in deep femoral venous O(2) content and quadriceps tissue oxygenation, reflecting elevations in muscle and skin perfusion. The increase in LVC occurred despite an augmented plasma norepinephrine (P < 0.05) and was associated with elevations in muscle temperature (r(2) = 0.85; P = 0.001) and arterial plasma ATP (r(2) = 0.87; P < 0.001). Isolated leg heat stress accounted for one-half of the increase in LBF with severe whole body heat stress. Our findings suggest that local hyperthermia also induces vasodilatation of the skeletal muscle microvasculature, thereby contributing to heat stress and exercise hyperemia. The increased limb muscle vasodilatation in these conditions of elevated muscle sympathetic vasoconstrictor activity is closely related to the rise in arterial plasma ATP and local tissue temperature.     

Effect of noradrenaline on reactive myocardial hyperemia in dogs

The effect of norepinephrine (NE) on reactive myocardial hyperemia (RH) after a brief (20 sec) flow arrest was studied in 9 closed-chest anesthetized dogs. NE infusion into the left ventricle resulted in the increase of RH peak during coronary flow and the elevation of the left ventricular pressure and its first derivative. The increased coronary dilatation may be explained by the activation of beta 1-adrenergic myocardial receptors. RH peak decreased later, with the coronary flow, left ventricular pressure and its first derivative returning to the control level. This RH decrease can be explained by the activation of alpha-adrenergic receptors of the coronary vessels and the competition between alpha-receptors for vasoconstriction and metabolic vasodilatation.     

O2 extraction of right and left ventricles.

O2 extraction was measured simultaneously in right and left ventricles of dogs. Extraction was about 2.5 vol% higher in left ventricle. This figure, together with flow measurements of others (1-3), indicates that VO2/100g is at least twice as great in left ventricle as in right.     

Cardiovascular effects of the respiratory muscle metaboreflexes in dogs: rest and exercise.

In awake dogs, lactic acid was injected into the phrenic and deep circumflex iliac arteries to elicit the diaphragm and abdominal muscle metaboreflexes, respectively. At rest, injections into the phrenic or deep circumflex iliac arteries significantly increased mean arterial blood pressure 21 +/- 7% and reduced cardiac output 6 +/- 2% and blood flow to the hindlimbs 20 +/- 9%. Simultaneously, total systemic, hindlimb, and abdominal expiratory muscle vascular conductances were reduced. These cardiovascular responses were not accompanied by significant changes in the amplitude or timing of the diaphragm electromyogram. During treadmill exercise that increased cardiac output, hindlimb blood flow, and vascular conductance 159 +/- 106, 276 +/- 309, and 299 +/- 90% above resting values, lactic acid injected into the phrenic or deep circumflex iliac arteries also elicited pressor responses and reduced hindlimb blood flow and vascular conductance. Adrenergic receptor blockade at rest eliminated the cardiovascular effects of the respiratory muscle metaboreflex. We conclude that the cardiovascular effects of respiratory muscle metaboreflex activation are similar to those previously reported for limb muscles. When activated via metabolite production, the respiratory muscle metaboreflex may contribute to the increased sympathetic tone and redistribution of blood flow during exercise.     

Sympathetic restraint of muscle blood flow at the onset of dynamic exercise.

Little attention has focused on sympathetic influences on skeletal muscle blood flow at the onset of exercise. We hypothesized that 1) the sympathetic nervous system constrains muscle blood flow and 2) the decline from peak blood flow is mediated by increasing sympathetic vasoconstrictor tone. Mongrel dogs (n = 7) ran on a treadmill after intra-arterial infusion of saline (control) or combined alpha(1)- and alpha(2)-adrenergic blockade (prazosin and rauwolscine). Immediate and rapid increases in hindlimb blood flow occurred at commencement of exercise with peak iliac blood flows averaging 933 +/- 79 and 1,227 +/- 90 ml/min during control and blockade conditions, respectively. At 1 min of exercise, hindlimb blood flow had decreased to 629 +/- 54 and 1,057 +/- 89 ml/min. In the absence of sympathetic vasoconstrictor tone, there was an enhanced peak blood flow at the onset of exercise. In addition, alpha-blockade attenuated the overshoot of hindlimb blood flow compared with the control condition. These data suggest that an immediate and sustained increase in sympathetic outflow restrains hindlimb blood flow at the onset of exercise and is responsible, at least in part, for an overshoot of blood flow to exercising skeletal muscle.     

