Pulse Pressure–Related Changes in Coronary Flow In Vivo Are Modulated by Nitric Oxide and Adenosine
Acute increases in arterial pulsatile load imposed on the left ventricle can increase coronary flow without commensurate changes in myocardial oxygen consumption. One explanation is that augmenting pulsatile perfusion at the same mean pressure itself stimulates flow by releasing endothelium-mediated vasorelaxant factors such as NO. The present study tested this hypothesis and determined whether NO and adenosine modulate this response. In open-chest anesthetized dogs, the distal left anterior descending coronary artery (LAD) was whole-blood–perfused by a novel servopump system to control mean and pulsatile perfusion pressure within the isolated vascular bed. Central aortic pressure was measured, stored to computer memory, and then digitally modified (varying the pulse pressure [PP]) to generate a real-time servocommand that was still synchronous with ventricular contraction. Left heart workload was unchanged. LAD flow was measured before and after increasing the PP (to 60 to 100 mm Hg) from baselines of either 0 or 40 mm Hg. With normal basal coronary vascular tone, raising the PP increased flow (+9±2% at a PP of 100 mm Hg). This response was markedly amplified (+39±8%) when basal tone was first partially reduced by adenosine. Competitive inhibition of NO synthase by Nω-monomethyl-l-arginine reduced acetylcholine and PP-dependent flow responses by 50%. Thus, enhanced pulsatile perfusion increases in vivo coronary flow in part by triggering NO release. The marked augmentation of the PP response with reduced basal coronary tone from adenosine suggests that this mechanism may play a role in improving myocardial perfusion during exercise.
The central arterial PP nearly doubles during normal dynamic exercise in young healthy subjects1 and may rise even more in older individuals.2 This occurs in concert with rising heart rate and cardiac output, resulting in elevations of mean and oscillatory cardiac work and MV̇O2 that are normally matched by enhanced coronary flow.1 3 Flow reserve is in large part mediated by a reduction in arteriolar tone due to release of catabolic factors, such as CO2, H+, and adenosine.3 However, recent studies suggest that hearts ejecting into a stiff vasculature and perfused with a widened PP have increased coronary flows even without changes in MV̇O2.4 Such higher flows could be indirectly mediated by mechanical interactions between altered LV contraction patterns and the vasculature5 or by direct influences of pulsatile perfusion on vascular tone.
Recent in vitro studies have shown that after several hours of exposure to pulsatile stretch6 or shear,7 endothelial NOS gene expression increases. Chronic exercise also enhances NO/EDRF-dependent coronary dilation and increases endothelial NOS expression.8 9 NO-dependent flow enhancement from increased pulsatile perfusion and increased pulse frequency10 11 during exercise might contribute to this response. The present study was designed to test the hypothesis that increasing the pulse pressure of in vivo coronary perfusion in the absence of altered LV contraction enhances flow and that NO release plays an important role in this response. We also tested whether PP flow alterations are modulated by adenosine-induced changes in basal coronary tone, such as might accompany increased demand during exercise.
Materials and Methods
Adult mongrel dogs (25 kg, n=15) were anesthetized with pentobarbital (30 mg/kg IV) and fentanyl (50 μg/kg IV), intubated, and ventilated on 30% inspired O2. Maintenance anesthesia was achieved by continuous infusion of both agents (3 mg/kg per hour for pentobarbital and 10 μg/kg per hour for fentanyl). To enhance stability of the preparation during extracorporeal circulation, the following were also administered before surgery: hydrocortisone (100 mg), indomethacin (25 mg), diphenhydramine (25 mg), penicillin G (106 IU), and gentamicin (40 mg). Arterial blood pH, Po2, and Pco2 were maintained in the physiological range by adjusting ventilation and/or administering NaHCO3 as required.
Left external jugular and femoral veins and left carotid and femoral arteries were cannulated for fluid administration and withdrawal of oxygenated blood for the servopump system. The chest was opened via a left lateral thoracotomy, and the heart suspended in a pericardial cradle. A micromanometer catheter (SPC 350, Millar Instruments) was placed through the mid-LV free wall to measure cavity pressure. Aortic root pressure was measured by micromanometer; flow, by ultrasound probe (model 2R, Transonics). After heparinization (8000 IU bolus, 1000 IU/h), the LAD was cannulated distal to the first major diagonal branch. Left carotid artery blood was diverted through this cannula, maintaining perfusion to the distal bed until flow could be provided by the servopump.
