Biomedical subjects

S Curello

Publications and source records attributed to S Curello.

At least 37 records · Page 2Linked to original sources

PubMed1998

Catecholamines: the cardiovascular and neuroendocrine system.

The development of profound autonomic dysfunction and of neuroendocrine activation characterizes and possibly contributes to the progression of heart disease to congestive heart failure. Sympathetic activation is a generalized process and the proposed mechanisms for neurohumoral activation include decreased input from excitatory afferences and increased input from excitatory chemoceptors and metabaroceptor. These phenomena vary to a great extent in different subjects: in the more impaired patients, renal and cardiac overflow of catecholamines can increase three- and ten-fold, respectively, accounting for about 60% of the increase of noradrenaline in congestive heart failure. Efficient methods to quantify sympathetic cardiovascular influences and neuroendocrine indices have been developed and it has been recognized that sympathoneural activation independently predicts the survival of patients. The pathophysiological role and the clinical relevance of neuroadrenergic abnormalities also constitute the grounds for the understanding of the therapeutic benefit obtained with interventions aimed at mitigating the harmful consequences of adrenergic hyperactivity.

Cardiovascular System↗

PubMed1998

The neuroendocrine and sympathetic nervous system in congestive heart failure.

A review of recent randomized clinical trials has shown that neurohormonal activation starts early in the natural history of left ventricular dysfunction and levels of the circulating hormones increase in proportion to the severity of heart failure. Most studies suggest that high levels of neurohormones predict a poor prognosis. Among the several neurohormones, the sympathetic system is the one which is activated earlier, it increases in proportion to the severity of the disease and has a negative prognostic implication. These concepts have been also proven in untreated patients. Augmented sympathetic activity in the syndrome of heart failure is initially beneficial, appears to be adaptive and helps support blood pressure and cardiac output. Prolonged and excessive sympathetic activation has deleterious effects with adverse consequences at both cardiac and vascular levels which aggravates the clinical status of the syndrome and negatively affects its prognosis. Evidence is accumulating that, contrary to popular belief, beta-blockers may be beneficial in heart failure by inhibiting sympathetic activation. In addition to neuroendocrine activation, another class of biologically active molecules, termed cytokines, are excessively secreted by cells in heart failure. Important among these cytokines are tumour necrosis factor-alpha and interleukin-6. They appear to exert deleterious effects on the heart and circulation which may be also involved in the progression of heart failure.

Adrenergic beta-Antagonists↗

PubMed1998

Endothelial function and dysfunction in heart failure.

The endothelium controls vascular smooth muscle tone by secreting substances that cause relaxation and contraction. Under physiological, basal conditions the endothelium constantly releases nitric oxide, a process closely regulated by the effect of shear stress on endothelial cells. Recent data raise the possibility that, among many other substances, bradykinin also plays an important role in the regulation of vascular tone. Bradykinin is a vasodilator that increases the activity of constitutive nitric oxide. Congestive heart failure (CHF) is a complex clinical syndrome in which abnormal vascular endothelial function has been shown to occur at both the experimental and clinical level. The reduced nitric oxide-mediated vasodilation in CHF is multifactorial. Constitutive nitric oxide synthase is downregulated as shear stress is reduced. Vascular angiotensin-converting enzyme (ACE), which produces angiotensin II and inactivates bradykinin, is up-regulated. Angiotensin II is a powerful vasoconstrictor, and the reduced availability of bradykinin will further down-regulate constitutive nitric oxide synthase. The CHF-induced activation of tumour necrosis factor also leads to a down-regulation of constitutive nitric oxide synthase and to an increased rate of endothelial-cell apoptosis. These observations suggest that abnormalities of endothelial function in CHF may contribute to increased peripheral vasomotor tone both at rest and during exercise, and raise the possibility that the beneficial effects of ACE inhibition in CHF may be due in part to improved endothelial function.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Recognized molecular mechanisms of heart failure: approaches to treatment.

