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PubMed1980

Assessment of function of contractile segments in patients with left ventricular aneurysms by quantitative first pass radionuclide ventriculography. Haemodynamic correlation at rest and exercise.

Thirteen patients with left ventricular aneurysms complicating myocardial infarction were studied by contrast angiography and by first pass radionuclide ventriculography. The ejection fraction of the contractile segment (EFCS) was measured from both studies using a double hemishperoid model, and the values correlated closely. There was a monotonic relation between EFCS and stroke volume index measured from thermodilution cardiac outputs carried out simultaneously with the radionuclide study. When radionuclide ventriculography was performed at submaximal supine exercise, changes in EFCS paralleled changes in the total left ventricular ejection fraction in 10 of the 13 cases. In nine patients, changes in EFCS paralleled changes in stroke volume index and the relation between EFCS and stroke volume index was maintained at exercise. After administration of the vasodilator isosorbide dinitrate to 12 patients, repeat exercise radionuclide ventriculography showed an improvement in left ventricular ejection fraction and in eight patients EFCS improved. First pass radionuclide ventriculography can accurately estimate EFCS, which may be an important factor in predicting the likely response to aneurysmectomy. Changes in EFCS on exercise are reflected in changes in total left ventricular ejection fraction and stroke volume index. Isosorbide dinitrate may improve contractile segment function on exercise.

Adult↗
PubMed1992

Comparative electrophysiological effects of captopril or hydralazine combined with nitrate in patients with left ventricular dysfunction and inducible ventricular tachycardia.

OBJECTIVE: To assess the electrophysiological and antiarrhythmic effects of pharmacological load manipulation by an angiotensin converting enzyme (ACE) inhibitor (captopril) and a direct vasodilator (hydralazine plus isosorbide mononitrate) in patients with inducible ventricular tachycardia and impaired left ventricular function. DESIGN: Randomised open label cross-over comparison of three regimens. SETTING: Tertiary arrhythmia referral centre. SUBJECTS: Eight patients with reduced left ventricular function and sustained ventricular tachycardia inducible by programmed stimulation. INTERVENTIONS: Three treatment regimens each of 48 hours duration: captopril, hydralazine plus isosorbide mononitrate, and control (no vasodilator). MAIN OUTCOME MEASURES: Changes in central haemodynamics, electrophysiological parameters, and induction of ventricular tachycardia during treatment with captopril, or hydralazine combined with nitrate, compared with a control period. RESULTS: Both vasodilator treatments produced similar balanced reductions in peak systolic pressures and filling pressures compared with controls. Captopril had no effect on sinus cycle length, atrial refractoriness, or intraventricular conduction, but prolonged ventricular effective and functional refractory periods and QT interval during constant rate atrial pacing. Hydralazine combined with nitrate did not significantly alter any electrophysiological variable. Ventricular tachycardia was similarly inducible during all three periods. CONCLUSIONS: Load manipulation by captopril but not hydralazine combined with nitrate prolonged ventricular refractoriness and repolarisation, possibly reflecting a combination of mechano-electrical effect with the restraining influence of ACE inhibitors on reflex sympathetic stimulation.

Aged↗
PubMed1996

Relation of basal coronary tone and vasospastic activity in patients with variant angina.

OBJECTIVE: To examine the vasoconstrictor response to ergonovine and the vasodilator response to isosorbide dinitrate in spastic and non-spastic coronary segments from 31 patients undergoing serial angiographic follow up of variant angina. METHODS: Coronary angiograms and ergonovine provocation tests were repeated at an interval of 45 (SD 15) months apart. While all 31 patients showed a positive response to ergonovine initially, vasospastic responsiveness persisted in only 16 patients at follow up (group 1) and not in the other 15 patients in whom symptoms of variant angina had resolved (group 2). Mean luminal diameter of 170 normal or near normal entire coronary segments (American Heart Association classification) were measured (a) at baseline, (b) after the administration of ergonovine, and (c) after the administration of isosorbide dinitrate, during both the initial and follow up angiograms using a computer based quantitative angiography analysis system (CAAS II). RESULTS: In vasospastic patients (initial and follow up angiograms in group 1, and initial angiogram in group 2), basal tone was significantly higher in spastic segments compared to adjacent segments or segments in non-spastic vessels. The diagnostic sensitivity and specificity at 20% increase in basal coronary tone for the prediction of vasospasm were 77% and 73%, respectively. CONCLUSIONS: Coronary artery tone may change in proportion to the activity of variant angina over several years. Contrary to some previous reports, the estimation of basal coronary tone may be useful in the assessment of vasospastic activity in patients with variant angina.