In a subset of five animals, a single pair of sonomicrometers (Triton) was positioned in a short-axis orientation at the midwall level of the distal anterior wall to assess regional function.
PP Servopump System
The servopump perfusion system was divided into two principal components (Fig 1⇓). Mean flow was controlled by a peristaltic pump (A) (Harvard apparatus M-14962). PP was controlled by a linear displacement motor (D) (model 411, Ling Electronics) linked to a piston that formed the floor of a plastic cone-shaped chamber (base diameter, 2 cm; volume, 39 mL). The piston was fitted with two rolling rubber diaphragms (Bellofram) separated by vacuum, which isolated the motor from blood. Arterial blood was withdrawn from a femoral artery, passed through the peristaltic pump (A), through the heat exchanger and blood filter (B), through the pulse-generator pump (C and D), and then into nylon-reinforced tubing (Tygon, ≈45 cm, 7-mm internal diameter) (E) attached to the coronary artery cannula. An in-line ultrasound flow probe (model 2F, Transonics) measured phasic and mean flow.
As shown in Fig 1⇑, pressure in the coronary perfusion line was measured by micromanometer (F) placed 8 cm distal to a pulse chamber (C). This signal was low pass–filtered at 30 Hz, separated into mean and pulsatile components, and used to generate servocommand inputs to each pump using digital proportional-integral-derivative–feedback control. Several consecutive central aortic pressure waveforms were stored to computer memory and averaged. This array was mathematically altered to yield a desired mean pressure and PP amplitude and was then used as the servocommand signal, maintaining full synchrony with the cardiac cycle. In this fashion, the mean pressure and PP of the isolated vascular bed were independently controlled, while the pattern of ventricular contraction and regional and global workload remained constant. The stored aortic waveform was updated frequently throughout the experiment to adjust for any heart rate changes and alterations in the shape of the real aortic pressure wave. Blood temperature from the pump was continuously monitored and maintained at 37°C. Blood gases matched values in the general circulation.
The isolated distal LAD region was initially perfused by blood diverted from the carotid artery, and steady state flow was measured. After ≈20 to 30 minutes from switching to servopump perfusion, the same resting flow rate was reestablished. At this time, the servosystem was set to perfuse at a mean pressure of 100 mm Hg, and this level was subsequently held constant. Baseline flow was measured at one of two reference states: zero PP or physiological PP (40 mm Hg). PP was then increased to 40, 70, or 100 mm Hg (from 0 mm Hg baseline) or 70 or 100 mm Hg (for 40 mm Hg baseline), in random order. Data were recorded before and for 2 to 3 minutes after the change in PP. Each switch to a new PP was preceded by return to the corresponding reference state (ie, 0 or 40 mm Hg PP).
Experiments were performed with normal basal coronary tone and with vasomotor tone reduced by intracoronary adenosine. Adenosine infusion (5 to 25 μg/min) was titrated to raise baseline flow two to three times (measured at PP of 0 mm Hg), and then this rate was maintained while PP was again changed as described above. To test the role of NO release to the PP-flow response, L-NMMA (200 mg in 20 minutes) was administered into the servoperfusion line. The flow response to widening PP from 0 to 100 mm Hg (in the presence of adenosine) was compared before and after L-NMMA. The extent of NOS inhibition from L-NMMA was independently tested by the flow response to intracoronary ACh (50 μg/min IC). L-NMMA experiments were performed in six animals.
Effects of altered pulsatile perfusion on cardiac function were assessed at the chamber level in all hearts and in the region subtended by the isolated LAD of the subset of five animals. Segment length was used to determine fractional shortening: (end-diastolic length−end-systolic length)/end-diastolic length×100. Pressure-length loops were constructed, and the area was digitally integrated to index regional work.
