Delayed Enhanced Nitric Oxide–Mediated Coronary Vasodilation Following Brief Ischemia and Prolonged Reperfusion in Conscious Dogs
Abstract The goal of this study was to determine both the early and delayed effects of a brief (10-minute) coronary artery occlusion (CAO) and prolonged (5-day) reperfusion (CAR) on coronary endothelial function. Fourteen mongrel dogs were chronically instrumented to measure aortic and left ventricular pressures, wall thickness, and left circumflex coronary blood flow (CBF). Before CAO and during CAR, coronary vascular reactivity was investigated by 15-second CAO and subsequent reactive hyperemia (RH) and by the selective intracoronary infusion of acetylcholine (ACh, 10 μg/min) and bradykinin (BK, 2.5 μg/min), endothelium-dependent vasodilators, and sodium nitroprusside (SNP, 40 μg/min), an endothelium-independent vasodilator. CBF responses to ACh and BK began to increase after 6 hours of CAR, reached a peak after 1 to 2 days of CAR, and then subsided over the subsequent 4 days. After 1 day of CAR, compared with before CAO, enhanced CBF responses (P<.05), associated with increased coronary sinus oxygen content, were observed for ACh (+66±20%), BK (+74±24%), and RH (+24±5%) but not SNP (−2±10%). Production of NO metabolites (nitrate and nitrite), measured as their coronary arteriovenous difference×CBF, was significantly increased after 1 to 2 days of CAR, both at baseline (153±56%) and during BK infusion (220±76%) (P<.05). Holding CBF at pre-CAO levels during the initial CAR period did not attenuate the delayed enhanced endothelial vasodilation to ACh and BK. However, NO blockade with intracoronary NG-nitro-l-arginine blocked the enhanced coronary vasodilation to ACh and BK. Thus, in contrast to previous studies, these data indicate that brief ischemic episodes induce delayed enhanced coronary endothelial function, which is delayed in onset and prolonged in duration. This can be explained by an upregulation of coronary vascular NO production, potentially involved in the mechanism of the delayed window of preconditioning.
Brief periods of CAO, 5 to 15 minutes, induce prolonged functional impairment of myocardial contraction, ie, myocardial stunning.1 2 3 Compared with numerous studies examining the stunned myocardium, relatively few studies examined the effects of stunning on coronary vasoactivity. Previous studies, using isolated coronary artery ring preparations, have shown that vascular injury is not observed until 60 to 90 minutes after CAO and that endothelium-dependent vasodilator function is impaired for only a few hours without morphological damage.4 5 6 However, studies have also noted endothelial dysfunction in association with shorter periods of myocardial ischemia and reperfusion7 8 ; Nicklas and Gips7 reported that a transient period of myocardial ischemia (15 minutes) significantly decreased coronary flow reserve, whereas Kim et al,8 using isolated coronary artery ring preparations, demonstrated that 10-minute ischemic episodes also induce stunning of endothelium, ie, transiently impaired vasodilation to ACh, without smooth muscle dysfunction or any endothelial structural damage.
Interestingly, there is no information available on the delayed effects of brief periods of ischemia on endothelial function of the coronary circulation. This may be due to the fact that most previous studies used acute preparations, which are not suitable for studying long periods after the initial ischemic insult. Thus, the present investigation is unique in examining both the early and delayed effects (up to 5 days) of brief periods (10 minutes) of myocardial ischemia on coronary endothelial function in chronically instrumented conscious dogs. Another important aspect of the experimental design is the utilization of a chronically implanted intracoronary catheter, which minimizes alterations of hemodynamic factors and concomitant changes in myocardial oxygen demand and in neurohumoral reflexes induced by the intravenous administration of drugs. Once it was established that brief periods of myocardial ischemia induced delayed enhanced vasodilator responses to intracoronary ACh and BK, endothelial vasodilators, the second goal was to determine whether the enhanced vasodilation resulted in the appearance of increased levels of NO in the coronary sinus effluent. The third goal of the present study was to determine whether these effects could be attenuated either by administration of an NO synthesis inhibitor9 or by preventing the hyperemia during early CAR, which would provide information on the mechanism of the delayed enhanced endothelial function, ie, whether it was triggered by the period of ischemia or by increased shear stress associated with the marked hyperemia characteristic of early CAR.
