Effects of different proton pump inhibitors on cardiac contractility in isolated human failing myocardium.
Samuel SossallaHanna SchotolaJan D. SchmittoKarl ToischerChristian SohnsHarald SchwörerGerd HasenfußLars S. MaierWolfgang Schillinger
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Abstract:
Proton pump inhibitors (PPI), e.g. pantoprazole (PP), esomeprazole (EP) and omeprazole (OP), work as anti-ulcer/gastrointestinal reflux drugs. Also, they are widely used in postoperative care of patients in cardiac surgery to prevent upper gastrointestinal bleeding. Therefore, in western industrial countries they play a major economic role, representing one of the most important drugs in open heart cardiac surgery.Intact muscle strips (n=32) were isolated from the right ventricle wall of failing human hearts. In four different groups (PP, EP, OP, control group, each n=8), force amplitudes were recorded at a frequency of 60 beats per minute (bpm) with increasing PPI concentrations (0 to 320 µm/mL).In isometrically contracting muscle strips, significant negative inotropic effects were observed in the presence of all three PPI-groups (PP, EP and OP) with doses of 2.5 µg/mL and higher compared to the control group (p < 0.05 each). With high doses (320 µm/mL), force amplitudes could be almost completely depressed. The half maximal inhibitory concentration (IC50) for EP was 35.7 (confidence interval: 17.3-73.6) vs. OP 29.3 (6.8-126.6) vs. PP 25.1 (14.6-43.1) µg/mL (n.s.). No significant differences were found between the different proton pump inhibitors (PP, EP, OP) throughout the range of all concentrations. Relaxation was impaired in all PPI subgroups with prolonged time to 90% relaxation (RT90%) and maximum relaxation velocity (‑df/dt) was reduced, too. These effects were partially reversible after wash-out of the drugs.We conclude that proton pump inhibitors show significant negative inotropic effects on isolated human failing myocardium. There is no apparent difference seen in the magnitude of the effects of each PPI-group. Further, in-vivo investigations are necessary to reveal the clinical evidence of PPI's negative inotropic effects, e.g. in cardio-surgical patients with heart failure.Keywords:
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Experimental studies were carried out to compare the efficacy of various agents such as calcium antagonists, phosphodiesterase inhibitors, adrenocorticosteroids, coenzyme Q10 (CoQ10), insulin, beta-blocking agent and reduced glutathion (GSH) on the enhancement of myocardial protection. Eighty-five isolated rabbit hearts were subjected to 2 hours of cardioplegic arrest, and maximum developed tension, heart rate, coronary blood flow and coronary arteriovenous oxygen difference following reperfusion were compared between groups pretreated with different agents. The greatest value of maximum developed tension was obtained in the verapamil-treated group (0.2-0.5 mg/kg), followed by dilazep (1 mg/kg), pentoxifylline (30 mg/kg) and CoQ10 (10 mg/kg) treated groups. The time required for the recoveries of spontaneous beating (normal sinus rhythm) on reperfusion was shortest (44 +/- 8 sec) in the group treated with a cardioplegic solution containing a low concentration of betamethasone (0.03-0.05 mg/ml), but the so-called stone hearts and cardiac arrhythmias were most frequently seen in this group. On the contrary, in the group pretreated with calcium antagonists, the time required for the restoration of sinus rhythm was much longer (88-180 sec). Hence, the shortest recovery time was not necessarily associated with a better recovery of myocardial function.
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Summary. The effect of a four‐week treatment with propranolol and metoprolol on blood pressure and regional haemodynamics of the lower extremity at rest, after exercise and during reactive hyperaemia was studied in 34 patients with essential hypertension, but without peripheral arterial disease, in a randomized placebo‐controlled trial. No significant difference in side‐effects recorded during the trial was observed between these two drugs. Treatment with beta‐adrenergic blocking drugs reduced systemic blood pressure. Calf blood flow during vasodilatation was also decreased. The most marked changes were observed during reactive hyperaemia; mean calf blood flow was reduced from about 250 ml/min/litre of tissue to 200 ml/min/litre of tissue ( P <0·01) by propranolol and to 214 ml/min/litre of tissue ( P <0·01) by metoprolol. Both drugs caused a significant increase in peripheral resistance above the initial level during reactive hyperaemia ( P <0·05). No significant difference in peripheral resistance was observed, however, when the active drugs were compared with the placebo. There was no difference between propranolol and metoprolol in any of the parameters. Thus, the flow reduction can mainly be attributed to the diminished perfusion pressure due to the decreased cardiac output caused by beta‐blockade of the heart.
