Effects of proadrenomedullin N-terminal 20 peptide and calcitonin on isolated perfused rat hearts.

OBJECTIVE: There are evidences that proadrenomedullin N-terminal 20 peptide (PAMP) and calcitonin may be involved in cardiovascular function. Therefore, we studied effects of rat PAMP and human PAMP as well as rat calcitonin and salmon calcitonin on coronary perfusion pressure, heart rate and contractile force. METHODS: Isolated rat hearts were perfused under constant flow condition and rat PAMP (1.10 and 100 nM), human PAMP (1,10 and 100 nM), rat calcitonin (10.100 and 1000 nM) or salmon calcitonin (10.100 and 1000 nM) were infused to the hearts. Coronary perfusion pressure, heart rate, left ventricular developed pressure and +dP/dtmax were measured. Statistical analysis was performed using repeated measures ANOVA and Bonferroni posthoc tests. RESULTS: Rat PAMP (1.10 and 100 nM) did not alter perfusion pressure. However, it increased heart rate from 257.83+/-23.89 to 282+/-24.98 beats/min (p<0.001), from 259.83+/-25.05 to 289.8+/-19.5 beats/min (p<0.001) and from 249.66+/-19.19 to 280.50+/-25.26 beats/min (p<0.001) for 1.10 and 100 nM, respectively. Rat PAMP decreased left ventricular developed pressure from 90.5+/-18.5 to 79+/-15.3 mmHg (p<0.05), from 88.00+/-10.12 to 73.00+/-12.38 mmHg (p<0.05) and from 79.83+/-8.98 to 64.83+/-10.12 mmHg (p<0.05) for 1.10 and 100 nM, respectively. The peptide also decreased +dP/dtmax from 3710.5+/-370.6 to 3223.8+/-261.1 mmHg s-1 (p<0.001), from 3683.16+/-327.27 to 3040.6+/-423.8 mmHg s-1 (p<0.01) and from 3746.16+/-315.76 to 3009.83+/-204.64 mmHg s-1 (p<0.001) for 1.10 and 100 nM, respectively. Rat calcitonin (10.100 and 1000 nM) did not change perfusion pressure but it decreased heart rate from 269.16+/-22.6 to 253.6+/-22.84 beats/min (p<0.05), from 263.8+/-27.3 to 247.00+/-36.63 beats/min (p<0.05) and from 285.0+/-32.4 to 264.00+/-39.83 beats/min (p<0.01) for 10.100 and 1000 nM, respectively. Rat calcitonin did not significantly affect left ventricular developed pressure. Human PAMP or salmon calcitonin did not change perfusion pressure, heart rate and left ventricular developed pressure. CONCLUSION: We conclude that rat PAMP may induce positive chronotropic and negative inotropic effect while rat calcitonin may produce a negative chronotropic effect. Human PAMP or salmon calcitonin could not alter perfusion pressure, heart rate and contractility in isolated, perfused rat hearts.

Dietary polyphenol quercetin protects rat hearts during reperfusion: enhanced antioxidant capacity with chronic treatment.

OBJECTIVE: Quercetin is an important member of dietary flavonoid family and widely present in red wine and Mediterranean diet. The major objective of the this study is to evaluate the beneficial effects of quercetin in protecting the myocardium from the deleterious effects of ischemia reperfusion (I/R) injury in chronic quercetin treatment with or without an acute quercetin infusion protocols. METHODS: Forty male Sprague-Dawley rats were included in this experimental randomized study/ Langendorff perfused isolated rat hearts were subjected to 60-min of global ischemia period following 60-min of reperfusion. All animals were randomly divided into 4 groups. Group 1 animals were kept as controls. Group 3 and 4 animals received 50 mg/kg quercetin via an intragastric tube for 7 days for chronic treatment. Group 2 and 4 animals received an acute 15 mmol/L infusion for 30 minutes before the onset of ischemia. The myocardial postischemic recovery was compared using hemodynamic data (peak systolic pressure, end-diastolic pressure and +dP/dtmax), coronary flow, biochemical parameters (lactate dehydrogenase, creatine kinase-MB fraction, cardiac troponin I) from coronary effluent, and oxidative stress markers (malondialdehyde, glutathione, glutathione reductase and nitrite) from heart tissue homogenates in each group. RESULTS: Quercetin has provided increased preservation in myocardial recovery in both chronic and acute treatment protocols compared to non-treated group. According to all estimated hemodynamic parameters, while the statistical difference between acute treated hearts and control hearts was significant (p<0.05); this significance was more clear in chronic treated groups (group 3 and 4) when compared to control (p<0.01). Likewise, biochemical and oxidative stress markers displayed significant differences in acute treated and chronic treated hearts when compared to control (p<0.05 and p<0.01, respectively). CONCLUSION: As a major dietary flavonoid, due to its antioxidant and cytoprotective actions, quercetin has the capacity to protect the myocardial tissue against global ischemia and reperfusion injury. In instances where the molecule is administered for the purpose of acute therapy, this cardioprotective effect of a significant degree can be observed to; however, this potency is further accentuated upon administration as a chronic treatment protocol for seven days.