Abnormalities of cytosolic calcium handling and myocyte energetics appear to play an important role in mediating contractile dysfunction in heart failure. Systolic and diastolic dysfunction in the failing heart are related to abnormalities of the excitation-contraction mechanism as well as myofilament calcium sensitivity. These abnormalities can be viewed as a compensatory mechanism as the myocytes by down regulating its function and metabolic activity preserve energy consumption and allow better maintenance of basal cellular homeostasis. The end point of myocyte dysfunction, however, is a reduced contraction, which, in turn, might cause a reduced cardiac output and a threatening of arterial pressure. This causes a second level of adaptation, which implies a neuroendocrine response of the whole organism. Consequently, the syndrome of congestive heart failure is characterized not only by impaired ventricular function, but also by an increase in some endogenous substances leading to vasoconstriction and water and salt retention. Although activation of the systems that release these substances is presumed to be compensatory, the sympathetic nervous system and renin-angiotensin-aldosterone system as well as the endothelins may contribute to the pathogenesis of the syndrome. Opposite to the effects of these systems are those evoked by the release of atrial natriuretic peptides. The peptides exert a potent direct vasodilatation and natriuresis. In addition, atrial natriuretic peptides inhibit the release of norepinephrine from nerve terminals and suppress the formation of renin. However, the natriuretic and vasodilator effects of these peptides in patients with congestive heart failure are outweighed by the sodium retention and vasoconstriction caused by sympathetic stimulation and activation of the renin-angiotensin-aldosterone system. The reasons for this are not entirely known. The atrial stretch receptors that are responsible for the release of the atrial peptides become impaired, and it has been suggested that patient with heart failure may adapt to the physiologic effects of atrial natriuretic peptides. The possibility that congestive heart failure is in part a humoral disease is reviewed here and consequently pharmacologic treatment aimed at reducing the effects of the neuroendocrine response as to be advantageous for patients with heart failure.

Animals↗

PubMed1998

[Etiopathogenesis of acute myocardial infarction: role of early leukocytosis].

It has recently been suggested that inflammation may play an important role in the pathogenesis of acute ischemic syndromes. It may therefore be important to relate their clinical features with plasma indexes of inflammation. We have studied leukocyte, platelet and fibrinogen blood levels in 57 consecutive patients with acute myocardial infarction admitted to our Intensive Care Unit within 90 min after the onset of chest pain and treated with primary coronary angioplasty. Patients were divided into two groups on the basis of blood leukocyte levels: Group A, 24 patients, 17 males, mean age 54.2 +/- 13.7 years, with high blood leukocytes and Group B, 33 patients, 28 males, mean age 60.9 +/- 10.3 years, with normal blood leukocytes. Group A patients also had higher serum fibrinogen (p = 0.05) and blood platelet levels (p < 0.05). The stenosis observed after guidewire advancement was significant (> 75%) in 33% of the patients with leukocytosis vs 94% of the others (p < 0.01). No difference between the two groups was observed in the success rate of coronary angioplasty and prevalence of stent placement (100 vs 97%, and 43 vs 42% of the patients of Group A and B, respectively). In contrast, a tendency to rethrombosis requiring Rheopro administration was observed in 62% Group A patients vs 21% Group B patients (p < 0.01). In conclusion, the finding of leukocytosis in the acute phase of myocardial infarction suggests that coronary occlusion is mainly caused by a coronary thrombus occurring at the site of a non significant stenosis. In contrast, when blood leukocytes are normal, the underlying coronary stenosis is more often critical and the thrombotic process is less important. The high blood leukocytes, platelet and fibrinogen levels of Group A patients are consistent with a significant role of inflammation in the pathogenesis of the thrombotic process while hemodynamic and local mechanical factors are probably more important in patients with normal blood leukocytes.

Adult↗

PubMed1997

[Evolution in coronary stenting: use of ticlopidine with and without oral anticoagulants].

