Ann Thorac Surg 1999;67:1254-1261
© 1999 The Society of Thoracic Surgeons
Original Articles
Endothelium-derived nitric oxide enhances the effect of intraaortic balloon pumping on diastolic coronary flow
Eiji Toyota, MD, PhDa,
Masami Goto, MD, PhDa,
Hiroshi Nakamoto, MD, PhDa,
Jun Ebata, MDa,
Hiroyuki Tachibana, CEa,
Osamu Hiramatsu, CEa,
Yasuo Ogasawara, PhDa,
Fumihiko Kajiya, MD, PhDa
a Department of Systems Cardiology and Medical Engineering, Kawasaki Medical School, Okayama, Japan
Accepted for publication October 20, 1998.
Address reprint requests to Dr Toyota, Department of Systems Cardiology and Medical Engineering, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan
e-mail: toyota{at}me.kawasaki-m.ac.jp
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Abstract
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Background. High shear rate with pulsation is one of the major stimuli for the release of endothelium-derived nitric oxide leading to coronary arteriolar dilation. Intraaortic balloon pumping mechanically enhances shear rate and diastolic-to-systolic flow oscillation. We aimed to evaluate whether or not coronary blood flow augmentation during intraaortic balloon pumping is mediated by coronary arteriolar dilation through endothelium-derived nitric oxide release.
Methods. Using a charge-coupled device intravital videomicroscope, we observed epicardial coronary arterioles (40 to 220 µm in diameter) in anesthetized open-chest dogs (n = 10) during 2:1 mode of intraaortic balloon pumping. Endothelium-derived nitric oxide-mediated vasodilatory effects of intraaortic balloon pumping were evaluated by comparing end-diastolic arteriolar diameters between the coupled beats of on and off intraaortic balloon pumping before and after intracoronary endothelium-derived nitric oxide synthesis inhibition with N
-nitro-L-arginine (L-NNA, 2 µmol/min) administration.
Results. Intraaortic balloon pumping increased coronary arteriolar diameters and coronary blood flow by 11.4% ± 1.8% (p < 0.0001) and 33.4% ± 4.1% (p < 0.001), respectively. Vasodilation was greater in small arterioles (<110 µm; 15.4% ± 2.2%) than in large arterioles (
110 µm; 4.2% ± 1.2%, p < 0.0001). L-NNA attenuated the intraaortic balloon pumping-induced vasodilation and augmentation of coronary blood flow to 4.6% ± 1.0% (p < 0.001) and to 20.8% ± 2.1%, (p < 0.05), respectively. Attenuation of vasodilatory effect by L-NNA was observed mainly in small arterioles (from 15.4% ± 2.2% to 5.9% ± 1.2%).
Conclusions. Intraaortic balloon pumping augmented coronary blood flow by dilating coronary arterioles in diastole, more significantly in small arterioles than in large arterioles. Endothelium-derived nitric oxide inhibition markedly attenuated these effects. We conclude that, in a canine model, endothelium-derived nitric oxide contributes to mechanical enhancement of the coronary blood flow with diastolic arteriolar vasodilation during intraaortic balloon pumping.
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Introduction
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A growing number of experimental and clinical evidence indicate that nitric oxide plays an important and necessary role in the dynamic regulation of coronary vascular tone for adequate myocardial perfusion under various physiologic and pathologic conditions [1–4] being released in pulsatile fashion synchronized with the cardiac cycles [5]. Flow-induced shear stress is one of the major stimuli for the release of endothelium-derived nitric oxide (EDNO) [6] and the flow-induced release of EDNO is involved in the regulation of coronary blood flow [1, 2]. Oscillation in shear stress further enhances the EDNO release in vitro [7] and the pulsatile perfusion, recently reported, increases the coronary flow mediated by EDNO in the canine heart [8].
