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1. Ro 22-9124 produced tonic block of sodium currents (INa) with a Hill coefficient of 1.01 and a dissociation constant of 0.12 microM at a holding potential of - 100 mV, and use-dependent block at 2 Hz in conjunction with an increase in pulse duration (5-300 msec). 2. Ro 22-9194 blocks INa, at least partially, due to binding to the activated state. 3. The course of recovery from the use-dependent block, which was not affected by the membrane potential, was 4.0 sec, suggesting that Ro 22-9194 belongs to the intermediate kinetic class I drugs and it probably acts via a hydrophobic pathway.

The effect of thromboxane A2 synthetase inhibitor (OKY-046) on myocardial metabolism and contractility during ischemia and reperfusion was examined by the phosphorus 31-nuclear magnetic resonance (31P-NMR) in Langendorff rabbit hearts with use of an artificial blood substitute, perfluorochemical emulsion Fluosol-43. After normothermic fifteen-minute global zero-flow ischemia or fifteen-minute global low-flow ischemia (coronary perfusion pressure = 20 mmHg), reperfusion of sixty minutes was carried out. OKY-046 was administered from forty-five minutes prior to the global ischemia. Adenosine triphosphate (ATP), creatine phosphate (CrP), inorganic phosphate (Pi), pH, left ventricular systolic developed pressure (LV Dev.P) and coronary flow were continuously measured. Twenty-eight heart were divided into four experimental groups consisting of 7 hearts each; Group I consisted of controls with zero-flow ischemia; Group II, perfusion with OKY-046 (10(-6) M) in zero-flow ischemia; Group III, controls with low-flow ischemia; and Group IV, perfusion with OKY-046 in low-flow ischemia. Group II showed a significant inhibition of the increase in Pi and of the decrease in ATP, CrP, and pH during global ischemia compared with Group I, and a suppression of the overshoot of CrP observed after postischemic reperfusion. Group IV also showed a significantly marked improvement of ATP, CrP, and pH and significant suppression in Pi during low-flow ischemia compared with Group III. These were no differences in LV Dev.P and coronary flow among any groups. In conclusion, OKY-046 has a significantly beneficial effect on metabolism during both myocardial ischemia and reperfusion.

The effect of glucocorticoid on the metabolism and contractility in the stunned myocardium was examined by phosphorus 31 nuclear magnetic resonance (31P-NMR) in Langendorff rabbit hearts by use of an artificial blood substitute, perfluorochemical emulsion Flusol-43. After normothermic global ischemia of fifteen minutes, postischemic reperfusion of sixty-five minutes was carried out. Methylprednisolone sodium succinate (MPSS) was administered either prior to global ischemia or during postischemic reperfusion. Adenosine triphosphate (ATP), creatine phosphate (CrP), inorganic phosphate (Pi), pH, left ventricular systolic developed pressure (LV DevP) and coronary flow were continuously measured. Thirty-six hearts were divided into three experimental groups consisting of 12 hearts each; CONT consisted of controls, Pre-MPSS perfusion with MPSS-containing solution (10(-4)M) from forty-five minutes prior to global ischemia, and Post-MPSS with the same MPSS solution immediately after postischemic reperfusion. Pre-MPSS showed a significant inhibition of the increase in Pi and of the decrease in ATP and pH during global ischemia, in comparison with the other groups, and a suppression of the overshoot of CrP observed immediately after postischemic reperfusion. LV DevP of Pre-MPSS showed a marked improvement during the postischemic reperfusion as compared with CONT. In Post-MPSS, Pi was significantly increased and ATP decreased during the postischemic reperfusion as compared with the other two groups. There were no differences in coronary flow during postischemic reperfusion among the three groups. In conclusion MPSS has a beneficial effect on metabolism and contractility of the stunned myocardium when it is administered prior to ischemia.

The mechanism of exercise-induced ST-segment elevation in previous myocardial infarction was investigated using isoproterenol infusion with atrial pacing to simulate exercise hemodynamics in seven closed chest dogs with myocardial infarction. The myocardial infarction was induced by cellulose embolization of the left anterior descending artery. One week after infarction, 1) isoproterenol 0.3 microgram/min infusion, 2) right atrial pacing alone, and 3) isoproterenol infusion after the injection of propranolol 0.5 mg/kg were performed. The heart rate was kept constant by atrial pacing during the examination. Precordial ST-segment deviation, left ventricular global and regional wall motions, lactate extraction ratio, and regional myocardial blood flow were measured. Isoproterenol induced a significant elevation of the ST-segment, i.e., the sum of ST-segment elevation at chest leads V2, V3 and V4, sigma STV234, increased from 0.32 +/- 0.11 (mean +/- SEM) to 0.82 +/- 0.22 mV (p < 0.01). However, pacing alone and isoproterenol with pretreated propranolol did not. During isoproterenol-induced ST-segment elevation, left ventricular ejection fraction increased (29.2 +/- 3.3 to 39.1 +/- 3.9%, p < 0.01), lactate extraction ratio decreased but within the normal range for lactate metabolism (30.2 +/- 7.0 to 16.7 +/- 4.2%, p < 0.01), and the inner/outer ratio of regional blood flow did not change significantly (0.81 +/- 0.18 to 0.97 +/- 0.13 in the non-infarct border area, NS; 0.37 +/- 0.04 to 0.42 +/- 0.07 in the infarct border area, NS). Isoproterenol enhanced ventricular wall motion in the border and non-infarct areas, but did not induce aggravation in the infarct area.(ABSTRACT TRUNCATED AT 250 WORDS)