Implantation of intracoronary stents has been rapidly increasing in the last few years, especially after a reduction of restenosis has been shown. The main limitation in the use of coronary endoprosthesis is still represented by acute and subacute thrombosis. In order to limit this dangerous complication a very strong coagulant regimen, which has been improved since 1993-94, was initially recommended. We report our experience with patients who underwent a stent implantation comparing two therapeutic regimens with or without oral coagulants associated with antiplatelet agents. During 700 consecutive coronary angioplasties 128 Palamatz-Schatz and Wiktor stents have been implanted in 118 patents (16.9%). After stent implantation, 33 patients underwent a traditional anticoagulant therapy with heparin followed by oral anticoagulants for 3 months. They were also treated with ticlopidine 250 mg/die started 2 days before the procedure and then kept at least one month (group A). Eighty-five patients were treated only with antiplatelet therapy (ticlopidine 500 mg/die) started 2 days before implantation (group B). These two groups of patients were similar in age, sex, type and number of treated vessels and in diameter of the vessel with stent implantation. Subacute thrombosis rate was not significantly different between groups (3 vs 2.3%, NS). The predictive factors of thrombosis were acute myocardial infarction and implantation of multiple stents. No significant differences were found between thrombosis of the stents implanted in bail-out conditions compared to the elective ones. Ticlopidine started 2 days before stent implantation seems to be sufficient to limit thrombosis rate; moreover it allows a reduction of the hemorrhagic complications and hospitalization period.

Administration, Oral↗

PubMed1996

Metabolic adaptation during a sequence of no-flow and low-flow ischemia. A possible trigger for hibernation.

BACKGROUND: Myocardial hibernation is an adaptive phenomenon occurring in patients with a history of acute ischemia followed by prolonged hypoperfusion. METHODS AND RESULTS: We investigated, in isolated rabbit heart, whether a brief episode of global ischemia followed by hypoperfusion maintains viability. Four groups were studied; group 1,300 minutes of aerobia; group 2,240 minutes of total ischemia and 60 minutes of reperfusion; group 3, 10 minutes of total ischemia, 230 minutes of hypoperfusion (90% coronary flow reduction), and 60 minutes of reperfusion; and group 4, 240 minutes of hypoperfusion followed by reperfusion. In group 3, viability was maintained. Ten minutes of ischemia caused quiescence, a fall in interstitial pH (from 7.2 +/- 0.01 to 6.1 +/- 0.8), creatine phosphate (CP), and ATP (from 54.5 +/- 5.0 and 25.0 +/- 1.9 to 5.0 +/- 1.1 and 15.3 +/- 2.5 mumol/g dry wt, P < .01). Subsequent hypoperfusion failed to restore contraction and pH but improved CP (from 5.0 +/- 1.1 to 20.1 +/- 3.4, P < .01). Reperfusion restored pH, developed pressure (to 92.3%), and NAD/NADH and caused a washout of lactate and creatine phosphokinase with no alterations of mitochondrial function or oxidative stress. In group 4, hypoperfusion resulted in progressive damage. pH fell to 6.2 +/- 0.7, diastolic pressure increased to 34 +/- 5.6 mm Hg, CP and ATP became depressed, and oxidative stress occurred. Reperfusion partially restored cardiac metabolism and function (47%). CONCLUSIONS: A brief episode of total ischemia without intermittent reperfusion maintains viability despite prolonged hypoperfusion. This could be mediated by metabolic adaptation, preconditioning, or both.

Adaptation, Physiological↗

PubMed1996

Aorta and skeletal muscle NO synthase expression in experimental heart failure.

