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The effect of lidocaine on conduction within normal and acutely ischemic ventricular myocardium was studied in 45 dogs in vivo. By recording pairs of local electrograms from the endocardium and epicardium and by stimulating the ventricle close to one of a pair of electrodes, we measured conduction times in the subendocardial layer (Endo 1-2), in the subepicardial layer (Epi 1-2), and from the endocardium to the epicardium (Endo-Epi). We then estimated the effect of lidocaine on each of them. In normal myocardium, lidocaine in a therapeutic dose (serum level 2.5 +/- 0.4 micrograms/ml) did not affect any of the three conduction times, but in a larger dose (serum level 6.5 +/- 0.7 micrograms/ml) it prolonged Endo-Epi significantly (P less than 0.05) and Endo 1-2 and Epi 1-2 slightly. In acutely ischemic myocardium caused by single stage ligation of the left anterior descending coronary artery, lidocaine in a therapeutic dose prolonged Endo 1-2 and Endo-Epi significantly (P less than 0.001) in the early stage after administration but did not affect Epi 1-2 simultaneously. Lidocaine in a larger dose, however, prolonged all three conduction times (P less than 0.001). The data indicate that within normal ventricular myocardium, lidocaine does not influence conduction unless its dose is toxic, and that within acutely ischemic ventricular myocardium, at a therapeutic dose, lidocaine prolongs conduction rapidly, but this effect is produced heterogeneously in the ischemic myocardium and is poor in the subepicardial layer.

We have developed a simple quantitative analysis system for coronary cineangiograms using a personal computer and a standard projector-video camera system. The selected frame of cinefilm was projected onto the target area of a CCD video camera. To decrease spatial fluctuations due to quantum noise, the digital data were smoothed spatially by applying a moving averaged filter and a median filter. Following the smoothing process, the digital data with gray level were transformed to binary data by quantifying the threshold property of their gray level. To minimize the geometric influence, mainly pincushion effect, a cinefilm of a 1 cm grid was placed against the input screen of the image intensifier to correct the distortion by using 3rd degree polynomials. The accuracy of the contour detection procedure was validated on the basis of phantom models filled with a contrast medium. Despite the potential influence of many radiographic variables on computerized diameter measurements, the overall accuracy was found to be 0.26-0.33 mm over a wide range of clinically relevant artery diameters and radiographic conditions. Using this system we demonstrated one method of examining the effects of acetylcholine and nitroglycerin on coronary artery diameter in adult humans.

To examine the effects of propranolol and nifedipine on exercise-induced attack in patients with variant angina, exercise 201Tl myocardial scintigraphy with quantitative analysis by emission-computed tomography was performed in 20 patients with variant angina after oral propranolol (80 mg), nifedipine (20 mg), and placebo. Exercise-induced attack occurred in 11 patients on placebo, in 14 on propranolol, and in none on nifedipine. The exercise duration was significantly shorter in those on propranolol (p less than .05), but significantly longer in patients on nifedipine (p less than .05) than in those on placebo. The peak rate-pressure product was significantly lower in patients on propranolol (p less than .01), but did not change in those on nifedipine, as compared with that in patients on placebo. The size of the perfusion defect as measured by 201Tl tomography was significantly greater in patients on propranolol (p less than .05), but significantly less in those on nifedipine (p less than .01) than in those on placebo. In conclusion, propranolol does not suppress but rather may aggravate exercise-induced attack in patients with variant angina, while nifedipine suppresses it. This unfavorable effect of propranolol on exercise-induced attack in patients with variant angina is likely to be due to a reduction of regional myocardial blood flow.