The coordinates of the ramifying points of the left coronary artery were measured using biplane coronary cineangiograms in 19 patients who were later diagnosed as normal. The spatial distances (segment length) between any two of these points were calculated and one cardiac cycle was plotted frame by frame in order to investigate shortening and relaxation characteristics of the segments. In most instances, the segments evidenced shortenings during systole and prolongations during diastole. The extent of shortening, as a percentage of maximum length ranged from 7.8 to 18.0%. The segments measured at the apex started shortening 77 msec sooner than those at the base, in other words, 90.3 +/- 6.2 msec before the R wave peak on the electrocardiograms. This indicates that the initial shortening at the apex contributes to the build up of left ventricular pressure. While at the base, since it begins to shorten after the completion of the build up in left ventricular pressure, it contributes more to the ejection of blood from the left ventricle. On the other hand, there is little systolic shortening at the atrioventricular groove and in some instances there is systolic expansion, suggesting that in comparison to the other portions of the left ventricle it is assigned an entirely different role.

In 16 patients with angina pectoris who had no histories of myocardial infarction, myocardial segment shortening was studied during angina-free periods. Myocardial segment length in the anterior wall of the left ventricle was calculated by measuring the spatial length between two points identified as junctions of ramifying branches of the left coronary arteries using biplane coronary cineangiography. Segment shortening was classified according to the severity of coronary arterial stenosis. The patients were categorized according to the severity of coronary arterial stenosis: as 1) the 0% stenosis (normal); 2) the 50% stenosis group; and 3) the 75-90% stenosis group. Total segment shortening in the normal group was the same as that in the 50% stenosis group (10.4 +/- 2.5%). However, in the 75-90% stenosis group, segment shortening was reduced to 7.3 +/- 2.5%. Effective segment shortening during the ejection period was reduced (5.0 +/- 1.8%) in the 75-90% stenosis group, as compared with the normal group (8.4 +/- 2.4%) and the 50% stenosis group (7.2 +/- 3.6%). This study demonstrated that segment shortening was reduced at rest in patients with angina pectoris who had had no previous infarction. A possible mechanism of this reduced segment shortening during angina-free periods may be irreversible myocardial alteration from recurrent ischemic attacks.

A mechanism for the genesis of early relaxation of the left ventricle was assessed. For 18 patients with coronary artery disease, biplane left coronary cineangiography was performed and the coordinates (x, y, z) of the points of the artery were measured by frame to frame basis throughout one cardiac cycle. The spatial distance (segment length) between any two points was calculated on each frame as (Formula: See text) to investigate shortening and relaxation characteristics of the ischemic and nonischemic segments. Coronary angiography was repeated during right atrial pacing to aggravate ischemia, and following nitroglycerin administration to ameliorate ischemia. From data of six normal subjects, 43 segments were calculated. All showed shortening during systole and lengthening in diastole. Right atrial pacing caused early relaxation in only two of the 43. Two hundred and fifteen segments were calculated for 18 patients with coronary artery disease. All but eight segments showed normal relaxation on control angiography. Following pacing, 115 segments showed early relaxation, and in 107 of the 115, normal relaxation were restored after nitroglycerin. Among the 107 segments, 44 were ischemic and 63 were normal. For 34 segments with early relaxation by pacing, pacing was repeated after administering nitroglycerin, and 15 did not reproduce early relaxation. The present study showed that early relaxation was observed in patients with coronary artery disease, which was effectively ameliorated by nitroglycerin, suggesting this phenomenon is closely related to the development of myocardial ischemia. The decreased active tension, reduced duration of tension, development and delay in electrical depolarization in the ischemic segment can be a reasonable inducement to early relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