Nitric oxide (NO), the free radical that accounts for the biological activity of endothelium-derived relaxing factor, is synthesized from L-arginine by NO synthase (NOS). There is evidence that NO availability is reduced in the peripheral vasculature of patients with congestive heart failure (CHF). The aim of this study was to investigate the expression of NOS in the descending aorta and in the skeletal muscles of rats subjected to heart failure. The alkaloid, monocrotaline, was used to induce pulmonary hypertension and cardiac failure in rats. The expression of both the constitutive (ecNOS) and the inducible (iNOS) isoforms of the enzyme was assessed by Western blot analysis. In CHF animals, the ecNOS location in the aorta is altered: the endothelial protein expression is substantially reduced (from 0.083 +/- 0.012 to 0.003 +/- 0.004 OD/microgram total proteins, P < 0.001) whereas the expression of ecNOS in the smooth muscle is increased (from 0.024 +/- 0.004 to 0.059 +/- 0.009 OD/ microgram total proteins, P < 0.01). The total aortic ecNOS is diminished in CHF respect to control animals (0.062 +/- 0.009 v 0.107 +/- 0.013 OD/microgram total proteins, P < 0.01). On the contrary, no difference in ecNOS protein expression was observed in the extensor digitorum longus and soleus muscles. Furthermore, iNOS was not detected in any of the tissues considered. In conclusion, experimental CHF causes a re-setting of the ecNOS protein expression in the descending aorta but not in skeletal muscles. The reduced abundance of ecNOS in the aortic endothelium is consistent with the impairment of the vasodilating function reported in patients with CHF.

Animals↗

PubMed1996

Skeletal muscle metabolism in experimental heart failure.

We studied peripheral skeletal muscle metabolism in monocrotaline-treated rats. Two distinct groups emerged: a percentage of the animals developed ventricular hypertrophy, with no signs of heart failure (compensated group), whilst others, besides ventricular hypertrophy, developed the syndrome of congestive heart failure (CFH group). Oxidative metabolism and redox cellular state were expressed in terms of creatine phosphate, purine (ATP, ADP and AMP) and pyridine (NAD and NADH) nucleotides tissue content. Skeletal muscles with different metabolism were studied: (a) Soleus (oxidative), (b) extensor digitorium longus (glycolytic) and tibialis anterior (oxidative and glycolytic). The results showed that in CFH animals a decreased high-energy phosphates content occurs in the soleus and extensor digitorum longus, but not in the tibialis anterior. In the soleus. ATP declined from 20.31 +/- 2.5 of control group to 9.55 +/- 0.61 mumol/g dry wt. while in the extensor digitorum longus ATP declined from 30.92 +/- 2.68 to 22.7 +/- 1.54 mumol/g dry wt. In both these muscles, a shift of NAD/NADH couple towards oxidation was also observed (from 26.58 +/- 3.34 to 6.95 +/- 0.97 and from 18.88 +/- 3.43 to 10.57 +/- 1.61, respectively). These alterations were more evident in the aerobic soleus muscle. On the contrary, no major changes occurred in skeletal muscle metabolism of compensated animals. The results show that: (1) a decrease in muscle high-energy phosphates occurs in CFH; (2) this is accompanied by a decrease of NAD/NADH couple suggesting an impairment in oxygen utilization or availability.

Adenosine Diphosphate↗

PubMed1996

Is stunning an important component of preconditioning?

