Myocardial Norepinephrine Release Research Articles

Cardioprotection of electroacupuncture against myocardial ischemia-reperfusion injury by modulation of cardiac norepinephrine release

Augmentation of cardiac sympathetic tone during myocardial ischemia has been shown to increase myocardial O(2) demand and infarct size as well as induce arrhythmias. We have previously demonstrated that electroacupuncture (EA) inhibits the visceral sympathoexcitatory cardiovascular reflex. The purpose of this study was to determine the effects of EA on left ventricular (LV) function, O(2) demand, infarct size, arrhythmogenesis, and in vivo cardiac norepinephrine (NE) release in a myocardial ischemia-reperfusion model. Anesthetized rabbits (n = 36) underwent 30 min of left anterior descending coronary artery occlusion followed by 90 min of reperfusion. We evaluated myocardial O(2) demand, infarct size, ventricular arrhythmias, and myocardial NE release using microdialysis under the following experimental conditions: 1) untreated, 2) EA at P5-6 acupoints, 3) sham acupuncture, 4) EA with pretreatment with naloxone (a nonselective opioid receptor antagonist), 5) EA with pretreatment with chelerythrine (a nonselective PKC inhibitor), and 6) EA with pretreatment with both naloxone and chelerythrine. Compared with the untreated and sham acupuncture groups, EA resulted in decreased O(2) demand, myocardial NE concentration, and infarct size. Furthermore, the degree of ST segment elevation and severity of LV dysfunction and ventricular arrhythmias were all significantly decreased (P < 0.05). The cardioprotective effects of EA were partially blocked by pretreatment with naloxone or chelerythrine alone and completely blocked by pretreatment with both naloxone and chelerythrine. These results suggest that the cardioprotective effects of EA against myocardial ischemia-reperfusion are mediated through inhibition of the cardiac sympathetic nervous system as well as opioid and PKC-dependent pathways.

Endothelin-Converting Enzyme Inhibition in the Rat Model of Acute Heart Failure: Heart Function and Neurohormonal Activation

Endothelin-1 (ET-1) has been implicated in many cardiovascular diseases, including acute heart failure (AHF) due to myocardial ischemia. Previously we described the oral endothelin-converting enzyme (ECE) inhibitor, PP36, and in this study, we investigated its cardioprotective effect in more detail, and examined the role of PP36 in the neurohormonal activation in rats that had been subjected to acute myocardial ischemia due to the microsphere embolization of coronary microcirculation. PP36 treatment (3.5 x 10(-5) M/kg/day) led to a significant fourfold decrease in hypertensive response when big-ET-1 was administered to healthy, conscious rats. ECE inhibition did not affect mortality during the first 48 hours after ischemia initiation. Systemic hemodynamic, heart function, and neurohormonal activation were analyzed in the healthy control group, the AHF group, and the AHF+PP36 group two days after AHF induction. In conscious rats in the AHF+PP36 group, mean arterial pressure (MAP) was restored and became similar to that of the MAP of the control group. In anesthetized rats, in the AHF+PP36 group, MAP was not restored and was 22% lower than the MAP of the control group. Myocardial contractility was partially restored and cardiac relaxation significantly improved after PP36 application. Further analysis of cardiac output and peripheral resistance in anesthetized rats revealed no differences between the AHF group and the AHF+PP36 group. There were no differences in plasma ET-1 concentration, serum angiotensin converting enzyme activity, and in the adrenal glands' catecholamine content between the AHF group and the AHF+PP36 group. However, rats in the AHF+PP36 group demonstrated a 60% decrease in cardiac endothelial nitric oxide synthase (eNOS) protein expression, and a 56% reduction of myocardial norepinephrine release, when compared with the AHF group's animals. These results suggest that PP36 can preserve heart function during the recovery from acute ischemic injury, and may modulate the cardiac norepinephrine release and eNOS protein level.