Materials and Methods
Fourteen mongrel dogs of either sex weighing 24 to 30 kg were sedated with xylazine (0.5 to 1.0 mg/kg IM). General anesthesia was induced with sodium thiopental (8 to 10 mg/kg IV) and, after intubation, was maintained with halothane (0.5 to 1.5 vol%). By use of a sterile surgical technique, the heart was exposed through a left thoracotomy at the fifth intercostal space and instrumented as illustrated in Fig 1⇓. Tygon catheters were implanted in the descending aorta and in the left atrium for measurement of pressures and radioactive microsphere injection. LV pressure was measured by implanting a solid-state miniature pressure gauge (model P7, Konigsberg Instruments) in the LV through an apical incision. The left circumflex coronary artery was dissected free for a distance of ≈3 cm; care was taken not to damage the vessel adventitia and surrounding nerves.10 11 A Transonic transit time flow probe (Transonic Systems Inc) was implanted around the base of the left circumflex artery for measurement of CBF, and a hydraulic occluder was placed distal to the flow probe to occlude the coronary artery. A coronary arterial catheter was implanted distal to the occluder in 11 of the 14 dogs. Another Silastic catheter was inserted into the coronary sinus for myocardial venous blood sampling. Two pairs of 5-mHz ultrasonic crystals were implanted transmurally across the LV free wall in the anterior and in the posterior regions for measurement of regional myocardial wall thickening.
After the surgical preparation was completed, the catheters, occluder, and the lead wires were tunneled under the skin to exit between the scapula. The ribs were approximated, the incision was closed in layers, and the thoracic cavity was evacuated. Antibiotics and analgesics were given for 5 days or as needed. The indwelling catheters were flushed daily with heparinized saline to maintain patency. Animals used in the present study were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and the Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services Publication No. [NIH] 85-23, revised 1985).
Aortic and left atrial pressures were measured with Statham strain-gauge transducers (model P23-XL, Spectra-Med, Inc), which were calibrated using a mercury manometer. A cardiotachometer (Beckman), triggered by the LV pressure pulse, provided a continuous recording of heart rate. LV dP/dt was derived from the LV pressure signals using an electronic differentiator. The solid-state LV pressure gauge was cross-calibrated against measurements of systolic aortic and left atrial pressures. During each experiment, hemodynamic variables were recorded continuously both on a multichannel tape recorder (Honeywell) and played back on a direct-writing oscillograph (Gould). Regional myocardial blood flow was measured before and during CAO with radioactive labeled microspheres (15±2 μm, New England Nuclear).
Plasma levels of NO metabolites, nitrate (NO3−), and nitrite (NO2−), an index of endothelium-derived NO, were measured as previously described.12 Dogs were fasted for >12 hours before the experiments so that dietary NO3− would not affect the serum levels of NO3−.13 Briefly, duplicate blood samples (each 4 mL) were obtained from the aorta and coronary sinus in heparinized tubes. The blood was centrifuged at 4000g for 20 minutes, and then the plasma was frozen for at least 24 hours before analysis. For measurement of plasma nitrate plus nitrite, nitrate was reduced to nitrite by adding to each tube 10 μL (0.2 U) Aspergillus nitrate reductase (reconstituted in distilled water as 20 U/mL), 10 μL (0.1 μmol) flavin adenine dinucleotide, and 10 μL (0.1 μmol) reduced NADP (Boehringer-Mannheim Biochemicals). Tubes were capped immediately with a rubber septum (Suba-Seal Septa, Aldrich Chemical Co), and the oxygen in the headspace above the sample was removed and replaced with argon. Samples were incubated at 36°C for 1 hour under the inert argon atmosphere to allow conversion of nitrate to nitrite. After incubation, 40 μL concentrated HCl was added through the seal to each reaction tube to achieve a pH <2. Tubes were incubated for an additional 5 minutes at 36°C. A 250-μL sample of the headspace gas was removed from the sealed tubes at the end of the incubation and injected into the NO analyzer to quantify the NO released into the headspace gas. Standard curves for nitrate were constructed. To calculate the intra-assay coefficient of variation, the basal nitrate and nitrite in each assay were run in triplicate, and the differences were compared.