KCa+ channels contribute to exercise-induced coronary vasodilation in swine

Coronary blood flow is controlled via several vasoactive mediators that exert their effect on coronary resistance vessel tone through activation of K(+) channels in vascular smooth muscle. Because Ca(2+)-activated K(+) (K(Ca)(+)) channels are the predominant K(+) channels in the coronary vasculature, we hypothesized that K(Ca)(+) channel activation contributes to exercise-induced coronary vasodilation. In view of previous observations that ATP-sensitive K(+) (K(ATP)(+)) channels contribute, in particular, to resting coronary resistance vessel tone, we additionally investigated the integrated control of coronary tone by K(Ca)(+) and K(ATP)(+) channels. For this purpose, the effect of K(Ca)(+) blockade with tetraethylammonium (TEA, 20 mg/kg iv) on coronary vasomotor tone was assessed in the absence and presence of K(ATP)(+) channel blockade with glibenclamide (3 mg/kg iv) in chronically instrumented swine at rest and during treadmill exercise. During exercise, myocardial O(2) delivery increased commensurately with the increase in myocardial O(2) consumption, so that myocardial O(2) extraction and coronary venous Po(2) (Pcv(O(2))) were maintained constant. TEA (in a dose that had no effect on K(ATP)(+) channels) had a small effect on the myocardial O(2) balance at rest and blunted the exercise-induced increase in myocardial O(2) delivery, resulting in a progressive decrease of Pcv(O(2)) with increasing exercise intensity. Conversely, at rest glibenclamide caused a marked decrease in Pcv(O(2)) that waned at higher exercise levels. Combined K(Ca)(+) and K(ATP)(+) channel blockade resulted in coronary vasoconstriction at rest that was similar to that caused by glibenclamide alone and that was maintained during exercise, suggesting that K(Ca)(+) and K(ATP)(+) channels act in a linear additive fashion. In conclusion, K(Ca)(+) channel activation contributes to the metabolic coronary vasodilation that occurs during exercise. Furthermore, in swine K(Ca)(+) and K(ATP)(+) channels contribute to coronary resistance vessel control in a linear additive fashion.     

Exercise hyperemia and vasoconstrictor responses in humans with cystic fibrosis.

ATP released from circulating erythrocytes is a potential signal regulating muscle blood flow during exercise (exercise hyperemia), and intravascular ATP appears to blunt sympathetic vasoconstriction during exercise. Erythrocytes from patients with cystic fibrosis (CF) do not release ATP. The goal of the present study was to determine whether increases in forearm blood flow during exercise are blunted in CF patients and whether CF patients exhibit greater vasoconstrictor responsiveness during exercise. Nine control subjects and 10 CF patients who were free of other disease complications (approximately 96% O2 saturation) performed incremental rhythmic forearm exercise at 5, 10, and 15% of maximum handgrip strength for 21 min (7 min at each workload). We used a cold pressor test to evoke sympathetic vasoconstriction under resting conditions and at each exercise workload. As a control, subjects performed a second exercise bout without the cold pressor test. Continuous brachial artery blood velocity was monitored beat-to-beat, and vessel diameter was assessed by Doppler ultrasound. Artery diameter, as well as blood pressure, heart rate, and O2 saturation, was measured at steady-state exercise and at 1 min into the cold pressor stimulus. Blood pressure and heart rate responses to the forearm exercise and each cold pressor test were similar in both groups (P > 0.05). Contrary to our hypothesis, forearm blood flow (P = 0.91) and forearm vascular conductance (P = 0.82) were similar at rest and at each level of exercise between CF patients and controls. Additionally, there was no difference in the degree of sympathetic vasoconstriction between groups at rest and at each level of exercise (P = 0.22). Our results suggest that ATP released from the deformation of erythrocytes is not an obligatory signal for exercise hyperemia in human skeletal muscle.     

Adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise

The purpose of this investigation was to quantitatively evaluate the role of adenosine in coronary exercise hyperemia. Dogs (n = 10) were chronically instrumented with catheters in the aorta and coronary sinus, and a flow probe on the circumflex coronary artery. Cardiac interstitial adenosine concentration was estimated from arterial and coronary venous plasma concentrations using a previously tested mathematical model. Coronary blood flow, myocardial oxygen consumption, heart rate, and aortic pressure were measured at rest and during graded treadmill exercise with and without adenosine receptor blockade with either 8-phenyltheophylline (8-PT) or 8-p-sulfophenyltheophylline (8-PST). In control vehicle dogs, exercise increased myocardial oxygen consumption 4.2-fold, coronary blood flow 3.8-fold, and heart rate 2.5-fold, whereas mean aortic pressure was unchanged. Coronary venous plasma adenosine concentration was little changed with exercise, and the estimated interstitial adenosine concentration remained well below the threshold for coronary vasodilation. Adenosine receptor blockade did not significantly alter myocardial oxygen consumption or coronary blood flow at rest or during exercise. Coronary venous and estimated interstitial adenosine concentration did not increase to overcome the receptor blockade with either 8-PT or 8-PST as would be predicted if adenosine were part of a high-gain, negative-feedback, local metabolic control mechanism. These results demonstrate that adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise.     

Effects of ATP-induced leg vasodilation on VO2 peak and leg O2 extraction during maximal exercise in humans

During maximal whole body exercise VO2 peak is limited by O2 delivery. In turn, it is though that blood flow at near-maximal exercise must be restrained by the sympathetic nervous system to maintain mean arterial pressure. To determine whether enhancing vasodilation across the leg results in higher O2 delivery and leg VO2 during near-maximal and maximal exercise in humans, seven men performed two maximal incremental exercise tests on the cycle ergometer. In random order, one test was performed with and one without (control exercise) infusion of ATP (8 mg in 1 ml of isotonic saline solution) into the right femoral artery at a rate of 80 microg.kg body mass-1.min-1. During near-maximal exercise (92% of VO2 peak), the infusion of ATP increased leg vascular conductance (+43%, P<0.05), leg blood flow (+20%, 1.7 l/min, P<0.05), and leg O2 delivery (+20%, 0.3 l/min, P<0.05). No effects were observed on leg or systemic VO2. Leg O2 fractional extraction was decreased from 85+/-3 (control) to 78+/-4% (ATP) in the infused leg (P<0.05), while it remained unchanged in the left leg (84+/-2 and 83+/-2%; control and ATP; n=3). ATP infusion at maximal exercise increased leg vascular conductance by 17% (P<0.05), while leg blood flow tended to be elevated by 0.8 l/min (P=0.08). However, neither systemic nor leg peak VO2 values where enhanced due to a reduction of O2 extraction from 84+/-4 to 76+/-4%, in the control and ATP conditions, respectively (P<0.05). In summary, the VO2 of the skeletal muscles of the lower extremities is not enhanced by limb vasodilation at near-maximal or maximal exercise in humans. The fact that ATP infusion resulted in a reduction of O2 extraction across the exercising leg suggests a vasodilating effect of ATP on less-active muscle fibers and other noncontracting tissues and that under normal conditions these regions are under high vasoconstrictor influence to ensure the most efficient flow distribution of the available cardiac output to the most active muscle fibers of the exercising limb.     

Effect of sildenafil on coronary active and reactive hyperemia

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.