Temporal changes in myocardial adrenergic regulation with the progression to pump dysfunction after chronic β-adrenoreceptor activation in rats

We evaluated the relationship between myocardial norepinephrine release or inotropic responsiveness to adrenergic stimulation and intrinsic myocardial function after the progression to pump dysfunction induced by chronic beta-adrenoreceptor activation (isoproterenol [ISO], 0.1 mg/kg/day for 1 month or 6 months) in rats. Left ventricular (LV) systolic chamber dysfunction occurred after 6 months, but not after 1 month of beta-adrenoreceptor activation, as evidenced by reduced LV endocardial fractional shortening determined by echocardiography and a decrease in the slope of the LV systolic pressure-volume relations assessed in isolated, perfused heart preparations. A reduced pump function at 6 months of ISO administration was associated with chamber dilatation, while LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relations (isolated heart preparations), indices of intrinsic myocardial function, were unchanged. After 1 month of ISO administration, reduced beta1- and beta2-adrenoreceptor-mediated and sustained alpha-adrenoreceptor-mediated inotropic responses were noted. Nevertheless, increased inotropic potency of beta-adrenoreceptor agonists and upregulation of alpha-adrenoreceptor-mediated contractile responses were noted after 6 months of ISO administration. Increased adrenergic-inotropic responsiveness after 6 months of ISO administration was associated with depleted LV norepinephrine stores, as evidenced by reduced desipramine-stimulated norepinephrine concentrations in the coronary effluent. In conclusion, in the progression from compensated cardiac hypertrophy to pump dysfunction after chronic sympathetic activation, a preserved intrinsic myocardial contractility is accounted for by paradoxical upregulation of adrenergic-mediated contractile responses.

Rat strain-related differences in myocardial adrenergic tone and the impact on cardiac fibrosis, adrenergic responsiveness and myocardial structure and function

Sprague–Dawley (SD) rats have been reported to have a higher sympathetic activity than Wistar–Kyoto (WKY) rats. In the present study we sought to determine if these rat strain-related differences in sympathetic activity exist at a myocardial level and whether they translate into changes in cardiac fibrosis, contractile responsiveness to adrenergic agonists, and cardiac structure and function. Coronary effluent noradrenaline concentrations, as determined in isolated, perfused heart preparations, were higher in 5-month-old SD as compared to age-matched WKY male rats. This difference was accompanied by higher resting heart rates in SD rats as assessed in vivo. However, increases in myocardial noradrenaline release in SD rats did not translate into enhanced myocardial fibrosis, cardiac hypertrophy or remodeling, changes in basal ventricular systolic and diastolic function, or to down-regulation of inotropic responses to the β-adrenoreceptor agonists, noradrenaline, isoproterenol and dobutamine. Although age-matched male SD rats were heavier, no differences in absolute heart weights were noted between rat strains. Moreover, left ventricular (LV) posterior wall thickness as assessed by echocardiography, as well as cardiac myocyte dimensions as determined by laser scanning confocal microscopy were similar between rat strains. Furthermore, LV internal diameters as determined in vivo, as well as LV diastolic volume intercept determined in isolated, perfused heart preparations were similar between rat strains. Increases in myocardial noradrenaline release in SD rats also did not translate into differences in LV systolic chamber and myocardial function as assessed in vivo (LV endocardial and midwall fractional shortening) and at controlled loads and heart rates ex vivo (the slope of the LV developed pressure–volume relation determined). Likewise, neither myocardial hydroxyproline content nor LV chamber stiffness as assessed by the slope of the LV end-diastolic pressure–volume relation were different in SD and WKY rats. In conclusion, rat strain-related differences in cardiac adrenergic tone do indeed exist, but in young animals these differences do not translate into cardiac phenotypes known to contribute to progressive cardiac dysfunction.

