P. Stulz

Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. A new mechanism of vasospasm?

Endothelin-1 is an endothelium-derived vasoconstrictor peptide. Its circulating levels are below those known to evoke direct vascular effects. To study whether low concentrations of endothelin-1 potentiate the effects of other vasoconstrictor hormones, we suspended isolated human internal mammary and left anterior descending coronary artery rings in organ chambers for isometric tension recording. In mammary artery rings, the contractions to norepinephrine (3 x 10(-8) M) were potentiated by threshold (3 x 10(-10) M) and low concentrations (10(-9) M) of endothelin-1 (96 +/- 35% and 149 +/- 58% increase from control; p less than 0.01 and 0.001; n = 6). The inhibitor of endothelial nitric oxide formation L-NG-monomethyl arginine did not affect the potentiating effects of the peptide. The calcium antagonist darodipine (10(-7) M) prevented the potentiation of the response to norepinephrine evoked by endothelin-1. Similarly, contractions to serotonin (10(-7) or 3 x 10(-8) M) were amplified by endothelin-1 (3 x 10(-10) M) in the mammary (30 +/- 9%) and in the coronary arteries (59 +/- 25%). Endothelin-1 (10(-9) M) further potentiated the response (57 +/- 23% in mammary and 87 +/- 26% in coronary arteries; p less than 0.05; n = 7 and 3). The sensitivity of mammary arteries to calcium chloride was markedly enhanced in the presence of endothelin-1 (3 x 10(-10) M; concentration shift, eightfold; p less than 0.01; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction between endothelin-1 and endothelium-derived relaxing factor in human arteries and veins.

Endothelin-1 is a 21-amino acid endothelial vasoconstrictor peptide that may be the physiological antagonist of endothelium-derived relaxing factor (EDRF). Endothelin-1 (10(-11)-3 x 10(-7) M) evoked potent contractions of isolated internal mammary arteries, internal mammary veins, and saphenous veins, which were enhanced in internal mammary veins as compared with internal mammary arteries (concentration shift, 6.3-fold; p less than 0.05) but not in the saphenous veins. Endothelial removal augmented the response to the peptide (at 3 x 10(-7) M) in internal mammary arteries (p less than 0.05) but not in veins. In the artery, EDRF released by acetylcholine or bradykinin reversed endothelin-1-induced contractions; in saphenous veins, both agonists were much less effective compared with the artery and veins contracted with norepinephrine (p less than 0.005-0.01). This inhibition of endothelium-dependent relaxations in veins occurred at half-maximal contractions but was most prominent at maximal contractions to the peptide. Nitric oxide similarly inhibited contractions to endothelin-1 and norepinephrine in internal mammary arteries, whereas in veins that were contracted with endothelin-1 but not with norepinephrine, the relaxations were blunted (p less than 0.005). The nitric oxide donor SIN-1 and sodium nitroprusside induced complete relaxations of internal mammary arteries but were less effective in veins contracted with endothelin-1 (p less than 0.005). Thus, in normal human arteries, EDRF inhibits endothelin-1-induced contractions, whereas the peptide specifically attenuates the effects of EDRF and nitrovasodilators in veins. This may be important in pathological conditions associated with increased levels of endothelin-1 and in veins used as coronary bypass grafts.

Effect of High Intensity Exercise Training on Central Hemodynamic Responses to Exercise in Men With Reduced Left Ventricular Function