Angina Pectoris, Variant↗
PubMed2002

Low-dose dexamethasone in the rat: a model to study insulin resistance.

The main aim of this study was to set up a new animal model to study insulin resistance. Wistar rats (6 or 7 per group) received the following for 4 wk in experiment 1: 1) vehicle, 2) 2 microg/day subcutaneous dexamethasone, 3) metformin (400 mg x kg(-1) x day(-1) os), and 4) dexamethasone plus metformin. In experiment 2 the rats received the following: 1) vehicle, 2) dexamethasone, 3) dexamethasone plus arginine (2%; as substrate of the nitric oxide synthase for nitric oxide production) in tap water, and 4) dexamethasone plus isosorbide dinitrate (70 mg/kg; as direct nitric oxide donor) in tap water. Insulin sensitivity was significantly reduced by dexamethasone already at week 1, before the increase in blood pressure (day 15) and without significant changes in body weight compared with vehicle. Dexamethasone-treated rats had significantly higher triglycerides, hematocrit, and insulin, whereas serum total nitrates/ nitrites were lower compared with vehicle. The concomitant treatment with metformin minimized all the described effects of dexamethasone. In experiment 2, only isosorbide dinitrate was able to prevent the observed dexamethasone-induced metabolic, hemodynamic, and insulin sensitivity changes. Chronic low-dose subcutaneous dexamethasone (2 microg/day) is a useful model to study the relationships between insulin resistance and blood pressure in the rat, and dexamethasone might decrease insulin sensitivity and increase blood pressure through an endothelium-mediated mechanism.

Animals↗
PubMed2005

Use of simultaneous pressure and velocity measurements to estimate arterial wave speed at a single site in humans.

It has not been possible to measure wave speed in the human coronary artery, because the vessel is too short for the conventional two-point measurement technique used in the aorta. We present a new method derived from wave intensity analysis, which allows derivation of wave speed at a single point. We apply this method in the aorta and then use it to derive wave speed in the human coronary artery for the first time. We measured simultaneous pressure and Doppler velocity with intracoronary wires at the left main stem, left anterior descending and circumflex arteries, and aorta in 14 subjects after a normal coronary arteriogram. Then, in 10 subjects, serial measurements were made along the aorta before and after intracoronary isosorbide dinitrate. Wave speed was derived by two methods in the aorta: 1) the two-site distance/time method (foot-to-foot delay of pressure waveforms) and 2) a new single-point method using simultaneous pressure and velocity measurements. Coronary wave speed was derived by the single-point method. Wave speed derived by the two methods correlated well (r = 0.72, P < 0.05). Coronary wave speed correlated with aortic wave speed (r = 0.72, P = 0.002). After nitrate administration, coronary wave speed fell by 43%: from 16.4 m/s (95% confidence interval 12.6-20.1) to 9.3 m/s (95% confidence interval 6.5-12.0, P < 0.001). This single-point method allows determination of wave speed in the human coronary artery. Aortic wave speed is correlated to coronary wave speed. Finally, this technique detects the prompt fall in coronary artery wave speed with isosorbide dinitrate.

Aorta↗
PubMed1981

Evaluation of effect of drugs on the exercise ECG.

The result of an exercise ECG can be represented on an XY chart by four monovariate (normal) distributions: heart rate (divided by X axis); blood pressure (divided by Y axis); Working time deficit (-X axis); ST depression (-Y axis); and two bivariate (elliptic) distributions: double product (divided by X divided by Y quadrant); ST X time-deficit index (-X -Y quadrant). Charts for 100 normal men, 100 normal women, 100 coronary men, and 100 coronary women were first of all built up. Charts of 100 patients under propanolol, 33 under atenolol, 47 under nidefipine, 13 under verapamil, and 44 under isosorbide dinitrate were then compared with those from coronary men. Beta blockers produced a shift in all six parameters; nifedipine modified blood pressure, double product, ST and time deficit; verapamil only changed blood pressure and time deficit; isosorbide changed ST, time deficit and the ST X time-deficit index.

