Protective effects of nipradilol, isosorbide dinitrate, and bunazosin on coronary artery constriction induced by intracoronary injection of acetylcholine in pigs.

STUDY OBJECTIVE: Protective effects of nipradilol, a newly synthesised vasodilating beta adrenoceptor antagonist, isosorbide dinitrate, and bunazosin on coronary artery constriction induced by intracoronary injection of acetylcholine were determined by coronary arteriography and compared in vivo in pigs. DESIGN: Acetylcholine (12.5, 25, 50, 100 and 200 micrograms) was given into the right coronary artery under left ventricular pacing to maintain constant systemic haemodynamics. Percentage narrowing of the major epicardial coronary artery was used as an indicator of constriction of the large coronary arteries, and the time required for the contrast medium to reach the posterior descending coronary artery from the ostium of the right coronary artery (blood flow delay) was used as an indicator of constriction of the small coronary arteries. SUBJECTS: 15 farm pigs weighing 80 to 90 kg were used. MEASUREMENTS AND MAIN RESULTS: A marked blood flow delay of over 7.0 s (control: less than or equal to 1.8 s) with less than 34% narrowing of the epicardial major coronary artery was observed in 13 of 15 pigs with 12.5-50 micrograms of acetylcholine, and in the other two pigs with 100 micrograms of acetylcholine. When marked blood flow delay occurred, the perfused right ventricular myocardium became macroscopically anaemic (ischaemic). Over 75% narrowing of the major epicardial coronary artery was induced in six of the 15 pigs, and over 50% narrowing in 12, with marked blood flow delay with 100 to 200 micrograms of acetylcholine. However, after intracoronary infusion of 10 micrograms of nipradilol, acetylcholine induced narrowing in the epicardial major coronary artery was significantly reduced from 44-79% in control to 19-37% despite 200 micrograms of acetylcholine, though the time delay in coronary blood flow did not change significantly. By pretreatment with intracoronary isosorbide dinitrate (2.5 mg), the percent narrowing of the large coronary artery and the time delay in coronary blood flow were significantly reduced (narrowing from 32-84% to 10-27%; time delay from 7.6-41.6 s to 2.7-22.7 s). Pretreatment with intracoronary bunazosin, an alpha 1 adrenoceptor antagonist (100 micrograms), showed no protective effect on narrowing of the epicardial major coronary artery or blood flow delay. CONCLUSIONS: Isosorbide dinitrate prevents coronary artery constriction induced by acetylcholine in swine. Nipradilol prevents large, but not small, coronary artery constriction, probably through a direct nitrate like vasodilating action.

Hypertrophy of surviving myocytes overlying the infarct in human old myocardial infarctions with abnormal Q waves.

The time course of hypertrophy of surviving myocytes overlying the infarct after the onset was examined and the hypertrophy was analyzed in relation to the transmural extent of infarct in 34 autopsied hearts with Q wave infarction. The 34 hearts were divided into 4 groups according to the length of time between the onset of infarction and death. This was less than 5 days in group 1 (n = 10), 20-30 days in group 2 (n = 7), 40-60 days in group 3 (n = 7), and 12-24 months in group 4 (n = 10). To clarify the regional hypertrophy of myocytes overlying the infarct, the size of the surviving myocytes in the outer third of the left ventricular wall in the 1-cm wide central zone of the infarct was compared with that of the myocytes in the outer third of the left ventricular wall without infarction (control wall) in the same heart. To exclude factors which stimulate the hypertrophy of the whole left ventricle, the ratio of the monocyte diameter in the infarcted wall to that in the control wall was examined. It was 1.0 +/- 0.0 (mean +/- SD) in group 1, 1.0 +/- 0.1 in group 2, 1.2 +/- 0.1 in group 3, and 1.3 +/- 0.1 in group 4. The ratio was significantly higher in group 3 than in group 1 and 2, and was highest in group 4. In group 4, the corrected percentage transmural extent of infarct indicating the original transmural extent of infarct at the acute stage was 63 + 8%, and this transmural extent correlated positively with the ratio of myocyte diameter.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of cardiac tumor found during examination in orthostatic hypotension].

We report a case of left atrial myxoma found when examination was made for the cause of orthostatic hypotension. The case was that of a man of 61 years of age. For the previous 2 years, the man had felt dizzy only at the standing or sitting position. The blood pressure was 90/50 at recumbency and 64/40 at the sitting position. Echocardiographic study revealed a left atrial tumor, which fell into the left ventricular cavity and prevented the blood from filling the left ventricular cavity. This effect was more severe at the sitting position than at recumbency. Resection of the tumor was carried out. It was a myxoma with a diameter of 3.5 cm with a stalk adhering to the postero-inferior wall of the left atrium. After the removal of the tumor, the patient's complaint and orthostatic hypotension disappeared; blood pressure was 102/60 at recumbency and 98/64 at sitting position. Orthostatic dizziness has been reported in some cases as one of the symptoms of the intracardiac tumor. But the state of aggravation at the sitting position has never been observed during actual echocardiographic study. The myxoma adhered to the postero-inferior wall of the left atrium, which site might be associated with the symptom (orthostatic hypotension).

