Myocardial Catecholamine Depletion Research Articles

Different effects of long- and short-acting loop diuretics on survival rate in Dahl high-salt heart failure model rats

We compared therapeutic effects of furosemide, a short-acting loop diuretic, and azosemide, a long-acting one, in hypertensive heart failure rats to test the hypothesis that long-acting diuretics are superior to short-acting types in heart failure. Dahl salt-sensitive rats fed an 8% NaCl diet from age 8 weeks were divided at age 21 weeks (compensated hypertrophic stage) into three groups: rats treated with furosemide (40 mg/kg/day), those treated with azosemide (80 mg/kg/day) and untreated rats. Rats fed a 0.3% NaCl diet served as controls. Both medications prevented left ventricular systolic dysfunction and enlargement at age 31 weeks, and attenuated macrophage infiltration, reactive oxygen species generation, and gelatinolytic activity to the same degree. Azosemide suppressed left ventricular fibrosis to the control level, but furosemide did not. Azosemide ameliorated myocardial catecholamine depletion and improved survival rate. Furosemide increased plasma norepinephrine levels and did not exert such beneficial effects. Azosemide provided better prognosis in heart failure rats compared with furosemide, partly through attenuation of the reflex increase in cardiac sympathetic neuronal activity caused by the development of heart failure. The current findings suggest a need for clinical trials examining whether long- and short-acting diuretics provide a different prognosis in patients with heart failure.

Mechanoelectrical feedback: role of beta-adrenergic receptor activation in mediating load-dependent shortening of ventricular action potential and refractoriness.

Augmented preload increases myocardial excitability by shortening action potential duration (APD). The mechanism governing this phenomenon is unknown. Because myocardial stretch increases intracellular cAMP, we hypothesized that load-dependent changes in myocardial excitability are mediated by beta-adrenergic stimulation of a cAMP-sensitive K(+) current. The effects of propranolol on load-induced changes in electrical excitability were studied in 7 isolated ejecting canine hearts. LV monophasic APD at 50% and 90% repolarization (MAPD(50) and MAPD(90)) and refractoriness were determined at low (9+/-3 mL) and high (39+/-4 mL) load before and after beta-adrenergic blockade. During control, the MAPD(50) decreased from 193+/-26 to 184+/-26 ms with increased load, as did the MAPD(90) (238+/-28 to 233+/-28 ms), P</=0.04. Similar changes were observed in ventricular refractoriness. Treatment with propranolol completely abolished these load-induced effects. Myocardial catecholamine depletion with reserpine in 2 hearts also abolished changes in MAPD and excitability in response to increased preload. Increases in ventricular load mediate a decrease in ventricular APD and refractoriness through activation of the beta-adrenergic receptor. An increase in a cAMP-mediated K(+) current, possibly the slowly activating delayed rectifier I(Ks), may account in part for this form of mechanoelectrical coupling.

Chronic catecholamine depletion switches myocardium from carbohydrate to lipid utilisation.

Chronic cardiac transplantation denervation (i.e., global sympathetic denervation with myocardial catecholamine depletion, plus parasympathetic denervation) is known to inhibit myocardial oxidation of glucose. It is not known whether this is due to increased utilization of lactate, lipid or ketone bodies. The purpose of the present study was to test the hypothesis that the extraction and contribution of blood-borne fatty acids (FA) to overall oxidative energy conversion is increased. In anaesthetised dogs (control n = 6, cardiac denervated n = 6), we investigated fatty acid (FA) utilization. The studies were made at least four weeks after surgical cardiac denervation. Measurements were made of total FAs and with a radio-labelled tracer (U-14C palmitate). The contribution of FA utilisation to overall substrate oxidation rose from 31% (control) to 48% (cardiac denervated). The increase in the ratio (%) of CO2 production from palmitate oxidation to total CO2 production increased from 4.0 +/- 1.8 (control) to 10.6 +/- 5.8 (denervated, p = 0.04). The time from uptake of FA to release of CO2 product was unaltered. We conclude that the contribution of FA oxidation to overall energy conversion is increased in chronically denervated hearts, which is postulated to result from a decline in the active form of pyruvate dehydrogenase. This would appear to be a result of chronic catecholamine depletion.

Dopaminergic responses in the Fischer 344 rat heart: preserved chronotropic and dromotropic responses with aging.