We tested the hypothesis that stunning following a brief period of ischaemia is a component of cardioprotection afforded by preconditioning in an in vitro model of global normothermic ischaemia. Isolated Langendorff-perfused rat hearts, after 120-150 min of aerobic perfusion, were divided into four groups. Groups 1 and 2 constituted the aerobic and ischaemic controls. The other hearts were preconditioned by two 2-min ischaemia/reperfusion cycles. Two ischaemic preconditioning protocols were used, the only difference being prolongation of the reperfusion cycle from 5 (group 3) to 20 min (group 4) before the onset of severe ischaemic insult. Mechanical function, energetic metabolism and the rate of enzyme release were followed throughout. In group 3, myocardial function remained significantly downregulated before the onset of severe ischaemia. This resulted in cardiac protection as evidenced by enhanced recovery of systolic pressure (37.7 +/- 3.6 v 61.9 +/- 5.7 mmHg for groups 2 and 3, respectively; P < 0.02), reduced rise in diastolic pressure (55.8 +/- 5.9 v 34.3 +/- 5.2 mmHg; P < 0.02), reduced creatine kinase (CK) release (957.3 +/- 175.7 v 541.5 +/- 85.9 mU/min/gww; P < 0.05) and higher contents of high-energy phosphate at the end of ischaemia [3.6 +/- 0.3 v 25.3 +/- 2.9 mumol/gdw for creatine phosphate (CP), P < 0.001] as well as after reperfusion (16.8 +/- 2.4 v 31.4 +/- 1.8 for CP, P < 0.01, and 3.9 +/- 0.5 v 6.2 +/- 0.8 mumol/gdw for ATP, P < 0.05). When severe ischaemia was started only after complete recovery of mechanical function (group 4), no protection was observed. Our data suggest that a decrease in mechanical function or stunning occurring after the short period of ischaemia causes ATP sparing and constitutes an additional mechanism of preconditioning cardioprotection in vitro.

Animals↗

PubMed1996

Activation of the neuroendocrine response in heart failure: adaptive or maladaptive process?

Congestive heart failure is a clinical syndrome in which the capacity of the heart to maintain cardiac output is impaired. As a consequence, blood pressure is threatened and endocrine and paracrine mechanisms are activated to preserve circulatory homeostasis and to maintain blood pressure. At terminal stages, a complex multiorgan syndrome develops with severe pump failure, intense systemic vasoconstriction, and avid water and sodium retention. Increasing evidence points to humoral circulating or locally synthesized substances as one of the causes of the terminal consequences of heart failure. Therefore, the hypothesis that the syndrome of heart failure is, at least in part, a humoral disease has developed and is obtaining scientific credibility. Consequently, the neuroendocrine response to heart failure is no longer viewed as a compensatory beneficial mechanism. Instead, we have learned through the years that pharmacological treatment aimed at reducing the effect of the neuroendocrine response is indeed clinically and prognostically advantageous for the patient.

Adaptation, Physiological↗

PubMed1996

Cardioprotective effect of angiotensin-converting enzyme inhibitors in patients with coronary artery disease.

Clinical and experiments study with angiotensin-converting enzyme (ACE) inhibitors suggest that these agents may improve coronary artery disease by acting at multiple sites in the series of events leading to end-stage heart disease. These agents reduce blood pressure, improve prognosis and symptoms in patients with severe heart failure and in patients after acute myocardial infarction with left ventricular dysfunction. They are useful in the early, acute phase of myocardial infarction. More recently, ACE inhibitors have been shown to reduce in vitro vascular hypertrophy, to attenuate arteriosclerosis, and to maintain endothelium function. Whether these effects occur at clinical levels is still uncertain. The exciting clinical data have led to the proposal that alteration of ACE activity, particularly in tissue, is an important factor in development and progression of CAD. The ACE system is complex, with endocrine, paracrine, and autocrine effects. ACE is present in cardiac and vascular tissue. Therefore, the beneficial effects of ACE inhibitors can be classified as "cardio" and "vasculo" protective. This article summarizes a number of independent and complementary mechanisms pointing to a role of ACE and ACE inhibition in coronary artery disease.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Continuous versus intermittent warm blood cardioplegia: functional and energetics changes.

