Mepacrine-induced inhibition of human platelet cyclic-GMP phosphodiesterase.

The effect of mepacrine (DL-quinacrine-HCI), a specific inhibitor of phospholipase C, on cyclic-GMP levels in human platelets was investigated. The concentrations of mepacrine producing 50% inhibition of human platelet aggregation induced by 5 microM ADP and 3 micrograms/ml of collagen were 50 +/- 8 and 70 +/- 15 microM, respectively. Addition of mepacrine to human platelet suspension resulted in increases in cyclic GMP. In contrast to cyclic-GMP levels, cyclic-AMP content was not affected by mepacrine. Mepacrine did not stimulate guanylate cyclase, but did specifically inhibit human platelet cyclic-GMP phosphodiesterase, separated from cyclic-AMP phosphodiesterase or other forms of phosphodiesterase on DEAE-cellulose columns. Stimulation by cyclic GMP of human platelet cyclic-GMP-stimulated cyclic-AMP phosphodiesterase activity was not inhibited by mepacrine. The IC50 value of the drug for cyclic-GMP phosphodiesterase was 40 microM, and IC50 for cyclic-AMP phosphodiesterase was 1.2 mM. Mepacrine was 30-times more potent as an inhibitor of human platelet cyclic GMP than of cyclic-AMP phosphodiesterase. Mepacrine blocks arachidonate release from human platelets by inhibiting phosphatidylinositol-specific phospholipase C. The increase in cyclic-GMP levels produced by addition of mepacrine will explain part of the pharmacological action of this drug.

Prognosis of completely asymptomatic adult patients with hypertrophic cardiomyopathy.

OBJECTIVES: We investigated the long-term prognosis of completely asymptomatic adult patients with hypertrophic cardiomyopathy (HC). Diagnosis of HC was suspected because of an abnormal electrocardiogram and/or cardiac murmur and confirmed by echocardiography and/or left ventricular angiography, and hemodynamic investigation. BACKGROUND: Hypertrophic cardiomyopathy shows marked heterogeneity in clinical expression and prognosis. The prognosis of asymptomatic patients with HC has not been fully defined. METHODS: Of 128 consecutive adult patients with HC, 58 asymptomatic patients (Group 1, mean age 42.8 years) and 70 symptomatic patients (Group 2, mean age 50.4 years) were studied to assess cardiac mortality. Mean follow-up periods were 11.0 years for Group 1 and 9.1 years for Group 2. RESULTS: At presentation, Group 1 patients were younger and had smaller left atrial dimensions than did Group 2 patients. The annual cardiac mortality rate and the rate for sudden death alone in Group 1 were significantly lower than in Group 2 (0.9% vs. 1.9%, p < 0.05, 0.1% vs. 1.4%, p < 0.05, respectively). Although about one-third of the survivors in Group 1 had cardiac symptoms at their most recent evaluation, only one patient died suddenly compared with eight in Group 2. The annual mortality rate due to heart failure was similar in each group. Only a syncopal episode was associated with both cardiac death and sudden death for both groups combined. CONCLUSIONS: The cardiac mortality rate for completely asymptomatic adult patients with HC was very low, significantly lower than that of symptomatic patients, and there was a disproportionately low incidence of sudden death.

Myocardial contractile force at high coronary arterial oxygen tension in dogs.

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.

Increased lung uptake of iodine-123-MIBG in diabetics with sympathetic nervous dysfunction.

UNLABELLED: Scintigraphy with 123I-MIBG and 201TI was compared in patients with various diseases including diabetes mellitus, with and without sympathetic nervous dysfunction. This study was done to assess lung uptake of these tracers semiquantitatively. METHODS: Thirty-eight patients with diabetes mellitus, seven patients with dilated cardiomyopathy (DCM), 12 patients with hypertrophic cardiomyopathy (HCM) and eight healthy subjects were studied. Sympathetic nervous dysfunction was observed in 13 of the 38 diabetic patients. Simultaneous imaging with 123I-MIBG and 201TI was performed. The ratio of lung to total injected dose count and washout rate in the lung were calculated from dynamic images acquired in the initial 2 min and static images acquired at 15 min and at 4 hr after injection of the tracers. RESULTS: Lung uptake of 123I-MIBG at 4 hr was significantly increased in the diabetic group as compared with those in the other groups. In diabetic patients with sympathetic nervous dysfunction, the lung uptake ratio of 123I-MIBG at 4 hr was significantly higher than that in the diabetic patients without sympathetic nervous dysfunction, due to decreased clearance of 123I-MIBG from the lung. On the other hand, increased lung uptake of 201TI was observed in DCM patients at both 15 min and 4 hr. There was no significant difference between lung uptake of 201TI in diabetic patients and that in healthy subjects. CONCLUSION: Lung uptake of 123I-MIBG was increased and lung washout of 123I-MIBG was decreased in diabetic patients with sympathetic nervous dysfunction, while lung uptake of 201TI was not altered. lodine-123-MIBG scintigraphy of the lung may provide information on sympathetic nervous activity in diabetic patients. It is a promising method for studying the kinetics of norepinephrine in the lung because MIBG is taken up in the lung by the same mechanism as norepinephrine.