At least 10 to 14 days of recovery from surgery was allowed before experimentation was begun. During this period, dogs were trained to lie quietly on the table. Hemodynamic variables (aortic pressure, LV pressure, left atrial pressure, rate of change of LV pressure [dP/dt], LV anterior and posterior wall thicknesses, heart rate, and lead II ECG) were monitored continuously throughout the study. All animals received an injection of morphine sulfate (0.2 mg/kg IM) before CAO. After control measurements were recorded, including the first injection of microspheres, CAO was accomplished by inflating the hydraulic occluder. At 5 minutes after CAO, microspheres were injected again. Ventricular premature contractions were prevented and treated with bolus left atrial injections of 2% lidocaine. After 10 minutes of CAO, the coronary artery occluder was released slowly over 30 seconds. Hemodynamic variables during CAR were monitored continuously for 6 hours and then at 1, 2, and 5 days, until full recovery of regional myocardial and vascular function.
To determine the magnitude and duration of altered endothelial or nonendothelial coronary vascular reactivity after 10 minutes of occlusion and 5 days of reperfusion, the direct coronary effects of ACh and BK, endothelium-dependent vasodilators, and SNP, an endothelium-independent vasodilator, were investigated in each of the 8 dogs at the following infusion rates: (1) ACh (10 μg/min), (2) BK (2.5 μg/min), and (3) SNP (40 μg/min). The concentrations of these vasodilators were formulated so that an identical infusion rate was used for each drug (0.5 mL/min). The low infusion rate and concentrations were selected to avoid both hemodilution and systemic effects secondary to recirculation. The order of the intracoronary infusions was randomized by drug, and at least 15 minutes intervened between each intracoronary infusion to permit recovery and acquisition of predrug control values before the subsequent infusion. The responses to intracoronary vasodilators were assessed before CAO (baseline) and after 30 minutes, 1 hour, 3 hours, 6 hours, 1 day, 2 days, and 5 days of reperfusion. At baseline and after 1 day of reperfusion, blood samples from the aorta and coronary sinus were taken to determine oxygen content and measurement of NO metabolites at steady-state condition during infusion of each vasodilator from respective control conditions. Coronary reactive hyperemia was determined after the release of a 15-second CAO at baseline and after 30 minutes and 1 day of reperfusion.
To determine whether the enhanced endothelial function following 10-minute coronary occlusion could be attenuated or prevented by treatment with an NOS inhibitor, L-NA was administered (2 mg/min IC for 25 minutes) in 3 additional dogs at least 12 hours before CAO, 30 minutes before CAO, and after 1 day of CAR, and then the responses to the vasodilators were repeated during reperfusion (see above). L-NA was dissolved in saline after 20 to 30 minutes of sonication as described by Moore et al.9 There was no significant change in baseline CBF between pre–and post–L-NA values (32±7 vs 28±7 mL/min) (n=3).
To determine whether the delayed enhanced endothelial function could be eliminated by preventing the marked increase in CBF following the release from the 10-minute CAO, in 3 of the original 8 dogs studied, the occluder was deflated until CBF reached pre-CAO levels during the initial reperfusion period and was maintained at pre-CAO levels. During reperfusion, the protocol for the intracoronary infusion of vasodilators was repeated (see above).
To determine whether the intracoronary catheter was responsible for the enhanced endothelial function, in 3 dogs without an intracoronary catheter the protocol was conducted with intravenous administration of ACh (3 μg/kg) and SNP (4 μg/kg).
An additional 4 dogs were instrumented but were not included in the data analysis because of ventricular fibrillation during the 10-minute CAO.
Data are reported as mean±SE. Differences between means were considered statistically significant if the probability of their occurring by chance was <5% (P<.05). For all comparisons, data within and among the protocols were analyzed for statistical significance using one-way ANOVA for repeated measures, contrast analysis for individual comparisons, and Student’s t test for paired data (baseline versus 1-day CAR, left circumflex territory [ischemic zone] versus left anterior descending territory [nonischemic zone], and presence versus absence of NO blockade).14
Systemic Hemodynamics and Regional Myocardial Function
Fig 2⇓ represents mean values for systemic hemodynamics (mean aortic pressure, left atrial pressure, LV dP/dtmax, and heart rate) during 10-minute CAO and CAR for 5 days. During CAO (at 9-minute CAO), mean aortic pressure, left atrial pressure, and heart rate increased significantly, whereas LV dP/dtmax decreased significantly. However, after CAR all measurements of systemic hemodynamics returned to baseline levels by 30 minutes and did not change further during CAR. During CAO, the posterior wall thickening (ischemic zone) was significantly reduced (−108±15% from baseline) (P<.05) and did not recover to baseline after 6 hours of CAR, indicating myocardial stunning, whereas anterior wall thickening (nonischemic zone) did not change significantly throughout the experiment (Fig 3⇓). Ten-minute CAO caused significant decreases in subendocardial and subepicardial blood flows in the left circumflex territory (from 1.03±0.14 to 0.03±0.02 and from 0.82±0.16 to 0.17±0.08 mL·min−1·g−1, respectively) (P<.05), whereas transmural myocardial blood flow in the left anterior descending territory did not change.