Atenolol↗
PubMed1991

Importance of coronary collateral circulation for increased treadmill exercise capacity by nitrates in patients with stable effort angina pectoris.

The purpose of this study was to elucidate the mechanism that induces an improvement in exercise capacity by nitrates in patients with stable effort angina pectoris. The study population was composed of 19 patients: group A, 10 patients with chronic stable effort angina who had a well-developed coronary collateral circulation to the potentially ischemic region; group B, 9 patients with chronic stable effort angina who had no collateral circulation to the jeopardized myocardium. Treadmill exercise was performed according to the standard Bruce protocol with and without pretreatment with orally administered 10 mg isosorbide dinitrate. Percent increases (mean +/- SE) in exercise duration were not significantly different between groups A and B (25 +/- 6 vs. 14 +/- 6%). Percent increases in the maximal rate-pressure product tended to be greater in group A than in group B (27 +/- 6 vs. 10 +/- 6%). Percent increases in the rate-pressure product at the onset of angina pectoris were significantly greater in group A than in group B (37 +/- 7 vs. 7 +/- 6%; p less than 0.01). Percent increases in the rate-pressure product at 0.1 mV S-T segment depression were also significantly greater in group A than in group B (26 +/- 6 vs. 1 +/- 5%; p less than 0.01). These results suggest that isosorbide dinitrate dilates epicardial collateral vessels with smooth muscle layers, but fails to dilate the coronary arteries with significant organic stenoses.

Angina Pectoris↗
PubMed1994

Use and limitations of Holter electrocardiography in assessing drug therapy of myocardial ischemia during the peri-PTCA period.

Incidence and pattern of myocardial ischemia during the peri-PTCA (percutaneous transluminal coronary angioplasty) period and the possible role of continuous intravenous isosorbide dinitrate in its prevention were examined prospectively in 30 patients. Holter electrocardiographic monitoring was performed for 21 +/- 3 h before PTCA and continued during and for 41 +/- 8 h after the procedure. Before PTCA, 19 ischemic episodes were present in 10 (33%) of 30 patients. PTCA produced an abrupt decrease in number (p = 0.015) and duration (p = 0.03) of spontaneous ischemic episodes. The rarity of recurrent myocardial ischemic events by Holter monitoring after PTCA negated any attempt at assessing the efficacy of intravenous isosorbide dinitrate in their prevention. Holter monitoring could not be used as an early predictor of late coronary restenosis.

Adult↗
PubMed2003

Effect of different intensities of exercise on endothelium-dependent vasodilation in humans: role of endothelium-dependent nitric oxide and oxidative stress.

BACKGROUND: Aerobic exercise enhances endothelium-dependent vasodilation in hypertensive patients, patients with chronic heart failure, and healthy individuals. However, it is unclear how the intensity of exercise affects endothelial function in humans. The purpose of the present study was to determine the effects of different intensities of exercise on endothelium-dependent vasodilation in humans. METHODS AND RESULTS: We evaluated the forearm blood flow responses to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate, an endothelium-independent vasodilator, before and after different intensities of exercise (mild, 25% VO2max; moderate, 50% VO2max; and high, 75% VO2max; bicycle ergometers, 30 minutes, 5 to 7 times per week for 12 weeks) in 26 healthy young men. Forearm blood flow was measured using a mercury-filled Silastic strain-gauge plethysmograph. Twelve weeks of moderate-intensity exercise, but not mild- or high-intensity exercise, significantly augmented acetylcholine-induced vasodilation (7.5+/-2.4 to 11.4+/-5.8 mL/min per 100 mL tissue; P<0.05). No intensity of aerobic exercise altered isosorbide dinitrate-induced vasodilation. The administration of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, abolished the moderate-intensity exercise-induced augmentation of the forearm blood flow response to acetylcholine. High-intensity exercise increases plasma concentrations of 8-hydroxy-2'-deoxyguanosine (from 6.7+/-1.1 to 9.2+/-2.3 ng/mL; P<0.05) and serum concentrations of malondialdehyde-modified low-density lipoprotein (from 69.0+/-19.5 to 82.4+/-21.5 U/L; P<0.05), whereas moderate exercise tended to decrease both indices of oxidative stress. CONCLUSIONS: These findings suggest that moderate-intensity aerobic exercise augments endothelium-dependent vasodilation in humans through the increased production of nitric oxide and that high-intensity exercise possibly increases oxidative stress.