An alternative agent for radial arterial graft spasm: application of topical iloprost.

OBJECTIVE: This study is planned bringing about a new choice for the prophylaxis of RA spasm which is topical iloprost and compares its efficacy with papaverine and diltiazem. DESIGN: Twenty eight CABG patients with RA grafts were categorized into four groups by taking into account the topical vasodilator (papaverine, diltiazem, iloprost and saline) that was utilized during harvesting. Arterial segments were separated into four rings and were than soaked with KCL, norepinephrine, phenylephrine and serotonin. Then, acetylcholine was given to induce relaxation and the preparations were put to rest for 10 minute. RESULTS: The contraction response achieved by the vasoreactive agents was most effectively inhibited by papaverine. The effectiveness of the response obtained by iloprost was similar to that of papaverine and significantly stronger than that of diltiazem. Especially at high vasoreactive substance concentrations, diltiazem had a contraction close to that of the control while the protective effect was weaker than those of papaverine and iloprost. CONCLUSION: Iloprost can be recommended as a strong alternative to the topical agents used for preventing arterial graft spasm.

An old friend is still at work: 34-year-old well functioning Starr-Edwards aortic prosthesis without anticoagulation.

The Starr-Edwards caged-ball valve prosthesis is the beginning mark of the valve replacement era, and was used widely in many centers worldwide in the past decades. Despite long term results with this prosthesis have been reported with satisfactory hemodynamic performance, only a few cases have been reported exceeded 30 years of durability. We report the case of a patient with a 34-year-old well-functioning Starr-Edwards ball prosthesis in aortic position using neither antiaggregant nor anticoagulant therapies.

Protective effects of resveratrol in ischemia-reperfusion injury of skeletal muscle: A clinically relevant animal model for lower extremity ischemia.

Ischemia and reperfusion injury of the skeletal muscle is a common and serious condition observed in patients admitting to peripheral vascular surgery, interventional radiology and cardiology departments. Resveratrol (RVT) being a strong natural antioxidant is found in deal of red wine and Mediterranean diet. In the present study, male Spraque-Dawley rats were randomized into two groups of equal size. The first group was the control group, and these rats were administered with tap water with a gastric tube for fourteen consecutive days once daily. According to the same protocol, the rats in the second group were treated with tap water containing 20 mg/kg RVT. All the rats in the two groups were subjected to acute hind limb ischemia through clamping of the abdominal aorta for 120 min. Following this procedure, 60 minutes of reperfusion was applied by reestablishing blood flow in both iliac arteries. Ischemic damage in the skeletal muscle tissue was assessed by measuring myoglobin, lactate dehydrogenase, creatinine phosphokinase, aspartate transaminase enzymes in venous blood samples obtained at the end of the reperfusion period. Oxidative stress caused by reperfusion was determined by measuring MDA, carbonyl and protein sulphydryl levels in quadriceps muscle tissue retrieved at the end of the experiment. In Group II rats, all the measured ischemic enzymes and the markers of oxidative stress reflected robust anti-ischemic properties obtained by RVT administration. The data from both groups revealed statistically significant protection against acute skeletal muscle ischemia and reperfusion injury in Group II rats, compared to Group I. As a major dietary flavonoid RVT can protect the skeletal muscle tissue against global ischemia and reperfusion injury because of its strong antioxidant and cytoprotective properties.

Erythropoietin changes contractility, cAMP, and nitrite levels of isolated rat hearts.

There is enough evidence that erythropoietin (EPO) may be involved in cardiovascular function. Therefore we have investigated the possible effects of EPO on left ventricular developed pressure, +dP/dt(max), heart rate, tissue cAMP, and nitrite levels. Isolated rat hearts were perfused under constant flow (10 ml/min) conditions with modified Krebs-Henseleit solution and recombinant human erythropoietin at doses of 100, 200, 500, and 1,000 IU/kg was administered as bolus injections. EPO at 100 IU/kg decreased, but higher doses (500 and 1,000 IU/kg) raised the developed pressure and +dP/dt(max). However, it did not affect heart rate or coronary perfusion pressure when all the respective doses were applied. EPO at 100 IU/kg increased nitrite, and at 1,000 IU/kg it raised cAMP. Our results suggest that EPO may produce dose-dependently negative and positive inotropic effects on myocardial contractility in isolated rat hearts. NO and cAMP may be involved in negative and positive inotropic effects of EPO, respectively.