CBF Responses to Vasodilators
Intracoronary infusions of ACh, BK, and SNP caused significant increases in CBF without any changes in systemic hemodynamics. Fig 4⇓ depicts a representative tracing of CBF during intracoronary infusion of ACh and BK at baseline and after 3 hours, 6 hours, 1 day, 2 days, and 5 days of CAR, demonstrating enhanced coronary vasodilation to both endothelial vasodilators after 1 and 2 days of CAR. Fig 5⇓ summarizes CBF response to these vasodilators before CAO and during CAR. The 10-minute ischemic episode induced a biphasic effect on coronary endothelial function (Fig 5⇓). Initially, the endothelium-dependent coronary vasodilator response to ACh was depressed significantly at 30 minutes after CAR (−19±8%) (P<.05). In contrast, endothelium-dependent coronary vasodilator responses to both ACh and BK began to increase after 6 hours of reperfusion, with a maximum vasodilator response 1 to 2 days later, and then subsided over the subsequent 4 days, as shown in Figs 4⇓ and 5⇓. After 1 day of CAR, CBF responses to ACh and BK were increased significantly compared with pre-CAO baseline responses (from 106±12% to 174±25% and from 105±13% to 174±21%, respectively) (P<.05), whereas there were no significant differences in endothelium-independent vasodilator response to SNP (Fig 5⇓). In brief, SNP increased CBF from 34±3 to 58±2 mL/min before CAO and, similarly, from 32±4 to 57±2 mL/min after 10-minute CAO and 24-hour CAR.
To determine whether the enhanced endothelium-dependent coronary vasodilator response observed after 1 to 2 days of CAR was partially due to inadvertent side effects of the intracoronary catheter, a bolus dose of ACh (3 μg/kg) was given intravenously to 3 dogs without chronic intracoronary catheters before CAO and after 1 day of CAR. After 1 day of CAR, CBF responses to intravenous ACh were also increased significantly from 149±12% to 212±34% (P<.05). After 5 days of CAR, the response to ACh returned to pre-CAO levels. This indicates that the intracoronary catheter was not responsible for the enhanced endothelium-dependent coronary vasodilator responses after 1 to 2 days of CAR. Holding coronary flow to pre-CAO levels during the initial reperfusion period in 3 dogs did not prevent the delayed, enhanced (P<.05), endothelium-dependent vasodilator responses to both ACh (from 98±3% to 186±50%) and BK (from 89±13% to 155±56%), but not SNP, after 1 day of CAR.
Reactive Hyperemia at Early and Late Reperfusion
Table 1⇓ summarizes changes in peak flow and peak/baseline flow and repayment/debt ratio before CAO and after 30 minutes and 1 day of CAR following 10-minute CAO (n=5). At 30 minutes after CAR, peak reactive hyperemia and the ratio of peak/baseline and repayment/debt were significantly reduced (−23±8%, −19±7%, and −30±11%, respectively) (P<.05). In contrast to the depressed response after 30 minutes of CAR, these values were increased significantly after 1 day of CAR (+23±5%, +16±9%, and +30±4%, respectively) (P<.05).
Coronary Arteriovenous O2 Content and NO Metabolites
Table 2⇓ summarizes the changes in CBF, arterial and venous oxygen content, and percent changes in posterior wall thickening during intracoronary infusion of ACh, BK, and SNP at baseline and after 1 day of CAR (n=4). After 1 day of CAR, intracoronary ACh and BK, but not SNP, significantly increased both CBF and coronary sinus oxygen content compared with respective pre-CAO responses. However, intracoronary infusion of vasodilators did not affect posterior wall thickening or systemic hemodynamics either at baseline or after 1 day of CAR.
Table 3⇓ summarizes the production of NO metabolites before (n=6) and during (n=3) intracoronary infusion of BK before CAO (pre-CAO) and after 1 day of CAR. Compared with pre-CAO values, production of NO metabolites was increased significantly both at baseline (153±56%) and during BK administration (220±76%) after 1 day of CAR. Thus, the delayed and enhanced coronary vasodilation after 1 day of CAR can be explained by an upregulation of coronary vascular NO production.