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

There is no direct evidence to indicate that pump dysfunction in a dilated chamber reflects the impact of chamber dilatation rather than the degree of intrinsic systolic failure resulting from myocardial damage. In the present study, we explored the relative roles of intrinsic myocardial systolic dysfunction and chamber dilatation as mediators of left ventricular (LV) pump dysfunction. Administration of isoproterenol, a beta-adrenoreceptor agonist, for 3 mo to rats (0.1 mg.kg(-1).day(-1)) resulted in LV pump dysfunction as evidenced by a reduced LV endocardial fractional shortening (echocardiography) and a decrease in the slope of the LV systolic pressure-volume relation (isolated heart preparations). Although chronic beta-adrenoreceptor activation induced cardiomyocyte damage (deoxynucleotidyl transferase-mediated dUTP nick-end labeling) as well as beta(1)- and beta(2)-adrenoreceptor inotropic downregulation (attenuated contractile responses to dobutamine and salbutamol), these changes failed to translate into alterations in intrinsic myocardial contractility. Indeed, LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress-strain relation (isolated heart preparations) were unchanged. A normal intrinsic myocardial systolic function, despite the presence of cardiomyocyte damage and beta-adrenoreceptor inotropic downregulation, was ascribed to marked increases in myocardial norepinephrine release, to upregulation of alpha-adrenoreceptor-mediated contractile effects as determined by phenylephrine responsiveness, and to compensatory LV hypertrophy. LV pump failure was attributed to LV dilatation, as evidenced by increased LV internal dimensions (echocardiography), and a right shift and increased volume intercept of the LV diastolic pressure-volume relation. In conclusion, chronic sympathetic stimulation, despite reducing beta-adrenoreceptor-mediated inotropic responses and promoting myocyte apoptosis, may nevertheless induce pump dysfunction primarily through LV dilatation, rather than intrinsic myocardial systolic failure.

Impact of chronic β-adrenoceptor activation on neurotensin-induced myocardial effects in rats

In heart failure chronic sympathetic activation results in contractile dysfunction in part through down-regulation of the β-adrenoceptor-cAMP system. However, the impact of chronic adrenergic activation on cardiac sympathetic neuromodulator systems is unclear. In this study, we sought to determine whether chronic adrenergic activation modifies myocardial norepinephrine release and contractile responses elicited by neurotensin, a neuropeptide found in cardiovascular system. Chronic administration of isoproterenol, a β-adrenoceptor agonist, to rats (0.05 mg/kg daily for 1 month, i.p.), produced cardiac hypertrophy with preserved baseline ventricular systolic function, but reduced contractile responses to exogenous norepinephrine as shown in isolated, isovolumically-contracting heart preparations. Neurotensin produced a marked increase in coronary effluent norepinephrine release, an effect abolished by SR 48692, a specific neurotensin receptor antagonist. In isoproterenol-treated rats, neurotensin has no significant impact on myocardial norepinephrine release. Consistently, concentration-dependent positive inotropic responses elicited by neurotensin in control rat hearts were blunted over a wide range of neurotensin concentrations (10 − 10 –10 − 5.5 M) in isoproterenol-treated rats. In conclusion, these data indicate that following chronic β-adrenoceptor activation, neurotensin-induced effects on norepinephrine release and subsequent contractile changes are markedly down-regulated.

Adenosine A1 receptor-mediated inhibition of myocardial norepinephrine release involves neither phospholipase C nor protein kinase C but does involve adenylyl cyclase