OBJECTIVES The aim of this study was to evaluate the effects of high intensity exercise training on left ventricular function and hemodynamic responses to exercise in patients with reduced ventricular function. BACKGROUND Results of studies on central hemodynamic adaptations to exercise training in patients with chronic heart failure have been contradictory, and some research has suggested that training causes further myocardial damage in these patients after a myocardial infarction. METHODS Twenty-five men with left ventricular dysfunction after a myocardial infarction or coronary artery bypass graft surgery were randomized to an exercise training group (mean age +/- SD 56 +/- 5 years, mean ejection fraction [EF] 32 +/- 7%, n = 12) or a control group (mean age 55 +/- 7 years, mean EF 33 +/- 6%, n = 13). Patients in the exercise group performed 2 h of walking daily and four weekly sessions of high intensity monitored stationary cycling (40 min at 70% to 80% peak capacity) at a residential rehabilitation center for a period of 2 months. Ventilatory gas exchange and upright hemodynamic measurements (rest and peak exercise cardiac output; pulmonary artery, wedge and mean arterial pressures; and systemic vascular resistance) were performed before and after the study period. RESULTS Maximal oxygen uptake (VO2max) increased by 23% after 1 month of training, and by an additional 6% after month 2. The increase in VO2max in the trained group paralleled an increase in maximal cardiac output (12.0 +/- 1.8 liters/min before training vs. 13.7 +/- 2.5 liters/min after training, p < 0.05), but maximal cardiac output did not change in the control group. Neither stroke volume nor hemodynamic pressures at rest or during exercise differed within or between groups. Rest left ventricular mass, volumes and EF determined by magnetic resonance imaging were unchanged in both groups. CONCLUSIONS High intensity exercise training in patients with reduced left ventricular function results in substantial increases in VO2max by way of an increase in maximal cardiac output combined with a widening of maximal arteriovenous oxygen difference, but not changes in contractility. Training did not worsen hemodynamic status or cause further myocardial damage.

Different activation of the endothelial L-arginine and cyclooxygenase pathway in the human internal mammary artery and saphenous vein.

The endothelium releases substances controlling vascular tone and platelet function. We investigated mediators of endothelium-dependent responses in human internal mammary arteries and saphenous veins. The inhibitor of nitric oxide formation, NG-monomethyl L-arginine, enhanced the sensitivity to norepinephrine (fivefold) and evoked more pronounced endothelium-dependent contractions in internal mammary arteries (19 +/- 6% of 100 mM KCl) than in saphenous veins (2 +/- 1%; p less than 0.005). In internal mammary arteries, NG-monomethyl L-arginine, but not indomethacin, markedly reduced endothelium-dependent relaxations to acetylcholine (from 95 +/- 2% to 39 +/- 7%; p less than 0.005) and prevented those to histamine (78 +/- 6% to 4 +/- 3%; p less than 0.005). In saphenous veins, endothelium-dependent relaxations to acetylcholine were weak (24 +/- 11%), while nitric oxide caused comparable relaxations (85 +/- 3%) as in internal mammary arteries (80 +/- 5%; NS). NG-Monomethyl L-arginine prevented the relaxations to acetylcholine and unmasked endothelium-dependent contractions (30 +/- 10%). Indomethacin and the thromboxane synthetase inhibitor CGS-13080 augmented relaxations of saphenous veins to acetylcholine from 24 +/- 11% to 46 +/- 9% (p less than 0.05). Histamine-evoked contractions were converted to endothelium-dependent relaxations by indomethacin and the thromboxane A2/endoperoxide receptor antagonist SQ-30741 (38 +/- 3% and 40 +/- 6%; p less than 0.05) but not CGS-13080. Thus, 1) nitric oxide mediates endothelium-dependent relaxations in human arteries and veins; 2) internal mammary arteries release more nitric oxide than do saphenous veins, and 3) in saphenous veins, the effects of nitric oxide are reduced by endothelium-derived contracting factors originating from the cyclooxygenase pathway.

Prevention of Supraventricular Tachyarrhythmias After Open Heart Operation by Low-Dose Sotalol: A Prospective, Double-Blind, Randomized, Placebo-Controlled Study☆

BACKGROUND The aim of this prospective, double-blind, placebo-controlled trial was to assess the preventive effect and safety of low-dose sotalol after heart operation. METHODS Two hundred fifty-five consecutive patients referred for elective coronary artery bypass grafting (n = 220) or aortic valve operation (n = 35) were randomized to receive either 80 mg of sotalol twice daily (n = 126) or matching placebo (n = 129) for 3 months, with the first dose given 2 hours before operation. RESULTS There were no significant baseline differences between the groups. Overall, supraventricular tachyarrhythmias occurred in 36% of patients (82% atrial fibrillation). Hospital stay was 11.6 +/- 5 days in patients with supraventricular arrhythmias, versus 9.5 +/- 2.4 days in patients without it (p < 0.0001). Low-dose sotalol reduced the rate of supraventricular arrhythmias from 46% (placebo) to 26% (sotalol; p = 0.0012), or by 43%. On the fourth postoperative day, heart rate was lower in the sotalol group (74 +/- 12 beats/min versus 85 +/- 15 beats/min; p < 0.0001) but the QT interval corrected for the heart rate was not prolonged (sotalol group, 0.44 +/- 0.03 second; placebo group, 0.43 +/- 0.03 second; p = not significant). Study medication had to be discontinued because of side effects in 5.6% of sotalol and 3.9% of placebo patients (p = not significant), with one possible proarrhythmic event occurring in a patient receiving sotalol. CONCLUSIONS Because more than 90% of supraventricular arrhythmic episodes occurred within 9 days after operation and 70% of all possibly sotalol related side effects occurred after day 9, the findings in this study imply that prophylactic treatment with sotalol may be limited to the first 9 postoperative days.

