Redistribution of Myocardial Blood Flow With Topical Nitroglycerin in Patients With Coronary Artery Disease
Background Unlike nonselective coronary vasodilators, nitroglycerin (GTN) is said to exert its primary vasodilatory effect on epicardial conductance vessels. Thus, in experimental models of coronary occlusion GTN appears to preferentially direct blood flow to poststenotic zones of ischemia. This phenomenon has, to date, not been tested in humans. Using positron emission tomography we examined the effect of transdermal GTN on global and regional myocardial perfusion in patients with angiographically proven coronary artery disease.
Methods and Results Myocardial perfusion with [13N]ammonia was estimated from dynamic time-activity curves at baseline and 3 hours following application of either a 0.4 mg/h GTN skin patch (n=10) or a placebo patch (n=10) in a double-blind parallel design. From resliced cross-sectional images, regional flow, expressed as [13N]ammonia retention, was estimated from 216 myocardial sectors. Ischemia was defined as a significant reduction (>2 SDs from average counts/pixel in maximally perfused zones) in [13N]ammonia retention within 10 contiguous myocardial sectors coupled with an increase or no change in counts derived from [18F]fluorodeoxyglucose. There was no change in global myocardial blood flow as expressed by [13N]ammonia retention following either placebo (0.61±0.14 to 0.62±0.12 min−1) or GTN (0.75±0.22 to 0.74±0.19 min−1). Conversely, there was a significant increase in the proportion of blood flow to the ischemic zones with GTN (73.9±12.6% to 94.9±17.8%; P<.05). No change in the distribution of blood flow to either ischemic or nonischemic zones was observed with placebo. A slight but insignificant decrease in [13N]ammonia retention in nonischemic zones was observed with GTN (1.01±0.31 to 0.93±0.26 min−1).
Conclusions This study suggests that under resting conditions topical GTN alters myocardial perfusion by preferentially increasing flow to areas of reduced perfusion with little or no change in global myocardial perfusion in patients whose angina is responsive to GTN.
Ever since T. Lauder Brunton first recorded relief of angina with inhaled amyl nitrite in 1867,1 investigators have puzzled over the mechanism by which nitroglycerin exerts its antianginal effects. Systemic (as opposed to intracoronary nitroglycerin) appears to redress the supply-demand imbalance of the anginal state by virtue of either or both of its venodilatory2 3 and afterload reducing actions.4 5 Despite its epicardial vasodilatory properties, nitroglycerin does not alter global myocardial blood flow under resting conditions,6 7 but neither is there a significant change in cardiac work.
In 1968, Fam and McGregor8 reported a unique observation on the heterogeneity of coronary flow based on differential sites of action of various coronary vasodilators. They demonstrated that intravenous nitroglycerin selectively relaxes the epicardial (conductance) vessels, thereby facilitating flow through collateral channels to zones of myocardial ischemia. Conversely, dipyridamole exerted its potent vasodilating action on the smaller resistance vessels, thus directing blood away from obstructed vessels with impaired autoregulatory function. The authors suggested that the difference in the sites of action of the drugs may explain their contrasting pharmacologic effects in patients with coronary artery disease.
It was therefore inferred that nitroglycerin may exert part of its antianginal effect by preferentially directing nutrient flow to ischemic myocardium. To our knowledge this has only been tested in humans by using either washout rates of intramyocardial 133Xe in anesthetized open-chest hearts9 or by computer-assisted measurements of luminal stenosis.10 11 Positron emission tomography (PET) offers a noninvasive approach that permits quantitative measurements of both global and regional myocardial perfusion in patients with coronary artery disease. Using [13N]ammonia as a flow tracer, we set out to quantify changes in global and regional myocardial perfusion in response to a single topical application of nitroglycerin in patients with angiographically proven coronary artery disease.
The study group was made up of 20 patients with chronic stable angina responsive to sublingual nitroglycerin. Subjects had to be ambulatory and between 30 and 79 years of age; the study was open to men and women. All patients had prior coronary angiograms within a mean±SD interval of 35±20 weeks of the PET study. There were no intervening revascularization procedures or changes in clinical status. For each patient there was at least one coronary artery with a cross-sectional stenosis occupying more than 50% of the luminal diameter. Eighteen patients showed evidence of exercise-induced myocardial ischemia as determined by a positive maximum exercise test (>1 mm flat ST segment depression for at least 80 msec). Reversible zones of myocardial ischemia were detected by an exercise 201Tl single-photon emission computed tomographic study (n=13) or a new wall-motion abnormality on an exercise radionuclide angiogram (n=8).