BACKGROUND: The aim of this study was to compare the protective effects of continuous warm blood cardioplegia (CWBC) and intermittent warm blood cardioplegia (IWBC) in an experimental model of blood-perfused, isolated rabbit heart. METHODS: In the CWBC group, cardiac arrest was induced by continuous infusion of blood cardioplegia (10 mEq/L KCl) followed by 30 minutes of reperfusion with blood. In the IWBC group, after 5 minutes of perfusion with blood cardioplegia (10 mEq/L KCl), coronary flow was abolished for 10 minutes, followed by reperfusion with blood cardioplegia for 5 minutes. This sequence was repeated three times for a total period of 45 minutes. Finally the hearts were reperfused for 30 minutes with blood. RESULTS: Infusion of potassium induced a marked increase in coronary perfusion pressure (from 50 +/- 3 to 98 +/- 1 mm Hg; p < 0.01), which remained elevated throughout in the CWBC group, whereas in the IWBC group, it dropped to 0 during each no-flow period. In both groups, cardioplegia resulted in a significant reduction in oxygen consumption (from 5.5 +/- 0.2 to 0.6 +/- 0.03 mL O2.min-1.100 g-1 wet wt; p < 0.01). During CWBC, glucose extraction was significantly reduced (from 152 +/- 10 to 64 +/- 18 micrograms.min-1.g-1 wet wt; p < 0.01). Free fatty acid uptake and creatine kinase and lactate release were not affected. During IWBC, in contrast, a transient but significant release of creatine kinase (from 643 +/- 254 to 2,234 +/- 296 mU.min-1.g-1 wet wt; p < 0.01) and lactate (from 63 +/- 22 to 374 +/- 32 micrograms.min-1.g-1 wet wt; p < 0.01) occurred after each period of ischemia. Despite these metabolic differences, both cardioplegic procedures allowed a prompt and complete recovery of mechanical function and tissue content of high-energy phosphates. CONCLUSIONS: Both CWBC and IWBC exert optimal protection in the isolated blood perfused rabbit heart. Thus, IWBC can be safely used to improve visualization of the surgical field.

Adenine Nucleotides↗

PubMed1996

Left ventricular dysfunction due to the new ischemic outcomes: stunning and hibernation.

Several potential manifestations and outcomes are associated with myocardial ischemia and reperfusion. When ischemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. When ischemia is less severe or shorter in duration, recovery of contraction may occur instantaneously or more commonly, after considerable delay, which is the condition recognized as "stunned myocardium." Stunning is defined as a transient left ventricular dysfunction that persists after reperfusion despite the absence of irreversible damage and restoration of normal or near-normal coronary flow. Oxidative stress and alteration of calcium homeostasis during reperfusion are the probable causes of stunning. Clinically, stunning may occur after acute infarction, successful thrombolysis, unstable angina, angioplasty, resolution of coronary spasm, open-heart surgery, or transplantation. It can be treated with interventions aimed at prevention or reversal. When ischemia is prolonged but less severe, myocytes may remain viable but exhibit depressed contraction. Under these conditions, reperfusion restores normal contractile performance. This type of ischemia, leading to a reversible, chronic left ventricular dysfunction, has been termed "hibernating myocardium." The intrinsic mechanisms of this condition are unknown. Clinically, it is very important to diagnose hibernation because reperfusion of the hibernating myocardium by angioplasty or heart surgery restores contraction, and this correlates with long-term survival. A number of methods are available to access the hibernating myocardium. These include cardiac imaging techniques that evaluate myocardial viability, such as positron emission tomography and thallium myocardial imaging, or methods that evaluate contractile reserve, such as low-dose dobutamine echocardiography. Interestingly, reperfusion of patients with end-stage ischemic cardiomyopathy and hibernating myocardium can be considered an alternative to transplantation.

Cardiomyopathies↗

PubMed1996

[Activation and role of the tumor necrosis factor-alpha in congestive heart failure].