Marked decreases in cardiac responses to beta-adrenergic stimuli have been found in cellular, animal, and human models of physiologic aging. As another probe of receptor-regulated cardiovascular changes with aging, responses to dopamine were studied. Responses were studied with and without depletion of myocardial catecholamines to eliminate effects secondary to myocardial catecholamine release. Responses of heart rate (A-A intervals), atrioventricular conduction (AV intervals and AV Wenckebach block cycle length) to 0-50 microM dopamine were studied in Langendorff perfused hearts from 10 mature (6.2 +/- 0.8 mo, mean +/- SD) and 9 senescent (23.6 +/- 0.7 mo) Fischer 344 rats and in hearts from 10 mature (5.3 +/- 0.4 mo) and 8 senescent (23.9 +/- 0.8) Fischer 344 rats after myocardial catecholamine depletion by reserpine (0.25 mg/kg i.p. x 5 days). Dopamine decreased A-A (p < .0001) and AV conduction intervals (p < .0001) and increased peak developed pressure (p < .0001) and dP/dt (p < .001) in hearts from nonreserpine treated mature and senescent rats. Greater decreases in A-A intervals and AV conduction were seen in senescent compared to mature hearts (p < .0001). Contractile responses were greater in mature hearts (p < .001). After reserpine, A-A interval and paced AV conduction dose vs response relationships shifted rightward (p < .0001), but peak responses and age-related differences in responses were not significantly affected. In contrast, increases in peak developed pressure were greatly reduced in mature hearts (p < .0001) and age-related differences in contractile responses to dopamine were eliminated in hearts from reserpine-treated rats. (a) A-A interval and AV conduction responses to dopamine were greater in senescent hearts even after catecholamine depletion, suggesting age-related differences in sinus and AV nodal responses to direct dopaminergic stimuli exist. (b) Age-related differences in contractile responses to dopamine were eliminated by reserpine suggesting basal age-related differences in response were secondary to age-related differences in responses to myocardial catecholamine release.

Myocardial ischaemia induces platelet activation with adverse electrophysiological and arrhythmogenic effects.

The aim was to investigate how platelet activation during myocardial ischaemia can induce electrophysiological and arrhythmogenic effects, and examine the involvement of different platelet membrane receptors in producing these effects. Transmembrane action potentials and electrograms were recorded from isolated, Langendorff perfused guinea pig hearts during normal perfusion, global myocardial ischaemia, and reperfusion during infusion of human platelets. Platelet reactivity was altered by treating platelets with forskolin, aspirin, the platelet activating factor (PAF) receptor antagonist BN 52021, the thromboxane A2 (TP) receptor antagonist GR 32191B, and the alpha 2 adrenoceptor antagonist yohimbine. Myocardial catecholamine depletion was induced by treatment with 6-hydroxydopamine. Platelet infusion had no electrophysiological effects during normal perfusion, but during ischaemia it enhanced the reduction in action potential duration at 95% repolarisation [APD95, 110(SEM 3) ms v 121(5) ms, p < 0.05, at 15 min] and increased the incidence of ventricular arrhythmias (from 56% to 94%, p = 0.04) compared to hearts receiving buffer but no platelets. The reductions in APD95 and the arrhythmogenic effects were attenuated when forskolin treated, aspirin treated or GR 32191B treated platelets were infused (VF: 50% v 94%, p = 0.03; 50% v 94%, p = 0.02; 22% v 94%, p < 0.001, respectively). Similar results were obtained when normal platelets were infused into catecholamine depleted hearts (VF: 60% v 94%, p = 0.0549). These differences were associated with inhibited aggregatory responses to thrombin (for forskolin treated platelets) and the thromboxane mimetic U44069 (for GR 32191B treated platelets). Yohimbine was antiarrhythmic in the presence and absence of platelets, suggesting direct myocardial effects, but BN 52021 had no antiarrhythmic effects. Myocardial ischaemia causes platelet activation resulting in electrophysiological and arrhythmogenic effects. PAF receptor antagonism does not prevent these effects, but inhibition of platelet reactivity, platelet thromboxane receptor antagonism, and myocardial catecholamine depletion are effective. These findings suggest that the arrhythmogenic effects of platelet activation during myocardial ischaemia are principally mediated by a thromboxane dependent mechanism, while catecholamine release has a contributory role.