Excluded were patients with an acute myocardial infarction or a revascularization procedure within 3 months prior to the study. Also excluded were patients with uncontrolled arrhythmias, systolic hypotension (<100 mm Hg), intolerance to nitrates, and associated cardiovascular conditions such as tight aortic stenosis, diabetes mellitus, congestive heart failure, or cardiomyopathy. The protocol was approved by the Institutional Review Board of McMaster University Medical Centre. All patients gave written informed consent prior to the study.
This was a double-blind randomized placebo control study. Each patient entered the nuclear medicine laboratory following a 48-hour washout period during which time all cardiac medications (β-blockers, calcium blockers, angiotensin-converting enzyme inhibitors, and long-acting nitrates) were discontinued. Sublingual nitroglycerin was allowed as needed, and the number, dose, and time of administration were carefully documented. Patients were permitted a light breakfast between 7 and 8 am, and all studies began between 8:30 and 9 am.
To identify surface landmarks for accurate positioning of the heart within the 10-cm field of view of the tomograph scanner, patients were first placed under a gamma camera and given an intravenous injection of 99mTc–sulfur colloid (2.5 mCi) to outline the liver. The diaphragmatic and apical borders of the heart were identified as contiguous with the left superior edge of the liver and so marked on the patient’s precordium. Patients were then positioned within the gantry of an ECAT 953/31 (Siemens, Hoffman Est. Il) tomograph scanner. The scanner was equipped with 16 detector rings, which allowed acquisition of 31 contiguous transaxial slices. To verify anatomic landmarks and to correct for tissue attenuation, a rectilinear and transmission scan using a 68Ge ring source was acquired over 30 minutes. All patients then received 12 to 15 mCi [13N]ammonia as an IV injection over 30 seconds. Dynamic images were acquired over 24.33 minutes (12 frames at 5 s/frame, 4 frames at 20 s/frame, 2 frames at 60 s/frame, and the final image acquired over 20 minutes).
Immediately following this baseline scan, 20 patients were randomly allocated to receive a precordial skin patch containing either nitroglycerin (Nitro-Dur 0.4 mg/h; n=10) or placebo (n=10). Serial blood samples were drawn at baseline (just prior to patch application), 1.5 hours, and 3 hours for determination of 1,2- and 1,3-dinitroglycerin plasma levels.12
Two hours following patch application, patients were given a glucose drink (Trutol; 50 gm) to facilitate uptake of fluorodeoxyglucose (FDG) based on substrate concentration. At 3 hours they reentered the scanner. A second transmission scan followed by a second [13N]ammonia study were repeated in an identical manner as described above. Following this [13N]ammonia dynamic acquisition study and approximately 90 minutes into a glucose-loaded state, 8 to 10 mCi 18FDG was injected intravenously. At the end of a 45-minute equilibration period, emission data for myocardial 18FDG were acquired over 30 minutes. The FDG study was done to help differentiate zones of ischemia from those of infarction (vida infra). A three-lead ECG (II, III, and V5), heart rate, and cuff blood pressure were continually monitored before and every 10 minutes during each acquisition study.
With the aid of a computerized coordinate system developed in our laboratory, each set of transaxial images was realigned along the longest base-to-apex axis to display images in both sagittal and anteroposterior planes. From these sets, cross-sectional images perpendicular to the long axis were reconstructed. Using the junction of the right ventricular wall with the anterior interventricular septum as a landmark, the images were sectioned circumferentially into 36 equal segments for each of 6 base-to-apex equidistant slices for a total of 218 sectional pies (Fig 1⇓). The mean count density, expressed as counts · pixel−1 · second−1, was computed for each myocardial sector.