A recent study from our laboratory [9] demonstrated that an abrupt inflation of the intraaortic balloon during diastole caused a forced augmentation of coronary blood flow (CBF) in the distal portion of the coronary arteries, which reflects coronary inflow into the myocardium. Because intraaortic balloon pumping (IABP) causes the increases in both the diastolic flow-related wall shear stress and diastolic-to-systolic flow oscillation during the cardiac cycle, we hypothesized that the release of EDNO is involved in the dilation of the coronary resistance arterioles by IABP. In the present study, using IABP we evaluated (1) the direct effects of mechanical enhancement of coronary flow oscillation with high diastolic shear stress on the dilation of coronary arterioles in respect of size-dependent sensitivity and (2) the role of EDNO in the IABP-induced changes of the coronary arteriolar diameter during the cardiac cycle. We observed epicardial coronary arterioles using our needle-probe, charge-coupled device (CCD) intravital videomicroscope [10] during IABP in 2:1 mode (switch on; IABP-on and off; IABP-off, alternatively) in open-chest anesthetized dogs. We compared the coronary arteriolar diameters between the coupled beats of IABP-on and IABP-off [9] before and after inhibition of EDNO by intracoronary administration of an EDNO synthesis inhibitor, N-nitro-L-arginine (L-NNA).
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Material and methods
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Animal preparations
Adult mongrel dogs (n = 10) of either sex weighing 15 to 25 kg were initially sedated with an intramuscular injection of ketamine (200 mg) and fully anesthetized with intravenous injection of pentobarbital sodium (30 mg/kg). Additional doses were given as needed throughout the experiment. The dogs were subsequently ventilated by a respirator pump (3 to 5 L/min oxygen; VS600; Instrumental Development, Pittsburgh, PA). Arterial blood samples were taken periodically and analyzed for pH, arterial oxygen tension, arterial carbon dioxide tension, and base excess (IL1304; Instrumentation Laboratory, Milan, Italy). These variables were kept in the physiologic ranges by adjusting inspired oxygen concentration, minute ventilation, and intravenous infusion of 7% NaHCO3. Body temperature was kept at 37°C using a heating pad regulated by a controller (TC80; Aika, Tokyo, Japan). Intravenous heparin sodium (1,000 U hourly; Takeda, Osaka, Japan) and intravenous ibuprofen (12.5 mg/kg; Sigma Chemical, St. Louis, MO) were administered to prevent coagulation and to inhibit the formation of cyclooxygenase production, respectively. The electrocardiogram was recorded from standard leads. An arterial pressure catheter (model SPC-784A; Millar, Houston, TX) was inserted through the right carotid artery to measure the aortic pressure (AoP) and the left ventricular pressure (LVP).
After median sternotomy and left thoracotomy, the heart was exposed and supported in a pericardial cradle. The heart rate was kept at 100 beats/min throughout the experiment by right atrial pacing after an injection of 37% formaldehyde solution into the sinoatrial node. A 24-gauge catheter was introduced into a diagonal branch of the left anterior descending artery for intracoronary injection of indocyanine green and drugs. We dissected the left anterior descending artery or its branch, or both, to evaluate the increasing response of CBF by intracoronary administration of acetylcholine (ACh) and the effect of IABP on coronary flow augmentation. Coronary blood flow was measured with a transit-time ultrasonic flowmeter (T206 Flowmeters; Transonic System, Ithaca, NY). Systemic hemodynamic and coronary flow data were recorded on a data recorder (XR510; TEAC, Tokyo, Japan).
An intraaortic balloon (volume, 15 mL; diameter, 10.5 mm; length, 170 mm; Aisin, Aichi, Japan) was inserted into the thoracic aorta through the left femoral artery. The top of the balloon was advanced into the descending aorta and positioned just below the left subclavian artery, as confirmed by palpation. The IABP (CORAT BP1; Aisin) was performed with the 2:1 mode (IABP-on and IABP-off, alternatively); the balloon was inflated every other heart beat to compare the coronary arteriolar diameters between IABP-on and IABP-off with minimal coronary metabolic regulation [9].
Measurement of coronary arteriolar diameter
To measure the epicardial coronary arteriolar diameters, we used our needle-probe videomicroscope with a CCD camera (VMS 1210, Nihon Kohden, Tokyo, Japan) [10]. This CCD system and its validity were described in detail previously [10–12]. In brief, the needle probe (diameter, 4.5 mm; length, 180 mm) contains a gradient index (GRIN, two pitch) lens surrounded by an annular light-guide with 18 optical fibers. Images on the CCD are converted into a color video signal every 33 milliseconds to be monitored and recorded on a 8 mm video standard (Fujifilm, Tokyo, Japan). The CCD image sensor has 510 by 492 pixels and 330-line horizontal resolution. The maximum depth of the observable field is about 250 µm. The needle probe is enclosed in a Silastic 14F double lumen sheath. A doughnut-shaped balloon on the top of the sheath prevents direct compression of the vessels in the area of observation. To obtain a clear image and to keep a physiologic condition, the space between the top of the needle probe and the epicardial surface inside the doughnut-shaped balloon was perfused with a warmed (37°C) Krebs-Henseleit buffer (Sigma Chemical) solution, injected through a microtube in the sheath. An arteriole was differentiated from a venule by an intracoronary bolus injection of indocyanine green (Daiichi, Tokyo, Japan) and an operator maintained the probe position on the vessels manually [10] by monitoring the image. The vascular images stored on VCR were transferred off-line to a computer by appropriate software (Power Macintosh 8100/80AV computer (Cupertino, CA) and VideoFusion 1.61 (Maumee, OH), respectively) and the vascular images were then automatically analyzed using a modified density profile evaluation method [10], which is highly reliable to detect the vascular edge. The calculated vascular edges in the region of interest (ROI) were automatically drawn with lines, after two experts verified the calculated diameters.