I‐123 metaiodobenzylguanidine—thallium‐201 mismatch following myocardial infarction

Experimental data show that myocardial infarction (MI) results in regional depletion of myocardial catecholamines more extensively than necrosis. To investigate the extent of adrenergic denervation post MI in humans, we examined 16 patients, 59 +/- 12 years old, with recent (7-12 days) MI. Resting thallium-201 (201Tl) single photon emission computerized tomography (SPECT) imaging was performed to assess necrosis; metaiodobenzylguanidine I123 (MIBG) SPECT was used to evaluate adrenergic denervation. 201Tl and I123 MIBG defects were evaluated quantitatively using polar maps, and differences in defects were expressed as percent of total polar map. In all patients, I123 MIBG defect was larger than 201Tl defect, and difference ranged from 19 to 61% (39.5 +/- 13.2%). Thrombolysis and age > 60 did not influence the difference. Anterior MI showed larger differences (44 +/- 13 vs. 32 +/- 11%, p < 0.05); patients with ischemic electrocardiographic (ECG) changes in leads without abnormal Q waves had larger differences (45 +/- 9 vs. 33 +/- 14%, p < 0.05). It was concluded that (a) patients with recent MI present denervation larger than 201Tl perfusion defect, and (b) patients with anterior MI and ischemic ECG changes present a larger area of denervation.

Myocardial contractile actions of endothelin-1 in rat and rabbit papillary muscles. Role of endocardial endothelium.

The actions of endothelin on the contractile and twitch configuration characteristics of rat and rabbit papillary muscles were evaluated before and after endocardial endothelium removal. In rabbit papillary muscles, endothelin produced a dose-dependent (10(-11) to 10(-7) M) increase in tension (T) (from 2.7 +/- 0.2 to 8.9 +/- 0.7 g/mm2, p less than 0.01), dT/dt, and Vmax (from 1.14 +/- 0.03 to 3.0 +/- 0.13 Lmax/sec, p less than 0.01), a decrease in time to peak tension (from 251 +/- 9 to 216 +/- 7 msec, p less than 0.05), and an increase in time to half relaxation (from 168 +/- 9 to 293 +/- 14 msec, p less than 0.01). Increasing calcium concentration in the bath from 1.25 to 15 mM greatly attenuated these changes. In the presence of propranolol (10(-5) M), endothelin increased all indexes of contractility but to a lesser extent (T = 2.6 +/- 0.3 to 6.5 +/- 0.2 g/mm2, p less than 0.01; Vmax = 1.16 +/- 0.10 to 2.06 +/- 0.10 Lmax/sec, p less than 0.01). Myocardial catecholamine depletion with reserpine had effects similar to those of propranolol. The myocardial contractile and twitch configuration characteristics of endothelin were similar to those of phenylephrine (10(-4) M), a strong stimulator of the phosphatidylinositol pathway and a moderate beta-adrenergic stimulator. The effects of phenylephrine and endothelin were modified in a similar manner by propranolol (10(-5) M). The presence of nicardipine (3 X 10(-7) M) decreased the absolute increase in contractility caused by endothelin but did not alter the percent change or shift the dose-response curve of endothelin. The actions of endothelin in rat papillary muscles studied at physiological calcium concentrations (Ca2+ = 1.25 mM) were less marked than those of rabbit studied at physiological calcium (Ca2+ = 1.25 mM) but similar to those of rabbit studied at high calcium concentrations (Ca2+ = 15 mM). Removing the endocardial endothelial layer of rabbit papillary muscles did not alter the absolute changes in contractility caused by endothelin but shifted the dose-response curve to the left and markedly altered the effects of endothelin on twitch configuration characteristics. Thus, it would appear that endothelin increases contractility and modifies twitch configuration. It does so more at lower rather than higher extracellular calcium concentrations and in a species, such as rabbit, that responds more to interventions that increase intracellular calcium.(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic doxorubicin induced cardiomyopathy in rabbits: mechanical, intracellular action potential, and adrenergic characteristics of the failing myocardium