Measurement of 13N Retention
From the final image of each dynamic acquisition series, the radioactivity within the myocardial wall was determined as follows. For each of the six cross-sectional slices a circle was fitted to the pixels containing the maximum counts within the myocardial wall. The region of interest for each myocardial sector was then defined by an area extending 5 pixels toward the epicardium and 4 pixels toward the endocardium from points within the circle of best fit. The size of each pixel was 1.9 mm. This region of interest had to be contained within the thickness of the wall as determined by visual analysis. The arterial input function was determined from the center of the blood pool best defined as lying within the basal segment of the transaxial image. A γ variate function was fit to the washout of the [13N]ammonia blood activity curve, and the integral was determined.13 14 13N retention was then calculated as the ratio of the 13N concentration in myocardium divided by the corresponding integrated input function.15 13N retention has been shown to be proportional to myocardial blood flow.13 15
Global and Regional Myocardial Perfusion Measurements
Regional perfusion expressed as 13N retention was calculated for each of the 216 sectors (36 pies×6 slices). Global myocardial perfusion was determined as the average of all 13N retention measurements. Regional myocardial perfusion was defined as the average 13N retention for selected segments containing at least five contiguous sectors incorporating two adjacent slices. The regions designated as reduced perfusion, or “ischemic,” were defined as a reduction in 13N counts by at least 2 SDs below the mean of the maximum count density in the normally perfused or “nonischemic” sectors. The latter was defined as the five contiguous sectors incorporating two adjacent slices that contained the maximum count density. These nonischemic zones always corresponded to myocardial regions subtended by patent coronary arteries as seen angiographically. The ischemic zones were also required to demonstrate no change or an increase in FDG uptake (mismatch).
In the glucose-loaded state, 18FDG myocardial radioactivity was derived from counts · pixel−1 · second−1 of the last frame normalized for the blood radioactivity at 20 minutes. Accepting the fact that glucose utilization rates are highly variable, even in normally perfused myocardium, a region characterized as an infarct zone or scar had to show a net reduction both in FDG radioactivity (>2 SDs below the mean counts in zones of maximal FDG uptake) and a corresponding reduction in 13N retention as defined above for ischemic zones. This is illustrated in Fig 2⇓, in which normally perfused zones are seen alongside zones of reduced perfusion and scar in the same patient.
A paired Student’s t test was used to test the difference in the effect of nitroglycerin and placebo on both global and regional retention of [13N]ammonia compared with baseline values. All values are expressed as mean±SD. χ2 analysis was used for categorical variables, and nonpaired t test was used for comparing continuous variables between the groups’ demographic and clinical characteristics. Reproducibility and variability of regional count density for all sectors was assessed by coefficient of variation values, and the intraclass correlation coefficient was used to compare baseline with placebo values.
The placebo and nitroglycerin groups were comparable in terms of demographic, clinical, and angiographic characteristics (Table 1⇓). Patients in both groups experienced moderate effort-induced angina, with Canadian Cardiovascular Society grades of 2.1±0.3 and 2.3±0.4 for the placebo and nitroglycerin groups, respectively. The extent of coronary artery stenoses and left ventricular dysfunction was also similar in both groups. Most patients had more than one coronary vessel containing stenotic lesions of at least 50%. There were no differences in the amount or type of cardiac medications prescribed for each group. All patients were taking either long-acting oral or topical nitroglycerin prior to the study. All cardiac medications including nitroglycerin were discontinued at least 48 hours prior to the study. One patient took a sublingual nitroglycerin tablet (0.3 mg) on the morning of his study, but the 2,3-dinitroglycerin plasma level in this patient was undetectable by the time the [13N]ammonia acquisition scan was performed.
To illustrate the flow and metabolic characteristics of different zones in multivessel disease, a linear display of a circumferential sector from one of the patients is shown in Fig 2⇑. This patient had an anteroapical infarct (sectors 12 through 20), wherein is seen a reduction in both 18FDG and 13NH3 retention values and between baseline and post–nitroglycerin patch values. Note is made of the mismatch between the elevated 18FDG and depressed baseline 13NH3 values in the posterolateral zone of reduced perfusion (sectors 25 through 35). Nitroglycerin appears to have redistributed flow to the ischemic zone.