Because of the limited temporal resolution of our CCD system (30 frames/sec), it was difficult to obtain the precise phasic pattern of vascular diameter change in a cardiac cycle. Accordingly, we evaluated the maximum diameter with clear image from late- to end-diastole to analyze the vasodilatory effect of IABP on coronary arterioles. We called the maximum diameter the "end-diastolic" one. The minimum diameter with clear image from late- to end-systole recognized from the AoP dicrotic notch was measured as the "end-systolic" diameter. Thus, percentage-change in end-diastolic arteriolar diameter between IABP-on and IABP-off was calculated by ( 
. Percentage-change in pulsation amplitude of arterioles in a cardiac cycle was calculated by ( 
. By simultaneous monitoring of electrocardiographic and AoP waveforms, these cardiac phases were carefully matched between before and after drug administrations such as L-NNA and L-arginine (as described in the experimental protocol).
We observed coronary arterioles of larger than 40 µm in diameter, as the measurement of the diameter changes for vessels smaller than 40 µm was considered to be difficult due to the limited spatial resolution (diameter change, 2.5 µm). We were compelled to evaluate subepicardial arterioles, as it was technically difficult to maintain the probe on the target vessels in the subendocardium for a long time (40 minutes as described in the experimental protocol) in each dog.
Experimental protocol
First, to evaluate the responses in the vascular segments, CBF was measured before and after intracoronary administration of ACh. The initial dose of ACh was 100 ng/kg body weight. If the value of CBF after this dose of ACh was less than twice the value before the administration, an increased dose of ACh (10 µg/mL) was administered. In all dogs studies, CBF increased by more than twice with these ACh administrations. Once CBF had returned to the baseline level before ACh administration, IABP was started at a 2:1 mode. After pilot studies, it was decided to obtain steady-state changes of diameter and flow variables, coronary arteriolar diameters, and systemic hemodynamic variables 5 minutes after the beginning of IABP. These variables were compared between a coupled beat of IABP-on and IABP-off. After the measurements under the control conditions (n = 10), IABP was stopped. After the hemodynamic variables and CBF returned to baseline levels before IABP, L-NNA (Sigma Chemical) was administered intracoronarily for 40 minutes (2 µmol/min) to inhibit EDNO synthesis. To inhibit EDNO synthesis specifically we used non-alkyl esters L-arginine analogue but not alkyl esters such as L-NAME, as absence of nonspecific vasoconstricting effects such as muscarinic antagonist was reported [13]. Then, ACh (same dose as control conditions in each animal) was again given to evaluate the inhibitory effect of L-NNA. After confirming about 50% attenuation of CBF response to ACh compared with that of the baseline conditions, the measurements with IABP were repeated (n = 10). Finally, L-arginine (Sigma Chemical) was administrated intracoronarily (0.2 mmol/min) for 20 to 40 minutes to evaluate the supplementary effects of EDNO source on EDNO synthesis inhibition. Effects of ACh (the same dose as before L-NNA) on CBF (n = 10) and the measurements with IABP were repeated (n = 4).
After the experiment was completed, each dog was killed by intravenous injection of a lethal dose of KCl. Experimental procedure and the protocol were conducted according to the institutional guidelines approved by the Animal Research Committee of Kawasaki Medical School (No.95010; 1995 and No.96005; 1996).