Acetylcholine↗
PubMed1999

Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects: role of endothelium-derived nitric oxide.

BACKGROUND: Several nonpharmacological interventions, including exercise, are recommended in primary prevention of hypertension and other cardiovascular diseases in which the pathogenetic role of endothelial dysfunction has been suggested. We studied the effects of long-term aerobic exercise on endothelial function in patients with essential hypertension. METHODS AND RESULTS: The forearm blood flow was measured by strain-gauge plethysmography. The responses of forearm vasculature to acetylcholine were smaller in the hypertensive patients than in the normotensive subjects. There was no significant difference in forearm vascular responses to isosorbide dinitrate in the normotensive and hypertensive subjects. We evaluated the effects of physical exercise for 12 weeks on forearm hemodynamics in untreated patients with mild essential hypertension who were divided randomly into an exercise group (n=10) and a control group (n=7). After 12 weeks, the forearm blood flow response to acetylcholine increased significantly, from 25.8+/-9.8 to 32.3+/-11.2 mL. min(-1). 100 mL tissue(-1) (P<0.05), in the exercise group but not in the control group. The increase in the forearm blood flow after isosorbide dinitrate was similar before and after 12 weeks of follow-up in both groups. The infusion of N(G)-monomethyl-L-arginine abolished the exercise-induced enhancement of forearm vasorelaxation evoked by acetylcholine in the exercising group. In normotensive subjects also, long-term aerobic exercise augmented acetylcholine-stimulated nitric oxide release. CONCLUSIONS: These findings suggest that long-term physical exercise improves endothelium-dependent vasorelaxation through an increase in the release of nitric oxide in normotensive as well as hypertensive subjects.

Acetylcholine↗
PubMed2000

Effects of sildenafil citrate (Viagra) combined with nitrate on the heart.

BACKGROUND: Sildenafil citrate (Viagra) is indicated for the treatment of erectile dysfunction. Large and sudden decreases in systemic blood pressure were reported in a substantial number of patients taking sildenafil citrate combined with nitroglycerin. We studied the effect of sildenafil citrate on the relationship between changes in systemic blood pressure and coronary blood flow. METHODS AND RESULTS: Healthy male beagles were used to assess systemic blood pressure, pulmonary arterial pressure, and flow in the left circumflex artery (in which a critical stenosis was established) and left anterior descending coronary artery. After measurement of the hemodynamic variables, 2 mg/kg sildenafil citrate was administered via a nasogastric tube. Hemodynamic changes were monitored for 1 hour. Subsequently, the acute effect of nitrate combined with sildenafil citrate was studied by the bolus injection of 0.2 mg isosorbide dinitrate before and after sildenafil citrate. Systemic blood and pulmonary arterial pressures and circumflex flow did not change during this study; however, left anterior descending coronary arterial flow increased from 16.0+/-5.8 to 24.6+/-8.7 mL/min 1 hour after administration of sildenafil citrate. The prolongation of systemic blood pressure decrease and the circumflex flow decrement induced by isosorbide dinitrate after sildenafil citrate were significantly larger and longer than those before sildenafil citrate. CONCLUSIONS: Sildenafil citrate had the effect of vasodilation in a normal coronary artery; however, a combined effect with nitrate resulted in large and protracted decreases in systemic blood pressure and coronary blood flow in vessels with critical stenosis.

Administration, Oral↗
PubMed1981

Acute and long-term effects of vasodilator therapy on resting and exercise hemodynamics and exercise tolerance.