Reproducibility and stability of the perfusion method was analyzed by comparing the sector count densities for 13N retention between baseline and placebo states (Table 2⇓). The mean 13N retention values were 0.61±0.14 and 0.62±0.12 min−1 for baseline and placebo, respectively (Tables 2⇓ and 3⇓). Although the intergroup values were almost identical, the interpatient perfusion values varied widely, with coefficients of variation of 22.9% and 19.4% for baseline and placebo groups, respectively, and an intraclass correlation coefficient of .51. There was, however, remarkable reproducibility within patients from one state to the next, with an average percent difference of mean count density of only 2.70±1.42. The average global 13N retention for both states was 0.62 min−1 with confidence limits from 0.47 min−1 to 0.77 min−1 at the 95% level.
Fig 3A⇓ shows an example of the reproducibility of 13N retention data expressed as a percent change from baseline 3 hours following application of a placebo skin patch. The change from baseline was less than 5% for all sectors and slices. By contrast, Fig 3B⇓ shows considerably more variability in a patient who had received a nitroglycerin patch; the significant increase in 13N retention in the anterolateral zone (sectors 28 through 35) corresponds to a high-grade circumflex artery stenosis. The apparent decrease in perfusion of sectors 5 through 15, a zone identified as subtending a patent left anterior descending artery, may represent either redistributed flow attributed to the effect of nitroglycerin on conductance vessels or a decrease in wall stress and left ventricular end-diastolic pressure due to the unloading effect of nitroglycerin.
The relation between global myocardial perfusion as measured by the average 13N retention counts in all sectors and the work of the heart expressed as the double rate-pressure product is shown in Table 3⇑. Under resting supine conditions, there were no significant changes in either heart rate or systolic blood pressure for either group. If anything, there was a slight but insignificant decrease in the average peak systolic blood pressure with nitroglycerin, from 127±10 to 119±11 mm Hg, 3 hours following patch application. Although the baseline values for global 13N retention appear to differ between placebo and nitroglycerin groups (0.61±0.14 versus 0.75±0.22 min−1), the variability between patients was high, with a coefficient of variation ranging from 13% to 29%. This interpatient variation in myocardial perfusion contrasts sharply with the intrapatient reproducibility of the 13N retention taken 3 hours apart for the placebo group (Table 2⇑ and Fig 3A⇑). Neither the global perfusion as expressed by 13N retention nor the double rate-pressure product was altered significantly with nitroglycerin. External work per unit flow, roughly expressed as the ratio of the double rate-pressure product to 13N retention, was unchanged by the application of either placebo or nitroglycerin patch.
The time-dependent changes in the double rate-pressure product with either nitroglycerin or placebo are illustrated in Fig 4⇓. Superimposed is the time course of plasma levels for 1,2-dinitroglycerin. Despite a progressive increase in plasma levels of nitroglycerin, the double rate-pressure product remained constant and, as a consequence, so did the requirement for myocardial perfusion (Table 3⇑). Plasma levels for 1,3-dinitroglycerin were also assayed and showed a similar time course.
In sharp contrast to the lack of change in global myocardial perfusion, the topical application of nitroglycerin significantly altered the regional distribution of myocardial perfusion. Comparison of regional 13N retention between normal zones of perfusion and zones of reduced perfusion (ischemic segments) is shown in Table 4⇓. There were no changes in regional perfusion to either nonischemic or ischemic zones following topical application of the placebo patch. However, nitroglycerin appeared to preferentially increase perfusion to ischemic zones by increasing the relative myocardial retention of [13N]ammonia, from 73±13% to 94.9±18% (P<.05). As expected, proportional uptake of 13N radioactivity in the ischemic zone was, on average, less than in the nonischemic zone for both placebo and nitroglycerin groups at baseline (overall mean difference, −0.17±0.16 min−1; P<.002). The preferential enhancement of flow to the ischemic zones with nitroglycerin is illustrated in Fig 5⇓. There was less than a 5% change in regional perfusion following application of the placebo patch regardless of which zone was analyzed. Similarly, the apparent decrease in regional perfusion to the nonischemic zone following nitroglycerin was less than 5% (P=NS). A change in radioactive uptake of less than 5% with any intervention is within the experimental error of the technique. On the other hand, there was a significant 11.3±3% increase in 13N retention in the ischemic zone following topical application of nitroglycerin.
