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Glucose output was investigated in bivascularly perfused rat liver. Flow rate was 1 ml/min/g from hepatic artery and 2 ml/min/g from portal vein. Basal glucose output (130 +/- 30 microM/min) from bivascularly perfused liver was significantly (p less than 0.02) higher than that (80 +/- 20 microM/min) from usual monovascularly perfused (3 ml/min/g from portal vein) liver. However, glucagon-induced (1 ng/ml) increment in glucose output from bivascularly perfused liver 589 +/- 127 microM/30 min) was not significantly different from that (630 +/- 127 microM/30 min) of monovascularly perfused liver. These results suggest that glucagon-dependent glucose output was similar in monovascularly and bivascularly perfused rat liver, and that arterial blood supply may have some role in glycogenolysis in the perfused rat liver.

To evaluate the possible role of the adrenergic mechanism in hyperketonemia in hyperthyroidism and starvation, the plasma concentrations of FFA, acetoacetate (AcAc), and beta-hydroxybutyrate (BOHB) were measured in thyrotoxic and starved rats for 96 hours. Thyrotoxemia was induced in rats by a daily subcutaneous thyroxine (100 micrograms/kg/day) injection carried out for 7 days. Some of the thyrotoxic and starved rats were administered subcutaneous phentolamine (2 mg/kg, twice daily) or propranolol (0.1 mg/kg, twice daily). Plasma levels of FFA, AcAc, and BOHB were significantly increased in thyrotoxic and starved rats compared with the control rats. Phentolamine and propranolol administration did not alter plasma levels of FFA, AcAc, and BOHB in thyrotoxic rats. In starved rats, propranolol did not alter plasma levels of FFA, AcAc, and BOHB, however, phentolamine did increase plasma levels of FFA, AcAc, and BOHB. These results indicate that the adrenergic mechanism may not contribute to the hyperketonemia in thyrotoxic rats, but may have a slight inhibitory effect on ketogenesis in starvation probably due to alpha-antilipolytic action.

To evaluate the effect of aging on hepatic extraction of insulin, peripheral plasma insulin and C-peptide levels after an oral glucose ingestion were measured in 39 non-obese healthy subjects with normal glucose tolerance test. The subjects were divided into two groups. One age group was below 30 years (n = 17) and another was above 50 years (n = 22). Blood glucose level was significantly higher in elderly subjects than in young at 30 and 60 min, and insulin level was also significantly higher in elderly subjects than in young subjects at 60 min after glucose ingestion. C-peptide response after glucose ingestion was similar in both groups. The molar ratio of C-peptide to insulin after glucose ingestion in elderly subjects was slightly lower than that in young subjects, and the difference between the incremental areas of C-peptide and insulin divided by the incremental area of C-peptide were significantly lower in elderly subjects. These results suggest that hepatic insulin extraction after glucose loading is decreased in elderly subjects and this may partly be responsible for the slightly altered glucose metabolism in elderly subjects with normal glucose tolerance test.

To determine the effect of maturation on glucose-induced insulin release after starvation, we investigated the insulin release from perfused pancreas of young adult rats after fasting for 18-20 hr. In the rats weighing 300-400 g (12-14 w) and 200-250 g (7-8 w), the glucose-induced insulin secretion from perfused pancreas of starved rats was similar to that of fed rats. While, in the rats weighing 100-150 g (4-5 w), both the first and the second phase of glucose-induced insulin secretion from perfused pancreas of starved rats was markedly decreased compared with that of fed rats. These results suggest that insulin response to glucose is not matured in young below 150 g (5 w).

Two cases of acute eosinophilic pneumonia following cigarette smoking are analyzed for characteristic features. The first patient noted dyspnea 14 days after initiation of smoking. The second patient noted dyspnea 12 days after beginning to smoke. Both cases had characteristic features including occurrence at an age younger than 30 years; less than 1 month duration of cigarette smoking before onset of disease; and no identifiable cause of acute eosinophilic pneumonia apart from smoking. We believe that acute eosinophilic pneumonia following cigarette smoking, which has characteristic features as described above, should be considered as a distinct subtype of AEP.

The effects of enalapril on exercise capacity and neurohumoral factors during exercise were evaluated in 10 patients with heart failure. Echocardiograms and exercise testing with expired gas analysis were performed before and after enalapril. Blood samples were obtained before and after exercise. Both ejection fraction and percent fractional shortening increased with enalapril (p0.05). The anaerobic threshold and peak VO2 did not change with enalapril. Epinephrine and norepinephrine levels at peak exercise decreased with enalapril (p0.1). Plasma renin both at rest and at peak exercise increased with enalapril (p0.1). Angiotensin II was lower after enalapril both at rest and at peak exercise (p0.1 and p0.05, respectively). Aldosterone was lower after enalapril both at rest and at peak exercise (p0.05). Atrial natriuretic peptide (ANP) was lower after enalapril both at rest and at peak exercise. There was no significant correlations between peak VO2 and changes in neurohumoral factors before and after enalapril during exercise. In conclusion, neurohumoral changes with enalapril occurred during exercise even if exercise capacity did not improve. Moreover, the improvement of cardiac function at rest and neurohumoral factors with enalapril did not lead to a change of exercise capacity.

In order to examine the current status of antihypertensive drug therapy for elderly hypertensive patients, and the effect of clinical characteristics and drugs on their prognosis, 1669 hypertensive patients in the Chugoku and Shikoku districts, aged between 65 and 84 years, were enrolled and followed for 3 years. Of the 1669 patients enrolled, 1459 were selected for evaluation and 1127 patients were followed. Group A comprised 955 patients who had not suffered from any accident, group B comprised 139 patients who had suffered from a cerebral, cardiac, renal or other non-fatal accident, and group C comprised 33 patients who died. The mortality rate was 10.7/1000 patient.years and the morbidity rate was 55.6/1000 patient.years. The number of patients who received monotherapy was 736 (calcium channel blockers: #436, beta blockers: #100, angiotensin converting enzyme inhibitors: #80, diuretics: #64, alpha blockers: #16; others: #13). In group C, there were more male, and the patients were older and showed a higher level of serum creatinine concentration at enrollment compared with other groups. The use of diuretics and beta blockers tended to be low in this group. Among the three groups, however, there was no difference in blood pressure, heart rate or the use of each drug at enrollment. In summary, it is suggested that the different antihypertensive drug therapies die not influence the prognosis of elderly hypertensive patients.