Data Analysis and Statistics
Data were digitized at 200 Hz and analyzed off-line with custom software. Mean and pulsatile flow, systolic, diastolic, and mean coronary pressure, and LV pressure and aortic flow were measured in each study. Global chamber workload was indexed by the product of LV systolic pressure times cardiac output.12 The influence of altered PP on phasic coronary flow was analyzed by separation of the waveform into systolic (onset of ejection to dicrotic notch) and diastolic portions, as previously described.4 The integral under each was determined to derive mean percent systolic and diastolic coronary flow. Not all animals contributed data at all PP points under all conditions. Data were therefore analyzed by two- or three-way ANOVA, with pulse pressure and coronary tone (±adenosine) serving as categorical variables. Data before and after L-NMMA were compared by paired t test. Data are presented as mean±SEM, with P<.05 considered statistically significant.
Performance of Servoperfusion System
Fig 2⇓ displays a typical example of real-time central aortic pressures and simultaneous pressures generated by the servopump system in an isolated coronary bed. A plot of one signal versus the other (Fig 2⇓, right) revealed excellent reproduction of the real pressures, with little phase lag (ie, linear plot) or amplitude modification.
Basal Coronary Flow Response to PP
Baseline mean coronary flow in the distal-LAD territory with the servopump perfusion set at a PP of 40 mm Hg was 30±4.9 mL/min, similar to native flow in the same vascular territory.4 When the PP was raised to 70 or 100 mm Hg at the same mean pressure, mean coronary flow also increased. Fig 3A⇓ displays an example of this response. At the time indicated by the vertical arrow, PP was abruptly changed from 40 to 100 mm Hg in the LAD region. Mean flow (top trace of Fig 3A⇓) began increasing after two beats and continued rising over the ensuing 10 to 12 cycles, after which it plateaued. On average, a plateau was observed 17±1 beats (5 to 10 seconds) after the switch to a higher PP. The lower two traces of Fig 3A⇓ display simultaneous ventricular pressure and aortic flow, revealing constant global chamber function. Qualitatively similar flow responses were also observed when PP was increased above 40 mm Hg from a baseline of 0 mm Hg.
Mean percent flow changes at varying PPs relative to the respective baselines of 0 or 40 mm Hg are shown in Fig 3B⇑. Flow augmentation was modest but significant when PP was increased to 100 mm Hg (+8.8±2.2% relative to a baseline of 40 mm Hg, +5.4±1.3% relative to baseline of 0 mm Hg). Raising PP from 0 to 40 mm Hg resulted in a small but significant flow decline (−2.16±0.7%), and an example of this response is shown in Fig 4⇓. For the combined set of PP interventions, the mean percent change in the LV pressure-flow product (load index) was minimal and statistically insignificant (−0.8±0.8%); thus, the changes in flow were not associated with global LV contractile change.
Fig 3C⇑ displays phasic coronary flow and pressure waveforms for 40 and 100 mm Hg PP. Raising the PP augmented flow during the systolic period (S), and this change was primarily responsible for the increase in overall mean flow. Mean systolic flow averaged 24.6±6.4% of the total at 40 mm Hg PP versus 32.1±6.8% at the higher PP (P<.01).
Influence of Reduced Coronary Tone on PP-Flow Response
The modest flow enhancement due to PP widening with normal coronary tone was markedly amplified when tone was first lowered by adenosine to raise flow two to three times above resting levels (78.9±5.4 and 87.5±2.2 mL/min for PPs at 0 and 40 mm Hg, respectively). As shown by the example in Fig 5A⇓, under these conditions, increasing PP from 40 to 100 mm Hg elevated mean flow by nearly 40%. Phasic flow waveforms (right traces of panel A) also revealed enhanced systolic flow. Group data (Fig 5B⇓) were consistent with this example. Raising PP from 40 to 70 or from 40 to 100 mm Hg significantly increased flow by 21.5±3.2% and 39.2±8.2%, respectively. Similar responses were observed when the baseline PP was 0 mm Hg, although the flow increases were somewhat smaller (P<.05 by two-way ANOVA). Thus, there was some additional enhancement of the PP-dependent flow response if perfusion was already pulsatile at baseline. If sufficient adenosine was administered to raise basal flow to near maximum (more than fourfold), increasing PP did not further augment flow (data not shown).
