Abstract P500: Naltrindole And Naltrindole Derivatives Exhibit Potent Cardioprotection In Myocardial Ischemia Reperfusion Injury

Previously, naltrindole (NTI; selective delta opioid receptor antagonist) was shown to improve post-reperfused cardiac function and reduced infarct size when given prior to ischemia (I)/ reperfusion (R) in ex-vivo rat hearts. Conversely, naloxone (NX, broad-spectrum opioid antagonist) and nor-binaltrophine (BNI, selective kappa receptor antagonist) were similar to control hearts. In this study, the effects of NTI derivatives naltriben (NTB, delta receptor antagonist) and guanidonaltrindole (GNTI, kappa receptor antagonist) were compared to NTI, BNI, and NX. Isolated hearts from male SD rats (300g) were subjected to global I(30min)/R(45min). Treatments were given 5 min before I (preconditioning) and during the first 5 min of R. Left ventricular (LV) cardiac function was measured using a pressure transducer. At the end of reperfusion, infarcted heart tissue was compared to total tissue weight. Data were evaluated using ANOVA. As shown in Table 1, NTI, NTB, and GNTI significantly improved post-reperfused cardiac function and reduced infarct size compared to control hearts. NTI and NTB elicited direct effects on cardiac function when given during preconditioning in contrast to all other study groups and were the most robust at reducing infarct size and restoring post reperfusion cardiac function. The negative inotropic effects of NTI and NTB were correlated with a decrease in the rise of ischemic pressure. GNTI also elicited significant improvement in post-reperfused cardiac function and reduction of infarct size compared to BNI which suggests a separate cardioprotective mechanism that this NTI derivative may exert in contrast to kappa opioid receptor inhibition. Results suggest that NTI and derivatives, GNTI and NTB, are cardioprotective against I/R injury resulting in reduced ischemic peak pressure (NTI/NTB) and infarct size. In future studies, we will examine the mechanism of the protective effects of NTI and derivatives in hearts subjected to I/R injury.

Description of the Mechanism of Positive Inotropic Action of the Isoquinoline Alkaloid F-18

This study evaluated the mechanism of inotropic effect of an isoquinoline alkaloid derivative, 1-(2´-bromine-4´,5´-dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline (F-18) using electrically stimulated rat left ventricular papillary muscle of rat. The F-18 alkaloid have been shown to have positive inotropic effect on papillary muscle contraction activity, IC50 value -14,6 µM. Са2+L-channel blocker - nifedipine was used in experiments. Inotropic effects of F-18 isoquinoline alkaloid on cardiomyocytes were suggested, based on results obtained in experiments carried in cardiomyocytes SR Ca2+- transport systems modulation.

Evaluation of Negative Inotropic Effects of a Isoquinoline Alkaloid N-14

In studies, the alkaloid 1-(2-Chloro-4,5-methylenedioxyphenyl)-2-hydroxyethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (N-14) had a negative inotropic effect on the activity of the papillary muscle contraction of the rat heart detected. Ca2+ ions from SR play an important role in the process of contraction of the heart muscle. With this in mind, the negative inotropic effect of the N-14 alkaloid was investigated with the modification of the accumulation processes of Ca2+ ions to SR. To clarify this, we examined the effects of the alkaloid being studied on SERCA2a and RyR2. To do this, the inhibitor of SERCA2a - cyclopiazonic acid (CPA) and RyR activator caffeine, which provide the accumulation of Ca2+ ions in SR, were used.

β1-Blockers Enhance Inotropy of Endogenous Catecholamines in Chronic Heart Failure

Although β1-blockers impressively reduce mortality in chronic heart failure (CHF), there are concerns about negative inotropic effects and worsening of hemodynamics in acute decompensated heart failure. May receptor theory dispel these concerns and confirm clinical practice to use β1-blockers? In CHF, concentrations of catecholamines at the β1-adrenoceptors usually exceed their dissociation constants (KDs). The homodimeric β1-adrenoceptors have a receptor reserve and display negative cooperativity. We considered the binomial distribution of occupied receptor dimers with respect to the interaction of an exogenous β1-blocker and elevated endogenous agonist concentrations > [KDs], corresponding to an elevated sympathetic tone. Modeling based on binomial distribution suggests that despite the presence of a low concentration of the antagonist, the activation of the dimer receptors is higher than that in its absence. Obviously, the antagonist improves the ratio of the dimer receptors with only single agonist activation compared with the dimer receptors with double activation. This leads to increased positive inotropic effects of endogenous catecholamines due to a β1-blocker. To understand the positive inotropic sequels of β1-blockers in CHF is clinically relevant. This article may help to eliminate the skepticism of clinicians about the use of β1-blockers because of their supposed negative inotropic effect, since, on the contrary, a positive inotropic effect can be expected for receptor-theoretical reasons.