A peptide (extra signal peptide) comprising amino acids 1-29 of pig liver pre-mitochondrial aspartate aminotransferase (p-mAAT) was synthesized chemically. The peptide was found to block the import of rat liver p-mAAT into rat liver mitochondria. An antibody raised against the peptide immunoprecipitated rat liver p-mAAT synthesized in a rabbit reticulocyte cell-free translation system. These results suggested that the extra signal peptide sequence of p-mAAT is essential for import of p-mAAT into the mitochondria and that there is structural homology between the extra signal peptides of pig and rat liver p-mAAT. An anti-idiotypic antibody against the peptide was also prepared and purified by affinity chromatography on an Affi-Gel 10 anti-peptide IgG column and was then characterized.

The localization of cytosolic (s-) and mitochondrial (m-) glutamic oxaloacetic transaminase (GOT) was examined in the rat trigeminal, jugular and dorsal root ganglia by means of an indirect immunofluorescence method using antibodies specific for s- and m-GOT. Staining of s-GOT-like immunoreactivity was seen in giant, large, medium and small cells in these ganglia. On the other hand, m-GOT-like immunoreactivity was not seen in them. The distribution of GOT suggests that glutamate may be a transmitter released from primary sensory neurons.

We reported the case of a 46-year-old man with thymolipoma whose chest X-ray initially suggested cardiomegaly. Computed tomography (CT) clearly demonstrated the existence of a large mass adjoining the left ventricular wall in the mediastinum. CT also allowed estimation of the character of the mass including its size, extent, and consistency. At thoracotomy, the tumor was excised and thymolipoma was diagnosed histopathologically.

We examined electrophysiological properties of the ischemic myocardium of the canine heart. Multiple bipolar electrodes for stimulation or for recording electrograms were placed on the epicardial surface and at the endocardium of the ventricle. The time course of changes in excitability threshold, in effective refractory period and in local conduction time during ischemia was estimated at the epicardial and endocardial sides of the central ischemic zone, at the epicardial side of the peripheral ischemic zone and at both sides of the normal zone. Soon after left anterior descending coronary artery occlusion, a rise of excitability threshold, a lengthening of effective refractory period and a prolongation of conduction time consistently occurred in all portions of the ischemic zone. The degree of changes, however, was not uniform: it was greater at the epicardial side of the central ischemic zone. In most experiments, the changes reached maximum within 10 min after occlusion. Then, altered electrophysiological properties recovered to some extent or stabilized. The results indicate that electrophysiological properties deteriorate momentarily after coronary occlusion but then recover or stabilize, and that their changes during acute ischemia are not uniform in the ischemic region but severer at the central zone and epicardial side.

Acute myocardial infarction was precipitated by hyperventilation in a 65 year old man. His coronary arteriogram in the chronic phase showed almost normal coronary arteries. Injection of acetylcholine (50 micrograms) into the left coronary artery induced spasm of the circumflex artery with chest pain in association with ST-segment elevation in the inferior leads and ST-segment depression in the precordial leads. In this patient there may have been atherosclerosis of the coronary arteries with absent or dysfunctional endothelium, despite an almost normal angiographic appearance. In the absence of endothelium the response of the smooth muscle to acetylcholine is constriction.

Induction of cytosolic aspartate aminotransferase (glutamic oxaloacetic transaminase) was observed in rat liver on administration of a high-protein diet. The enzyme activity in the liver of rats given 60% and 80% protein diet increased to 1.8- and 1.9-fold that in the liver of rats maintained on 20% protein diet, with about 2-fold increases in the levels of functional sGOT mRNA, measured by in vitro translation. Whereas the activity of mitochondrial aspartate aminotransferase did not increase. Induction of cytosolic aspartate aminotransferase was also detected immunocytochemically.

Mitochondrial glutamic oxaloacetic transaminase is synthesized in the cytoplasm as a larger precursor and then imported into mitochondria in association with its processing to mature form. The precursor corresponded to about 0.05-0.1% of the total proteins synthesized on membrane-free polysomes. Gel permeation chromatography showed that the molecular weight of the precursor was about 100,000 daltons, which was slightly larger than that of mature enzyme (homodimer: 45,000 x 2). On the other hand, sodium dodecylsulfate treated precursor had the molecular size (about 50,000 daltons) slightly larger than that of the subunit of mature one by the gel permeation chromatography. These results suggest that the precursor of mitochondrial glutamic oxaloacetic transaminase exists as a dimer.