The aim was to assess myocardial, electrophysiological, and adrenergic changes caused by chronic administration of doxorubicin. Doxorubicin induced cardiotoxicity was produced in three groups of rabbits by injecting doxorubicin 0.75 mg.kg-1 three times a week for 7, 9 and 11 weeks. There were 36 controls. All studies were conducted within 16 to 36 h after the last injection. Histological, mechanical, and action potential changes produced by doxorubicin were examined in vitro. The effects of doxorubicin on beta adrenergic receptors and cyclic adenosine monophosphate (AMP) generation in myocardial membrane preparations were also evaluated. 145 New Zealand white rabbits, 2.4-2.7 kg, were used. After excision of the heart, a papillary muscle was used for mechanical studies, a portion of the septum for intracellular action potential studies, and the rest of the heart for histological or biochemical studies. Histological studies showed widespread myocardial damage that became more severe as the cumulative doses increased. Right ventricular papillary muscles of doxorubicin treated rabbits had lower total tension (1.5 v 3.3 g.mm-2 for controls, p less than 0.05) and dT/dt, shorter contraction duration, and lower velocity of shortening than the control muscles under all loading conditions. The changes progressed as the cumulative doxorubicin dose increased. Action potential duration was shorter in the doxorubicin treated groups (APD50 = 76 v 62 ms for controls, p less than 0.01), although resting action potential amplitude was normal. Tension-frequency response (6-36 stimuli.min-1) and response to increasing calcium concentrations (2.54-6.32 mM) were attenuated in the doxorubicin group. Percent change in tension and dT/dt in response to noradrenaline (50 microM), isoprenaline (20 microM), or dibutyryl cyclic AMP (40 mM), was increased in the doxorubicin group v controls (300-600% v 100-200% respectively), despite chronic increase in circulating catecholamines, depletion of myocardial catecholamines, and no change in beta adrenergic receptor number or affinity. The apparent increase in beta adrenergic responsiveness in the doxorubicin group may have been partly due to decreased basal cyclic AMP production (13 v 31 pMol.mg-1 protein.min-1, p less than 0.01), although maximum catecholamine stimulated cyclic AMP production was only mildly decreased (251 v 315 pMol.mg-1 protein.min-1, p less than 0.05). CONCLUSIONS - The subacute effects of chronic doxorubicin become progressively more marked as the cumulative dose increases, and there are significant differences in the myocardial characteristics between this chronic model and other models of heart failure. These differences may be related to the cytotoxic effects of doxorubicin on membranes and membrane bound enzymes.

Arrhythmias and mortality in congestive heart failure

The extent and severity of myocardial dysfunction and risk of dying are associated with the occurrence of ventricular arrhythmias. However, there is a dissociation between the frequency of ventricular arrhythmias and the prevalence of sudden death among patients with congestive heart failure. Sudden death occurs in 8 to 10% of New York Heart Association functional class I patients and in 20% of class II, III and IV patients, despite increased frequency of malignant arrhythmias and functional deterioration. Yearly mortality rates increase from 12 to 15% in class I and II and is 60% in class IV. Sudden death in class I and II is 50 to 60% of all deaths, whereas in class IV it amounts to only 20 to 30%. The most important cause of death in class IV is progressive congestive heart failure. Ventricular arrhythmia is a trigger event in the development of fatal arrhythmia which depends on a substrate of myocardial scar tissue, hypertrophy and aberrant conducting pathways. However, regional myocardial ischemia, transmembrane electrolyte differences and myocardial stores of catecholamines are important modulators. Depletion of myocardial catecholamines and down-regulation of myocardial β-adrenergic receptors in the myocardium may explain tolerance to ventricular tachyarrhythmias observed in patients with severe congestive heart failure and intolerance to conventional antiarrhythmic drugs. Although angiotensin-converting enzyme (ACE) inhibitors may reduce ventricular arrhythmias, the important role of ACE inhibitors in severe congestive heart failure is to prevent progression of myocardial dysfunction and congestive heart failure. To date, however, ACE inhibitors have not been demonstrated to have a significant effect on the incidence of sudden death. This does not preclude an effect on fatal arrhythmias among patients with milder heart failure and intact stores of myocardial catecholamines.