We investigated the characteristics of decreased heart rate variability (HRV) in diabetic patients with ischemic heart disease (IHD). Twenty-one healthy control subjects, 17 diabetic patients without IHD, and 33 diabetic patients with IHD were studied. The diabetic patients with IHD were subdivided into 2 groups according to the severity of their IHD: severe or mild. HRV was evaluated in all subjects using the spectral variables of the all-frequency, Iow-requency, high-frequency (AF, LF, HF) components and the LF/HF ratio were determined from Holter recordings. The AF and LF components in patients with diabetes only or diabetes and severe IHD were significantly lower than in control group, but the HF component was significantly lower only in the group of patients with diabetes and severe IHD. The LF/HF ratio did not differ significantly among the 4 groups, but was the lowest in diabetic patients without IHD. Patients with diabetes and mild IHD showed a slight decrease in HRV, but this was not significant. With regard to the circadian rhythm of HRV, the AF and LF components in patients with diabetes-only or diabetes and severe IHD were significantly decreased and showed the same pattern throughout the day. However, the HF component was decreased during more time zones in patients with diabetes and severe IHD, whereas the LF/HF ratio was lower during more time zones in the diabetes-only group. All spectral variables showed a tendency to be inversely related to the duration of diabetes in all diabetic patients. In particular, the LF/HF ratio showed a significant negative correlation. The HRV of diabetic patients was characterized by a decreased LF/HF ratio. It was concluded that, although HRV in diabetic patients with severe IHD was reduced mainly as a result of diabetic neuropathy, this was also partly due to a decline in parasympathetic tone as a result of myocardial injury. (Jpn Circ J 1996; 60: 925 - 932)

1. 1. The quinidine-induced modification of intracellular Ca 2+ concentration ([Ca 2+ ] i ) was studied in guinea-pig myocardium using fura-2. Quinidine reduced the systolic fluorescence signal level for [Ca 2+ ] i and enhanced the end-diastolic signal level during a stimulation train. 2. 2. The diastolic decay of [Ca 2+ ] i fitted 2 exponential curves. Quinidine distorted the stimulation frequency-dependent acceleration of rapid [Ca 2+ ] i decay, and prolonged the mean time constant of rapid decay after 2 Hz stimulation, from 154.4 to 205.3 msec (20 μM), and to 259.7 msec (60 μM quinidine). The time constant of slow recovery from [Ca 2+ ] i accumulation after the stimulation train was not affected by stimulation frequency, or by quinidine, or caffeine. 3. 3. These results suggest that quinidine modulates [Ca 2+ ] i via a balance between the slowing of rapid [Ca 2+ ] i decay and the reduction of the systolic [Ca 2+ ] i . This effect may contribute to the anti-arrhythmic and pro-arrhythmic effects exerted by quinidine in some conditions.

We examined the responses of plasma catecholamine and plasma renin activity (PRA) during mental (arithmetic) stress and dynamic exercise in 15 normal subjects. Compared to rest values, there was a significant increase in the plasma epinephrine concentration (E), but not in the plasma norepinephrine concentration (NE) or PRA during mental arithmetic. During dynamic exercise, there were significant increases in both NE and E and in PRA. The ratio of E to NE was significantly higher during mental arithmetic than during dynamic exercise. NE was significantly correlated with PRA at rest, during mental arithmetic and dynamic exercise. No significant correlations were observed between E and PRA. Dynamic exercise primarily induces a sympathetic nervous response, and mental (arithmetic) stress mainly induces an adrenal response. The renin-angiotensin-aldosterone system response may in part be regulated by sympathetic nervous activity during both mental (arithmetic) stress and dynamic exercise.(Internal Medicine 34: 618-622, 1995)

A 26-year-old man with Graves' hyperthyroidism associated with central diabetes insipidus (DI), initially showed hypercalcemic crisis. Initially, very low serum levels of intact parathyroid hormone (PTH) and 1, 25-dihydroxy vitamin D3 and a moderate rise of serum C-terminal PTH related protein (C-PTHrP) were observed which strongly suggested a humoral hypercalcemia of malignancy due to PTHrP. However, the serum C-PTHrP level later became normal. Mild hyperprolactinemia, no responses of growth hormone (GH) to insulin-induced hypoglycemia despite a normal growth hormone releasing hormone (GRH) test and mild thickening of the pituitary stalk on magnetic resonance imaging were observed. Thus, an autoimmune nature of his central DI is considered; it is noteworthy that the serum C-PTHrP level may be elevated by renal failure in patients with hypercalcemia due to causes other than PTHrP.(Internal Medicine 34: 924-928, 1995)

We studied the causes of exercise-induced ST-segment elevation. Group I consisted of 15 patients with anterior myocardial infarction in the absence of a coronary artery luminal narrowing of 75% or more. Group II consisted of 36 patients with predominantly exertional angina and a luminal narrowing of 90% or more in the left anterior descending coronary artery in the absence of previous myocardial infarction. In group I, exercise-induced ST-segment elevation occurred frequently during treadmill exercise (15/15, 100%). None of the patients showed 201Tl redistribution. The standard deviation of the phase in radionuclide ventriculography increased during bicycle exercise. Of group II patients, only those with 99% narrowing and poor collaterals showed exercise-induced ST-segment elevation (13/14, 93%), whereas none of those with complete occlusion or 99% narrowing and good collaterals, or 90% narrowing showed ST-segment elevation. In group II, patients with exercise-induced ST-segment elevation showed lower 201Tl uptake during exercise and washout in the territory of the diseased vessel than those without exercise-induced ST-segment elevation. In conclusion, wall motion abnormalities may cause exercise-induced ST-segment elevation independently of myocardial ischemia. In patients with predominantly exertional angina, exercise-induced ST-segment elevation may be a marker for 99% narrowing with poor collaterals and severe myocardial ischemia.