Fig 6⇓ illustrates two polar maps of 13N radioactivity in a patient who received topical nitroglycerin. The left hand map (prepatch) shows the variation in regional uptake of [13N]ammonia throughout the left ventricle with reduced perfusion in the anteroapical and posterior segments (areas in blue). Three hours after application of nitroglycerin, the anteroapical segments (just above the center zone) appear to have filled in, with little or no change elsewhere. This example is a visual illustration of preferential perfusion to an ischemic zone with nitroglycerin under resting supine conditions.
This study demonstrated that topical nitroglycerin (0.4 mg/h) increased the myocardial retention of [13N]ammonia in ischemic zones by more than 11% while little or no change in nonischemic or global myocardial perfusion occurred. Placebo skin patches had no effect on either regional or global perfusion as determined by 13N retention. These dynamic adjustments in regional blood flow with nitroglycerin occurred in the supine rest state, where little or no change in left ventricular work, as determined by the double rate-pressure product, was observed. The ability to study the heterogeneous effects of nitroglycerin on the coronary vasculature of humans had to await quantifiable measurements of global and regional blood flow. PET offers a unique approach to examine and quantify regional coronary blood flow and, thereby, possible mechanisms of drug action, but it is not without limitations and requires careful scrutiny.
Myocardial zones of reduced perfusion were designated as “ischemic” and arbitrarily defined as a contiguous set of five sectors in two adjacent slices having average count · pixel−1 · second−1 of retained [13N]ammonia at least 2 SDs below the average counts in nonischemic zones. These measurements were done in the rest supine state. The data would perhaps have been more persuasive had the patients been subjected to exercise in order to induce ischemia. However, the use of exercise with PET is fraught with problems, not the least of which is exact repositioning of the heart in the tomograph scanner.13 Furthermore, interpretation of myocardial blood flow as an expression of [13N]ammonia extraction (or retention) by the myocardium is hazardous since any increase in net extraction in a high-flow state may seriously underestimate the true changes in myocardial perfusion.16 These drawbacks were mitigated by the combined use of 13NH3 and 18FDG, which enabled us to identify and dissociate zones of ischemia from infarcted tissue.
Validation of our methods was supported by two observations. First, there was less than a 5% variation in 13N retention in any of the 216 sectors when comparing baseline with 3 hours of placebo patch (Table 2⇑ and Fig 3⇑). Second, there was over 90% concordance between a significant decrease in 13N retention of a myocardial sector (>2 SDs below the mean) and the presence of a significant stenosis (>50%) in the artery supplying that zone.
Instead of relying solely on static extraction data, regional perfusion was expressed as 13N retention derived from dynamic acquisition data. This provides more reliable and accurate estimates of flow.13 17 Contamination of myocardial retention data by partial volume and spillover effects becomes especially relevant when estimating radioactivity in areas of myocardial infarct thinning. This was partially avoided by calculating the arterial input function from the center of the ventricular lumen of the most basal segment, which minimizes spillover but does not eliminate it entirely. We were encouraged, however, by the consistent reproducibility of the 13N retention images before and after placebo. In all 10 patients receiving the placebo patch, the percent difference of the means for global and regional counts varied by less than 5% between baseline and placebo states.
The average 13N retention value for global 13N retention (Table 3⇑) appears less than some of the average regional perfusion values (Table 4⇑). This is explained by the wide regional variation in [13N]ammonia uptake in hearts with multivessel disease containing several regions of reduced perfusion and previous myocardial infarcts. Moreover, the baseline global retentions for the placebo group (0.61±0.14 min−1) were, on average, actually less than the nitroglycerin group (0.75±0.22 min−1). However, the interpatient variation was quite high (coefficients of variation, 20% and 22%, respectively, for the placebo and nitroglycerin groups), which is not surprising considering the variability of segmental disease and myocardial scar in these patients. On the other hand, the intrapatient reproducibility for 13N retention was very narrow for the placebo group, and it was the percent change in relative myocardial perfusion that was measured, using each patient as his or her own control. Furthermore, the baseline global value for the nitroglycerin group (0.75±0.22 min−1) was within the confidence intervals of the values derived from both the baseline and placebo states (Table 2⇑).