Trimetazidine-induced enhancement of myocardial recovery during reperfusion: a comparative study in diabetic and non-diabetic rat hearts.

BACKGROUND: Diabetes mellitus (DM) is a major predisposing factor for ischemic heart disease. Metabolic disturbances in diabetic heart including impaired myocardial glucose uptake and elevated plasma free fatty acids and increased rate of fatty acid beta-oxidation are probably important contributing factors to greater mortality. Trimetazidine (TMZ), a well-studied anti-ischemic agent, has been demonstrated to be beneficial in treatment of coronary artery disease as well as in treatment of diabetic patients. However, studies reporting the effects of the drug against global myocardial ischemia/reperfusion injury, particularly in diabetic hearts, are rare. This study was mainly aimed to investigate the cardioprotective action of TMZ against global ischemia in diabetic hearts and to compare its protective efficiency level with non-diabetics. METHODS: Twenty streptozotocin-induced diabetic and 20 non-diabetic rats were divided into two groups each. Group I (diabetic, n = 10) and group III (non-diabetic, n = 10) rats were given saline in both pretreatment and acute treatment protocols and reserved as control groups. Group II (diabetic, n = 10) and group IV (non-diabetic, n = 10) rats were both pretreated orally with 3 mg/kg TMZ twice daily for 5 days and treated with TMZ infusion at a concentration of 10(-6) M for 30 min during the experiment. Isolated hearts from each rat were submitted to Langendorff perfusion and a period of 60 min of global ischemia following 60 min of reperfusion. Myocardial post-ischemic recovery was compared in each group using hemodynamic data (peak systolic pressure, end diastolic pressure, +dP/dt(max)), coronary flow, biochemical parameters (CK-MB, cTnT) from coronary effluent, and obtained data were statistically analyzed by both MANOVA and two-sample Hotelling's T2 tests. RESULTS: Both hemodynamic and biochemical findings signaled a significantly enhanced myocardial recovery provided by TMZ treatment in diabetic and non-diabetic hearts as compared to non-treated hearts. Although efficiency level of TMZ on mechanical recovery was not different between diabetics and non-diabetics, the protective action of TMZ on myocardial damage measured by biochemical parameters was more evident in diabetic hearts than in non-diabetics. CONCLUSIONS: Shifting myocardial energy metabolism away from fatty acids toward glucose oxidation and regulating transmembrane ion disturbances by TMZ can be considered as an appropriate adjunctive treatment in diabetics, especially in patients undergoing open-heart surgery who will be exposed to global myocardial ischemia.

Leptin protects the cardiac myocyte cultures from hypoxic damage.

Leptin, a circulating hormone mainly produced by adipose tissue, regulates fatty acid metabolism and causes multiple systemic biological actions even the regulation of cardiovascular function. It is previously known that leptin is a hypoxia-inducible hormone, that hypoxic conditions increase the expression of this peptide in various tissues such as placenta, pancreas and also in the heart. Since leptin receptors are present in the heart, we hypothesized that whether leptin was a protector response for tissues especially for the heart against the deleterious effects of hypoxia. Cultured cardiomyocytes from newborn rats were initially treated with 3000 ng/ml leptin incubation for 1, 5 and 20 h separately, then subjected to 120 min of hypoxia. Hypoxic damage of myocytes was assayed using the measurements of both lactate dehydrogenase and creatine kinase releases into the medium and performing morphological observations (ultrastructural and immunocytochemical) of plates. The obtained results from leptin treated and non-treated control groups were compared to each other, and these data have demonstrated that 5 h of leptin treatment before hypoxia provides a significant protection for cardiomyocytes against hypoxia. Neither 1- nor 20-h leptin treated groups exhibited sufficient protection against hypoxia. In conclusion, leptin protects the cardiomyocyte cultures from hypoxia, but this effect is selective and evident only in the 5-h treated myocytes.

Does radial artery harvesting for coronary revascularization cause neurological injury in the forearm and hand?

OBJECTIVE: Radial artery (RA) is now used widely as a conduit of choice in coronary artery bypass grafting. Although RA removal is considered safe in the presence of adequate collateral arterial supply, there is still a considerable suspicion on the functional status of the forearm and hand. However, a neurological dysfunction may occur owing to either surgical trauma or ischemic neuropathy. This study was aimed to investigate the functional outcome of the donor forearm nerves of the patients who underwent coronary artery bypass grafting surgery with RA conduits. METHODS: A consecutive series of 50 patients who underwent coronary artery bypass graft surgery with one or two RA grafts were investigated in the study. Motor and sensory functions of donor forearm nerves were measured by ENMG studies, pre- and postoperatively at the third week and sixth month of the operation. The conduction velocities, distal latencies and amplitudes of action potentials for motor and sensorial conductions of radial, ulnar and median nerves were measured in each ENMG examination. Neurologic status of the donor forearm and hand was assessed by the same neurologist who performed a detailed neurologic physical examination and ENMG studies. Results were statistically compared using one-way ANOVA test. RESULTS: The incidence of any neurologic symptoms was 32% in early postoperative period. All reported neurologic complaints were associated with sensory conduction deceleration in ENMG investigations of related nerves. In postoperative assessment, median nerve sensory-motor, and ulnar nerve motor conduction records were slightly lower than the preoperative values, but no statistical difference was observed. Pre- and postoperative radial nerve motor and sensory conduction records were statistically similar (P>0.05). CONCLUSIONS: We advocate that removal of RA does not lead to any major neurologic hand complications in the presence of adequate collateral arterial blood supply. ENMG studies confirmed minimal conduction alterations with no statistical significance, even if neurologic symptoms were stated.