The effects of monatepil, a new calcium antagonist with alpha 1-blocking activity, and nitrendipine on lipoprotein and carbohydrate metabolism in 86 patients with mild-to-moderate hypertension were examined in a randomized, open-label, multicenter (32 hospitals) study. Thirty-nine patients treated with monatepil and 33 patients treated with nitrendipine completed the 12-week study. Monatepil and nitrendipine each significantly decreased both systolic and diastolic blood pressure. Changes in heart rate were not seen in either group. Monatepil administration significantly decreased total cholesterol, low density lipoprotein (LDL) cholesterol, the LDL cholesterol to high density lipoprotein (HDL) cholesterol ratio, apolipoprotein (Apo) B levels, and HbA1c levels, whereas no changes in these measurements were observed in nitrendipine-treated patients. Monatepil also significantly decreased lipoprotein(a) levels, but there were no significant changes in HDL cholesterol, Apo-AI, or Apo-E levels. After nitrendipine treatment, the C peptide concentration decreased significantly, although no significant changes were observed in fasting blood glucose or immunoreactive insulin levels. On the basis of these results, it can be concluded that monatepil belongs to a new class of antihypertensive calcium antagonist with favorable carbohydrate metabolism and lipid-lowering activity, although the clinical importance of these findings has not been established.

The QRS axis of 130 consecutive patients with coronary artery disease undergoing percutaneous transluminal coronary angioplasty (PTCA) were measured before balloon inflation and just before balloon deflation. Patients were divided into two groups. Group A (103) had angina pectoris and/or non-transmural old myocardial infarction with no abnormal Q waves; group B (27) had an old transmural myocardial infarction with abnormal Q waves. In group A, the QRS axis had significantly shifted to the left in patients with left anterior descending artery (LAD) occlusion (from 68.0 +/- 42.7 degrees to 40.2 +/- 44.6 degrees, P < 0.001); however in those patients without involvement of the major septal branch, significant axis changes were not observed (from 53.6 +/- 34.1 degrees to 49.8 +/- 33.1 degrees). When the right coronary artery (RCA) was occluded in group A, the QRS axis shifted to the right significantly (from 63.2 +/- 40.0 degrees to 89.8 +/- 30.1 degrees. P < 0.01); during left circumflex artery (LCX) occlusion, no significant axis shift was observed. In group B, no significant axis shift was observed either in patients with occlusion of the LAD or the RCA. It is concluded that transient left axis deviation reflects an obstructive lesion of the proximal portion of the LAD with involvement of the major septal branch, and transient right axis deviation reflects an obstructive lesion of the RCA.

To elucidate the effects of fatty acids on the uptake of glucose and insulin in the muscle, the effects of oleic and palmitic acids on the uptake of glucose and insulin were investigated in perfused hind-quarters of rats. In the absence of insulin, glucose uptake in the hindquarter was slightly, but not significantly, decreased by the addition of oleic and palmitic acids. In the presence of 100 or 500 microU/ml insulin, glucose uptake in the hindquarter (243 +/- 58 or 282 +/- 65 mumol/30 min) was significantly decreased by the addition of 1000 microM oleic acid and 500 microM palmitic acid (175 +/- 50 or 207 +/- 47 mumol/30 min). The decrease in insulin uptake rate, although not significant at 500 microU/ml insulin, is of similar magnitude to the decrease in glucose uptake. In the presence of 1000 microU/ml insulin, glucose and insulin uptake was not significantly altered by the addition of fatty acids. These results indicate that fatty acids directly inhibit the muscular glucose uptake via the decrease in muscular insulin uptake at a physiological concentration of insulin.

One hundred patients with frequent (>1, 000 beats/day) ventricular premature contractions (VPCs) were followed for 4 years. All of the patients, except those with non-cardiac death (n = 8), were classified into 3 groups based on their outcome. Group A consisted of 29 patients with idiopathic VPCs who survived the study period. Group B consisted of 49 patients with underlying diseases who survived the study period. Group C consisted of 14 patients who suffered cardiac death. There was no significant difference in the daily number of VPCs. However, groups B and C had more patients with Lown grade 4a or 4b VPCs than group A. The mean coupling interval was significantly longer in group C than in group A, and the standard deviation of the coupling interval was significantly larger in group C than in group A. Forty patients underwent serial Holter monitorings to assess changes in the number of VPCs. VPCs spontaneously decreased in 13 patients, while the other 27 patients continued to have frequent VPCs. Most of these 13 patients were classified as Lown grade 2. The results suggest that in patients with frequent VPCs, longer and more varied coupling intervals may predict a poor prognosis, and Lown grade 2 may predict a spontaneous regression.

1. 1. The relationship between the negative inotropic and chronotropic effects of tocainide and 5 other class I antiarrhythmic drugs was evaluated in Langendorff-perfused guinea-pig hearts. 2. 2. All 6 drugs reduced the contractile force (Fc) and the heart rate (HR) of spontaneously beating guinea-pig hearts in a dose-dependent manner. The order of crude negative inotropic potency was: quinidine (Qui) = aprindine (Apr) > mexiletine (Mex) > lidocaine (Lid) > disopyramide (Dis) > tocainide (Toc); and the order of negative chronotropic effect was: Apr > Qui > Mex > Dis > Lid > Toc. 3. 3. The order of the negative inotropic potency relative to chronotropic effect (expressed as a ratio: ID 50 for Fc/ID 50 for HR) was Lid > Qui > Dis > Toc > Mex > Apr ( n = 6). 4. 4. For heart electrically stimulated at a constant rate, the order of crude negative inotropic potency was: Apr > Qui > Mex > Dis > Lid > Toc, and the order of negative inotropic potency (determined by the ratio: ID 50 for Fc in driven heart/ID 50 for spontaneously beating HR) was: Mex > Apr > Toc > Dis > Qui > Lid ( n = 6). 5. 5. There was a significant influence of negative chronotropic effect on the inotropic potency and the order was: Lid > Qui > Dis > Toc > Apr > Mex. The potency of various drugs is clinically useful in the choice of drugs when considering cardiac function and heart rate.