Endothelium-derived relaxing factor and protection against contractions induced by histamine and serotonin in the human internal mammary artery and in the saphenous vein.

We investigated the release of endothelium-derived relaxing factor (EDRF) in response to serotonin and histamine in the human internal mammary artery and saphenous vein. The arteries and veins were obtained intraoperatively and were suspended in organ chambers to record isometric tension. In mammary arteries, histamine (10(-8) to 3 X 10(-6) M) induced relaxations in rings with (70 +/- 5%, IC50, 6.5 +/- 0.2) but not without endothelium (p less than 0.005 for rings with compared with those without endothelium, n = 7-10). The response was inhibited by methylene blue or hemoglobin, but not meclofenamate, and, therefore, EDRF was delineated as the mediator. Because chlorpheniramine but not cimetidine inhibited the response, EDRF was released by the H1-histaminergic receptor (n = 5-8). In contrast, in saphenous veins, histamine caused only weak or absent endothelium-dependent relaxations, but contractions were enhanced in rings with endothelium (p less than 0.05, n = 6). Serotonin did not induce endothelium-dependent relaxations, but contractions were markedly greater in veins compared with arteries (p less than 0.005, n = 6). The endothelium inhibited the maximal contraction to serotonin in arteries (p less than 0.034) but not in veins. Thus, EDRF protects against contractions induced by histamine and serotonin in the mammary artery but not in the saphenous vein. This may be important for improved graft function and patency of the artery compared with that of the vein.

Different interactions of platelets with arterial and venous coronary bypass vessels

We studied the interaction of platelets with the wall of human internal mammary arteries and saphenous veins, suspended in organ chambers for measurement of isometric tension. Vessels were obtained during coronary bypass surgery and cut into 5 mm rings; in some the endothelium was chemically removed. Rings from several patients were randomly chosen for each experiment, and in each ring six concentrations of platelets (from healthy blood donors; 1-75 x 10(3)/microliters) were tested consecutively and concentration-response curves constructed; the areas under these curves were used for statistical comparisons. In rings of internal mammary artery contracted in response to noradrenaline, aggregating platelets induced endothelium-dependent relaxation which was prevented by apyrase (0.67 U/ml ADPase activity) and L-NG-monomethylarginine (1 mmol/l). By contrast, in saphenous vein rings contracted in response to noradrenaline, aggregating platelets induced only a further increase in tension. In quiescent vessels, the platelet-induced contraction did not occur in arteries with endothelium but that in veins was greater and facilitated by endothelium. Preincubation of platelets with aspirin (10 mumol/l) reduced the contraction in both vessels, but contraction was abolished only in the presence of both the thromboxane receptor antagonist SQ-30741 and the serotoninergic (5HT2) receptor antagonist ketanserin. These findings show that platelet-derived ADP causes release of nitric oxide by the endothelium of internal mammary artery but not of saphenous vein; thromboxane A2 and serotonin mediate contraction in vein but not artery with endothelium. These differences may contribute to differences in graft function and the clinical efficacy of antiplatelet drugs.

Significance of Supraventricular Tachyarrhythmias After Coronary Artery Bypass Graft Surgery and Their Prevention by Low-Dose Sotalol: A Prospective Double-Blind Randomized Placebo-Controlled Study