Antiarrhythmic and electrophysiological effects of alpha adrenoceptor blockade during myocardial ischaemia and reperfusion in isolated guinea-pig heart

An isolated buffer perfused guinea-pig heart preparation has been used to study the antiarrhythmic and cellular electrophysiological effects of alpha adrenoceptor blockade during myocardial ischaemia and reperfusion. Phentolamine 5 X 10(-6) M and indoramin 2 X 10(-6) M significantly reduced the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) during ischaemia and reperfusion. Both drugs prolonged action potential duration (APD) and refractory period and reduced Vmax during normal perfusion and these effects were maintained during ischaemia. Reperfusion led to prompt recovery in all hearts but with initial transient shortening of APD. Phentolamine and indoramin abolished shortening of the APD whether added prior to ischaemia or immediately prior to reperfusion, and attenuated the reduction in refractory period, due to higher values at the end of ischaemia. Myocardial catecholamine depletion also significantly reduced ventricular tachycardia and ventricular fibrillation during ischaemia and reperfusion. Catecholamine depletion had similar effects on APD, refractory period and conduction, but phentolamine produced no additional effects when added to catecholamine depleted hearts suggesting that the effects observed here are mediated via adrenergic rather than direct myocardial effects.

Electrophysiological Effects of α-Adrenoceptor Stimulation in Normal and Ischemic Myocardium

To investigate the mechanism by which alpha-adrenoceptor blocking drugs prevent ventricular arrhythmias associated with myocardial ischaemia and reperfusion, we studied the effects of alpha blockade, alpha-adrenoceptor agonists, and myocardial catecholamine depletion on arrhythmias and cellular electrophysiology during ischaemia and reperfusion in isolated perfused guinea pig hearts. Perfusion with phentolamine or indoramin significantly reduced ventricular tachycardia (VT) and ventricular fibrillation (VF) during ischaemia and reperfusion, and phentolamine was equally effective during reperfusion when added at the end of ischaemia. Both drugs prolonged action-potential duration (APD) and refractory period during ischaemia and reperfusion, and studies with phentolamine, in catecholamine-depleted hearts, indicated that its action was related to the presence of catecholamines. Myocardial catecholamine depletion also significantly reduced VT and VF during ischaemia and reperfusion. Perfusion with an alpha 1-adrenoceptor agonist, however, significantly reversed this antiarrhythmic effect, increasing the incidence of VT and VF during ischaemia and reperfusion. This arrhythmogenic effect was associated with a reduction in APD and refractory period, i.e., a reversal of the electrophysiological effects of catecholamine depletion. These results indicate that alpha-adrenoceptor stimulation is arrhythmogenic during myocardial ischaemia and reperfusion, and that the antiarrhythmic action of alpha-adrenoceptor antagonists is mediated via adrenergic rather than direct myocardial effects.

The deleterious effects of myocardial catecholamines on cellular electrophsiology and arrhythmias during ischaemia and reperfusion

Action potentials and ECGs were recorded from Langendorff perfused guinea pig hearts during ischaemia and reperfusion. Arrhythmias were significantly more frequent during low flow (10% of control) than zero flow ischaemia and were most frequent during reperfusion following 30 minute ischaemia. Arrhythmias during low flow ischaemia were preceded by spontaneous recovery in action potential amplitude and Vmax and marked shortening of refractory period which did not occur during zero flow ischaemia. Reperfusion VF was always preceded by further shortening of the action potential. Myocardial catecholamine depletion, by pre-treatment with 6-hydroxydopamine significantly reduced the incidence of arrhythmias during ischaemia and reperfusion. Catecholamine depletion blunted the ischaemia-induced reduction in action potential amplitude and Vmax, prevented any spontaneous recovery and abolished reperfusion induced shortening of action potential duration. Methoxamine given to catecholamine-depleted hearts, having only minor effects during normal perfusion, significantly reversed the anti-arrhythmic and electrophysiological effects of catecholamine depletion during ischaemia and reperfusion. Phentolamine and propranolol in anti-arrhythmic concentrations, profoundly modified the electrophysiological effects of ischaemia and reperfusion. These results suggest that release of endogenous myocardial catecholamines contributes through alpha and beta-adrenoceptor stimulation to the electrophysiological changes and arrhythmias during myocardial ischaemia and reperfusion.

Effects of myocardial catecholamine depletion on cellular electrophysiology and arrhythmias during ischaemia and reperfusion.