Lack of change in global LV function and the pressure-flow product did not rule out a regional mechanical effect of increased pulsatile perfusion. However, regional data did not support such functional changes. Fractional shortening was 8.4±2.2% at a PP of 40 mm Hg and 7.8±1.9% at a PP of 100 mm Hg, respectively, without adenosine. Both shortening fractions rose with adenosine, but there was again no effect of altering PP (11.9±3.9% and 10.6±3.5% for PPs at 40 and 100 mm Hg, respectively). Regional work indexed by the area of the pressure-segment loop was also not significantly altered with changes in PP (−3.3±2.2% without adenosine and −5.4±6% with adenosine; both P=NS).
Effect of L-NMMA
Fig 6⇓ displays results of experiments performed in the absence and presence of NOS inhibition by L-NMMA. The flow rise measured 2 to 3 minutes after increasing PP from 0 to 100 mm Hg (in the presence of adenosine) was reduced by 57.6±10.5% after treatment with L-NMMA (far right panel). This was not significantly different from the 50±5.3% decline in the ACh-induced flow change (far left panel). For flow data measured during ACh infusion, the PP was determined by native cardiovascular interaction and was 29.2±1.2 mm Hg before the administration of L-NMMA and 28.1±1.1 mm Hg after. Although the sustained flow rise was blunted by L-NMMA, NOS inhibition had minimal effect on the very early rapid flow response measured within 5 to 10 seconds after PP widening (middle panel; data were measured in four dogs).
The present study reports three major new findings: (1) Isolated elevation of coronary perfusion PP >40 mm Hg increases mean coronary flow. (2) This effect is markedly potentiated by partial vascular predilation with adenosine. (3) A substantial component of the stable PP-induced flow augmentation is mediated by NO release. These are the first in vivo data to demonstrate that flow pulsatility itself can influence vascular tone by endothelium-dependent mechanisms, lending support to recent data showing effects of cyclic stretch and shear on NOS regulation in endothelial cell culture systems.6 7 13 The results also help elucidate the mechanisms of coronary flow augmentation despite unaltered MV̇O2, which we previously reported in an aortic bypass model of enhanced pulsatile loading of the LV.4
Enhanced pulsatile perfusion is normally accompanied by a simultaneous rise in ventricular systolic forces that are thought to impede systolic flow via an intramyocardial pump.14 15 However, external vascular compression from cardiac contraction may also enhance flow by stimulating endothelial NO release.5 When both factors are present,4 the result can be a net increase in coronary flow. The present study isolated the influence of PP itself. Although coronary systolic pressures were therefore higher than ventricular pressures, diastolic pressures were simultaneously reduced, and mean pressures were unchanged. Since mean coronary flow is primarily determined by the ratio of mean pressure to resistance, the higher systolic pressure alone would not predict the change in flow, but the observed flow change implied a net decline in coronary tone and resistance. Indeed, the substantial rise in flow with larger increases in PP particularly in the presence of adenosine could only be explained by an effect on more distal resistance vessels.
PP Modulation of Coronary Vascular Tone
Although many in vitro studies have demonstrated vasorelaxation responses to laminar flow and shear,16 17 few have examined effects of oscillating stimuli. A recent study reported that endothelial cells exposed to several hours of cyclic shear display an 11-fold rise in endothelial NOS activity compared with no-flow conditions.7 Cyclic stretch of endothelial cells in the absence of flow has also been shown to increase NOS activity13 and endothelial NOS gene expression.6 In vivo studies have confirmed flow-mediated vasodilation in the coronary circulation, but in these studies, the effects of increased mean and pulsatile perfusion were inseparable.18 19 Canty and Schwartz10 recently reported that NO contributed to flow-dependent epicardial vasodilation in vivo during pacing tachycardia and suggested that PP frequency was an important trigger for NO release. However, pacing couples altered coronary pulsatile perfusion with simultaneous changes in cardiac contraction and load, making the precise stimulus less clear.
In the present study, nearly 60% of the stable PP-induced flow response was inhibited by L-NMMA, consistent with an important role of NO release. It is important to note that these data were obtained in the presence of adenosine (to enhance detection of an altered flow response), and the contribution of NO release with basal coronary tone might be less. L-NMMA is a competitive NOS inhibitor, and although we used a fairly high dose, it remained possible that incomplete inhibition resulted in residual flow changes. However, other mechanisms could have played a role as well, particularly since the very initial rise in flow was unaltered by L-NMMA. Indeed, the rapid onset of flow rise suggests potential mechanical factors as well as metabolic ones. Viscoelastic properties of the arterial wall,20 21 which are primarily related to the muscular components, are more evident when the PP exceeds 40 mm Hg.22 Consistent with these data, we recently reported that raising the PP to >40 mm Hg in isolated porcine carotid arteries produces a similar rapid onset and sustained increase in vessel diameter.23 This response was endothelium independent. Although we could not accurately measure coronary diameter changes in the distal LAD, it seems intriguing that the flow response to PP was also only observed when the PP exceeded 40 mm Hg.