The localization of cytosolic (s) or mitochondrial (m) glutamic oxaloacetic transaminase (GOT) was examined in the rat retina by means of an indirect immunofluorescence method using antibodies specific for s- and m-GOT. The m-GOT-like immunoreactive structures were seen on the inner segments of the photoreceptor cells and other outer and inner plexiform layers. These structures were dot-like in appearance. Somas were not labeled. In contrast, s-GOT-like structures were found on the inner segments and inner fibers of the photoreceptor cells, numerous cell somas in the inner nuclear layer (horizontal, amacrine and bipolar cells), and ganglion cell layer (displaced amacrine cells) and inner plexiform layer. The difference in distribution between s- and m-GOT isozymes suggests that they may be useful as markers for glutamatergic and/or aspartinergic neurons.

In ten patients with familial amyloid polyneuropathy (FAP), the effects of atropine and isoproterenol on the cardiac conduction system were studied using surface electrocardiogram (ECG) and His bundle electrograms. Intravenous administration of atropine sulfate, 1 mg, prolonged the sinus cycle length ( SNCL ) in 6 of 8, sinus node recovery time (SNRT) in 3 of 6, automaticity recovery time of the atrioventricular (A-V) node in one, A-H interval in 4 of 7, effective refractory periods of the atrium and A-V node in 4 of 6 and in 3 of 7 patients, respectively. Continuous intravenous administration of isoproterenol, 0.5 micrograms/min, shortened the SNCL , SNRT, A-H interval and refractory periods of the atrium and A-V node in all patients. We conclude that the therapeutic doses of atropine may be useless or potentially detrimental for bradyarrhythmias or conduction blocks in some patients with FAP, but that isoproterenol may have beneficial effects on those arrhythmias in FAP.

Induction of cytosolic aspartate aminotransferase (cAspAT) was observed in rat liver on administration of a high-protein diet, or glucagon and during fasting. The enzyme activity in the liver of rats given 80% protein diet or glucagon injection during starvation increased to 2- to 2.4-fold that in the liver of rats maintained on 20% protein diet, with about 2-fold increases in the levels of hybridizable cAspAT mRNA, measured by blot analysis using the cloned rat cAspAT cDNA as a probe. No increase in the enzyme was detected in kidney, heart, brain, or skeletal muscle. The activity of mitochondrial aspartate aminotransferase (mAspAT) did not increase. Induction of cAspAT was observed when glucose metabolism tended toward gluconeogenesis. The physiological function of the induction of cAspAT is considered to be to increase the supply of oxaloacetate as a substrate for cytosolic phosphoenolpyruvate carboxykinase (PEPCK) [EC 4.1.1.32] for gluconeogenesis.

By intravenous administration of isoproterenol, 0.5 micrograms/min, a catecholamine-sensitive bypass tract was confirmed in two patients with exercise-induced Wolff-Parkinson-White syndrome. In a 24 year old woman, an intravenous bolus injection of 5 mg of verapamil suddenly blocked conduction over a catecholamine-sensitive bypass tract. In a 62 year old man, the exercise-induced Wolff-Parkinson-White syndrome disappeared after 3 days of oral administration of verapamil (120 mg/day). These observations suggest that a slow inward calcium current plays an important role in conduction over a catecholamine-sensitive bypass tract in exercise-induced Wolff-Parkinson-White syndrome.