Effects of nicorandil, an antianginal potassium channel opener, on left ventricular systolic and diastolic function in patients with chronic coronary artery disease.

We compared the effects of nicorandil with nitroglycerin and nifedipine on left ventricular function. Intravenous nicorandil may be a balanced-typed vasodilator and useful in patients with left ventricular systolic and diastolic dysfunction.

Effects of diltiazem on cardiovascular responses during exercise in systemic hypertension and comparison with propranolol.

Sixteen patients with uncomplicated systemic hypertension were treated with placebo, diltiazem (180 mg/day) and propranolol (60 mg/day) for 1 month each. Each patient performed multistage symptom-limited treadmill exercise tests during each period of administration. There was no significant difference in maximal exercise duration between placebo, diltiazem and propranolol. Diltiazem significantly decreased both systolic and diastolic blood pressure (BP) and heart rate at rest, during submaximal exercise at the same work load and maximal exercise. Propranolol produced similar changes in systemic BP and heart rate at rest and during exercise. However, the reductions in systolic BP, heart rate and pressure-rate product with diltiazem during exercise were smaller than those with propranolol at small doses, suggesting that diltiazem in its usual therapeutic dose was almost devoid of beta-blocking activity. Thus, diltiazem may be of benefit to hypertensive patients because it reduces systemic BP even during exercise. It is particularly useful when systemic hypertension occurs in association with coronary artery disease because of its effects of coronary artery dilatation and heart rate reduction.

S-100 antigen and calmodulin in human leukemic cells.

Both S-100 antigen and calmodulin were shown in normal lymphocytes with S-100 being decreased in lymphocytic leukemia cells. Although small amounts of S-100 antigen and calmodulin were shown in acute myeloblastic leukemia cells, they could not be detected in normal granulocytes. In lymphoblastic leukemia, S-100 antigen levels in T-cell leukemia cells were higher than in B-cell leukemia cells, while calmodulin was decreased in chronic leukemia cells. In mitogen-stimulated lymphocytes, the levels of S-100 antigen were decreased, while those of calmodulin were either increased or unchanged. Calcium-dependent cyclic nucleotide phosphodiesterase was highest in acute lymphoblastic leukemia. These data suggest, therefore, that calcium ions may play a role in the proliferation, differentiation or leukemic change in lymphocytes and, hence, that measurement of calcium binding proteins may be useful in the investigation of leukemia cells or lymphocytes.

Pharmacological properties of platelet strips.

The pharmacological properties of human platelet strips were studied by recording changes in tension after the application of various compounds. The platelet strips were prepared by packing cold re-calcified human platelets over a sheer gelatinized nylon mesh. The contractile response of such a strip was dependent on the number of platelets sticking to the nylon mesh. The strip was contracted by the addition of platelet aggregation inducers such as ADP, norepinephrine, thrombin and collagen, thereby suggesting that the contractile response is mediated through membrane receptors on the platelets. The ED50 values of the aggregation agents which contracted the strip were much the same as those which induced platelet aggregation, thereby suggesting that contraction of the platelet strip is similar to platelet aggregation in platelet rich plasma (PRP). The addition of platelet aggregation inhibitors such as papaverine, W-7 and PGE1 relaxed the platelet strip. The ED50 values of the aggregation inhibitors which relaxed the platelet strip were also similar to those for platelet aggregation inhibition. The time course of the release of the preloaded [14C]serotonin from the platelet strips correlated well with that of the tension developed.

Exercise-induced coronary spasm: comparison of treadmill and bicycle exercise in patients with vasospastic angina.

BACKGROUND: We investigated whether exercise-induced coronary spasms are influenced by the different exercise modes. METHODS: We compared ischaemic ECG responses in 67 patients with vasospastic angina who underwent both treadmill and bicycle ergometer exercise and also coronary angiography. RESULTS: ECG ST-segment elevation was provoked more frequently during treadmill exercise than it was during bicycle exercise (19 versus 9%, P < 0.05). Of 45 patients without significant coronary stenosis (coronary artery luminal diameter narrowing < 75%), 19 patients manifested ST-segment depression during treadmill exercise, whereas only seven patients did during bicycle exercise (42 versus 16%, P < 0.01). All patients with ST-segment elevation or depression during bicycle ergometer exercise also had ST-segment changes during treadmill exercise. Although higher systemic blood pressure levels and lower heart rates were found during bicycle exercise compared with during treadmill exercise the pressure-rate products at peak exercise did not differ between the two exercise tests. CONCLUSIONS: It seems that treadmill and bicycle exercise are different stressors in patients with vasospastic angina, and that coronary spasms are provoked more frequently during treadmill exercise than they are during bicycle exercise. The cause of this difference is not known, but it may be related in part to the difference in systemic haemodynamic or neurohumoral response.