Trimetazidine improves recovery during reperfusion in isolated rat hearts after prolonged ischemia.

OBJECTIVE: Trimetazidine (TMZ) is a cellular anti-ischemic agent, which has been studied in clinical and experimental investigations, and was shown to have protective affects against myocardial ischemia and reperfusion injury. The major objective of this study was to investigate the cardio-protective effects of trimetazidine in prolonged global ischemia subjected Langendorff perfused rat hearts. METHODS: Twenty rats (Male Sprague-Dawley) were divided into two study groups. In Group 2 (n=10) TMZ was given by intra-gastric gavage (3 mg/kg BW twice daily for 5 days) prior to operation and was added to the Krebbs-Henseleit perfusate to create a 10-6 M solution to perfuse the isolated rat hearts. Group 1 (n=10) reserved as control group and received saline at the same time period. All hearts were paced at 300 beats/min. After a 20-minute of stabilization period, hearts in both groups were arrested for 120 minutes with crystalloid cardioplegia. After ischemic period, the hearts were then reperfused for 30 minutes. Hemodynamic measurements from left ventricular latex balloon, coronary flow, and creatine kinase (CK-MB) and troponin T (cTnT) levels determined from the coronary effluent were analyzed at the end of stabilization and at every 10-min intervals during reperfusion, and results were compared between two groups. RESULTS: No significant differences were observed in all entered hemodynamic and biochemical parameters between two groups at the end of the stabilization. However, peak systolic pressure, end diastolic pressure and +dP/dt values reflected improved mechanical myocardial recovery in Group 2 hearts after prolonged ischemia. Besides coronary flow measurements were higher in Group 2 compared with Group 1. CK-MB and cTnT levels indicated to less enzymatic damage in trimetazidine treated hearts during reperfusion. CONCLUSION: In conclusion, both pre-treatment and treatment protocols with TMZ reduce the myocardial damage caused by global ischemia following reperfusion. We could speculate that this beneficial effect of trimetazidine might be useful in open-heart surgery patients, who were subjected to global myocardial ischemia.

Improved myocardial function with the addition of pinacidil to custadiol.

BACKGROUND: This study investigates the efficacy of pinacidil, an adenosine triphosphate-sensitive potassium (KATP) channel opening agent, added to custadiol solution on myocardial protection during deep hypothermia and prolonged global ischemia on isolated rat hearts. METHODS: After 20 minutes of stabilization, 24 rats were divided into two groups. In group I (n=12), hearts were arrested with cold (4 degrees C) custadiol solution containing 50 micromol/L of pinacidil and subsequently dipped into the same solution for 120 minutes at 4 degrees C. Group I hearts were perfused with low-flow pinacidil-custadiol (PC) solution during the ischemic period. Group II (n=12) hearts, after the stabilization period, were arrested with cold custadiol solution only, then subsequently dipped and perfused with the same solution for 120 minutes at 4 degrees C. All hearts were reperfused with Krebb's-Henseleit solution at 37 degrees C for 60 minutes. Hemodynamic parameters (peak systolic pressure, end diastolic pressure, maximum rate of increase of left ventricular pressure [+dP/dt], ischemic contracture, and coronary sinus flow) were recorded at the end of the stabilization period and at 10-minute intervals during the reperfusion period. Biochemical data (creatine kinase [CK-MB] washout and troponin I [cTnI] levels) were compared between the two groups. RESULTS: There was no significant difference in any hemodynamic or biochemical parameters between the two groups during the stabilization period. The peak systolic pressure, +dP/dt, ischemic contraction amplitude, and coronary flow values were significantly higher in group I ( P<0.05) compared with group II during reperfusion. End diastolic pressures as well as CK-MB and cTnI levels were lower in the pinacidil-treated group, which is consistent with improved functional recovery during the reperfusion period. CONCLUSION: The addition of pinacidil to the preservation solution, custadiol, improves myocardial recovery after deep hypothermia and prolongs ischemia.