Dopa decarboxylase (DDC; aromatic-L-amino-acid decarboxylase; aromatic-L-amino-acid carboxylase, EC 4.1.1.28) was purified from rat liver and its partial sequence was determined. Synthetic oligonucleotides were used to construct and screen rat liver cDNA libraries, and three clones were isolated and sequenced. The 2 kilobases of DDC cDNA cloned consisted of a 5'-noncoding segment of 78 nucleotides, a coding region of 1440 nucleotides, and a 3'-noncoding region of 438 nucleotides. The encoded protein of 480 amino acid residues had a molecular weight of 54,000. A special feature of the primary structure of rat DDC was a repeating structure consisting of 29 amino acid residues. A sequence of 58 amino acid residues, including this repeating structure of rat DDC, was found to show homologies with those of rat tyrosine hydroxylase, human dopamine beta-hydroxylase, and bovine phenylethanolamine N-methyltransferase, other mammalian enzymes that synthesize catecholamines. These results indicate that catecholamine biosynthetic enzymes are structurally related and suggest that their homologous domains are important for catechol-protein interactions.

The difference in the electrophysiological properties between the subepicardial cells and the subendocardial cells (Purkinje fibers and ordinary myocardial cells) was examined in dogs using a microelectrode technique. The preparations were obtained one hour after coronary occlusion. Immediately after exposure to a hypoxic solution, spontaneous activities could be recorded in neither the subepicardial nor the subendocardial cells. The electrical activities induced by electrical stimulation disappeared 5-10 min after exposure to the hypoxic solution in the subepicardial cells, while they remained in the subendocardial cells. Vmax, action potential amplitude, action potential duration and resting membrane potential of the subendocardial cells were all reduced significantly in the hypoxic solution containing 7 mK K+ in contrast to those in the hypoxic solution containing 4 mM K+ (p less than 0.001). In the hypoxic solution containing 15 mM K+, all cardiac cells depolarized partially and became electrically quiescent in both normal and ischemic cardiac cells. These findings support the idea that during regional hypoxia and hyperkalemia resulting from acute coronary occlusion, heterogeneous changes in electrical activities occur between the subepicardium and the subendocardium in the ischemic regions.

We injected acetylcholine (ACh), the neurotransmitter of the parasympathetic nervous system, into the coronary arteries of 28 patients with variant angina. Injection of 10 to 80 micrograms ACh into the coronary artery responsible for the attack induced spasm together with chest pain and ST segment elevation or depression on the electrocardiogram in 30 of the 32 arteries of the 25 of the 27 patients. The injection of 20 to 100 micrograms ACh into the coronary artery not responsible for the attack in 18 patients resulted in various degrees of constriction in most of them, but no spasm in any of them. After intravenous injection of 1.0 to 1.5 mg atropine sulfate, the injection of ACh into the coronary artery responsible for the attack did not induce spasm or attack in any of the nine coronary arteries injected in eight patients. We conclude that the intracoronary injection of ACh induces coronary spasm and attack in patients with variant angina and that the activity of the parasympathetic nervous system may play a role in the pathogenesis of coronary spasm. We also conclude that the intracoronary injection of ACh is a useful test for provocation of coronary spasm.

To investigate the effect of collateral circulation on the electrophysiological properties of the acutely ischemic myocardium, acute myocardial infarction was produced in the canine heart by coronary artery occlusion alone, and by coronary artery occlusion plus embolization with vinyl latex. Multiple bipolar electrodes for stimulation or for recording electrograms were placed on the subepicardial layer and the subendocardial layer to examine the time course of changes in excitability threshold, effective refractory period, and conduction time. Soon after coronary occlusion plus embolization, electrophysiological properties of the ischemic subepicardium became severely and almost uniformly damaged and showed no recognizable recovery of electrical activities, whereas transient deterioration and subsequent recovery of the electrophysiological properties were observed after coronary occlusion alone. On the other hand, the subendocardium was much less affected electrophysiologically by either coronary occlusion alone or coronary occlusion plus embolization. These results indicate that collateral circulation plays an important role in the recovery from electrophysiological abnormalities in the ischemic subepicardium caused by acute myocardial ischemia, but has little effect on the electrophysiological properties of the ischemic subendocardium.