Recently, an activation of the immune system has been demonstrated in congestive heart failure (CHF). Aim of this study was to evaluate the effects of CHF on the activation of alpha tumor necrosis factor (TNF-alpha), a pleiotropic cytokine. Since the soluble forms of the TNF membrane receptors, sTNF-RI and sTNF-RII, have been shown to modulate TNF-alpha biological activity, we determined antigenic TNF-alpha, bioactive TNF-alpha, sTNF-RI and sTNF-RII in 52 patients with varying degrees of CHF (NYHA functional class II, III, IV). The etiology of CHF was coronary artery disease in 51% of the patients, idiopathic dilated cardiomyopathy in 38% and valvular disease in 11%. All patients were treated with ACE-inhibitors, digoxin and inotropic agents. Antigenic TNF-alpha was significantly increased in NYHA functional class IV patients (from 12.1 +/- 7.6 to 38.5 +/- 12.4 pg/ml, p < 0.001) whereas cytotoxic activity was always under the detection limit of the assay (100 pg/ml). Soluble TNF receptors were significantly elevated in NYHA functional class IV patients: sTNF-RI increased from 1.27 +/- 0.48 to 4.54 +/- 2.11 ng/ml (p < 0.001) and sTNF-RII from 2.25 +/- 0.55 to 7.78 +/- 2.13 ng/ml (p < 0.001). The possible modulation of TNF-alpha biological activity by the soluble receptors was investigated by means of spiking experiments after addition of 625 pg/ml human recombinant TNF-alpha to each serum sample. The biological activity of the added TNF-alpha was significantly inhibited by the high levels of soluble receptors present in the sera of NYHA functional class IV patients (from 625 to 249 +/- 176 pg/ml, p < 0.001). The results show that TNF-alpha and its soluble receptors are activated in severe CHF. The high concentration of soluble TNF receptors circulating in CHF patients are likely to play a protective role against TNF-alpha biological activity.

Aged↗

PubMed1996

Right heart failure chronically stimulates heat shock protein 72 in heart and liver but not in other tissues.

OBJECTIVES: During cardiac failure several ontogenically developed adaptional mechanisms are activated. Among these, heat-shock proteins (HSP) are expressed in response to stress. The aim of the present study was to investigate the HSP72 protein expression in lungs, liver, cardiac and skeletal muscles during congestive heart failure (CHF). METHODS: CHF was induced in Sprague-Dawley rats by a single intraperitoneal injection of monocrotaline (50 mg/kg). Two groups of animals emerged: a CHF group (n = 10) with right ventricular hypertrophy, pleural and peritoneal effusions, and an Hypertrophy group (n = 12) with right ventricular hypertrophy without CHF. The data for each group were compared with those of control (saline infused) age-matched rats. Lungs, liver, right and left ventricles, soleus, extensor digitorum longus and tibialis anterior muscles were excised and analyzed for HSP72 concentration by Western blot analysis using a specific monoclonal antibody. Noradrenaline levels in the heart were also measured using HPLC. RESULTS: The CHF group showed: (1) reduced right (0.460 +/- 0.090 vs 0.830 +/- 0.070 nmol/ventricle, P < 0.01) and left (1.10 +/- 0.09 vs 2.10 +/- 0.130 nmol/ventricle, P < 0.001) ventricular content of noradrenaline compared to the control; (2) significant activation of HSP72 concentration in right and left ventricles (39.4 +/- 1.6 vs 5 +/- 0.9% and 13 +/- 1.2 vs 3.5 +/- 0.6%, P < 0.001 both) and in the liver (39.8 +/- 11 vs 6 +/- 2%, P < 0.001); (3) no modification in HSP72 concentration in lungs and all of the peripheral muscles considered. The Hypertrophy group showed: (1) unchanged total noradrenaline tissue content as compared to the control; and (2) unmodified HSP72 concentration in all tissues analyzed. CONCLUSIONS: The present study demonstrates that CHF, but not compensatory hypertrophy, is a specific stimulus for chronic HSP72 induction in the heart and liver. On the contrary, CHF does not affect HSP in lungs and peripheral muscles. HSP 72 induction represents an intracellular marker of stress reaction which can persist chronically.

Animals↗

PubMed1995

In vitro administration of ergothioneine failed to protect isolated ischaemic and reperfused rabbit heart.