Comparative effects of diltiazem, nifedipine, and verapamil on large and small coronary artery constriction induced by intracoronary acetylcholine in pigs.

The in vivo protective effects of diltiazem, nifedipine, and verapamil on large and small coronary artery constriction induced by intracoronary injection of acetylcholine were compared by coronary arteriography in pigs. The percent narrowing of the epicardial major right coronary artery was used as an indicator of large coronary artery constriction, and the time required for contrast medium to reach the posterior descending coronary artery from the ostium of the right coronary artery was used as an indicator of small coronary artery constriction. Doses of 12.5, 25, 50, 100, and 200 micrograms of acetylcholine were administered into the right coronary artery under left ventricular pacing to keep the systemic hemodynamics constant. Marked prolongation of the flow time of contrast medium to greater than or equal to 8.1 s (control of less than or equal to 1.8 s) with mild narrowing of the epicardial major right coronary artery (less than or equal to 35%) was observed at doses of 12.5-50 micrograms of acetylcholine and was accompanied by myocardial ischemia. Over 50% narrowing of the epicardial major coronary artery plus markedly slow flow of contrast medium were induced in 12 of the 15 pigs by 100-200 micrograms of acetylcholine. Narrowing of the epicardial major coronary artery and the delay time of contrast medium flow induced by acetylcholine were both significantly reduced to 12-33% (control: 36-81%) and to 4.3-16.8 s (control: 16.2-37.7 s) after intracoronary injection of 100 micrograms of diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)

Dobutamine prevents both myocardial stunning and phosphocreatine overshoot without affecting ATP level.

Catecholamines can overcome myocardial stunning. However, a previous report on energy metabolism in stunned myocardium during catecholamine infusion was based on the conventional biochemical methods which might affect contractile function. Twenty farm pigs were anesthetized and underwent 15 min coronary artery occlusion and 2 h reperfusion. Ten pigs were given 10 micrograms/kg/min dobutamine from immediately after and throughout the reperfusion (dobutamine group). The other ten pigs were given saline (control group). Phosphorus-31 magnetic resonance spectroscopy and sonomicrometry were done alternately. Dobutamine improved percent segment shortening after reperfusion (control/dobutamine = 3.8%-5.7%/11.7%-13.4%; P < 0.01). At 15 min ischemia, adenosine triphosphate (ATP) decreased (control/dobutamine = 72 +/- 8%/73 +/- 10%, n.s.), and remained depressed after reperfusion in both groups. After reperfusion, phosphocreatine (PCr) returned to and maintained the preischemic value in the dobutamine group, while in the control group, PCr overshoot (112 +/- 5%) was observed. Except for the presence and absence of PCr overshoot, there was no significant difference of ATP and PCr between the two groups, although rate pressure product was significantly higher in the dobutamine group than in the control group. Regional myocardial blood flow after reperfusion was significantly higher in the dobutamine group. Dobutamine may improve "stunning" through effective improvement of energy utilization and production, indicated by the disappearance of PCr overshoot and maintained ATP level.

Failure to reduce infarct size by intracoronary infusion of recombinant human superoxide dismutase at reperfusion in the porcine heart: immunohistochemical and histological analysis.

Failure to Reduce Infarct Size by Intracoronary Infusion of Recombinant Human Superoxide Dismutase at Reperfusion in the Porcine Heart: Immunohistochemical and Histological Analysis. Journal of Molecular and Cellular Cardiology (1991) 23, 1287-1296. We quantitatively determined the extent of infarction and contraction band necrosis in porcine hearts, and analyzed the distribution of administered recombinant human superoxide dismutase (h-SOD) in the myocardium using a polyclonal antibody to h-SOD. After 1 hour of occlusion, h-SOD was infused for the first 30 min of reperfusion in SOD group, while pigs received only arterial blood in control group. The extent of infarction or contraction band necrosis was not significantly different between SOD group and control group. Positive staining by polyclonal antibody to h-SOD was detected only in the infarcted area in SOD group. Thus, h-SOD only entered irreversibly damaged myocytes and neither diminished reperfusion injury nor reduced infarct size in pigs.

Expression and distribution of atrial natriuretic peptide in human hypertrophic ventricle of hypertensive hearts and hearts with hypertrophic cardiomyopathy.