Direct measurements of regional MV̇O2 were not feasible in these experiments because of the distal and less easily delineated distribution of the cannulated vascular bed. Thus, we could not rule out a role of altered regional metabolic demand as a contributor to increased flow at higher PPs. However, several lines of evidence suggest that this was unlikely. First, regional work and shortening data were unchanged at higher PPs, both with and without adenosine. Second, although the PP change was identical before and after adenosine, the flow response was nearly three to four times greater. Were this due to substantial augmentation in MV̇O2 without any evidence of altered regional work, myocardial efficiency would have had to decline appreciably. We are unaware of a mechanism by which this might occur. If anything, NO has been recently shown to reduce MV̇O2 by inhibiting mitochondrial respiration via interaction with cytochrome oxidase.24 25 However, this effect is inhibited by pentobarbital,25 as used in the present study. Last, our prior study found that enhancing pulsatile load to the whole heart at constant MV̇O2 also increased coronary flow.4
Coronary flow declined slightly but consistently when PP was increased from 0 mm Hg to a physiological value of 40 mm Hg. This is consistent with a slight vasoconstrictor mechanism. Depression of basal and agonist-induced endothelium-dependent relaxation has been reported in response to step increases in mean pressure in vitro.26 This phenomenon appears mediated by depressed synthesis and/or release of EDRF. Other studies have reported that low levels of PP (≤10 mm Hg) can inhibit EDRF27 28 activity, with one study suggesting that PP exposure leads to production of oxygen radicals.28 It is possible that constriction dominates at low PPs but that this becomes overtaken at higher PP by vasorelaxation responses. It should also be emphasized that our studies examined relatively short-term responses, and more chronic exposure to elevated phasic perfusion might have more detrimental effects. For example, PP is a dominant predictor of vascular medial hyperplasia, and sustained elevation of systolic pressures to 200 mm Hg for 1 to 15 minutes has been found to damage the endothelial lining.29 Further studies are needed to explore the histological impact of sustained exposure to high PP (ie, cyclic systolic hypertension) on the endothelium.
Influence of Adenosine and Vascular Site of PP Response
PP widening had only modest influences on coronary flow at normal resting tone; however, this effect was markedly amplified after administering adenosine. This may be physiologically relevant, since conditions that increase metabolic demand typically induce coronary vasodilation while simultaneously widening the PP. The magnitude of flow rise from adenosine alone was designed to match levels reported during moderate exercise.30 In the present study, the adenosine infusion rate was kept constant despite higher coronary flow after the PP increase, so adenosine concentrations fell to some extent. Maintaining the concentration might have raised flow even more.
There are several possible mechanisms for a potentiating effect of adenosine. By increasing basal flow, adenosine would elevate pulsatile flow and shear even at the same PP, which might augment vasodilation. This would likely influence both proximal and intermediate-sized vessels. Adenosine could also enhance the transmission of pulsatile flow further downstream into the coronary vasculature, expanding the total interaction between endothelial surface and PP to yield a greater vasorelaxant response. Reduced smooth muscle tone would also raise vascular compliance, enhancing vascular stretch for the same change in pulse pressure. As previously noted, vascular stretch can itself augment NO release.13 Furthermore, since adenosine primarily affects distal resistance vessels (<100 μm), which normally contribute 55% of total resistance,31 dilation of these vessels could enhance the relative resistance attributable to more proximal (primarily NO-sensitive) vessels as well as the larger conduit vessels. Increased conductance of more proximal (>200-μm) vessels as well as further NO-mediated reduction in resistance of intermediate vessels would thereby explain the greater overall effect on flow in the presence of adenosine. Last, although adenosine was used because it is a physiological vasodilator of arterioles, some recent data have suggested that some of its vasorelaxant effects are themselves mediated by NO32 33 34 and that some direct interaction between the two is possible. To date, however, there are no data showing a synergistic effect of adenosine on mechanically stimulated NO release.