Statistical analysis
All group data are expressed as means ± standard error of the mean. Effects of ACh on CBF and effects of IABP on arteriolar size was compared under (1) control conditions, (2) conditions with L-NNA, and (3) conditions with L-arginine after L-NNA using repeated measure analysis of variance. Effects of IABP and inhibition of EDNO on coronary arteriolar diameters, CBF, and hemodynamic variables were analyzed by two-way analysis of variance followed by post-hoc tests. If an overall difference was found, comparisons were performed with a two-tailed Student’s t test or Wilcoxon signed-rank test. Percentage changes of CBF by ACh and percentage changes of CBF by IABP were analyzed using one-way analysis of variance followed by post-hoc tests. A linear regression analysis was performed to evaluate the relationship between coronary arteriolar diameter and its change by IABP. The criterion for statistical significance was p value less than 0.05.
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Results
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Effects of acetylcholine on coronary blood flow
Effects of ACh on LAD flow (CBF) are shown in Table 1. Under the control conditions, intracoronary ACh increased CBF by 215% ± 47% (p < 0.01). Forty minutes after L-NNA, this ACh-induced increase in CBF was attenuated to 82% ± 24% (p < 0.05; versus control). L-Arginine partially recovered the ACh-induced increase of CBF to 149% ± 33% (p = 0.22; L-NNA + L-arginine versus control). There were no significant changes in systemic hemodynamic variables except CBF by ACh administration in all conditions. We interpreted these findings as effective inhibition of coronary EDNO synthesis by the intracoronary L-NNA administration without significant changes in hemodynamic conditions.
Effects of intraaortic balloon pumping on hemodynamic variables
Systemic hemodynamic variables during IABP-on and IABP-off are summarized in Table 2. IABP increased end-diastolic AoP under control conditions as well as under conditions with L-NNA and with L-NNA + L-arginine (each condition, p < 0.0005; versus IABP-off), whereas it decreased end-systolic AoP in all conditions (p < 0.0005, p < 0.0005, p < 0.005, respectively, versus IABP-off). Systolic LVP was decreased by IABP under control conditions and after L-NNA administration (p < 0.0005, p < 0.01, respectively) but the decrease after L-arginine administration was not statistically significant (p = 0.07). Rate–pressure product was slightly decreased by IABP under control conditions (-3%; p < 0.0001), but did not change significantly after L-NNA (p = 0.17) and L-arginine administration (p = 0.87). L-Arginine administration caused a significant decrease in end-diastolic AoP (p < 0.05, L-NNA + L-arginine versus L-NNA), systolic LVP, and rate–pressure product both with and without IABP (p < 0.05, p < 0.01, respectively, L-NNA + L-arginine versus control; two-way analysis of variance).
Effects of intraaortic balloon pumping on coronary arteriolar diameters and coronary blood flow
Figure 1 shows typical examples of end-diastolic arteriolar images under control conditions and after L-NNA administration. In this case, IABP increased the end-diastolic diameters of two measured sites by 12% and 14%, respectively, in control conditions, whereas the diastolic increment decreased after L-NNA (percent increment of corresponding segments; 6% and 0%, respectively). Coronary arteriolar diameter changes during IABP under each condition were summarized in Table 3 and percentage changes of the end-diastolic coronary arteriolar diameter are illustrated in Figure 2. Under control conditions, IABP increased end-diastolic coronary arteriolar diameter by 11.4% ± 1.8% (p < 0.0001; versus IABP-off). The vasodilatory effect of IABP in individual arterioles was significantly correlated with the increasing rate of CBF to ACh administration (data not shown; r = 0.70, p < 0.005). L-NNA attenuated the IABP-induced increase in end-diastolic coronary arteriolar diameter to 4.6% ± 1.0% (p< 0.001; versus control). As shown in the right column of Table 2, IABP increased CBF by 33.4% ± 4.1% (p < 0.001; versus IABP-off) under control conditions, whereas the degree of the increment of CBF became smaller to 20.8% ± 2.1%, (p < 0.05; versus IABP-off) after L-NNA administration (p < 0.05; versus control).
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Fig 1. Microscopic images of the end-diastolic coronary arterioles during intraaortic balloon pumping (IABP) under control conditions and after N-nitro-L-arginine (L-NNA) administraion. Augmentation of the end-diastolic diameters under control condition is greater than after L-NNA.
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Fig 2. Effects of intraaortic balloon pumping (IABP) on end-diastolic diameters of coronary arterioles under control conditions, condition with N-nitro-L-arginine (L-NNA), and condition with L-arginine after L-NNA. Intraaortic balloon pumping increased coronary arteriolar end-diastolic diameter under control conditions (p < 0.0001). L-NNA attenuated the intraaortic balloon pumping-induced coronary arteriolar dilatory effect. Supplemental L-arginine administration partially recovered it.