To investigate the ventricular expression of atrial natriuretic peptide (ANP) in human hypertrophic hearts, we conducted an immunohistochemical study of 130 endomyocardial biopsy specimens obtained from the right side of the ventricular septum (RVB), left ventricular free wall (LVB), or both from a total of 80 patients: 44 patients with hypertrophic cardiomyopathy (HCM), 14 with apical hypertrophic cardiomyopathy (APH), 13 with hypertensive hearts (HHD), and nine without hypertrophy (controls). No patients had apparent congestive heart failure. ANP was not seen in ventricular myocytes in controls but was identified in biopsy specimens of hypertrophic hearts, and its distribution was characteristic in each hypertrophic group: 15 RVB (37%) and two LVB (7%) of the HCM group, one RVB (7%) and two LVB (18%) of the APH group, and zero RVB (0%) and five LVB (46%) of the HHD group. Clinical data (including echocardiographic, hemodynamic, and angiographic data) were not directly related to ventricular ANP expression in HCM, APH, or HHD with one exception. In HHD patients, LVB specimens with ANP showed greater ventricular wall thickness than LVB specimens without ANP. According to histological data, however, the ANP-present RVB specimens of HCM or ANP-present LVB specimens of HHD had greater myocyte size than did the ANP-absent specimens. In addition, in HCM patients, the ANP-present RVB specimens showed more severe fibrosis and myofiber disarray than did the ANP-absent specimens. We conclude that a failing state and hemodynamic overload are not likely to be indispensable for ANP expression in human hypertrophic ventricles and that ventricular ANP expression occurs as a response to disease-specific changes: hemodynamic overload in HHD and histological changes such as myocardial fiber disarray, hypertrophy of myocytes, and fibrosis in HCM, which may reflect the characteristic distribution of intraventricular ANP.

Relation between myoglobin and cardiac dysfunction in myocarditis--immunohistochemical study of endomyocardial biopsy specimens.

To investigate the mechanism of cardiac dysfunction in myocarditis, myoglobin, an intracellular oxygen-transport, was immunohistochemically examined in biopsy specimens obtained from the right side of the ventricular septum and left ventricular free wall in 58 patients with myocarditis and 19 controls. Sections 4 microns thick were stained by the indirect immunoperoxidase method using a polyclonal antibody to human myoglobin as the primary antibody. Under light microscopy, the intensity of myoglobin immunoreactivity in the tissue section was semiquantitatively classified from grade 0 to grade 3. Then, the grade of myoglobin staining was compared with clinical, hemodynamic and histopathologic parameters. In right and left ventricular specimens, the grade of myoglobin staining was positively correlated with ejection fraction, but inversely with left ventricular end-diastolic and end-systolic volume indices. The percentage of myocytes with grade 0 was correlated with the number of mononuclear cells in the specimens. In addition, the grade of myoglobin staining in right ventricular specimens was positively correlated with the duration of illness but inversely correlated with the number of mononuclear cells. In 4 patients who had serial biopsies, the ejection fraction was improved and the grade of myoglobin staining was increased in the convalescent stage. These results indicate that myoglobin staining reflects the intensity of myocarditis and a decrease of myoglobin may be important as one of the pathogenetic factors of cardiac dysfunction in myocarditis.

Identification and distribution of atrial natriuretic polypeptide in ventricular myocardium of humans with myocardial infarction.

The expression of atrial natriuretic polypeptide (ANP) in the ventricles of human hearts with myocardial infarction (MI) was studied immunohistochemically. Immunoreactive myocytes were identified in the ventricular tissues of all of 16 hearts with old MI (both with and without heart failure) and in all five hearts with subacute MI, but not in any of the eight hearts without MI nor in the five with acute MI. In the nonfailing hearts with MI, ANP positive myocytes surrounded the areas of infarction, and were also seen in the subendocardium of the infarcted segment. In the failing hearts with MI, ANP expression was noted in the whole ventricular subendocardial region, in addition to the border of infarcts. The sites of ANP expression corresponded well to those of marked stress attributable to tissue shrinkage or fibrosis due to MI, haemodynamic overload, or both. It thus appears that ANP expression is augmented in human hearts with MI regardless of the presence or absence of heart failure, and it is suggested that regional mechanical stress on the ventricular myocardium, as well as haemodynamic overload, may be very closely associated with ventricular ANP expression.

Clinicopathological study of myocardial infarction with normal or nearly normal extracardiac coronary arteries. Quantitative analysis of contraction band necrosis, coagulation necrosis, hemorrhage, and infarct size.