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The aim of this study was to examine the effects of positive inotropic drugs, including adrenaline, dopamine, and dobutamine on thyroid hormone levels following open heart surgery.We analyzed free thyroid hormones (FT3 and FT4) and thyroid-stimulating hormones (TSH) in 200 consecutive patients undergoing open heart surgery. Patients were divided into 5 groups according to the inotropic drug administration as follows: Group A (n = 46) received dopamine alone; Group B (n = 40), dopamine and dobutamine; Group C (n = 36), dopamine, dobutamine, and adrenaline; Group D (n = 32), adrenaline alone; and Group E (n = 46), placebo. Procedural factors affecting thyroid hormones were recorded and included cardiopulmonary bypass (CPB) time, cross-clamping time, degree of hypothermia, and the duration and doses of positive inotropic drugs. Blood samples for hormone assays were collected before initiation of inotropic drug therapy (baseline) and postoperatively at 24, 72, and 120 hours after drug therapy.FT3, FT4, and TSH levels at baseline were similar in all groups. Although there was a trend showing very slight increases in thyroid hormone levels from baseline to the 24th, 72nd, and 120th postoperative hours after drug therapy, these changes were not significant, and there were also no significant differences between the groups. There was also no significant statistical difference in CPB time, cross-clamping time, degree of hypothermia, and duration and doses of positive inotropic drugs between groups.Although thyroid hormone levels were affected by positive inotropic drug usage after open heart surgery, this effect was not significant and thyroid hormone levels remained within normal ranges.
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AR-L 115 BS is a new active noncatecholamine, non glycoside phenyl-imidazo-pyridine derivative inotropic agent. It has a strong inotropic effect in experimental animals. Its effectiveness and associated adverse effects were tested in 23 patients with severe heart failure (NYHA class III to IV). Intravenous administration of AR-L 115 BS at 1.4 mg/min for 6 hours in 11 patients increased cardiac index from 2.07 +/- 0.13 to 2.99 +/- 0.203 l/min/m2 (p less than 0.005) while pulmonary wedge pressure decreased from 23 +/- 2 to 13 +/- 2 mm Hg (p less than 0.005). Systemic vascular resistance fell from 1759 +/- 137 to 1263 +/- 71 dynes.sec. cm-5 (p less than 0.005). Heart rate and blood pressure remained unchanged. Following oral administration (450 mg) in 12 other patients, cardiac performance was similarly improved. Hemodynamic changes were apparent as early as 60 min after administration, and the duration of action ranged from 5 to 7 hours. No serious arrhythmias or side effects occurred. It could therefore be useful in the management of congestive heart failure.
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The effect of an anabolic steroid on canine left ventricular function was studied by catheterization exposing control (n = 7) and methandienone-treated (n = 6) dogs to pacing, volume and isoproterenol tests at the beginning of the experiment and 6 weeks later. The physical performance of the animals was evaluated by submaximal exercise test (SMT), in which the steroid-treated dogs had lower heart rate than the sedentary controls (P less than 0.001). Heart weight was greater in the steroid than in the control group (P less than 0.05). Isoproterenol infusion increased the maximum value of the left ventricular pressure curve (dP/dtmax) less in the steroid-treated than in the control animals (P less than 0.05). Also heart rate was lower in the steroid than in the control group after inotropic load, while end-diastolic, end-systolic and stroke volumes decreased significantly more in the control group (P less than 0.05). Systemic vascular resistance decreased in the steroid treated animals, but remained unchanged in the control group (P less than 0.05 between the groups). During volume overload dP/dtmax increased in the control group but decreased slightly in the steroid group (P less than 0.05 between the groups). The pressure-volume diagram showed that the left ventricle of the steroid-treated animals worked on higher ventricular volumes than in the control group. In conclusion, long-term methandienone treatment results in cardiac hypertrophy in dogs, reduces its response to an inotropic loads and leads to working on larger ventricular volumes.
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