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Inverse relations were found between end-diastolic coronary arteriolar diameters and their percentage changes by IABP both under control conditions and conditions with L-NNA (Fig 3 ). Consequently, the coronary arterioles were divided into two groups (ie, the vessels with diameter smaller than 110 µm and those with diameter larger than 110 µm according to our previous experiments [11, 12]. When the effects of IABP on the end-diastolic diameters were compared between these two vessel groups, the vasodilatory effect of IABP in small arterioles (15.4% ± 2.2%, p < 0.0001; Fig 4 ) was greater than that in large arterioles (4.2% ± 1.2%, p < 0.0001, p < 0.01; large versus small arterioles). The vasodilatory effect of IABP was attenuated by L-NNA to about one-third in small arterioles (p < 0.0001), whereas L-NNA caused a small effect on the end-diastolic diameter change in large arterioles (L-NNA versus control, p = 0.54), obscuring the size-dependent difference in the vasodilatory effects of IABP between small and large arterioles (5.9% ± 1.2% versus 2.4% ± 1.6%, respectively; p = 0.19). Supplemental L-arginine administration partly recovered the inhibitory effects of L-NNA administration on coronary arteriolar dilation by IABP (7.1% ± 1.5%, p = 0.07; versus control; Fig 2 and Table 3). In these conditions with L-NNA + L-arginine, small arterioles were more dilated than large arterioles by IABP (8.9% ± 1.7% versus 2.5% ± 1.5%, respectively, p < 0.05; Fig 4 and Table 3).
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Fig 3. Relations between end-diastolic coronary arteriolar diameters and their percentage changes by intraaortic balloon pumping (IABP). There were inverse relations between end-diastolic coronary arteriolar diameters and their percentage changes by intraaortic balloon pumping both under control conditions and under conditions with N-nitro-L-arginine (L-NNA). Dotted line indicates 95% confidence interval for each regression line.
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Figure 5 shows the effects of IABP on pulsation amplitude of the small and large arterioles. Intraaortic balloon pumping increased the pulsation amplitude in both small and large arterioles under control conditions (p < 0.0001, p < 0.05, respectively) from 1.2% ± 1.3% (IABP-off) to 12.0% ± 1.7% (IABP-on) on the average, but the percentage change in pulsation amplitude was greater in small arterioles than in large arterioles (p < 0.0001). Because there were no significant differences in end-systolic diameters between IABP-on and IABP-off (107.4 ± 10.1 mm versus 105.8 ± 10.1 mm, respectively, p = 0.50), IABP must have augmented the pulsation amplitude of the coronary arterioles by dilating the vessels in diastole. This effect was greatly attenuated to about one-third of that under control conditions by L-NNA in small arterioles (p < 0.0001). In large arterioles, however, there was no significant change from the control conditions after administration of L-NNA (p = 0.98). After additional administration of L-arginine, the pulsation amplitude was significantly augmented in small arterioles (p< 0.05 versus L-NNA), but changed little in large arterioles (p = not significant versus L-NNA).
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Comment
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This study observes directly the diastolic vasodilatory responses of the coronary arterioles due to mechanical pressure and flow enhancement by IABP. The major findings from the present study are as follows: (1) Inhibition of coronary EDNO synthesis by L-NNA significantly attenuated the diastolic arteriolar dilation and the augmentation of CBF by IABP. (2) The vasodilatory effect of IABP through EDNO was greater in small arterioles (< 110 µm) than in larger arterioles ( 110 µm) under control conditions. These findings indicate that the diastolic mechanical arteriolar dilation by IABP is augmented by EDNO, causing a further increase in diastolic coronary flow.