In order to clarify the pathogenesis of acute myocardial infarction (MI) in hearts with normal coronary arteries, infarct size, and the extent of contraction band necrosis (CBN), coagulation necrosis, and hemorrhage were quantitatively examined using an image analyzer in 5 autopsy cases of MI with normal or nearly normal extracardiac coronary arteries. One patient died 40 h after acute MI. A second patient with acute MI due to severe spasm of segment 6, confirmed by cineangiography, died three days later. The third patient had already suffered a subarachnoid hemorrhage, and died 10 h after the onset of acute MI. The fourth patient had aortic stenosis and regurgitation. She developed acute MI due to total occlusion of segment 6, confirmed by cineangiography 4 h after the onset, and died 61 days later. Autopsy revealed old anteroseptal MI with normal coronary arteries and valvular thrombi. The fifth patient had a malignancy, and died one day after the onset of acute MI. Autopsy revealed multiple occlusive thrombi in the small intramural coronary arteries of the left ventricular wall supplied by segment 14, without any stenosis in the feeding vessel. Most infarcts were localized in the territory supplied by 1 or 2 of the 3 epicardial coronary arteries, and coincided with the clinically diagnosed infarct site. The infarct size ranged from 3%-26% of the left ventricular wall, and infarcts were generally localized to the inner third of the wall (67 +/- 20%). Histological examination of the four patients with acute MI revealed diffuse CBN (86 +/- 14% of the infarcted area) and/or hemorrhage.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunohistochemical localization and semi-quantification of atrial natriuretic polypeptide (ANP) in formalin-fixed-paraffin-embedded normal human hearts--comparative study with radioimmunoassay.

The presence of atrial natriuretic polypeptide (ANP) was immunohistochemically demonstrated in the formalin-fixed and paraffin-embedded tissues of 25 autopsied normal human hearts using monoclonal antibody. The ANP amounts were immunohistochemically semiquantified and compared with amounts measured by radioimmunoassay (RIA). The 25 autopsied hearts were divided into 5 groups according to the interval of formalin fixation or the length of time between death and fixation. Formalin-fixation intervals were one week in group 1A and 1B; 1 year in group 2; 4 to 5 years in group 3 and 10 to 12 years in group 4. The hearts of group 1A, 2, 3 and 4 were fixed within 5 hours after death. Those of group 1B were fixed 14 to 18 hours at 4 degrees C. After fixation, the left and right atrial appendages (LAA and RAA), the left and right atrial free walls (LA and RA), the left and right ventricular free walls (LV and RV) and the ventricular septum (VS) were transmurally dissected from each heart. They were embedded in paraffin, cut into 4 microns sections and immunohistochemically stained by the avidin-biotin-peroxidase complex (ABC) method using monoclonal antibody against alpha-human ANP. Under a light microscope, they were evaluated semiquantitatively according to the incidence of ANP-positive cells and the intensity of immunostaining. For every heart in group 1A, the tissue concentrations of ANP in the different parts were also measured separately by RIA before fixation. ANP-positive myocytes were noted in the atria of all hearts of all groups, but no in any ventricular myocytes. Both their incidence and grade in the atria were similar among groups 1A, 1B and 2. However, they were less in group 3, and least in group 4 among all groups. For all groups, they decreased in the following order: LAA greater than RAA not equal to LA greater than RA; the inner 1/3 greater than the middle 1/3 greater than the outer 1/3 of the atrial walls. The order in LAA, RAA, LA and RA.(ABSTRACT TRUNCATED AT 250 WORDS)

Infarct size and the protection of ischemic myocardium in pig, dog and human.

To define whether recanalization after occlusion can reduce the myocardial infarct size, we compared the infarct size in 25 pig hearts without collateral circulation, 35 dog hearts with collateral circulation and 11 human autopsied hearts with coronary thrombolysis at 2 to 6 hours after the onset of acute myocardial infarction. The data showed that % infarct size in the risk area increased according to the duration of occlusion. In the pig, % infarct size was 80 +/- 9% in the recanalization after 1 hour occlusion and 96 +/- 2% in the recanalization after 2 hour occlusion. There was no significant difference between these and the permanent occlusion group (95 +/- 3%). In the dog, % infarct size was 35 +/- 31% in the recanalization after 4 hour occlusion and 59 +/- 27% in the permanent occlusion group. In human autopsied hearts, the infarct size was the same between the recanalization group (82 +/- 6%) and the permanent occlusion group (80 +/- 11%). The % infarct size in the recanalization groups was less than or the same as that in the hearts with permanent occlusion in dog, pig and human. Thus, it is concluded that, to reduce conclusively the infarct size, recanalization should be done within 1 hour after the occlusion in the hearts without collateral circulation and within 4 hours in the hearts with collateral circulation. So called reperfusion injury which means the greater expansion of the % infarct size than that in the permanent occlusion is not present.