Stimulation of adenosine A1 receptors in the heart exerts cardioprotective effects by inhibiting norepinephrine (NE) release from sympathetic nerve endings. The intraneuronal signal transduction triggered by presynaptic adenosine A1 receptors is still not completely understood. The objective of the present study was to determine whether phospholipase C (PLC), protein kinase C (PKC), and adenylyl cyclase (AC) are involved in the adenosine A1 receptor-mediated inhibition of endogenous (stimulation-induced) NE release in isolated Langendorff-perfused rat hearts as an approach to elucidate their role in the cardiovascular system. Activation of adenosine A1-receptors with 2-chloro-N6-cyclopentyladenosine (CCPA) decreased cardiac NE release by approximately 40%. Inhibition of PLC with 1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U 73122) as well as inhibition of PKC with 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl)maleimide (GF 109203X) slightly but significantly decreased NE release; however, the suppressive effect of CCPA on NE release was not modulated by U 73122 or GF 109203X. Blockade of AC with 9-(tetrahydro-2'-furyl)adenine (SQ 22536) reversed the inhibitory effect of CCPA on sympathetic neurotransmitter release irrespective of whether PKC was pharmacologically activated by phorbol 12-myristate 13-acetate or was not activated, indicating a PKC-independent but AC-dependent mechanism. Direct stimulation of AC with forskolin increased NE release by approximately 20%; an effect that was antagonized by either CCPA or SQ 22536. These data suggest that the adenosine A1 receptor-mediated inhibition of NE release does not involve PLC or PKC but does involve AC.

Neurotensin-Induced Myocardial Noradrenergic Effects in Spontaneously Hypertensive Rats

Although increases in myocardial synaptic norepinephrine concentrations contribute toward the progression to heart failure in hypertension, the stimuli for norepinephrine release are unclear. In this study we explored whether neurotensin, a neuropeptide found in heart tissue, could modify myocardial norepinephrine release in spontaneously hypertensive rats (SHR). Prior to the development of cardiac decompensation, baseline coronary effluent norepinephrine concentrations were higher in isolated heart preparations of spontaneously hypertensive rats than in Wistar Kyoto (WKY) control rat hearts. Neurotensin increased coronary effluent norepinephrine concentrations and induced positive inotropic responses, effects that were enhanced in spontaneously hypertensive rats compared with Wistar Kyoto rats. Although the neurotensin receptor antagonist, SR 48692, did not modify either baseline coronary effluent norepinephrine concentrations or left ventricular systolic function in spontaneously hypertensive rats, it dose dependently abolished neurotensin-induced cardiac norepinephrine release and contractile responses. Neurotensin-mediated inotropic responses were also abolished by co-administration of the beta-adrenoreceptor blockers, propranolol and atenolol. Inotropic responses to exogenous norepinephrine were similar in SHR and WKY rats. In summary, in the hypertensive heart there is an increased sensitivity to neurotensin's actions on myocardial norepinephrine release and subsequent contractile changes. Therefore, neurotensin receptor blockade may represent a novel therapeutic target in preventing the progression to heart failure in hypertension.

Contractile responses to selective phosphodiesterase inhibitors following chronic β-adrenoreceptor activation

Contractile responses to phosphodiesterase (PDE) inhibitors are attenuated in heart failure, an effect limiting the clinical value of these agents. In this study, we sought to determine whether abnormalities in the beta-adrenoreceptor (beta-AR)-cyclic adenosine monophosphate (cAMP) signal transduction are sufficient to account for downregulation of PDE inhibitor-induced inotropic responses following chronic sympathetic activation. Sustained beta-AR activation produced by administration of isoproterenol (ISO) (50 microg kg(-1) day(-1) i.p. for 1 month) to rats resulted in cardiac hypertrophy, but did not affect baseline cardiac systolic function, as assessed in vivo by echocardiography and ex vivo under controlled loading conditions and heart rate (left ventricular systolic pressure-volume and stress-strain relations). Moreover, chronic ISO administration did not alter the baseline myocardial norepinephrine release or inotropic responses to incremental concentrations of Ca(2+) in isolated, perfused heart preparations. However, left ventricular contractile responses to ISO, the PDE III inhibitor amrinone, and the PDE IV inhibitor rolipram were attenuated following chronic beta-AR activation. Myocardial cAMP concentrations after stimulation with amrinone and rolipram were similar in ISO-treated and control rats. However, in ISO-treated rats, a marked decrease in contractile responsiveness to the cell-permeable, PDE-resistant cAMP analogue, 8-bromoadenosine cAMP, was noted. In conclusion, these data suggest that in cardiac disease, sustained beta-AR activation, without producing ventricular systolic dysfunction or enhanced myocardial norepinephrine release, is sufficient to account for the downregulation of contractile responses to PDE inhibitors. This effect appears to be largely mediated through abnormalities in signal transduction between cAMP and Ca(2+)-induced Ca(2+) release.