Possible endothelium-dependent vasodilatory mechanisms induced by intraaortic balloon pumping
Coronary arterial vessels are subject to receive two major mechanical forces from the blood flow: (1) shear stress, the tangential frictional force produced by blood flow, and (2) transmural pressure, acting perpendicular to the vascular wall. IABP induced increase in coronary flow was observed during diastole not only in the proximal portion [14], but also in the distal portion of the coronary arteries [9]. Therefore, it is expected that IABP augments shear stress in diastole over a substantial area of the endothelium of the coronary resistance arterioles. Shear stress is the major stimuli in vivo of various endothelium-dependent vasodilatory mechanisms including nitric oxide [6], hyperpolarization [15], and prostacyclin [16]. Oscillatory shear stress further enhances the EDNO release [7]. Thus, it is conceivable that increased shear stress with greater pulsation amplitude contributes to IABP-induced coronary arteriolar dilation and the associated increase in CBF. In the present study, as inhibition of coronary EDNO synthesis by L-NNA greatly attenuated the IABP-induced coronary arteriolar dilation (Fig 2), EDNO is likely to play a major role during IABP as the link between mechanical coronary hemodynamic modulation and coronary arteriolar responses, resulting in a reinforcement of the coronary vasodilation and the augmentation of CBF. Supporting this explanation, supplemental administration of L-arginine after administration of L-NNA recovered the vasodilatory effects of IABP partly, although it was not statistically significant. In the present study, ibuprofen, a cyclooxygenase inhibitor, was administered at a dose that is high enough to inhibit the formation of cyclooxygenase products in the coronary circulation [17]. Thus, the influence of prostacyclin on the coronary arteriolar responses to IABP would be minimal. Hyperpolarization and its possible conduction along the vessels may also be involved in the mechanisms of the coronary arteriolar dilation caused by IABP. However, the relative contribution of hyperpolarization factor may be smaller, as L-NNA greatly attenuated the vasodilatory response.
Size-dependency of intraaortic balloon pumping-induced coronary arteriolar dilatory effect
In the present study, we observed a remarkable diastolic vasodilatory effect of IABP in the small arterioles and its inhibition by L-NNA compared to large arterioles (Figs 3 and 4). Why was the diastolic enhancement of the vasodilatory effect of IABP through EDNO greater in smaller arterioles? The first reason may be elevated pressure of small arterioles with EDNO-induced vasodilation. According to Chilian and colleagues [18], coronary vasodilation causes pressure elevation in smaller arterioles predominantly. Thus, the relatively elevated diastolic pressure in smaller arterioles by IABP may contribute to the diastolic enhancement of smaller arteriolar vasodilation with higher compliance by the vasodilation due to EDNO. Second, in isolated coronary arterioles, large arterioles (80 to 130 µm in diameter) are reported to be more responsive to shear stress stimulation, resulting in vasodilation [3]. However, in vivo side-to-side interaction between the vessels running in parallel may be present, as diffusion distance of nitric oxide reportedly amounted to approximately 175 µm [19]. This may cause the dilation of small arterioles under in vivo conditions by the interaction from larger to smaller arterioles. In addition, the shear rate in smaller arterioles was reported to be higher in rat mesenteric arterioles [20]. If the allocation of increased shear rate attributable to diastolic flow augmentation by IABP is greater in smaller coronary arterioles, the increase rate of EDNO release in smaller arterioles may be greater than that in larger arterioles, resulting in higher compliance (larger diastolic diameter) of the smaller arterioles by vasodilation. The other possibility might be higher sensitivity of EDNO response to pulsatile shear rate change in smaller arterioles in vivo.
Nitric oxide kinetics in the coronary circulation during intraaortic balloon pumping
Recent progress in the measurement of nitric oxide in tissue [21, 22] provided better understanding of the time course of EDNO released in response to a change in flow. Mochizuki and colleagues [22] demonstrated using a nitric oxide-sensing microelectrode that a stepwise increase in steady flow to an isolated canine femoral artery caused an immediate increase in nitric oxide from the vascular media (within a few seconds). Because specific GTP-binding protein is rapidly activated within 1 second from the start of flow [23], mechanochemical signal transduction in shear-stimulated endothelium may be quick enough to be regulated on a beat-to-beat basis at least partly. More recently, Pinsky and associates [5] demonstrated that using porphyrinic nitric oxide sensor, nitric oxide is released in pulsatile fashion (diastolic predominance) within a cardiac cycle of rabbit and rat beating hearts in vivo. Thus, the instantaneous (beat-to-beat) change of nitric oxide production and an overall increase in EDNO release by high diastolic shear stress and diastolic-to-systolic flow oscillation may enhance the diastolic flow augmentation of IABP. The contribution of EDNO delivered by the coronary blood flow stream to the coronary arteriolar dilation during IABP may be minimal, if any, because EDNO released into blood is considered to be rapidly inactivated by hemoglobin [24] and superoxide anion [25].