The acute hemodynamic response to vasodilators in patients with chronic heart failure has been well characterized, but less is known about the long-term hemodynamic effects of vasodilator therapy. We measured hemodynamic variables at rest and during upright exercise in 11 patients during the initiation of therapy with oral hydralazine and sublingual isosorbide dinitrate and, in eight of these, after 3 months of continuous treatment. Marked initial increases in resting cardiac output and stroke volume and reductions in wedge pressure were sustained during chronic therapy. Similarly, the early improvement in exercise hemodynamic measurements persisted in most subjects. Exercise tolerance, quantified as the maximum duration of treadmill exercise, increased modestly (7.7 +/- 2.6 to 8.9 +/- 3.3 minutes, 0.05 less than p less than 0.10) after several days on vasodilators and further (10.2 +/- 3.7 minutes, p less than 0.01) during long-term treatment. The acute hemodynamic effects of vasodilator therapy at rest or during exercise did not correlate well with the changes in exercise tolerance. Our findings suggest that the combination of hydralazine and isosorbide dinitrate improves cardiac performance at rest and during exercise in patients with chronic heart failure and that this improvement persists during chronic therapy. In most patients, this hemodynamic improvement is accompanied by greater exercise tolerance.

Acute Disease↗
PubMed1982

A new two-dimensional echocardiographic technique for evaluating right ventricular size and performance in patients with obstructive lung disease.

To compare two-dimensional (2-D) echocardiographic estimates of right ventricular size and performance to similar determinations from equilibrium radionuclide angiography (RNA) before and after isosorbide dinitrate, we evaluated 19 patients with severe chronic obstructive pulmonary disease. The end-diastolic and end-systolic volumes estimated from subcostal 2-D echocardiographic views of the right ventricle correlated with the RNA end-diastolic and end-systolic counts (r = 0.76 and 0.82, respectively). The 2-D echocardiographic and RNA right ventricular ejection fraction (EF) estimates also correlated (r = 0.80), and the average right ventricular EF measures of 42 +/- 11% and 40 +/- 12%, respectively, did not differ significantly. Nitrate administration produced a significant increase in heart rate (99 +/- 11 to 108 +/- 14 beats/min, p less than 0.001) and a decrease in systolic arterial pressure (139 +/- 23 to 120 +/- 22 mm Hg, p less than 0.001). Nitrates also significantly decreased the average 2-D echocardiographic end-diastolic and end-systolic volumes (22 +/- 16% and 18 +/- 12%, p less than 0.001), as well as RNA end-diastolic and end-systolic counts (33 +/- 17% and 32 +/- 22%, p less than 0.001), but did not significantly decrease the average right ventricular EF values (4 +/- 12% and 4 +/- 24%, respectively). Nevertheless, after isosorbide dinitrate, the 2-D echocardiographic right ventricular end-diastolic and end-systolic volume estimates continued to correlate with the corresponding RNA count measures (r = 0.76 and 0.79, respectively), as did the 2-D echocardiographic and RNA right ventricular EF values (r = 0.75). We conclude that 2-D echocardiographic evaluation of right ventricular size and performance is feasible in selected patients with chronic obstructive pulmonary disease, and that 2-D echocardiographic measures of right ventricular size and performance compare favorably with similar determinations by RNA at rest and after nitrate administration.

Blood Pressure↗
PubMed1985

Nitrates and endothelial prostacyclin production: studies in vitro.

The hypothesis that nitrates evoke prostacyclin production by vascular endothelium has been reevaluated on cultured umbilical vein endothelial cells and in vascular fragments, both obtained from humans. Endothelial cell monolayers (passages 1 and 2) were washed free of culture medium and exposed for 3 to 5 min to buffer or nitroglycerin (NTG), isosorbide dinitrate (ISDN), or isosorbide-5-mononitrate (ISMN) over a range of concentrations (10(-9)M to 10(-6)M) encompassing those usually attained in vivo, with or without 25 microM sodium arachidonate. Basal prostacyclin production, measured by radioimmunoassay of the stable metabolite 6-keto-PGF1 alpha, depended on cell density in the endothelial monolayer (being higher in preconfluent cultures) and on incubation time. Basal prostacyclin, however, was not altered by incubation with NTG (3.3 +/- 2.0 pg/1000 cells without drug vs 3.9 +/- 3.8 pg/1000 cells with drug, mean +/- SD), ISDN (3.1 +/- 1.9 vs 3.1 +/- 2.2), or ISMN (2.0 +/- 0.9 vs 2.3 +/- 1.5) at 10(-7)M (all differences NS). Also, long-term incubation (2, 6, and 24 hr) with ISDN and ISMN did not alter prostacyclin production over control. Over a 30-fold increase (p less than .001) in prostacyclin production was obtained with arachidonate stimulation, but incubation with nitrates did not significantly modify the stimulated production. Saphenous vein, mesenteric artery, and atrial appendage fragments incubated at 37 degrees C for 20 min in a shaking water bath with a control buffer produced 27.8 +/- 13.9, 189.7 +/- 75.2, and 662.3 +/- 390.6 pg 6-keto-PGF1 alpha/mg tissue, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Nitrate tolerance: the lack of effect of N-acetylcysteine.