In 34 mongrel dogs, the left anterior descending coronary artery was perfused with the dog's own femoral arterial blood at a constant flow rate and the myocardial contractile force was measured using a myocardial strain gauge arch. When the femoral arterial blood was oxygenated (pO2 61.7 kPa (463 mmHg)) using an artificial lung, so that the perfused myocardium became hyperoxic, the myocardial contractile force was increased by 11.1 +/- 2.3%. When the perfusion rate was reduced by approximately 20%, there was a smaller increase in myocardial contractile force, 8.0 +/- 2.3%. If, in addition, oxygen inhalation was performed the myocardial contractile force decreased by 4.1 +/- 2.1%. In 10 mongrel dogs, the carotid arteries were perfused at a constant flow rate with femoral arterial blood from a donor dog. Oxygen inhalation by the donor dog caused a reduction in the myocardial contractile force of the experimental dog of 5.9 +/- 1.6%. It is suggested that oxygen has a direct effect in increasing myocardial contractile force. This increase is counteracted by oxygen-induced coronary vasoconstriction in some part and by a neurohumoral effect or suppression of chemoreceptor activity.

The left ventricular diastolic properties of patients with hypertrophic cardiomyopathy are impaired. Since there is degeneration or disarray of myocardial fibers in patients with hypertrophic cardiomyopathy (HCM), the rate of expansion in diastole may become asynchronous. Biplane coronary cineangiograms were performed in eight normal subjects and nine patients with HCM. The coordinates (x,y,z) of the ramifying points of the left coronary artery were measured, and the distance between any two of the points of the coronary artery was calculated (segment length). Fifteen segment lengths were calculated for each subject. Since the onsets of expansion of these 15 segment lengths were not simultaneous, they expanded at different times and the onsets of expansion occurred within a very short period of time, nearly at end-diastole. The variance (standard deviation) of the timing of expansions of these 15 segments and the rate of expansion within the late 40 msec of the isovolumic relaxation period (% delta L) were calculated. The time constant of the left ventricular pressure fall (T) in normal subjects was 41.3 +/- 7.7 (SD) msec, T in HCM was prolonged to 52.7 +/- 11.1 msec. The variance was 47 +/- 17 msec in normal subjects, but it increased to 99 +/- 26 msec in HCM. The rate of expansion again decreased in HCM (Normal 2.24 +/- 0.60 vs HCM 1.40 +/- 0.96%). The conspicuous diastolic asynchrony in the onset of expansion and the reduced rate of diastolic expansion in HCM may be the mechanism of impairing the diastolic properties of the left ventricle.

In order to investigate relaxation characteristics of the infarcted wall, segment lengths of the left ventricular wall were calculated in 6 patients with anterior myocardial infarction and in 9 angiographically normal subjects. The biplane left coronary cineangiography was performed and coordinates of ramifying points of the left coronary artery on the infarcted or non-infarcted wall were measured and the spatial lengths (segment lengths) on each wall were calculated. If the two points are on the left anterior descending artery (LAD) in infarcted patients, a calculated length is regarded as a segment length in the infarcted portion, while if the length is calculated between the two points located on the coronary artery other than LAD, it is a non-infarcted segment. Each segment length was calculated in frame by frame covering one cardiac cycle. The maximum length (Lmax), minimum length (Lmin) and the length at the beginning of P wave of the electrocardiogram (LECG P) were calculated. The extent of relaxation of the segment caused by atrial kick was calculated as (Lmax--LECG P)/Lmax X 100, (% delta Lla). This value was 2.8 +/- 1.5 and 3.5 +/- 1.4% on anterior and inferior walls, respectively, in 9 normal subjects and 3.6 +/- 1.2 and 4.0 +/- 0.9% in 6 patients with anterior infarction, revealing no significant difference among 4 values. This indicates that the amount of lengthening of the segment by atrial kick remains unchanged even if the wall is infarcted. The extent of diastolic lengthening of the segment by rapid and slow fillings, which excludes atrial filling, was calculated as (LECG P--Lmin)/Lmax X 100, (% delta L1-la).(ABSTRACT TRUNCATED AT 250 WORDS)

This study was performed to clarify the difference of shortening characteristics between left ventricular epicardium and endocardium. Four to five pairs of radiopaque markers (lead beads, phi 0.3- 0.8 mm) were implanted just beneath the epicardium and endocardium, respectively in eight open-chest dogs. After the pericardium and thorax were closed, biplane cine-roentgenograms were obtained. The spatial distance (segment length) between any two of the markers was calculated using a digitizer-computer-plotter system. Left ventricular wall thickness (Th) was measured as a distance between epicardial and endocardial markers. The maximum left ventricular thickness (Thmax) was 9.4 +/- 3.4 mm (mean +/- SD), the minimum (THmin) 8.4 +/- 3.1 mm, and a percent increase of wall thickness [(Thmax-Thmin)/Thmin] was 12.7 +/- 6.5%. The value of epicardial segment length divided by endocardial segment length as normalized by each length at R wave of ECG was 1.088 +/- 0.071 at the end of systole and 0.979 +/- 0.016 at end diastole, indicating that endocardial segment shortened and distended more than epicardial segment during systole and diastole, respectively. Epicardial segment began to shorten 3 +/- 26 msec earlier and distend 4 +/- 50 msec earlier than endocardial one. This study revealed a small but consistent difference in the amount of shortening and its initiation and termination between the epicardium and endocardium.