To elucidate the peripheral disposal of ketone bodies in hyperketonemia accompanied with starvation, hyperthyroidism, or diabetes mellitus, the uptake of acetoacetic acid (AcAc) and beta-hydroxybutyrate (BOHB) was investigated in the perfused hindquarter and kidney of starved, thyrotoxic, and diabetic rats. Thyrotoxicity was induced by daily subcutaneous injection of thyroxine (100 micrograms/kg/day) for 7 days, and diabetes mellitus was induced by intraperitoneal streptozotocin (50 mg/kg) injection. Plasma concentration of AcAc and BOHB was significantly higher in starved, thyrotoxic, and diabetic rats than in controls. The hindquarter or kidney of rats was perfused with synthetic medium containing 0.2 or 1.5 mM AcAc or BOHB for 30 min at a flow rate of 0.5 ml/g muscle wt/min or 3.2-3.5 ml/kidney/min, respectively. In perfused hindquarter, the uptake of AcAc and BOHB was significantly reduced in starved and diabetic rats, but not in thyrotoxic rats. In perfused kidney, the uptake of AcAc and BOHB was not significantly different between the experimental and control rats. These results suggest that in starvation or diabetes mellitus, disposal of AcAc and BOHB was impaired in the hindquarter but not in the kidney, and that disposal of AcAc and BOHB by hindquarter and kidney was not impaired in thyrotoxic rats.

The effects of hypoxia on the beta-adrenoceptor-mediated slow channel responses of guinea pig ventricular muscle in a potassium-rich (27 mM) solution containing Ba2+ were examined using microelectrode techniques. Isoproterenol produced a small depolarization of the resting membrane and also induced repetitive discharges of action potentials at higher concentrations, mainly due to a beta-adrenoceptor-mediated increase in the slow channel conductance. Two different threshold concentrations of isoproterenol, one for inducing depolarization and one for inducing automatic activity, were measured to assess myocardial responsiveness to catecholamines. During hypoxia, the electrically triggered slow upstroke action potentials of muscle were gradually depressed and catecholamine-induced membrane responses mediated by the beta-adrenoceptor/slow channel system were enhanced. The enhancement of the catecholamine effects was accelerated by acidosis and reversed by reoxygenation. Methyl xanthine-induced responses, similar to those induced by catecholamines, were also enhanced during hypoxia. It is suggested that not only changes of catecholamine-beta-adrenoceptor interaction, but also changes of intracellular metabolic processes, may be responsible, at least in part, for the enhancement of abnormal automatic activity mediated by the myocardial beta-adrenoceptor/slow channel system under hypoxic conditions.

The present guidelines were prepared by the Guidelines Sub-Committee* of the WHO/ISH Mild Hypertension Liaison Committee. They represent the third revision of the WHO/ISH guidelines and were finalized after presentation and discussion at the 6th WHO/ISH Meeting on Mild Hypertension held in Chantilly, France on 28-31 March 1993. The previous WHO/ISH guidelines were published in Bull WHO 1989; 67: 493-498, and J Hypertens 1989; 7: 689-693. (Hypertens Res 1993; 16: 149-161)

To assess the perfusion reserve of coronary collateral circulation, we analyzed exercise-stress tomographic thallium-201 myocardial images in 12 patients who had total occlusion in the right coronary artery (RCA) or left circumflex coronary artery (LCX) with well-developed collateral circulation and 90% stenosis in the left anterior descending coronary artery (LAD). In 6 of the 12 patients, the collateral circulation was non-jeopardized (group A). In the remaining 6 patients, the collateral circulation was jeopardized (group B). All 6 of the patients in group A had an exercise-induced decrease in thallium uptake in the segments supplied by the occluded RCA or LCX with collateral circulation, and 3 (50%) of these 6 also showed a decrease in thallium uptake in the segments supplied by the LAD. All 6 of the patients in group B also had an exercise-induced decrease in thallium uptake in the segments supplied by the occluded RCA or LCX with collateral circulation, but none showed a decrease in thallium uptake in the segments supplied by the LAD. In conclusion, the perfusion reserve of collateral circulation is equal to or less than 90% stenosis and myocardial ischemia occurs first in the collateralized segments during exercise in patients with jeopardized collateral circulation.

We encountered a case of hypouricemia with increases both in urate clearance (Cur) and in the ratio of Cur to creatinine clearance (Cur/Ccr), the normal daily urinary excretion of urate, and urolithiasis. Pyrazinamide markedly decreased Cur and Cur/Ccr, and both probenecid and benzbromarone markedly increased Cur and Cur/Ccr, however, benzbromarone did not increase either Cur or Cur/Ccr under pretreatment with pyrazinamide in the patient. Thus, the diagnosis was made of renal hypouricemia due to enhanced tubular secretion of urate. The urinary pH of the patient tended to be acidic. Three months after the start of alkalization of the patient's urine by K+, Na(+)-citrate, both urolithiasis and the symptoms related to urolithiasis disappeared. These results suggest that renal hypouricemia due to enhanced tubular secretion of urate can result in urolithiasis and the alkalization of urine may be an effective treatment for uric acid stones.

To clarify the mechanisms of the cardiovascular responses to Intracerebroventricular administration (i.c.v.) of somatostatin=14 (SS-14), the effects of pretreatment by i.c.v. α-antagonists or intravenous administration (i.v.) of vasopressin antagonist were investigated in conscious male Wistar rats. Plasma arginine vasopressin (AVP) concentration was also measured. The i.c.v. SS-14 (1.0nmol/kg) caused an increase in mean arterial pressure (MAP) of 16±2mmHg and a decrease in heart rate (HR) of -20 ±3 beats/min, and an increase in plasma AVP concentration from 3.2±0.7 to 21.7±2.9pg/ml (p< 0.05). Pretreatment with either i.c.v. phentolamine (200μg/kg) or i.c.v. bunazosin (50μg/kg) significantly attenuated the pressor response (16±2 to 7±2mmHg, p

Thyroid hormone and thyrotropin (TSH) levels were evaluated before and after adrenal replacement in eight patients (six men and two women, 35-62 years old) with isolated adrenocorticotropin (ACTH) deficiency. Six patients (cases 1-6) showed TSH excess before treatment. Four patients (cases 1-4), who initially had subnormal thyroid hormone levels, showed resolution of biochemical features of primary hypothyroidism after treatment, although TSH excess has persisted in two patients (cases 1 and 2). Case 1 had an extremely high titer of antimicrosomal antibody (MCHA), and cases 2 and 3 showed histologically and cytologically chronic thyroiditis, despite negative results for MCHA and antithyroglobulin antibody, respectively. Two patients (cases 5 and 6), who had had normal thyroid hormone levels and did not show the significant rise in serum T3 in TSH releasing hormone testing, showed TSH normalization without changes in serum thyroid hormone levels after treatment. The other two patients (cases 7 and 8), who initially had normal TSH and thyroid hormone levels, did not show the significant changes in serum TSH and thyroid hormone levels after treatment. The prevalence of chronic thyroiditis coexistence in isolated ACTH deficiency may be higher than predicted. Therefore, TSH excess before adrenal replacement may be attributed to not only direct enhancement of TSH release due to chronic cortisol deficiency but also to thyroid dysfunction due to chronic thyroiditis. It is possible that hypothyroidism due to chronic thyroiditis can be improved only by adrenal supplementation.