The double rate-pressure product was used as an expression of left ventricular work in this study. This measurement ignores the contribution of left ventricular volume and wall stress as major determinants of oxygen demand and, hence, flow. However, it is well known that nitroglycerin reduces left ventricular filling volume,18 19 thereby maintaining or even reducing demand for global coronary blood flow in the face of an unchanged double rate-pressure product. Moreover, a decrease in left ventricular end-diastolic pressure by nitroglycerin would, theoretically, potentiate transmural blood flow, but this effect in the absence of a change in energy demand would be negligible. Moreover, it would be uniform for all segments.
As for the effect of nitroglycerin on the coronary circulation, it has been repeatedly observed that nitroglycerin visibly dilates the large epicardial branches of coronary arteries.20 Moreover, there is oftentimes evidence for relief of large vessel coronary spasm within minutes of sublingual nitroglycerin21 as well as vasodilation of stenotic segments.22 What is less well known is the site and mechanism of the complex effects of this drug on coronary dynamics. While nitroglycerin dilates large epicardial coronary arteries, it has little or no effect on total coronary blood flow or coronary vascular resistance.6 7
In a classic series of experiments Fam and McGregor8 23 compared the site and action of different coronary artery vasodilators. Using open-chest anesthetized dogs, they discovered that flow in the poststenotic coronary artery was enhanced with intravenous nitroglycerin by virtue of the relaxing effect of the drug on large conductance vessels. With no change in arteriolar resistance of the nonobstructed vascular bed, they postulated that coronary flow was preferentially directed through collaterals to the poststenotic zone of ischemia. By contrast, intravenous dipyridamole caused a significant reduction in coronary arteriolar resistance, thereby augmenting coronary flow to nonischemic myocardium at the expense of flow to the already dilated poststenotic vessel. Others have since substantiated the differential site of action of nitroglycerin on the coronary vasculature in experimental animals24 25 26 and humans.11
Kurz et al27 recently proposed an interesting and persuasive explanation for this heterogeneous coronary vascular response to nitroglycerin. The coronary arterioles apparently lack the necessary sulfhydryl-containing compound (l-cysteine) to convert nitroglycerin to its active metabolite, S-nitroso-l-cysteine.28 29 By suffusing epicardial microvessels in vivo with nitroglycerin, Kurz et al27 were able to show significant dilatation of the arteriolar vessels only in the presence of a thiol, l-cysteine. This was a stereospecific reaction, suggesting an intracellular or membrane-associated mechanism. Hence, the lack of available sulfhydryl groups in the small resistance coronary vessels may explain the failure of nitroglycerin to alter small vessel coronary vascular resistance while dilating the large epicardial vessels.
However, it is possible that the observed increase in 13N retention to ischemic zones may in part be due to improved regional wall motion or a favorable transmural pressure gradient due to a decrease in left ventricular end-diastolic pressure and wall stress. An alternative explanation is that the so-called redistribution was actually the consequence of a direct effect of nitroglycerin on increasing the luminal diameter of vessel stenosis.10 22 This effect was at a dose that may or may not be achievable by topical nitroglycerin. Such a direct increase in cross-sectional stenosis area would, conceivably, alter global myocardial blood flow, assuming no change in flow to nonischemic zones. Although such an effect was not seen in this study, a mechanism of a direct vasodilatory effect cannot be refuted by the present results. Fujita et al,11 also using computerized quantitatative coronary arteriography, found that intracoronary nitroglycerin dilated the recipient coronary arteries more than the donor arteries, suggesting an enhancement of flow through collateral channels.
In summary, our study shows that the application of topical nitroglycerin appears to exert changes in myocardial perfusion by preferential distribution of flow to areas of myocardial ischemia with little or no significant change in either total myocardial perfusion or cardiac work. This observation may help explain part of the antianginal properties of the coronary vasodilatory effects of nitroglycerin. The study also draws attention to PET as a potentially useful tool in unraveling the mechanisms of various interventions on regional myocardial blood flow.
This work was supported by an unrestricted grant from Schering Plough Research Institute. We wish to express special thanks to Gwen Woodcock, RN, for her expert help and to Alex Kotzeff and Margo Thompson for their technical assistance.
- Received September 26, 1994.
- Accepted October 3, 1994.