Background: The single most frequent complication after coronary artery bypass graft surgery is the occurrence of supraventricular tachyarrhythmias leading to a prolonged hospital stay. Although several drugs have been used to treat these arrhythmias, effective prevention was only possible with beta-blocking drugs in selected patients. It was, therefore, the aim of the present study to evaluate the significance of supraventricular tachyarrhythmias in presence of todays cardioprotective management in a broad spectrum of patients and to assess the possible preventive effect and safety of low-dose sotalol after coronary artery bypass graft surgery. Methods and Results: In a prospective randomized double-blind placebo-controlled trial, 220 consecutive patients referred for elective coronary artery bypass graft surgery were random ized to 80 mg sotalol twice daily (n = 110) or matching placebo (n = 110) for 3 months with the first dose given 2 hours before surgery. There were no significant differences in baseline charac teristics between the two groups. Low-dose sotalol reduced the rate of supraventricular arrhythmias from 43% (placebo) to 25% (sotalol, P <.01), which was atrial fibrillation in 83%, flutter in 7%, and other supraventricular arrhythmias in 10%. Only 7% of all arrhythmias were observed after day 9. Hospital stay was I 1 ± 4 days in patients with supraventricular arrhyth mias versus 9 ± 2 days (P < .001) in patients without. On the fourth postoperative day, heart rate was lower in the sotalol group (75 ± 12 versus 86 ± 14 beats per min; P < .0001), but QTc was not significantly prolonged (sotalol, 0.44 ± 0.03; placebo 0.43 ± 0.03; P. ns). Study medica tion had to be discontinued due to side effects in 6.4% of sotalol and 3.6% of placebo patients (P. ns), but relevant side effects occurred only in two sotalol patients late after surgery. Conclusions: These data show that without antiarrhythmic therapy the incidence of supraventricular arrhythmias after coronary artery bypass graft surgery is high (43%) and that supraventricular arrhythmias were associated with a prolonged hospital stay (+2 days). Prophylactic treatment with low-dose sotalol reduced the incidence of supraventricular arrhythmias significantly (by 40%), thereby reducing overall hospital stay in treated patients. Because more than 90% of all supraventricular arrhythmic episodes occurred within 10 days after surgery and considering the small proarrhythmic effect of sotalol late after surgery, prophylactic treatment with sotalol may be recommended for the first 10 postoperative days to safely reduce supraventricular tachyarrhythmias.

Development of nitrate tolerance in human arteries and veins: comparison of nitroglycerin and SPM 5185.

Summary: Nitrate tolerance is a clinical problem in patients with coronary artery disease and heart failure. Human internal mammary arteries and saphenous veins obtained intraoperatively were suspended in organ chambers, and isometric tension was measured. In the artery, nitroglycerin elicited a potent relaxation, which was significantly diminished after prolonged incubation with nitroglycerin (10–6 M, 1 h). In contrast, no tolerance occurred in saphenous vein under the same conditions. However, incubation with 10–5 M nitroglycerin also developed tolerance. Compared to nitroglycerin, the new cysteine-containing mononitrate SPM 5185 exhibited a lower sensitivity but comparable maximal relaxation in arteries and veins. In nitroglycerin-tolerant arteries and veins, SPM 5185 caused relaxations similar to those under control conditions. Our results show that in isolated blood vessels, vascular nitrate tolerance occurs more readily in the mammary artery than in the saphenous vein. SPM 5185 seems to be less prone to the development of tolerance, which may be advantageous during chronic nitrate therapy.

Long-term follow-up in pulmonary embolectomy: is NYHA (dyspnea) classification reliable?

In this retrospective investigation we carried out a thorough physical examination, ventilation/perfusion scintigraphy, echocardiography and lung function test in 19 of all 21 long-term survivors consecutively operated on for massive pulmonary embolism between 1968 and 1992. Two patients refused these investigations but were both asymptomatic. The mean follow-up was 8.4 years and 12 (57%) of the patients were in NYHA I and 6 (29%) in NYHA II. The three patients in NYHA III (there were none in class IV) underwent right heart catheterization and pulmonary angiography additionally. Our findings suggest that, generally, the results of scintigraphy, echocardiography, lung function tests and physical examination correspond to the subjective status expressed as NYHA (dyspnea) class, when evaluated in combination. However, in classes III and IV other causes of dyspnea apart from residual pulmonary vascular obstruction can be found. These may also occur in combination. We observed severe chronic obstructive lung disease, hemidiaphragmatic paralysis, obesity, pulmonary hypertension of unknown origin, atrial septal defect (ASD) and neurologic residual deficit with depressive state. Thus, in evaluating long-term results of pulmonary embolectomy with regard to vascular desobliteration, NYHA classification does not seem to be reliable for classes III and IV.