Fifty patients with atypical chest pain were studied to compare coronary responses to intracoronary and intraaortic ergonovine. The diameters of the proximal, middle (1) and (2) (proximal segments of segments 2 and 3 [AHA classification], respectively), and distal segments of the right coronary artery were measured before and after intracoronary ergonovine (4 micrograms/minute over 4 minutes) and isosorbide dinitrate (ISDN) (2 mg) in 24 patients, and before and after intraaortic ergonovine (0.2 mg) and ISDN (5 mg) in 26. Mean vasoconstriction by intracoronary and intraaortic ergonovine were 13 +/- 1.5% and 9 +/- 0.8%, respectively (p < 0.02). Irrespective of the methods of administration, the responses to ergonovine were similar in the 4 segments. Mean vasodilation by intracoronary and intraaortic ISDN, which were used to quantify the degree of basal coronary tone, were 25 +/- 2.2% and 27 +/- 1.5%, respectively (p = not significant [NS]). There were significant negative linear correlations between the responses to ergonovine and ISDN in the middle (2) (r = -0.51; p < 0.05) and distal (r = -0.53; p < 0.01) segments in patients with intracoronary injection, and the proximal (r = -0.41; p < 0.05), middle (1) (r = -0.66; p < 0.01) and middle (2) (r = -0.69; p < 0.01) segments in patients with intraaortic injection. These observations indicate that low-dose administration of intracoronary ergonovine produces sufficient coronary vasoconstriction, similar to or slightly greater than that of intraaortic ergonovine in patients with atypical chest pain, but basal coronary tone may influence the vasoreactivity to ergonovine.

Using the perfused liver and hindquarter of the rat, the uptake of glycosylated insulin and its effect on glucose output were investigated. Insulin was glycosylated in ambient high glucose concentration, and glycosylated insulin GI80 (insulin incubated with 0.08% glucose), GI350 (incubated with 0.35% glucose), and GI1000 (incubated with 1% glucose) were prepared. The liver and hindquarter were perfused with nonglycosylated insulin (N-GI) or glycosylated insulin at a concentration of 100 or 1000 microU/ml. There were no significant differences in the fractional uptake of insulin by perfused liver and hindquarter despite glycosylation. Insulin-induced decrement in glucose output was significantly lower in the liver perfused with GI1000 than that in the liver perfused with N-GI, GI80, and GI350 at an insulin concentration of 100 microU/ml. There were no significant differences in insulin-induced decrement in glucose output between the hindquarter perfused with N-GI, GI80, GI350, and GI1000. These results suggest that when insulin (100 microU/ml) is incubated with a markedly elevated concentration of glucose (1000 mg/dl) its biological activity is reduced in the liver, but not in the hindquarter.

In order to investigate the relationship between sympathetic activity and postexercise systolic blood pressure (SBP) and exercise-induced ventricular arrhythmias in patients with coronary artery disease (CAD), we studied 38 patients and 9 normal subjects who underwent treadmill testing. Peak pressure-rate product was similar in the 2 groups. The plasma concentrations of norepinephrine and epinephrine at rest and immediately after exercise were significantly higher in patients with CAD compared with normal subjects (norepinephrine at rest, p

We measured the cardiovascular and sympathetic nervous responses to mental stress in subjects with hyperthyroidism. Ten hyperthyroid subjects and 10 age- and sex-matched normal subjects performed mental arithmetic. At rest, the heart rate was higher in hyperthyroid subjects than in normal subjects, but systolic blood pressure, plasma norepinephrine, and epinephrine concentrations did not differ between the two groups. Systolic blood pressure and heart rate during stress, and the changes in blood pressure and in plasma epinephrine concentration from rest to stress, were higher in hyperthyroid subjects than in normal subjects. Therefore, cardiovascular and adrenal responses to mental stress were abnormally high in subjects with hyperthyroidism.(Internal Medicine 31 : 1175-1178, 1992)

Two patients with primary hyperparathyroidism had hyperuricemia due to the decrease in urate clearance. In analysis by 4-component model system, the tubular secretion of urate commonly decreased without changes in either filtered urate or presecretory reabsorption of urate. Both patients had a reduction of urea clearance, and both parathyroidectomy in the former case and intravenous infusion of saline in the latter case could reduce the serum urate level associated with the increase in the ratio of urate clearance to creatinine clearance. It is of interest that the former case with a higher serum urate level had a relatively higher postsecretory reabsorption, even with the decrease in tubular secretion of urate. However, the latter patient with a lower serum urate level had a decrease in postsecretory reabsorption of urate in proportion to the decrease in tubular secretion. These results suggest that in hyperuricemia patients with primary hyperparathyroidism, the reduction of tubular urate secretion via hypoperfusion of the capillary network is typically present, however, the severity of the hyperuricemia might be dependent on the dysfunction of the postsecretory reabsorption of urate.

To investigate the relationship among systolic blood pressure (SBP) during exercise (EX), left ventricular hypertrophy (LVH) and plasma norepinephrine concentration (NE) in patients with essential hypertension (HT), 20 patients with HT and 20 age- and sex-matched normal subjects were studied using treadmill testing. According to the change in SBP from rest to EX (delta SBP), patients with HT were classified into two groups (group I, n = 12, delta SBP less than 72 mmHg: group II, n = 8, delta SBP greater than or equal to 72 mmHg). There were no significant differences between the two groups with regard to SBP at rest, NE at rest and NE on EX. However, SBP at peak EX, delta SBP and the incidence of LVH were greater in group II than in group I. We conclude that exaggerated SBP response to EX in patients with HT is related to LVH.