The effect of myocardial catecholamine depletion on cellular electrophysiology and arrhythmias was assessed in Langendorff perfused guinea pig hearts during ischaemia and reperfusion. Myocardial noradrenaline was reduced to 0.17 +/- 0.04 microgram X g-1 by intracardiac injection of 6-hydroxydopamine (450 mg X kg-1 in six doses over 20 days) compared with 1.5 +/- 0.2 microgram X g-1 in vehicle injected controls. Myocardial catecholamine depletion significantly reduced the incidence of ventricular tachycardia and fibrillation during 30 min of global ischaemia and subsequent reperfusion. Myocardial catecholamine depletion prolonged action potential duration and refractory period during control perfusion and blunted ischaemia induced reduction in action potential amplitude, Vmax, and duration, but accentuated the prolongation in conduction time and QRS width. Catecholamine depletion abolished or attenuated reperfusion induced shortening of action potential duration and refractory period. Catecholamine depletion increased myocardial glycogen levels from 2.47 +/- 0.3 mg X g-1 wet weight to 4.39 +/- 0.3 mg X g-1; fasting animals for 48 h prior to study reversed this with no attenuation of the electrophysiological or antiarrhythmic action. These results provide further evidence that release of endogenous myocardial catecholamines contributes to the electrophysiological changes and arrhythmias associated with myocardial ischaemia and reperfusion.

Effect of chronic cardiac denervation on arrhythmias after coronary artery ligation.

Extrinsic cardiac denervation protects animals from fatal arrhythmias after coronary artery ligation and no change in heart rate or blood pressure is noted. Adequate time must elapse after surgical denervation for myocardial catecholamine depletion or arrhythmias will occur. Reserpine pre-treatment plus cervical vagotomy reduces the incidence of ventricular fibrillation. The relationship between myocardial catecholamines and arrhythmias is discussed.

Influence of Myocardial Catecholamines on the Cardiac Action of Ouabain

Toxic and lethal doses of ouabain and concomitant changes in myocardial contractility were determined in reserpine-pretreated and control cats. Reserpine pretreatment did not diminish the degree of myocardial contractility induced by ouabain. The effect of reserpine pretreatment on the toxicity of ouabain depended upon the manner in which the glycoside was administered and the physiological state of the preparation. Depletion of myocardial catecholamines by reserpine led to decreased cardiac glycoside toxicity when the ouabain was administered in the form of intermittent infusions into intact animals. However, pretreatment with reserpine did not alter appreciably the toxicity of ouabain when the drug was continuously infused into open-chest animals. Ouabain per se tended to have little effect on myocardial catecholamine content. Toxic and lethal doses of ouabain and concomitant changes in myocardial contractility were determined in reserpine-pretreated and control cats. Reserpine pretreatment did not diminish the degree of myocardial contractility induced by ouabain. The effect of reserpine pretreatment on the toxicity of ouabain depended upon the manner in which the glycoside was administered and the physiological state of the preparation. Depletion of myocardial catecholamines by reserpine led to decreased cardiac glycoside toxicity when the ouabain was administered in the form of intermittent infusions into intact animals. However, pretreatment with reserpine did not alter appreciably the toxicity of ouabain when the drug was continuously infused into open-chest animals. Ouabain per se tended to have little effect on myocardial catecholamine content.

ALTERATIONS IN CHEMICAL COMPOSITION OF CANINE HEART AFTER SYMPATHETIC DENERVATION.

Sympathetic denervation of the canine heart, which is extensive enough to insure depletion of myocardial catecholamines, results in an increased accumulation of myocardial fat and carbohydrate substances. Myocardial histamine, ubiquinone and nitrogen contents are unaffected. These observations provide additional evidence for the participation of the autonomic nervous system in the regulation of cardiac metabolism.

Chronic extrinsic cardiac denervation by regional neural ablation. Description of the operation, verification of the denervation, and its effects on myocardial catecholamines.

A technique for complete extrinsic denervation of the heart by the ablation of neural structures in the mediastinum is described. The completeness of denervation was verified by direct electrical stimulation of the main vagal and sympathetic trunks. Total deple tion of myocardial catecholamines followed the procedure in chronic survivors. Animals prepared in this manner are useful in the study of the neurologically isolated heart and simulate this aspect of the problem of cardiac transplantation.