Responses After Intracoronary L-NA
There were no significant changes in baseline systemic hemodynamics and CBF before versus after L-NA administration, verifying that intracoronary L-NA did not affect systemic hemodynamics. During CAO, mean aortic pressure, LV systolic pressure, LV end-diastolic pressure, and heart rate increased significantly, whereas these variables returned to baseline levels by 30 minutes and did not change throughout 5 days of CAR. However, L-NA (intracoronary) caused a significant delay in the recovery of posterior wall thickening (ischemic zone) following 10-minute CAO (data not shown).
Fig 6⇓ shows an example of CBF responses to ACh and BK before CAO and after 1 day of CAR in the presence of NO blockade (n=3). Before 10 minutes of CAO, intracoronary NO blockade with L-NA caused significantly blunted endothelium-dependent dilation with ACh (−60±15%) and BK (−61±15%) (P<.05), but not SNP (−1±12%). After 1 day of CAR, CBF responses to ACh and BK were not enhanced compared with responses in the presence of NO blockade (after L-NA), whereas CBF responses to SNP were not different. In the 3 dogs studied, baseline CBF fell from 32±7 to 28±7 mL/min and remained at 26±5 mL/min after 1 day of CAR. After L-NA administration, ACh increased CBF to 53±15 mL/min and by a similar amount (50±11 mL/min) after 1 day of CAR. Similarly, after L-NA administration, BK increased CBF to 60±15 mL/min and by a similar amount (62±14 mL/min) after 1 day of CAR.
The effects of brief periods of CAO and CAR, resulting in myocardial stunning, have been studied extensively on myocardial function and with more prolonged ischemia leading to infarction.1 2 3 Less information is available on the effects of brief ischemic episodes on coronary reactivity. Ku5 and VanBenthuysen et al,6 using isolated coronary artery ring preparations, observed depressed vascular reactivity to endothelium-dependent vasodilators after 60 to 90 minutes of ischemia. Since then, many studies have focused on the time course and the causes of endothelial dysfunction induced by ischemia.15 16 17 18 Tsao et al18 found that endothelial dysfunction did not occur before reperfusion at least in ischemic periods of up to 90 minutes and that endothelial dysfunction occurred very early after reperfusion (ie, within 2.5 minutes) and was severe (ie, a 75% impairment). However, relaxation in response to the endothelium-independent dilator NaNO2 was preserved, indicating that the defect in vasodilation was in the endothelium rather than the coronary vascular smooth muscle. Many studies have also confirmed that vascular injury is not observed until 60 to 90 minutes after CAO or that endothelium-dependent vasodilator function is impaired for only a few hours without morphological damage. 7 18 Studies have also noted endothelial dysfunction in association with shorter periods of myocardial ischemia and reperfusion.7 8 Nicklas and Gips7 reported that a transient period of myocardial ischemia (15 minutes) significantly decreased coronary flow reserve, whereas Kim et al8 demonstrated that 10-minute ischemic episodes also induce stunning of endothelium without smooth muscle dysfunction or any endothelial structural damage. They found that vasodilator responses to ACh were impaired during the first hour of reperfusion but gradually improved over 90 minutes after ischemia. The present study also demonstrated that a 10-minute brief ischemic episode induced transient endothelial dysfunction at 30 minutes after reperfusion, which was confirmed by blunted coronary vasodilator responses to ACh and reactive hyperemia.