Two patients with diabetes mellitus had persistent hypouricemia due to increased urate clearance; the degree of the apparent renal hypouricemia with uricosuria was quite mild. At the onset of diabetes, their serum urate levels were normal. Even after good diabetes control in both cases, hypouricemia continued. Based on the pharmacological evaluation in both patients, pyrazinamide administration could partially decrease urate clearance, however, suppression by pyrazinamide was less than in normal subjects, and probenecid increased urate clearance. These results suggest that the present cases had a renal abnormality affecting tubular presecretory reabsorption of urate, which might be due to diabetes mellitus.

To elucidate the peripheral ketone body uptake and the role of insulin in regulating peripheral ketone body utilization in starvation and diabetes mellitus, uptake of beta-hydroxybutyrate (BOHB) was investigated in the perfused hindquarter of starved (72 hour) or streptozotocin-induced (65 mg/kg, intraperitoneally) diabetic rats. Blood concentration of BOHB was significantly higher in diabetic (1,380 +/- 250 mumol/L) and starved (1,229 +/- 245 mumol/L) rats than in controls (104 +/- 8 mumol/L). The hindquarter was perfused with synthetic medium at a flow rate of 0.5 mL/g muscle weight/min. BOHB was added to the medium at a concentration of 0.1, 0.5, 2, or 10 mmol/L, and insulin was added at a concentration of 20, 100, or 500 microU/mL. In the hindquarter perfused with 0.1, 0.5, 2, or 10 mmol/L BOHB, fractional uptake of BOHB in the absence or presence of insulin was significantly lower in diabetic and starved rats than in controls. The addition of 100 or 500 microU/mL insulin significantly increased BOHB uptake in the perfused hindquarter of control rats; however, insulin addition did not significantly increase BOHB uptake in the perfused hindquarter of starved and diabetic rats. These results suggest that BOHB uptake is markedly reduced in the perfused hindquarter of starved and diabetic rats, and that physiological dose of insulin stimulates BOHB uptake in control rats, but not in starved and diabetic rats.

The electrophysiological effects of urapidil, a new alpha 1-adrenoceptor antagonist, were assessed in the reserpinized guinea-pig ventricular myocardium. Urapidil suppressed the maximal rate of rise (Vmax) of steady-state action potentials elicited by the fast responses at high concentrations independently of blockade of myocardial alpha-adrenoceptors, but not the Vmax of Ca(2+)-dependent slow action potentials of partially depolarized muscles in concentrations tested (up to 1.1 mM). Urapidil at high concentrations prolonged the action potential durations of the fast and slow responses in a manner similar to the quinidine-like antiarrhythmic drugs. These results suggest that the inhibitory effect of urapidil on the slow inward Ca2+ current and the Na+ current is in practice negligible.

Study objective – The aim was to investigate whether the use dependent effects of antiarrhythmic drugs on the Na+ current could be applied to explain their effects on impulse conduction. Design – Trains of rapid stimuli were applied to guinea pig papillary muscles via an electrode in the presence of quinidine (20 and 60 μmol·litre−1), and the conduction velocity was determined from the time difference between two signals of the maximal rate of rise (dV/dtmax) of the action potentials at two separate sites. The relationship of the time constants of the onset and recovery from the use dependent inhibition induced by quinidine was determined for the dV/dtmax and the conduction velocity. Experimental material – Six male Hartley guinea pigs weighing 200 to 300 g were killed by a blow to the head and the papillary muscles were rapidly excised from the right ventricles. The preparations were superfused with Tyrode solution. Measurements and main results – The rate of onset of the use dependent inhibition of conduction velocity and that of the square of conduction velocity were both faster than the simultaneously measured rate of onset of dV/dtmax inhibition induced by 20 μmol·litre−1 quinidine at high frequency stimulation. The relation between the rates of onset of the use dependent inhibition of conduction velocity (and the square of conduction velocity) and dV/dtmax became weak with low frequency stimulation and in the presence of 60 μmol·litre−1 quinidine. However, the recovery of conduction velocity (and the square of conduction velocity) from quinidine induced use dependent blockade, as measured by the extrastimulation method, appeared to be slower than the recovery of dV/dtmax. These results may be explained by a transient change in intracellular and intercellular conditions, such as an increase in internal resistance. Conclusions – The onset and recovery of the use dependent inhibition of conduction by antiarrhythmic drug may not always parallel the changes of the dV/dtmax of action potential in multicellular muscle preparations.

The coronary artery response to ergonovine (EM) and nitrate of the proximal, middle and distal segments of the three major coronary artery branches and the main trunk was quantified in 67 patients without coronary spasm and in 69 patients with coronary spasm without significant organic stenosis. The changes in control diameter and diameter after EM administration compared to diameter after nitrate were used as the index of coronary artery tone. EM increased coronary artery tone regardless of the occurrence of coronary spasm (p less than 0.01). In all segments, basal coronary artery tone was greater in patients with spasm than in patients without spasm (p less than 0.01) in a way similar to the coronary responses to EM (p less than 0.01). In patients with spasm, both coronary artery tone after EM and basal coronary tone were greater in the spastic segments than in the nonspastic segments (p less than 0.01), which were greater than those in patients without spasm (p less than 0.01). Our data suggest that patients with spasm may have increased basal tone, and that coronary artery spasm may be based on increased coronary tone. Clinically, evaluation of the basal tone and response to EM in the entire coronary artery tree may be useful for predicting the presence of coronary artery spasm.