Potential Relevance of PP-Flow Enhancement
Vascular pulsatility has historically been considered as wasted energy for overall circulatory economy,35 since the heart must expend more energy to achieve the same mean arterial pressure and cardiac output.36 Loss of part of this energy due to viscous properties of the systemic vasculature19 adds to the inefficiency. However, the present studies support the hypothesis that pulsatility may have a beneficial role in maintaining perfusion, in part by enhancing NO-mediated vasorelaxation, particularly in partially dilated vascular beds. Future studies will need to confirm that this occurs without an increase in MV̇O2, but prior data suggest that this is the case.4
PP-related flow augmentation could contribute to flow reserve during exercise. In young healthy individuals, aerobic exercise augments the central aortic PP nearly twofold, and peripheral vascular PP nearly threefold the resting values.1 Although no analogous data exist in older individuals, the rise in pulsatility with aging and faster pulse-wave velocity would predict even greater PP increases with exercise. Recent studies also indicate that exercise enhances coronary vascular NO production and endothelial NOS gene expression in experimental animals,8 9 as well as flow-dependent dilation in patients with congestive heart failure.37 Pulsatility of flow during exercise may play a signaling role to these changes. The role of NO-mediated flow reserve has been found to be particularly relevant when alternative vasodilator mechanisms are limited, such as with coronary stenoses38 or after blocking ATP-sensitive K+ channels or adenosine receptors.39 Abnormal vasoreactivity, such as occurs with atherosclerosis40 or heart failure,41 may limit the PP-flow response, contributing to reduced exercise flow reserve in these disorders. The present study only evaluated acute effects of PP widening, and future studies will be required to determine the chronic relevance of PP-mediated flow augmentation in these and other conditions.
Selected Abbreviations and Acronyms
|EDRF||=||endothelium-derived relaxing factor|
|LAD||=||left anterior descending coronary artery|
|LV||=||left ventricle (ventricular)|
|MV̇O2||=||myocardial oxygen demand|
This study was supported by National Health Service grant HL-47511 (Dr Kass) and a grant from the American Heart Association, Maryland Affiliate, Inc (Dr Recchia). The authors thank Richard Tunin for his excellent surgical assistance in performing these studies.
- Received April 10, 1996.
- Accepted July 12, 1996.
Rowell LB, Brengelmann GB, Blackmon JR, Bruce RA, Murray JA. Disparities between aortic and peripheral pulse pressures induced by upright exercise and vasomotor changes in man. Circulation. 1968;37:954-964.
Feigl EO. Coronary physiology. Physiol Rev. 1983;63:1-161.
Saeki A, Recchia F, Kass DA. Systolic flow augmentation in hearts ejecting into a model of stiff aging vasculature: influence on myocardial perfusion-demand balance. Circ Res. 1995;76:132-141.
Lamontagne D, Pohl U, Busse R. Mechanical deformation of vessel wall and shear stress determine the basal release of endothelium-derived relaxing factor in the intact rabbit coronary vascular bed. Circ Res. 1992;70:123-130.
Awolesi MA, Sessa WC, Sumpio BE. Cyclic strain upregulates nitric oxide synthase in cultured bovine aortic endothelial cells. J Clin Invest. 1995;96:1449-1454.
Noris M, Morigi M, Donadelli R, Aiello S, Foppolo M, Todeschini M, Orisio S, Remuzzi G, Remuzzi A. Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions. Circ Res. 1995;76:536-543.
Sessa W, Pritchard K, Seyedi N, Wang J, Hintze TH. Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression. Circ Res. 1994;74:349-353.
Wang J, Wolin MS, Hintze TH. Chronic exercise enhances endothelium-mediated dilation of epicardial coronary artery in conscious dogs. Circ Res. 1993;73:829-838.
Canty JM, Schwartz JS. Nitric oxide mediates flow-dependent epicardial coronary vasodilation to changes in pulse frequency but not mean flow in conscious dogs. Circulation. 1994;89:375-384.
Jones CJH, Kuo L, Davis MJ, DeFily DV, Chilian WM. Role of nitric oxide in the coronary microvascular responses to adenosine and increased metabolic demand. Circulation. 1995;91:1807-1813.