- Copyright © 1995 by American Heart Association
Brunton TL. On the use of nitrate of amyl in angina pectoris. Lancet. 1867;2:97-98.
Burggraf GW, Parker JO. Left ventricular volume changes after amyl nitrite and nitroglycerin in man as measured by ultrasound. Circulation. 1974;49:136-143.
Ganz W, Marcus HS. Failure of intracoronary nitroglycerin to alleviate pacing-induced angina. Circulation. 1972;46:880-886.
Gorlin R, Brachfeld N, MacLeod C, Bopp P. Effect of nitroglycerin on the coronary circulation in patients with coronary artery disease or increased left ventricular work. Circulation. 1959;19:705-718.
Winbury MM, Gabel LP. Effect of nitrates on nutritional circulation of heart and hindlimb. Am J Physiol. 1967;212:1062-1066.
Fam WM, McGregor M. Effect of nitroglycerin and dipyridamole on regional coronary resistance. Circ Res. 1968;22:649-659.
Horwitz LD, Gorlin R, Taylor WJ, Kemp HG. Effects of nitroglycerin on regional myocardial blood flow in coronary artery disease. J Clin Invest. 1971;50:1578-1584.
Brown GB, Lee AB, Bolson EL, Dodge HT. Reflex constrictions of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise. Circulation. 1984;70:18-24.
Noonan PK, Kanfer I, Riegelman S, Benet LZ. Determination of picogram nitroglycerin plasma concentrations using capillary gas chromatography with on-column injection. J Pharm Sci. 1984; 73:923-927.
Krivokakpich J, Smith GT, Huang SC, Hoffman EJ, Ratib O, Phelps MI, Schelbert HR. 13N ammonia myocardial imaging at rest and with exercise in normal volunteers: quantification of absolute myocardial perfusion with dynamic positron emission tomography. Circulation. 1989;80:1328-1337.
Bellina CR, Parodi O, Camici P, Salvadori PA, Taddei L, Fusani L, Guzzardi R, Klassen GA, L’Abbate A, Donato L. Simultaneous in vitro and in vivo validation of nitrogen-13-ammonia for the assessment of regional myocardial blood flow. J Nucl Med. 1990; 31:1335-1343.
Muzik O, Beanlands R, Hutchins G, Mangner T, Wolpers G, Nguyen N, Schwaiger M. Experimental validation of a tracer kinetic model for N13-ammonia in comparison to 150 water for quantification of myocardial blood flow. J Nucl Med. 1991;32:926. Abstract.
Feldman RL, Pepine CJ, Curry RC, Conti CR. Coronary arterial responses to graded doses of nitroglycerin. Am J Cardiol. 1979; 43:91-96.
Gordon J, Ganz P, Nabel E, Fish R, Zebede J, Mudge G, et al. Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise. J Clin Invest. 1989;83:1946-1952.
Fam WM, McGregor M. Effect of coronary vasodilator drugs on retrograde flow in areas of chronic myocardial ischemia. Circ Res. 1964;105:355-365.
Winbury MM, Howe BB, Hefner MA. Effect of nitrates and other coronary dilators on large and small coronary vessels: an hypothesis for the mechanism of action of nitrates. J Pharmacol Exp Ther. 1969;168:70-95.
Cohen MV, Kirk ES. Differential response of large and small coronary arteries to nitroglycerin and angiotensin: autoregulation and tachyphylaxis. Circ Res. 1973;33:445-453.
Bache RJ, Tockman BA. Effect of nitroglycerin and nifedipine on subendocardial perfusion in the presence of a flow-limiting coronary stenosis in the awake dog. Circ Res. 1982;50:678-687.
Kurz MA, Lamping KG, Bates JN, Eastham CL, Marcus ML, Harrison DG. Mechanisms responsible for the heterogeneous coronary microvascular response to nitroglycerin. Circ Res. 1991;68:847-853.
Gruetter DY, Gruetter CA, Barry BK, Baricos WH, Hyman AL, Kadowitz PH, Ignarrow LJ. Activation of coronary arterial guanylate cyclase by nitric oxide, nitroprusside, and nitrosoguanidine-inhibition by calcium, lanthanum and other cations enhancement by thiols. Biochem Pharmacol. 1980;29:2943-2950.