Impact and mechanisms of action of neurotensin on cardiac contractility in the rat left ventricle

Using immunoassay measurements, neurotensin was identified in rat ventricular tissue and in coronary effluent samples. Exogenous neurotensin evoked contractile responses in isolated ventricular preparations, which were equivalent in magnitude to those of norepinephrine and histamine, but greater than those for serotonin and angiotensin II. EC50 values revealed neurotensin to be as potent as serotonin, but more potent than norepinephrine, histamine and angiotensin II. Structure–activity studies indicated that the contractile effects are attributed to the C-terminal portion of neurotensin. Neurotensin-induced responses were decreased by SR 48692, a specific neurotensin receptor antagonist. Neurotensin elicited an increase in coronary effluent norepinephrine concentrations, and a strong relationship between the magnitude of neurotensin-induced contractile effects and increments in myocardial norepinephrine release were noted. Neurotensin-induced contractile responses were abolished by β-adrenoceptor antagonists, but not by histamine, serotonin or angiotensin II receptor antagonists. In conclusion, neurotensin increases ventricular contractility through stimulation of myocardial norepinephrine release.

Mechanisms of preserved baseline cardiac systolic function in rats with adrenergic inotropic downregulation

Despite reductions in β-adrenoreceptor (β-AR)-mediated inotropic effects induced by sustained sympathetic activation in cardiac disease, whether these changes necessarily result in reductions in systolic function under resting conditions (baseline function) is not clear. Moreover, possible compensatory mechanisms which might contribute to maintaining the baseline systolic function despite reductions in β-AR-mediated inotropic effects have not been systematically sought. In the present study, 1 month of daily administration of the β-AR agonist, isoproterenol (0.05 mg/kg/day, i.p.), to rats resulted in an attenuation of left ventricular inotropic responses to isoproterenol over a wide range of concentrations (10 − 8 – 10 − 4 M), whereas a decline of inotropic responses to norepinephrine, an endogenous inotrope, occurred only at high concentrations (10 − 5 – 10 − 4 M). However, chronic isoproterenol administration failed to modify baseline systolic chamber and myocardial function, as determined in vivo using echocardiography (endocardial and midwall fractional shortening), and in isolated, perfused heart preparations (end-systolic chamber and myocardial elastance) Sustained baseline chamber function despite profound β-AR-mediated inotropic downregulation was not attributed to alterations in cardiac loading conditions, resting heart rate, chamber remodeling, increased myocardial norepinephrine release, or enhanced contractile responses to alternative receptor/signal transduction pathways mediating positive inotropy (as assessed from histamine, serotonin, forskolin, angiotensin II or phenylephrine responsiveness). These findings indicate that baseline cardiac contractile function might be unaltered despite a profound impairment of β-AR-induced responsiveness, an effect related to a preserved stimulatory influence of low physiological concentrations of endogenous norepinephrine constituting adrenergic tone at rest.