The characteristics of the coupling interval (CI) of ventricular premature contraction (VPC) were studied in 100 patients with frequent VPCs using 24 h ambulatory ECG recording. All R-R intervals were registered on computer to determine the mean value of CIs (Mean CI) and the standard deviation of CIs (SD-CI). We compared the Mean CI and the SD-CI between idiopathic VPCs and VPCs with organic heart disease (OHD). In addition, we evaluated the efficacy of disopyramide (DP) and mexiletine (MX) and we examined the relationship between the efficacy of these drugs and the characteristics of CI. The Mean CI of VPCs with OHD was longer than that of idiopathic VPCs (530 vs. 494 msec, p less than 0.05). The SD-CI of VPCs with OHD was larger than that of idiopathic VPCs (54.1 vs. 39.3 msec, p less than 0.01). In all treated cases, the drug efficacy was not different between DP (11/18, 61%) and MX (9/19, 47%). However when we isolated cases of OHD, we found a tendency that DP (9/12, 75%) was more effective than MX (7/16, 44%). In cases where DP was administered, the Mean CI of VPCs was not different between effective and ineffective cases, while in cases where MX was administered, the Mean CI of ineffective cases had a tendency to be longer than that of effective cases (552 vs. 506 msec, p less than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

1. Effect of bunazosin, an alpha 1-adrenoceptor antagonist, upon the slow inward Ca2+ current (ICa) was studied in single ventricular myocytes of the guinea-pig using a whole-cell patch-clamp technique. 2. Bunazosin (10-100 microM) decreased ICa in a concentration-dependent manner with an IC50 of 60 microM during depolarization to + 10 mV from the holding potential of -40 mV. 3. As for the inactivation process of ICa, the steady-state inactivation (f infinity) curve was shifted toward more negative potentials from -12 mV to -17 mV and -21 mV at f infinity = 0.5, by 30 microM and 70 microM bunazosin. 4. Inhibition of ICa by the compound (10 microM) was also dependent on stimulation frequency, with greater block induced at 2 Hz (50%) than at 0.33 Hz (13%). 5. It is concluded that bunazosin possesses a direct Ca2+ channel-blocking (class 4) action in a rate-dependent fashion.

To elucidate the possible role of the stomach in enteroinsular axis, rats had both an inflow gastric cannula and an outflow diversion cannula and a duodenal inflow cannula. The effects of intragastric infusion of glucose (1 mL in 10% solution) or mannitol (1 mL in 10% solution) on blood glucose and plasma insulin responses to subsequent intraduodenal glucose (1.5 g/kg in 10% solution) or amino acids (1.0 g/kg in 10% solution) infusion were investigated. Blood glucose and plasma insulin responses to intraduodenal amino acids were not altered by intragastric infusion of glucose or mannitol. However, higher blood glucose and lower plasma insulin responses to intraduodenal glucose were observed in the rat with intragastric infusion of glucose or mannitol compared with controls (intragastric infusion of distilled water). This phenomenon was abolished in the rat with preadministration of phentolamine. These results suggest that intragastric tonicity may suppress glucose-induced insulin secretion, probably through the α-adrenergic mechanism in the rat.

To elucidate the effect of intestinal osmolality on insulin secretion, we investigated insulin response to a subsequent intravenous infusion of glucose or arginine after intragastric or intraduodenal mannitol or NaCl instillation in the rat. After anesthesia with intraperitoneal pentobarbital sodium, mannitol solution (10% or 20%) or 2.7% NaCl was instillated into the stomach or duodenum for 5 min at a flow rate of 0.5 ml/min, and 20% glucose (0.5 g/kg) or 10% L-arginine (0.5 g/kg) was infused bolus into the femoral vein 45 min after intestinal instillation. Insulin response to intravenous glucose was significantly higher in the rat with intragastric or intraduodenal mannitol or NaCl infusion than in control rats with intragastric or intraduodenal instillation of distilled water. Insulin response to intravenous arginine was almost the same in all groups. Subcutaneous preadministration of propranolol (0.4 mg/kg), atropine (1.2 mg/kg), or phentolamine (0.8 mg/kg) did not alter the present phenomenon. These results suggest that intestinal osmolality may enhance insulin release to intravenous glucose, but not to arginine in the rat.

A 25-year-old woman with a history of Graves' disease, in remission for 8.5 years following 6 months of methimazole therapy, first came to our attention 5 months after her first delivery with clinical and biochemical hypothyroidism, markedly elevated titre of anti-thyroid microsomal antibody (MCHA; 1: 102400) and mildly elevated activity of thyrotropin-binding inhibitory immunoglobulins (TBII; 29.5%). After short-term (3 months) treatment with L-thyroxine therapy, the development of hyperthyroidism in the first trimester of the second pregnancy, which remitted through the second and third trimesters, was observed. TBII showed a peak value (93.1%) 1 month after the onset of hyperthyroidism, and a normal value (12.4%) 6 d after delivery. One month after the second delivery, the patient developed hyperthyroidism, with an elevation of 99mTc thyroid uptake (5.58%; normal range 0.5–2.5%), which was immediately followed by transient clinical and biochemical hypothyroidism. Concomitant increases in MCHA titre and TBII activity were observed after delivery, and both reached peak levels (1: 409600 and 81.0%, respectively) one and a half months after the onset of hypothyroidism. Thyroid-stimulating antibody (TSAb), measured using FRTL-5 thyroid cells, was detected at a weakly positive level (161%) on initial examination, and the serial change in TSAb was almost identical to that in TBII. Patients with Graves' disease may develop Graves' type hyperthyroidism, followed immediately by transient hypothyroidism due to coexisting destructive autoimmune thyroiditis during the early postpartum period, despite increasing TSAb activity.

To elucidate glucose intolerance in hyperthyroidism, insulin response to oral (75 g) and intravenous (IV) (20 g) glucose administration was investigated in 18 hyperthyroid patients and six normal control subjects. In oral glucose tolerance tests (OGTT), plasma insulin and C-peptide levels in hyperthyroid patients were not significantly different from that in controls; however, an impaired blood sugar response was observed in hyperthyroid patients. In IVGTT, blood sugar, plasma insulin, and C-peptide levels were significantly higher in hyperthyroid patients than in controls. Insulin secretion in proportion to blood sugar stimulus (the sum of increment in insulin divided by the sum of increment in blood sugar after glucose load, sigma delta IRI/sigma delta BS) in IVGTT was similar in hyperthyroid patients and controls; however, that in OGTT was significantly lower in hyperthyroid patients. After thyroid function tests had returned to normal by treatment with thiamazole, glucose tolerance and sigma delta IRI/sigma delta BS in OGTT were almost normalized. These results indicate that decreased insulin secretion after oral glucose may have an important role in abnormal oral glucose metabolism in hyperthyroidism.

Under whole cell patch conditions, 1389-S blocked the I Na in guinea-pig ventricular myocytes under steady state conditions (K d rest = 30 μ M, K d i = 2.4 μ M) with a shift of the inactivation curve to the hyperpolarizing direction. Both brief and long conditioning pulses could produce a use-dependent block of 1389-S. These results suggest that 1389-S had a higher affinity to the inactivated than to the rested state under steady state conditions and had a higher affinity to the activated state during train pulses as well as to the inactivated state, making channels unavailable for conduction upon activation.