Other possible effects of intraaortic balloon pumping on arteriolar vasomotor tone
The metabolic vasomotor change between the coupled beat of IABP-on and IABP-off would be negligible as indicated by the small change in the rate–pressure product by IABP, which is similar to the results in our previous study [9]. However, some vasodilatory mechanisms other than the shear stress-induced endothelial-dependent mechanisms may also contribute to the coronary arteriolar dilation during IABP. Recently, for example, Goto and colleagues [26] demonstrated that increasing the pulsatile transmural pressure amplitude applied to the isolated porcine coronary arterioles at a constant mean pressure caused dilation of these vessels. The pulsation-induced vasodilation occurred through endothelium-independent mechanisms. These mechanisms may also contribute to the IABP-induced coronary vasodilation. Some vasoconstrictive mechanisms may be concealed in the arteriolar vasodilatory responses caused by IABP. First, myogenic constriction might be activated by an increase in diastole AoP caused by IABP (Table 2). Second, the increased diastolic pressure in diastole by IABP might diminish EDNO synthesis in a pressure-dependent manner, as EDNO release is reported to be inversely correlated with the luminal pressure [27]. Third, shear stress-induced release of vasoconstrictive factors such as endothelin-1 [28] might diminish the effects of vasodilating factors induced by IABP. Nevertheless, IABP must have overcome these possible vasoconstrictory mechanisms, resulting in a significant enhancement of diastolic arteriolar vasodilation and coronary inflow into the myocardium.
Clinical implications
The present study indicated that IABP might be most efficient in the coronary inflow, when the coronary endothelial function is well preserved. In terms of individual differences of coronary endothelial function, various increasing responses of CBF to ACh administration under control conditions were observed in each vessel (Table 1). In fact, the vasodilatory effect of IABP in individual arterioles was significantly correlated with the increasing rate of CBF to ACh administration. This may suggest the clinical importance of endothelial function on IABP augmentation of diastolic coronary flow. Conversely, this beneficial effect of IABP through EDNO release could not be expected much in various cases of heart failure with endothelial dysfunction [29], for example, in heart failure with risk factors for coronary artery disease [4] and extensive coronary atherosclerosis in which coronary endothelial dysfunction has been demonstrated using ACh. However, it may be still advantageous for these patients to have a combination therapy of IABP with drugs, for example, an adequate dose of L-arginine that may regain normal endothelium-dependent function. Further studies are expected to find beneficial combinations of mechanical and pharmacologic modulations of the flow-induced endothelium-dependent coronary vasodilation.
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Acknowledgments
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This study was supported by Grant-in-Aid 08770527 for Encouragement of Young Scientists from the Ministry of Education, Science, Sports and Culture, Japan for 1996.
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References
|
|---|
-
Kelm M., Schrader J. Control of coronary vascular tone by nitric oxide. Circ Res 1990;66:1561-1575.[Abstract/Free Full Text]
-
Smith T.P., Jr, Canty J.M., Jr Modulation of coronary autoregulatory responses by nitric oxide. Evidence for flow-dependent resistance adjustments in conscious dogs. Circ Res 1993;73:232-240.[Abstract/Free Full Text]
-
Kuo L., Davis M.J., Chilian W.M. Longitudinal gradients for endothelium-dependent and independent vascular responses in the coronary microcirculation. Circulation 1995;92:518-525.[Abstract/Free Full Text]
-
Quyyumi A.A., Dakak N., Andrews N.P., et al. Nitric oxide activity in the human coronary circulation. Impact of risk factors for coronary atherosclerosis. J Clin Invest 1995;95:1747-1755.
-
Pinsky D.J., Patton S., Mesaros S., et al. Mechanical transduction of nitric oxide synthesis in the beating heart. Circ Res 1997;81:372-379.[Abstract/Free Full Text]
-
Vanhoutte P.M. Other endothelium-derived vasoactive factors. Circulation 1993;87(suppl 5):9-17.