Effects of 2-nicotinamidoethyl nitrate (SG-75) on isolated dog coronary artery and cat papillary muscle were investigated. SG-75 dose-dependently relaxed the isolated coronary arterial strips contracted with potassium. Large doses of SG-75 depressed contraction of papillary muscle driven with electrical stimulation and inhibited enhancement of contraction of papillary muscle induced by calcium and isoproterenol. From these results it is suggested that SG-75 may have a weak Ca++-antagonistic action.

A possible effectiveness of atropine on variant form of angina pectoris was investigated using the left circumflex coronary arterial strips of dogs. Acetylcholine 10(-5)--10(-3) Gm/ml dose-dependently constricted the isolated arterial strips during potassium-contracture in 6 cases, and repetitive applications of acetylcholine could produce the similar contractions to the control. In 18 strips atropine 10(-6) Gm/ml significantly depressed the contractions of coronary arteries induced by acetylcholine 10(-5)--10(-3) Gm/ml. In 5 arterial strips atropine 10(-6) Gm/ml significantly inhibited norepinephrine-induced responses of these arteries, and by 10(-5) Gm/ml further suppression of the responses was obtained. The results suggest that atropine may suppress the contractile responses of the coronary artery induce by acetylcholine and nonrepinephrine through a muscarinic-receptor blocking action and simultaneously partly through an adrenergic alpha-receptor blocking action.

We report the case of a 23-year-old man with coarctation of the aorta whose baroreceptor sensitivity was extremely reduced. Antihypertensive therapy was effectively performed after coarctectomy. Only one month after coarctectomy, baroreflex sensitivity had recovered. The present case is believed to be the first in which reduced baroreceptor sensitivity in coarctation of the aorta was reversible in the early phase after coarctectomy.

Multivessel coronary spasm has been described but its incidence in patients with variant angina still remains unclear. Thirty-three patients with variant angina were studied during coronary angiographic examination with selective intracoronary injection of acetylcholine (ACh). In all but three patients, the location of ischemia during attack was determined by the electrocardiographic findings, by exercise 201Tl myocardial scintigraphy, and by two-dimensional echocardiography during a hyperventilation test, and the coronary artery (or arteries) responsible for the attack was predicted before the study. ACh induced spasm of at least one coronary artery in all but one patient. ACh induced spasm of both the left and right coronary arteries (i.e., multivessel coronary spasm) in 24 patients: in two of the four patients who were predicted to have spasm of the left coronary artery, in six of the 11 predicted to have spasm of the right coronary artery, in 13 of the 15 predicted to have spasm of both the left and right coronary arteries, and in three of the three in whom coronary artery responsible for attack had not been predicted. This ACh-induced spasm of the left and right coronary arteries occurred separately and no patients showed hemodynamic instability during attack. In one patient in whom multivessel coronary spasm had been predicted and ACh failed to induice coronary spasm, ergonovine maleate (0.2 mg) induced spasm of both the left and right coronary arteries simultaneously, resulting in severe prolonged hypotension. Nineteen of the 25 patients in whom multivessel coronary spasm was documented showed angiographically normal or nearly normal coronary arteries after administration of nitroglycerin.(ABSTRACT TRUNCATED AT 250 WORDS)

The activity and the mRNA content of cytosolic aspartate aminotransferase (EC 2.6.1.1) were examined in cultured rat hepatocytes. Addition of glucagon (1 x 10(-7) M) in the presence of dexamethasone (1 x 10(-7) M) caused about 2-fold increase in the activity and mRNA content. Dibutyryl cAMP (1 x 10(-4) M) could replace glucagon for this effect. Maximal induction of cytosolic aspartate aminotransferase mRNA was observed 8 h after their additions. Insulin (1 x 10(-7) M) did not inhibit the enzyme induction by glucagon or dibutyryl cAMP. These results suggest that the cytosolic aspartate aminotransferase gene is regulated by cAMP, and not by insulin.