Aldosterone Receptor Blockade Prevents the Transition to Cardiac Pump Dysfunction Induced by β-Adrenoreceptor Activation

The transition from compensated to decompensated left ventricular hypertrophy (LVH) in hypertension involves excessive beta-adrenoreceptor (beta-AR) stimulation. To explore whether aldosterone receptor activation contributes toward beta-AR-induced left ventricular (LV) decompensation in hypertensive LVH, the effect of spironolactone (SPIRO; 80 mg x kg(-1) x day(-1)) on LV cavity dimensions, function, and chamber remodeling mechanisms was evaluated in spontaneously hypertensive rats (SHR) receiving a low dose of the beta-AR agonist isoproterenol (ISO) at 0.02 to 0.04 mg x kg(-1) . day for 4.5 months. ISO administered to SHR resulted in an increased 24-hour urinary aldosterone excretion and LV cavity dimensions, a right shift in LV diastolic pressure-volume relations, a decreased LV relative wall thickness, and increased total, noncross-linked, type I and type III myocardial collagen concentrations without further enhancing increased myocardial norepinephrine (NE) release. ISO reduced pump function without modifying intrinsic myocardial systolic function or inducing further myocyte necrosis or apoptosis. ISO only increased LV cavity volumes after prolonged periods of administration. SPIRO abolished ISO-induced chamber dilatation, wall thinning, and pump dysfunction and reduced total, noncross-linked, type I and type III myocardial collagen concentrations but failed to modify blood pressure, volume preloads, intrinsic myocardial systolic function, myocardial NE release, or the degree of necrosis or apoptosis. In conclusion, these results suggest that aldosterone receptor blockade, through load-independent effects, may be useful in preventing the transition from compensated LVH to dilatation and pump dysfunction mediated by chronic beta-AR activation.

K(ATP) channel opening during ischemia: effects on myocardial noradrenaline release and ventricular arrhythmias.

Cardioprotection by K(ATP) channel openers during ischemia is well documented although ill understood. Proarrhythmic effects may be an important drawback. K(ATP) channel modulation influences neurotransmitter release during ischemia in brain synaptosomes. Therefore, we studied the effects of K(ATP) channel modulation on myocardial noradrenaline release and arrhythmias in ischemic rabbit hearts. Isolated rabbit hearts were perfused according to Langendorff and stimulated. Local electrograms were recorded and K+-selective electrodes were inserted in the left ventricular free wall. Cromakalim (3 microM) or glibenclamide (3 microM) was added 20 min prior to induction of global ischemia. After 15, 20, or 30 min of ischemia, hearts were reperfused and noradrenaline content of the first 100 ml of reperfusate was measured. Cromakalim (n = 16) prevented the second rise of extracellular [K(+)] in accordance with its cardioprotective effect. Cromakalim significantly reduced noradrenaline release after 15 min (mean, 169 +/- SEM 97 pmol/gr dry weight vs. control 941 +/- 278; p < 0.05) and 20 min of ischemia (230 +/- 125 pmol/gr dry wt vs. control 1,460 +/- 433; p < 0.05), but after 30 min of ischemia, the difference in noradrenaline release was no longer significant (cromakalim 2,703 +/- 1,195 pmol/gr dry wt vs. control 5,413 +/- 1,310; p = 0.08). Ventricular fibrillation or ventricular tachycardia occurred in 10 of 13 control hearts (77%) (n = 19), in six of 10 glibenclamide-treated hearts (60%) (n = 15), and in six of 14 cromakalim-treated hearts (43%) (p = NS). Cromakalim significantly accelerated onset of ventricular tachycardia or fibrillation (mean +/- SEM onset after 12.5 +/- 1.6 min ischemia vs. control 16.2 +/- 0.7 min; p < 0.05). Noradrenaline release occurred only in cromakalim-treated hearts with early-onset arrhythmias whereas no noradrenaline release was observed in cromakalim-treated hearts without ventricular tachycardia or fibrillation. Our results show that activation of the K(ATP) channel by cromakalim during ischemia reduces myocardial noradrenaline release and postpones the onset of irreversible damage, contributing to the cardioprotective potential of K(ATP) openers during myocardial ischemia.

Vagosympathetic interactions in ischemia-induced myocardial norepinephrine and acetylcholine release.