In contrast to all the previous studies noted above, in the present investigation a 10-minute brief ischemic episode induced a significant increase in endothelium-dependent vasodilation in response to ACh and BK, which was first noted 6 hours after reperfusion, with a maximum response occurring 1 to 2 days later. Importantly, there was an increase in reactive hyperemia as well as endothelium receptor–mediated vasodilation (responses to ACh and BK). This increased endothelium-mediated vasodilation was primary, not secondary, to increased metabolic demand after 1 day of reperfusion, since coronary sinus oxygen content rose. Furthermore, there were no increases in posterior wall thickening, heart rate, arterial pressure, or hemodynamic factors that would result in coronary vasodilation secondary to increased myocardial metabolic demand. The mechanism of the enhanced vasodilation most likely involved upregulation of NO. In support of this concept, production of NO metabolites (nitrate and nitrite) was significantly increased 1 day after CAO and CAR at both baseline and during BK. Actually, the assessment of NO metabolites in coronary sinus blood may have been underestimated, because of the confluence of drainage from the nonischemic left anterior descending arterial bed. In further support, the experiments with L-NA, which inhibits the production of NO, demonstrated prevention of the enhanced endothelium-mediated coronary vasodilation after 1 day of CAR. Although the increased response after 1 day of CAR was abolished by NO blockade, ACh and BK still elicited some vasodilation, as expected, since L-NA is a competitive inhibitor of NOS.9 19 The experiments with L-NA did demonstrate intensification of the myocardial stunning, which has been shown previously.20 Which NOS of the three was responsible for the enhanced vasodilation was not determined. Endothelial cell NOS (NOS III) is most likely responsible for the enhanced NO production, since inducible NOS (NOS II) evokes substantial baseline arteriolar vasodilation and even hypotension. In addition, another characteristic of inducible NOS is sustained activity resulting in tissue damage,21 features not observed in the present study, where systemic hemodynamics and regional myocardial function were entirely normal after 1 day of CAR following 10-minute CAO. It is also important to consider the possibility that prostaglandins or hyperpolarizing factor may have played a role in the mechanism.22
In view of the delayed onset of the enhanced endothelium-dependent coronary vasodilation and its temporal relationship to a 10-minute ischemic preconditioning stimulus, it is tempting to speculate that the upregulation of NO production could be involved in the mechanism of the second window of preconditioning. Murry et al23 first described preconditioning as a mechanism of myocardial protection closely following the initial ischemic stimulus. More recently, a second window of protection has been described, which occurs ≈24 hours after the initial ischemic stimulus.24 25 The time course of the upregulation of NO production in the present study is consistent with that of the second window of ischemic preconditioning. In this connection, a study by Bolli et al26 in this issue of Circulation Research found that NO blockade prevented the delayed window of preconditioning against myocardial stunning in conscious rabbits, which is consistent with the findings in the present investigation.
The stimulus for the upregulation of NO production could be either the 10-minute period of ischemia or factors involved with reperfusion. For example, Beckman et al27 have proposed that reoxygenation after hypoxia may stimulate rapid NO synthesis by providing the O2 to produce NO, since the intracellular Ca2+ and other substrates (arginine and NADPH) would already be made available by the ischemic insult. Thus, the synthesized NO reacts rapidly with O2− to form peroxynitrite anion (ONOO−) and hydroxyl radical (HO−).27 The present investigation used a model of a brief period of ischemia, rather than hypoxia, which does not result in infarction, but only myocardial contractile stunning was observed after reperfusion. Furthermore, the upregulation of NO production was most likely protective, as it resulted in enhanced coronary vasodilation; when it was blocked with L-NA, intensification of the stunning was observed. Also associated with CAR is a marked hyperemia. It is well known that increases in blood flow velocity can result in augmented endothelium-mediated vasodilation.28 29 Accordingly, we repeated experiments in which the hyperemia was prevented but failed to attenuate the delayed, enhanced, endothelium-mediated coronary vasodilation. For these reasons, the 10-minute period of ischemia, rather than the reperfusion, was most likely the trigger for the upregulation of NO production.
One might argue that the genesis of the NO was derived from myocytes rather from coronary vessels. Although this is theoretically possible, it is unlikely because the vascular response was enhanced, whereas myocardial contractile responses to ACh and BK remained intact. Moreover, preliminary data using a microvascular preparation in vitro also showed enhanced NO metabolites in response to ACh and BK 1 day after 10-minute CAO and after 24 hours of CAR (authors’ unpublished data, 1997).
It is possible to speculate that this upregulation of NO-mediated coronary vasodilation is important not only in the second window of protection24 25 but also in coronary autoregulation. The latter phenomenon is composed of multiple mechanisms, all designed to protect the heart by maintaining its blood supply. Whereas the induction of coronary collaterals is a chronic compensatory adjustment to multiple ischemic episodes, it may be that upregulation of NO-mediated vasodilation may be an intermediate mechanism involved in coronary autoregulation.
Selected Abbreviations and Acronyms
|CAO||=||coronary artery occlusion|
|CAR||=||coronary artery reperfusion|
|CBF||=||coronary blood flow|
|LV||=||left ventricle (ventricular)|
This study was supported by US Public Health Service grants HL-33065, -30870, -33107, and -43023. Dr Kim was supported by a US Public Health Service grant (NRSA HL-09760).
- Received March 5, 1997.
- Accepted April 14, 1997.
- © 1997 American Heart Association, Inc.
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