The hemodynamic and antianginal effects of 30 mg of isosorbide dinitrate (ISDN) were assessed in 12 patients with chronic stable angina after initial dosing and after 7 to 10 days of therapy four times daily. During early therapy, ISDN produced significant hemodynamic and antianginal effects that persisted over a 3 hr observation period. During sustained therapy there was attenuation of the hemodynamic effects at rest, and treadmill exercise time to the onset of angina and to the development of moderate angina was increased 1 hr after dosing; no effect was apparent at 3 hr. During this state of nitrate tolerance, patients were treated with an infusion of normal saline or 100 mg/kg N-acetylcysteine and exercise testing was repeated. N-Acetylcysteine did not change the hemodynamic findings at rest or during exercise and there was no improvement in exercise tolerance. It is apparent that the short-term administration of reduced sulfhydryl groups does not reverse tolerance to the hemodynamic and antianginal effects of isosorbide dinitrate in an exercise test model.

Acetylcysteine↗
PubMed1993

Response of human coronary arteries to serotonin after injury by coronary angioplasty.

BACKGROUND: Atherosclerotic stenoses that have exaggerated vasomotor responses are especially prone to restenosis after coronary angioplasty. Experimental studies show that vasomotor responses in normal vessels are altered by acute mechanical injury, an alteration that in part reflects changes in the functional characteristics of endothelium that has regenerated after injury. METHODS AND RESULTS: We examined, by quantitative coronary arteriography, the response of dilated and control coronary segments to intracoronary infusions of graded doses of serotonin, an endothelium-dependent vasoactive agent, and to intracoronary injection of isosorbide dinitrate, an endothelium-independent smooth muscle dilator in 15 patients who had undergone a single percutaneous transluminal coronary angioplasty procedure and who had no clinical features of variant angina. Dose-dependent constriction to serotonin occurred at all measured sites. The mean +/- SEM diameter reductions, expressed as percent reduction in baseline diameter that was observed at proximal (18.1 +/- 2.9, 18.8 +/- 2.2) and distal (30.9 +/- 4.4, 35.4 +/- 5.3) control sites in the dilated and nondilated vessels, respectively, at the highest dose, were similar. The degree of constriction in distal segments was significantly (P < .01) greater than that in proximal segments. Total or subtotal occlusion occurred at the angioplasty site in 4 patients at the highest infused dose (10(-4) mol/L). The mean percent reduction in baseline diameter at previously dilated sites (53.8 +/- 5.9) at this dose was significantly (P < .05) greater than that observed at the adjacent proximal control sites and similar to that observed at distal control sites. All segments dilated significantly after intracoronary injection of isosorbide dinitrate. CONCLUSIONS: In dilated and nondilated vessels, serotonin caused significantly more marked constriction in distal than in proximal vessel segments. In dilated vessels, the vessel segments that had been subjected to angioplasty had a constrictor response to serotonin that was more marked than at adjacent proximal control sites and equivalent to that in the distal vessel segments. This enhanced constrictor response could be related to changes in endothelial cell function after regeneration or to hyperreactivity of smooth muscle cells at the angioplasty site.

Adult↗
PubMed1994

Effect of prolonged nitrate therapy on left ventricular remodeling after canine acute myocardial infarction.