To elucidate the pathophysiological roles of vagosympathetic interactions in ischemia-induced myocardial norepinephrine (NE) and acetylcholine (ACh) release, we measured myocardial interstitial NE and ACh levels in response to a left anterior descending coronary occlusion in the following groups of anesthetized cats: intact autonomic innervation (INT, n = 7); vagotomy (VX, n = 6); local administration of atropine (Atro, n = 6); transection of the stellate ganglia (TSG, n = 5); local administration of phentolamine (Phen, n = 6); and combined vagotomy and transection of the stellate ganglia (VX+TSG, n = 5). The maximum NE release was enhanced in the VX group (141 +/- 30 nmol/l, means +/- SE, P < 0.05) compared with the INT group (61 +/- 12 nmol/l). Neither the Atro (50 +/- 24 nmol/l) nor VX+TSG groups (84 +/- 25 nmol/l) showed enhanced NE release. The maximum ACh release was unaltered in the TSG and Phen groups compared with the INT group (19 +/- 4, 18 +/- 4, and 13 +/- 3 nmol/l, respectively). These findings indicate that the cardiac vagal afferent but not efferent activity reduced the ischemia-induced myocardial NE release. In contrast, the cardiac sympathetic afferent and efferent activities played little role in the ischemia-induced myocardial ACh release.

In vitro antiarrhythmic effect of prior whole body hyperthermia: implication of catalase.

The protective effect of heat stress against mechanical dysfunction and myocardial necrosis after prolonged ischemia is well known. We have investigated whether the protective effect of heat stress extends to reperfusion arrhythmias in the isolated perfused rat heart. Rats were exposed to 20 min of 42 degrees C hyperthermia. Twenty-four h later their hearts were isolated, perfused and subjected to a 5-min period of occlusion of the left coronary artery. The incidence and duration of reperfusion arrhythmias were assessed in the 30-min reperfusion period. Prior heat stress led to a reduction in the incidence (from 100 to 60%, P</=0.05) and duration (from 611+/-251 to 62+/-51 s, P</=0.05) of ventricular tachycardia and/or fibrillation, upon reperfusion following a 5-min ischemic period. This prevention of reperfusion arrhythmias was associated with a two-fold increase in endogenous catalase activity and an enhanced heat stress protein hsp 72 and 27 expression. Catalase inhibition by 3-amino triazole (AT) abolished the antiarrhythmic effect of heat stress. The incidence (80 v 100%) and duration (691+/-238 v 989+/-242 s) of reperfusion arrhythmias were not different between the group heat shocked + AT and the group treated only with AT. On the other hand, in the presence of AT, myocardial noradrenaline release was attenuated by prior heat stress (upon stabilization: 3.9+/-0.8 compared to 9.4+/-2.1 pg/ml/g tissue, P</=0.05; upon reperfusion: 42.7+/-7.3 compared to 69.8+/-9.5 pg/ml/g tissue, P</=0.05). In conclusion, heat stress leads to protection against reperfusion arrhythmias occurring after a short ischemic insult, in the isolated rat heart. Heat stress proteins and catalase seem to be implicated in this protective effect. Finally, we have shown that in presence of AT, heat stress decreases myocardial noradrenaline release.

"Escape" of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy.

Despite the findings in randomized trials of a significant effect of angiotensin-converting enzyme (ACE) inhibitors in reducing morbidity and mortality of patients with symptomatic left ventricular dysfunction, the morbidity and mortality of these patients remains relatively high. One potential strategy to further improve morbidity and mortality in these patients is blockade of a aldosterone. Many clinicians have assumed that ACE inhibitors would block both angiotensin II and aldosterone. However, there are data to suggest that aldosterone production may "escape" despite the use of an ACE inhibitor. An escape of aldosterone production has several important consequences, including: sodium retention, potassium and magnesium loss, myocardial collagen production, ventricular hypertrophy, myocardial norepinephrine release, endothelial dysfunction, and a decrease in serum high density lipoprotein cholesterol. Due to the potential importance of these mechanisms, the finding that there is a significant correlation between aldosterone production and mortality in patients with heart failure, as well as evidence that an aldosterone antagonist, spironolactone, when administered to patients with heart failure treated with conventional therapy including an ACE inhibitor results in increased diuresis and symptomatic improvement, an international prospective multicenter study has been organized, the Randomized Aldactone Evaluation Study (RALES Pilot Study), to evaluate the safety of blocking the effects of aldosterone in patients with heart failure treated with an ACE inhibitor.