Rooke GA, Feigl EO. Work as a correlate of canine left ventricular oxygen consumption, and the problem of catecholamine oxygen wasting. Circ Res. 1982;50:273-286.
Spann JAE, Breuls PW, Laird JD. Diastolic-systolic coronary flow differences are caused by intramyocardial pump action in the anesthetized dog. Circ Res. 1981;49:584-593.
Krams R, Sipkema P, Zegers J, Westerhof N. Varying elastance concept may explain coronary systolic flow impediment. Am J Physiol. 1989;257:H1471-H1479.
Davies PF. Flow-mediated endothelial mechanotransduction. Physiol Rev. 1995;75:519-560.
Rubany GM, Romero JC, Vanhoutte PM. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol. 1988;255:H783-H788.
Antony I, Lerebours G, Nitenberg A. Loss of flow-dependent coronary artery dilatation in patients with hypertension. Circulation. 1995;91:1624-1628.
Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Lüscher TF. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation. 1995;91:1314-1319.
Dobrin PB. Mechanical properties of arteries. Physiol Rev. 1978;58:397-460.
Armentano RL, Barra JG, Levenson J, Simon A, Pichel RH. Arterial wall mechanics in conscious dogs: assessment of viscous, inertial, and elastic moduli to characterize aortic wall behavior. Circ Res. 1995;76:468-478.
Recchia FA, Byrne BJ, Kass DA. Vasorelaxant effect of physiologic arterial pulsatility in isolated vessels. Circulation. 1994;90(pt 2):I-357. Abstract.
Shen W, Xu X, Ochoa M, Zhao G, Wolin MS, Hintze TH. Role of nitric oxide in the regulation of oxygen consumption in conscious dogs. Circ Res. 1994;75:1086-1095.
Rubanyi GM. Endothelium-dependent pressure-induced contraction of isolated canine carotid arteries. Am J Physiol. 1988;255:H783-H788.
Hutcheson IR, Griffith TM. Release of endothelium-derived relaxing factor is modulated both by frequency and amplitude of pulsatile flow. Am J Physiol. 1991;261:H257-H262.
Ryan SM, Waack BJ, Weno BL, Heistad DD. Increases in pulse pressure impair acetylcholine-induced vascular relaxation. Am J Physiol. 1995;268:H359-H363.
Lamping KG, Dole WP. Acute hypertension selectively potentiates constrictor responses of large coronary arteries to serotonin by altering endothelial function in vivo. Circ Res. 1987;61:904-913.
Khouri EM, Gregg DE, Rayford CE. Effect of exercise on cardiac output, left coronary flow and myocardial metabolism in the unanesthetized dog. Circ Res. 1965;17:427-437.
Chilian WM, Eastham CL, Marcus ML. Microvascular distribution of coronary vascular resistance in beating left ventricle. Am J Physiol. 1986;251:H779-H788.
Li J, Fenton RA, Cutler BS, Dobson JG Jr. Adenosine enhances nitric oxide production by vascular endothelial cells. Am J Physiol. 1995;269:C519-C523.
Smits P, Williams SB, Lipson DE, Banitt P, Rongen GA, Creager MA. Endothelial release of nitric oxide contributes to the vasodilator effect of adenosine in humans. Circulation. 1995;92:2135-2141.
O'Rourke MF. Steady and pulsatile energy losses in the systemic circulation under normal conditions and in simulated arterial disease. Cardiovasc Res. 1967;1:313-326.
Kelly RP, Tunin R, Kass DA. Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle. Circ Res. 1992;71:490-502.
Hornig B, Volker M, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation. 1995;93:210-214.
Duncker DJ, Bache RJ. Inhibition of nitric oxide production aggravates myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis. Circ Res. 1994;74:629-640.
Duncker DJ, van Zon NS, Pavek TJ, Herrlinger SK, Bache RJ. Endogenous adenosine mediates coronary vasodilation during exercise after K+ ATP channel blockade. J Clin Invest. 1995;95:285-295.
Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993;92:652-662.
Katz SD, Schwarz M, Yuen J, LeJemtel TH. Impaired acetylcholine-mediated vasodilation in patients with congestive heart failure: role of endothelium-derived vasodilating and vasoconstricting factors. Circulation. 1993;88:55-61.