This study was done to discover whether or not the oxygen-induced depression of sympathoadrenal activity contributes to a reduction of myocardial contractile force during oxygen breathing. In 10 open-chest dogs, myocardial contractile force was measured using a myocardial strain gauge arch during air and oxygen breathing before denervation (intact heart) and after bilateral vagotomies, sympathectomies and adrenalectomies with the intravenous administration of propranolol, phenoxybenzamine and atropin (denervated heart). One hundred percent oxygen breathing caused similar increases in arterial pO2 in both the intact (from 94 +/- 10 to 442 +/- 25 mmHg) and the denervated dogs (from 113 +/- 11 to 456 +/- 15 mmHg). Coronary blood flow measured at the left anterior descending coronary artery was reduced by oxygen breathing from 28.4 +/- 3.4 to 21.7 +/- 2.3 ml/min in the intact dogs, and from 19.4 +/- 3.4 to 14.9 +/- 2.6 ml/min in the denervated dogs. Myocardial contractile force was significantly reduced by oxygen breathing in the intact dogs (a reduction of 5.8 +/- 1.4%). In the denervated dogs, on the other hand, no significant changes in myocardial contractile force was seen. This study suggests that the reduction in myocardial contractile force is mediated through sympathoadrenal activity, and thus, is abolished by sympathoadrenal blockade.

We conducted this study in order to learn whether or nt oxygen inhalation reduces left ventricular size, one of the major determinants of myocardial oxygen demand. In 11 open-chest dogs, a Mercury-in-Silastic gauge was applied to measure left ventricular circumferential length while the dogs were being ventilated with either room air or 100% oxygen. Four characteristic notches were identified on the resulting length curve: L1, length at the beginning of ejection; L2, length at the end of ejection; L3, length in early diastole; and L4, length at end diastole, L1 was shortened from 24.9 +/- 10.5 to 24.4 +/- 9.9 mm (a decrease of 1.4 +/- 2.1%) by oxygen breathing, L2 was also shortened from 26.8 +/- 11.5 to 26.2 +/- 10.7 mm (a decrease of 1.5 +/- 2.9%), L3 from 17.5 +/- 4.4 to 17.4 +/- 4.3 mm (a decrease of 0.7 +/- 2.7%) and L4 from 17.7 +/- 4.8 to 17.5 +/- 4.7 mm (a decrease o 1.3 +/- 2.4%). These changes all disappeared when the inspiratory gas was changed from oxygen back to air. Heart rate and left ventricular end-diastolic pressure showed no significant changes but were accompanied by a slight reduction in aortic pressure and myocardial contractile force. This study demonstrated a small but consistent reduction in left ventricular circumferential length by oxygen breathing. This reduction in left ventricular size will reduce left ventricular tension and thus result in reduction of left ventricular myocardial oxygen demand when oxygen inhalation is applied to patients with ischemic heart disease.

To study relaxation characteristics of the infarcted myocardium, cyclic changes in the global left ventricular (LV) volume were measured in 20 patients with old myocardial infarction (OMI) and 17 normals (Normal) and those in the regional segment length were measured in 9 patients with anterior old myocardial infarction (anterior OMI) and 11 normals. The LV volume was calculated by using biplane LV cineangiograms. The regional segment length was calculated by measuring the spatial length between the 2 points of the ramifying branches on the left coronary arteries by using biplane coronary cineangiograms. The LV filling volume before atrial contraction (VR) was significantly less in the OMI compared with that in the normals (Normal 38 +/- 6 (mean +/- SD) ml/m2 vs 30 +/- 7 ml/m2: p less than 0.01), while filling volume by atrial contraction (Va) did not significantly differ (Normal 15 +/- 4 ml/m2 vs OMI 17 +/- 5 ml/m2). The lengthening of the segmental wall during diastole before atrial contraction (%LR) in the infarcted portion was 5.0 +/- 2.9% which was also significantly less than that in the non-infarcted portion (9.6 +/- 4.2%). The extent of lengthening by atrial contraction (%La) did not differ between the 2 portions (non-infarcted portion 3.8 +/- 1.1% vs infarcted portion 3.5 +/- 1.2%). Reduction of %LR was speculated to be caused by the incomplete relaxation in the myocardium adjacent to the infarcted portion and stiff myocardium in the infarcted portion. This study suggests that the infarcted myocardium may lead to a reduction of diastolic expansion before atrial contraction.