Intermittent v continuous ischernia 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.

Adrenomedullary epinephrine excretion and myocardial norepinephrine release during cardiopulmonary bypass

Adrenomedullary epinephrine excretion and myocardial norepinephrine release during cardiopulmonary bypass

Estimation of myocardial interstitial norepinephrine release after brain death using cardiac microdialysis.

Brain death is a pathophysiological condition associated with major hemodynamic changes, temporary myocardial ischemia, and histological damage of the heart. These modifications could be related to a major local release of norepinephrine from myocardial sympathetic nerve endings leading to norepinephrine cardiotoxicity. This study was designed to evaluate the utility of cardiac microdialysis to measure interstitial myocardial norepinephrine release resulting from brain death. The dialysis probe consisted in a 10 x 0.20-mm dialysis fiber with a 18,000 mol wt cutoff. Dialysis probes were implanted into the right and left ventricular walls of the beating heart in anesthetized pigs and perfused with Ringer solution at 2 microliters/min. Dialysate norepinephrine concentration was measured using HPLC with electrochemical detection. The relative recovery rate of norepinephrine in vivo was 34 +/- 4%. Interstitial fluid concentrations were obtained using the following formula: [C]interstitium = [C]dialysate/Recovery in vivo. After brain death, a transient increase in interstitial norepinephrine concentration was observed (from 0.74 +/- 0.20 to 4.50 +/- 0.60 ng/ml and 0.76 +/- 0.20 to 6.2 +/- 0.9 ng/ml in left and right ventricle, respectively, P < 0.01) which far exceeded plasma level increase (from 0.50 +/- 0.10 ng/ml to 0.91 +/- 0.20 ng/ml, P < 0.05). This increase in myocardial norepinephrine was, moreover, biphasic, with a second peak occurring 40 min after brain death. The present study confirms the onset of a dramatic increase in cardiac norepinephrine release from myocardial nerve endings following brain death, and demonstrate the utility of the new cardiac microdialysis technique to assess changes in interstitial fluid content.

Myocardial adrenergic changes at two stages of heart failure due to adriamycin treatment in rats

Changes in myocardial norepinephrine (NE) levels, turnover, uptake, and release in rats were examined at two stages of cardiac dysfunction induced by adriamycin (ADR) given intraperitoneally in six equal doses over a period of 2 wk for a cumulative dose of 15 mg/kg. At 3 wk posttreatment, ADR-treated animals showed no changes in left ventricular systolic pressure (LVSP), aortic systolic pressure (ASP), and aortic diastolic pressure (ADP) but left ventricular end-diastolic pressure (LVEDP) was significantly higher. At 6 wk posttreatment, LVSP, ASP, and ADP were significantly lower and LVEDP remained elevated. Animals in both ADR-treated groups showed signs of congestive heart failure as indicated by ascites, congestive liver, and elevated LVEDP. Structural changes typical of ADR cardiomyopathy were more pronounced in the 6-wk group. In vivo hemodynamic as well as in vitro muscle function response to different concentrations of epinephrine was depressed in its duration as well as extent in both 3- and 6-wk ADR-treated groups. Myocardial NE levels were increased in the 3-wk group but were depressed in the 6-wk group. NE turnover was faster in both 3- and 6-wk ADR groups, uptake was increased only in the 6-wk group, and release was unchanged. These data show increased cardiac sympathetic tone at both stages of ADR-induced congestive heart failure.