-
Noris M., Morgi M., Donadelli R., et al. Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions. Circ Res 1995;76:536-543.[Abstract/Free Full Text]
-
Recchia F.A., Senzaki H., Saeki A., Byrne B.J., Kass D.A. Pulse pressure-related changes in coronary flow in vivo are modulated by nitric oxide and adenosine. Circ Res 1996;79:849-856.[Abstract/Free Full Text]
-
Kimura A., Toyota E., Lu S., et al. Effects of intraaortic balloon pumping on septal arterial blood flow velocity waveform during severe left main coronary artery stenosis. J Am Coll Cardiol 1996;27:810-816.[Abstract]
-
Yada T., Hiramatsu O., Kimura A., et al. In vivo observation of subendocardial microvessels of the beating porcine heart using a needle-probe videomicroscope with a CCD camera. Circ Res 1993;72:939-946.[Abstract/Free Full Text]
-
Yada T., Hiramatsu O., Goto M., et al. Effects of nitroglycerin on diameter and pulsation amplitude of subendocardial arterioles in beating porcine heart. Am J Physiol 1994;267:H1719-H1725.[Abstract/Free Full Text]
-
Yada T., Hiramatsu O., Kimura A., et al. Direct in vivo observation of subendocardial arteriolar response during reactive hyperemia. Circ Res 1995;77:622-631.[Abstract/Free Full Text]
-
Buxton I.L., Cheek D.J., Eckman D., Westfall D.P., Sanders K.M., Keef K.D. NG-nitro L-arginine methyl ester and other alkyl esters of arginine are muscarinic receptor antagonists. Circ Res 1993;72:387-395.[Abstract/Free Full Text]
-
Kern M.J., Aguirre F.V., Tatineni S., et al. Enhanced coronary blood flow velocity during intraaortic balloon counterpulsation in critically ill patients. J Am Coll Cardiol 1993;21:359-368.[Abstract]
-
Olesen S.P., Clapham D.E., Davies P.F. Haemodynamic shear stress activates a K+ current in vascular endothelial cells. Nature 1988;331:168-170.[Medline]
-
Frangos J.A., Eskin S.G., McIntire L.V., Ives C.L. Flow effects on prostacyclin production by cultured human endothelial cells. Science 1985;227:1477-1479.[Abstract/Free Full Text]
-
Altman J.D., Bache R.J. The mechanism of coronary collateral vasoconstriction in response to cyclooxygenase blockade. Circ Res 1994;74:310-317.[Abstract/Free Full Text]
-
Chilian W.M., Layne S.M., Klausner E.C., Eastham C.L., Marcus M.L. Redistribution of coronary microvascular resistance produced by dipyridamole. Am J Physiol 1989;256:H383-H390.[Abstract/Free Full Text]
-
Leone A.M., Furst V.W., Foxwell N.A., Cellek S., Moncada S. Visualisation of nitric oxide generated by activated murine macrophages. Biochem Biophys Res Commun 1996;221:37-41.[Medline]
-
Pries A.R., Secomb T.W., Gaehtgens P. Design principles of vascular beds. Circ Res 1995;77:1017-1023.[Abstract/Free Full Text]
-
Kanai A.J., Strauss H.C., Truskey G.A., Crews A.L., Grunfeld S., Malinski T. Shear stress induces ATP-independent transient nitric oxide release from vascular endothelial cells, measured directly with a porphyrinic microsensor. Circ Res 1995;77:284-293.[Abstract/Free Full Text]
-
Mochizuki S., Goto M., Hirano K., Fukuhiro Y., Kajiya F. Direct measurement of nitric oxide in arterial wall using newly developed nitric oxide microsensor. Biomed Engineer Appl Basis Com 1996;8:336-341.
-
Gudi S.R., Clark C.B., Frangos J.A. Fluid flow rapidly activates G proteins in human endothelial cells. Involvement of G proteins in mechanochemical signal transduction. Circ Res 1996;79:834-839.[Abstract/Free Full Text]
-
Lancaster J.R., Jr Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc Natl Acad Sci USA 1994;91:8137-8141.[Abstract/Free Full Text]
-
Pryor W.A., Squadrito G.L. The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol 1995;268:L699-L722.[Abstract/Free Full Text]
-
Goto M., VanBavel E., Giezeman M.J., Spaan J.A. Vasodilatory effect of pulsatile pressure on coronary resistance vessels. Circ Res 1996;79:1039-1045.[Abstract/Free Full Text]
-
Hishikawa K., Nakai T., Suzuki H., Saruta T., Kato R. Transmural pressure inhibits nitric oxide release from human endothelial cells. Eur J Pharmacol 1992;215:329-331.[Medline]
-
Kuchan M.J., Frangos J.A. Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol 1993;264:H150-H156.[Abstract/Free Full Text]
-
Smith C.J., Sun D., Hoegler C., et al. Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. Circ Res 1996;78:58-64.[Abstract/Free Full Text]
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Abstract
Introduction