Regression of left ventricular hypertrophy with long-term treatment of nifedipine in systemic hypertension.

We investigated the regression of left ventricular (LV) hypertrophy with long-term treatment of nifedipine in patients with systemic hypertension. Echocardiograms of the LV were obtained in nine patients before and at a mean of 50 months (13-105 months) after nifedipine monotherapy (30-60 mg/day). Nifedipine significantly reduced both systolic and diastolic blood pressures (BP) by a mean of -46 mmHg and -21 mmHg, respectively. With systemic BP reduction, LV mass was significantly reduced by a mean of -15%, associated with a decrease in LV posterior wall thickness and end-diastolic dimension. There was no significant change in LV fractional shortening. We conclude that nifedipine may cause regression of LV hypertrophy in systemic hypertension, and that reversal of the increase in LV mass could be maintained during long-term nifedipine treatment.

[Clinical significance of exercise induced ST segment depression after successful percutaneous transluminal coronary angioplasty--assessment by thallium-201 SPECT].

To evaluate the clinical significance of ST segment depression during repeated Treadmill exercise after successful PTCA, Thallium-201 SPECT was performed. The Thallium-201 SPECT was performed before, one week after and 3-6 months after PTCA. All thirty-five patients had one vessel disease and positive Thallium-201 exercise test. During follow-up period for 3-6 months, 11 of 35 patients had persistent ST segment depression. Restenosis of dilated coronary lesion was demonstrated in 6 of 11 patients. In another 3 of 35 patients, exercise induced ST segment depression was disappeared during follow-up Treadmill exercise. In 14 patients with persistent or transient ST segment depression after PTCA, Thallium-201 SPECT demonstrated transient ischemia in 5 of 6 patients with restenosis. In other 8 patients without restenosis, SPECT images did not demonstrate myocardial ischemia and coronary arteriographic findings could not verify side branch stenosis or intimal dissection which might cause myocardial ischemia. The etiology of ST segment depression after successful PTCA in one vessel disease is not produced by exercise induced myocardial ischemia but still unknown mechanisms may be present.

[Effects of contrast media on left ventricular function. Comparison with iohexol and diatrizoate].

To investigate the effects of a low-osmolar nonionic (Iohexol: I) and a high osmolar ionic contrast media (Diatrizoate: D) on left ventricular (LV) function after left ventriculography (LVG), we studied 19 patients with coronary artery disease (I: 9 cases, D: 10 cases) during diagnostic cardiac catheterization. The first LVG was performed by injecting 40 ml of I or D at a rate of 12 ml/sec, measuring simultaneous LV pressure with a catheter tip manometer (Millar instruments). At 4 minutes after the first LVG, we repeated hemodynamic measurements and LVG. Single-plane volumes (RAO 30 degrees) were calculated every 20 msec (50 frame/sec) using the area-length method. LV systolic function was estimated by ejection fraction (EF), ratio of end-systolic pressure to end-systolic volume (ESP/ESV) and maximal (+)dP/dt. LV relaxation was assessed by the time constant (T) of LV pressure decay. LV diastolic compliance was evaluated by the diastolic pressure-volume (PV) relationship. Results. 1. LV end-diastolic pressure and volume were augmented more significantly in D than in I group, probably due to the difference of their osmolarity. 2. EF increased in D group with increase of LV preload after the first LVG, but didn't change in I group. ESP/ESV and maximal(+)dP/dt were not changed after the first LVG in both groups. 3. LV isovolumic relaxation remained unchanged with I and D. 4. LV diastolic PV relation curve shifted upward more in D than I group. We conclude that Iohexol has less influences on LV function than Diatrizoate and may be used in high risk patients.

[A case of congenital long QT syndrome associated with T wave alternans].

A case was presented in which a rare T wave alternans occurred in association with congenital long QT syndrome. A 71-year-old woman, who had experienced several syncopal attacks per year for the previous forty years, was admitted for further evaluation of the syncope. She had a family history of sudden death (sister) and QT prolongation (son). Electrocardiogram showed a corrected QT interval of 0.68 seconds. Treadmill exercise-tolerance test revealed both T wave alternans immediately after exercise and torsades de pointes 150 seconds after exercise. The syncope was induced by the mental excitation. A prolonged corrected QT interval reduced from 0.70 seconds to 0.58 seconds by the correction of her serum potassium and magnesium. The effect of propranolol, verapamil, phenytoin or mexiletine on T wave alternans and ventricular arrhythmia was evaluated by the treadmill exercise-tolerance test. The treatment with propranolol was most effective.