1. The use-dependent effects of pirmenol, a new antiarrhythmic drug, on the maximal rate of rise (Vmax) of the action potential, conduction velocity, and their corresponding recovery kinetics were studied in isolated papillary muscles of guinea-pig. Standard microelectrode techniques were used to monitor the conduction and action potential characteristics of the muscles. 2. Pirmenol decreased Vmax and the overshoot of action potentials in a dose-dependent fashion. Also, doses of pirmenol greater than 1 mM abolished the generation of action potentials. Low concentrations of pirmenol (3 and 10 microM) prolonged the action potential duration, while concentrations greater than 0.1 mM shortened it markedly. 3. The resting block of Vmax in the presence of 10 and 30 microM pirmenol was 9.48 +/- 3.12 and 20.36 +/- 3.61%, and that of conduction velocity 2.87 +/- 1.52 and 6.58 +/- 2.09%, respectively. 4. The degree of use-dependent block induced by 10 and 30 microM pirmenol during 0.2, 1, 2 and 3 Hz stimulations was dose- and rate-dependent. 5. In the presence of 30 microM pirmenol, mean values of time constants for the onset of the use-dependent inhibition of Vmax and conduction velocity during a 2 Hz stimulation were 1.32 +/- 0.15 and 1.28 +/- 0.09 s, respectively. The recovery time constants averaged 15.83 +/- 2.14 (for Vmax) and 27.80 +/- 8.74 (for conduction velocity) s in the presence of 30 microM pirmenol. 6. These results showed that the characteristics of the use-dependent inhibition of Vmax and conduction velocity induced by pirmenol are similar to those of slow kinetic drugs such as disopyramide rather than of fast ones.

To evaluate the cardiovascular and plasma catecholamine responses to dynamic exercise in patients with cardiac neurosis (CN), treadmill testing was performed. Thirty-four patients with CN were chosen for this study based on exercise tolerance and the results were compared with those in 31 patients with organic heart disease and 12 normal subjects. Patients with CN showed an augmentation of cardiovascular and plasma catecholamine responses. The augmentation of the norepinephrine response in patients with CN was not as remarkable as that in patients with organic heart disease. On the other hand, the augmentation of the epinephrine response was greater in patients with CN than in those with organic heart disease. Administration of metoprolol (40 mg/day) for two weeks improved exercise tolerance in patients with CN. We suggest that anxiety augments both sympatho-neural and sympatho-adrenal activity and that it is the symptoms induced by the augmented cardiovascular response which reduce exercise tolerance in patients with CN.

To evaluate the diagnostic value of an exercise-induced increase in R-wave amplitude (RWA) for detecting coronary artery disease (CAD), treadmill testing using the modified Bruce protocol was performed on a CASE II computerized system (Marquette) in 10 healthy young men, 35 patients (pts) with CAD, 22 subjects with normal coronary arteries, and 11 pts with aortic or mitral regurgitation. Based on the analysis of the patterns of serial changes in RWA in lead V5, we proposed new RWA criteria for detecting CAD. (1) During exercise, RWA increases in stage 1 and subsequently increases further or remains unchanged. (2) During exercise, RWA decreases in the early phase of exercise and subsequently increases. (3) In the recovery period, RWA shows a gradual and excessive increase. A combination of the above RWA criteria showed a sensitivity, specificity and accuracy of an equal value of 86%. We conclude that an exercise-induced RWA increase is a useful indicator for detecting CAD, especially when taking the patterns of serial changes into consideration, and that the abnormal RWA increase may be related to an increase in left ventricular (LV) end-diastolic volume due to exercise-induced LV dysfunction.

1. The electrophysiological effect of 9-amino-1,2,3,4-tetrahydroacridine (THA) on the rabbit sino-atrial node was studied using double-microelectrode voltage clamp methods. 2. THA (above 10 μM) caused statistically significant decreases in the maximum rate of rise, the action potential amplitude, the rate of diastolic depolarization, and increases in the spontaneous cycle length, the action potential duration at 50% repolarization. 3. On the current systems, THA obviously depressed the time-dependent outward K+ current. The compound also decreased the slow inward Ca2+ current and the hyperpolarization-activated inward current. 4. These findings indicate that THA exerts an inhibitory action on the automaticity of sino-atrial node via effects on both outward and inward current systems.

Study objective – To examine the effect of 9-amino-1,2,3,4-tetrahydroacridine (THA), a compound similar to the K+ blocker 4-aminopyridine, on potassium channels in the sinoatrial node. Design – The pace making portion of rabbit sinoatrial nodes was studied using the double microelectrode voltage clamp method in the presence of THA at various concentrations. Measurements and results – Above 1 μmol·litre−1, THA prolonged the spontaneous cycle length and the transmembrane action potential duration at 50% repolarisation. Above 10 μmol·litre−1, the compound also decreased the maximum rate of rise, the action potential amplitude, and the rate of diastolic depolarisation. Under voltage clamp conditions, THA reduced the time dependent K+ current (IK) in a dose dependent manner. Neither the decay process of IK nor its activation process were altered by THA. Conclusions – THA depresses sinoatrial node IK without changing its kinetics. Thus it may inhibit the open state of the potassium channels.

A 50-year-old woman with allergic granulomatous angiitis (AGA) presented with an elevated serum interleukin-5 (IL-5) level upon admission to a hospital. Administration of prednisolone showed marked improvement of asthmatic symptoms, reduced eosinophil counts of peripheral blood, and normalized serum IL-5 levels. This is the first report describing an elevated serum level of IL-5 in AGA. The present findings suggest that IL-5 is involved in the pathogenesis of AGA.

A 39-year-old man with anginal pain had multiple coronary artery to left ventricular communications. His electrocardiogram showed evidence of left ventricular hypertrophy, and an echocardiogram revealed a dilated left ventricle. A coronary angiogram revealed multiple coronary artery to left ventricular fistulae involving three major coronary arteries with no evidence of atherosclerotic lesions. Only 17 cases of such fistulous communications involving three major coronary arteries have been reported in the literature. It is suggested that the fistulous communications to the left ventricle was a cause of his angina pectoris, probably because of the coronary steal phenomenon.