Ergothioneine, a natural thiol-containing molecule, has recently been proposed to protect the heart against damage caused by ischaemia and reperfusion. We investigated the possibility that ergothioneine can have a role in maintaining the myocardial thiol/disulfide balance and consequently also a protective effect against ischaemic and reperfusion injury. We used isolated Langendorff-perfused rabbit hearts subjected to 45 min global and total ischaemia followed by 30 min reperfusion at baseline coronary flow (22 ml/min). Ergothioneine was delivered at 10(-5) M and 10(-4) M 60 min before ischaemia and during reperfusion. Myocardial damage was determined in terms of mechanical function, creatine kinase (CK) and lactate release, energy phosphate stores and the occurrence of oxidative stress. In our experimental conditions the treatment was unable to prevent myocardial damage. Ergothioneine, independently from the dosage used, failed to: (i) increase recovery of developed pressure upon reperfusion (14.4 +/- 2.3 mmHg in control hearts vs. 10.3 +/- 2.9 and 12.5 +/- 2.3 mmHg in 10(-5) M and 10(-4) M ergothioneine treated hearts, respectively); (ii) decrease the rise in diastolic pressure (44.3 +/- 4.4 mmHg in control hearts vs. 49.8 +/- 5.8 and 48.0 +/- 7.7 mmHg in treated hearts); (iii) decrease the release of CK and lactate; (iv) increase the levels of adenosine triphosphate (ATP) and creatine phosphate (CP) in tissue upon reperfusion; (v) maintain ratio between oxidized and reduced forms of adenine nucleotide coenzyme, as index of aerobic metabolism; (vi) prevent the decline of reduced glutathione (GSH), or the accumulation of oxidized glutathione (GSSG) as an index of oxidative stress.

Adenine Nucleotides↗

PubMed1995

Intermittent v continuous ischemia decelerates adenylate breakdown and prevents norepinephrine release in reperfused rabbit heart.

Myocardium tolerates intermittent ischemia followed by short reperfusions better than continuous ischemia of the same duration. We attempted to delineate the differential mechanism(s) involved in intermittent v continuous ischemia. Isolated, paced rabbit hearts were perfused at 22 ml/min. Coronary flow was stopped intermittently 12 x for 2 or 4 min, with 3-min reperfusions (total reperfusion period: 36 min). In two other groups, flow was stopped continuously for 24 or 36 min followed by a flat 36-min reperfusion. Following the first intermittent 2-min ischemia, adenosine efflux increased ninefold; in all subsequent ischemia/reperfusion cycles, adenosine and total purine releases were substantially less despite identical heart rates, coronary flows and ischemic periods. The rate-pressure product prior to the intermittent ischemias exhibited exponential correlations with total purine efflux during the 3 min of reperfusion. When intermittent ischemia was extended to 4 min, the initial attenuation of ATP breakdown during the prior 2-min occlusions was overcome, but during subsequent 4-min ischemia/reperfusion cycles, ATP breakdown was again attenuated relative to the first 4-min ischemia. After the prolonged continuous ischemias, purine efflux was up to 6 x higher than with intermittent ischemias of the same total time of zero flow. Lactate release and hence cellular H+ export after intermittent ischemias remained consistently elevated, but following the continuous ischemia of 36 min, release of lactate, and thus H+, was subsequentially decreased. Glycogen mobilization occurred regardless of the ischemia's nature, but it was markedly enhanced during continuous ischemias, where no fall in proglycogen levels occurred. Similarly, myocardial norepinephrine release increased substantially only during the prolonged continuous ischemias. Thus short intermittent ischemia attenuates cardiac adenylate degradation and glycogen mobilization; such ischemic insult also provides for better lactate and H+ washouts immediately upon reperfusion. Another beneficial effect of intermittent ischemia was the near-complete absence of free interstitial norepinephrine, which exacerbates myocardial ischemic insults. In addition, the exponential correlations between preischemic rate-pressure product and postischemic purine release suggest that preischemic energy demand may determine ATP breakdown in ischemic rabbit myocardium.

Adenine Nucleotides↗