BACKGROUND: Prolonged nitrate therapy during healing between 2 days and 6 weeks after anterior myocardial infarction has the potential for limiting further left ventricular remodeling (or changes in topography) and preserving function. Longterm therapy throughout healing over 6 weeks might be more beneficial than short-term therapy over the first 2 weeks after infarction. METHODS AND RESULTS: The effect of prolonged nitrate therapy between 2 days and 6 weeks during healing after infarction on serial parameters of ventricular remodeling (scar expansion, scar thinning, ventricular dilation, and hypertrophy) and function (asynergy or akinesis plus dyskinesis and ejection fraction) by serial two-dimensional echocardiography, hemodynamics, postmortem topography (computerized planimetry, geometric maps, and radiographs), and collagen content (hydroxyproline) was studied in 64 instrumented dogs randomized 2 days after left anterior descending coronary artery ligation to various nitrate regimens (n = 32) over the first 2 weeks (subgroup 1: 2% transdermal nitroglycerin at 8 AM and 4 PM, n = 6; subgroup 2: 2% transdermal nitroglycerin plus 2.6 mg of sustained-release oral nitroglycerin at 8 AM, 3 PM, and 10 PM, n = 5; subgroup 3: oral isosorbide dinitrate, 30 mg at 8 AM and 4 PM, n = 11) or 6 weeks (subgroup 4: isosorbide dinitrate, n = 10) and in matching controls (n = 32). Nitrate therapy reduced left atrial pressure, mean arterial pressure, and the rate-pressure product compared with controls over the 6 weeks. Postmortem scar mass and hydroxyproline were similar in control and nitrate groups. However, scar stretching and thinning, cavity dilation, noninfarct wall hypertrophy, and apical bulging were less with nitrates, especially in the long-term subgroup 4. In vivo remodeling parameters between 2 days and 6 weeks after ligation showed that, compared with controls, nitrate therapy prevented further stretching of the asynergic segment, decreased the expansion index, decreased further scar thinning, prevented the increase in ventricular volumes, reduced the frequency of ventricular aneurysm, prevented the increase in ventricular mass, reduced the extent of asynergy, and improved ejection fraction. Although the beneficial effect on topography and function was seen in all nitrate subgroups, the overall benefit was greater with long-term therapy over 6 weeks (subgroup 4) than short-term therapy confined to the first 2 weeks (subgroups 1, 2, and 3). CONCLUSIONS: Prolonged nitrate therapy, in various regimens during healing after infarction, effectively reduced left ventricular loading and prevented infarct thinning, further infarct expansion, progressive ventricular dilation, and the increase in mass. These effects were associated with decreased asynergy and improved ejection fraction. The beneficial effects were greater with long-term therapy over 6 weeks than short-term therapy over the first 2 weeks.

Animals↗
PubMed1997

Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin.

BACKGROUND: KII ACE, the enzyme that converts angiotensin I and inactivates bradykinin, is highly concentrated in the lungs; its blockade reduces exposure to angiotensin II and enhances exposure to prostaglandins generated by local kinin hyperconcentration. Our hypothesis is that ACE inhibitors improve pulmonary function in chronic heart failure (CHF) by readjusting lung vessel tone and permeability or alveolar-capillary membrane diffusion. METHODS AND RESULTS: In 16 CHF patients and 16 normal volunteers or mild untreated hypertensives, pulmonary function and exercise tests with respiratory gas analysis were assessed on placebo, enalapril (10 mg BID), enalapril plus aspirin (325 mg/d), or aspirin, in random order and double blind, for 15 days each. In CHF, enalapril increased pulmonary carbon monoxide diffusion (DLCO), oxygen consumption (VO2), and exercise tolerance and reduced the ratio of dead space to tidal volume (VD/VT) and the ventilatory equivalent for carbon dioxide production (VE/VCO2). On enalapril, VO2 (r = .80, P < .0001) and VD/VT (r = -.69, P = .003) changes from placebo correlated with those in DLCO. These effects were inhibited by aspirin and were absent in control subjects. In 8 additional patients, hydralazine-isosorbide dinitrate, as an alternative treatment for reducing pulmonary capillary wedge pressure (PCWP) and increasing exercise capacity, were more effective than enalapril for the PCWP but did not affect DLCO and VE/VCO2; amelioration in VO2 and VD/VT was unrelated to DLCO and was not modified by aspirin. CONCLUSIONS: ACE inhibition improved pulmonary diffusion in CHF. Hydralazine-isosorbide dinitrate failed to provide this result. Counteraction by aspirin, a prostaglandin inhibitor, bespeaks prostaglandin participation while on enalapril that might readjust capillary permeability or alveolar-capillary membrane diffusion.

Aged↗