Myocardial perfusion recovery induced by an α-calcitonin gene-related peptide analogue

Background Endogenous calcitonin gene-related peptide (CGRP) induces cardioprotective effects through coronary vasodilation. However, the systemic administration of CGRP induces peripheral vasodilation and positive chronotropic and inotropic effects. This study aims to examine the net effect on coronary perfusion of the systemically administered α-calcitonin gene-related peptide analogue, SAX, in rats during myocardial infarction. Methods Forty Sprague-Dawley rats underwent myocardial infarction. Following left anterior descending artery occlusion, [99mTc]Tc-sestamibi was administered to determine the myocardial perfusion before treatment. Twenty minutes, 24 and 48 h after [99mTc]Tc-sestamibi injection, the rats were treated with either SAX or placebo. Final infarct size was determined three weeks later by [99mTc]Tc-sestamibi SPECT/CT scan. Results Thirty-one rats survived the surgery and 20 completed the follow-up SPECT/CT scan (SAX n = 12; Placebo n = 8). At baseline, there was no difference in size of perfusion defect between the groups (P = .88), but at follow-up the SAX group had improved myocardial recovery compared to the placebo group (P = .04), corresponding to a relative perfusion recovery of 55% in SAX-treated rats. Conclusion The CGRP analogue, SAX, has a cardioprotective effect in this rat model of myocardial infarction, improving myocardial perfusion recovery after chronic occlusion of the coronary artery.

Histamine can be Formed and Degraded in the Human and Mouse Heart

Histamine is metabolized by several enzymes in vitro and in vivo. The relevance of this metabolism in the mammalian heart in vivo is unclear. However, histamine can exert positive inotropic effects (PIE) and positive chronotropic effects (PCE) in humans via H2-histamine receptors. In transgenic mice (H2-TG) that overexpress the human H2 receptor in cardiomyocytes but not in wild-type littermate mice (WT), histamine induced PIE and PCE in isolated left or right atrial preparations. These H2-TG were used to investigate the putative relevance of histamine degrading enzymes in the mammalian heart. Histidine, the precursor of histamine, increased force of contraction (FOC) in human atrial preparations. Moreover, histamine increased the phosphorylation state of phospholamban in human atrium. Here, we could detect histidine decarboxylase (HDC) and histamine itself in cardiomyocytes of mouse hearts. Moreover, our data indicate that histamine is subject to degradation in the mammalian heart. Inhibition of the histamine metabolizing enzymes diamine oxidase (DAO) and monoamine oxidase (MAO) shifted the concentration response curves for the PIE in H2-TG atria to the left. Moreover, activity of histamine metabolizing enzymes was present in mouse cardiac samples as well as in human atrial samples. Thus, drugs used for other indication (e.g. antidepressants) can alter histamine levels in the heart. Our results deepen our understanding of the physiological role of histamine in the mouse and human heart. Our findings might be clinically relevant because we show enzyme targets for drugs to modify the beating rate and force of the human heart.

Development of an automated closed-loop β-blocker delivery system to stably reduce myocardial oxygen consumption without inducing circulatory collapse in a canine heart failure model: a proof of concept study

Beta-blockers are well known to reduce myocardial oxygen consumption (MVO2) and improve the prognosis of heart failure (HF) patients. However, its negative chronotropic and inotropic effects limit their use in the acute phase of HF due to the risk of circulatory collapse. In this study, as a first step for a safe β-blocker administration strategy, we aimed to develop and evaluate the feasibility of an automated β-blocker administration system. We developed a system to monitor arterial pressure (AP), left atrial pressure (PLA), right atrial pressure, and cardiac output. Using negative feedback of hemodynamics, the system controls AP and PLA by administering landiolol (an ultra-short-acting β-blocker), dextran, and furosemide. We applied the system for 60 min to 6 mongrel dogs with rapid pacing-induced HF. In all dogs, the system automatically adjusted the doses of the drugs. Mean AP and mean PLA were controlled within the acceptable ranges (AP within 5 mmHg below target; PLA within 2 mmHg above target) more than 95% of the time. Median absolute performance error was small for AP [median (interquartile range), 3.1% (2.2–3.8)] and PLA [3.6% (2.2–5.7)]. The system decreased MVO2 and PLA significantly. We demonstrated the feasibility of an automated β-blocker administration system in a canine model of acute HF. The system controlled AP and PLA to avoid circulatory collapse, and reduced MVO2 significantly. As the system can help the management of patients with HF, further validations in larger samples and development for clinical applications are warranted.

Delayed diagnosis of dilated thyrotoxic cardiomyopathy with coexistent multifocal atrial tachycardia: a case report

Background Thyroid storm (TS) is a rare but potentially life-threatening sequelae of untreated or undertreated hyperthyroidism. While TS frequently causes high-output heart failure, low-output heart failure related to dilated cardiomyopathy (DCM) is extremely rare. Tachycardia is a common clinical presentation of TS, and β1-selective blockers are the first-line agents for treating TS-associated tachycardia. However, given that β-blockers have negative chronotropic and negative inotropic effects, amiodarone may be safe and effective for the treatment of TS-induced tachyarrhythmia in patients with moderate to severe heart failure. While long-term amiodarone administration causes hypothyroidism, or less frequently, hyperthyroidism, little is known about the effects of short-term amiodarone administration on thyroid function. Case presentation A 31-year-old healthy woman presented with worsening dyspnoea. She was tachycardic with multifocal atrial tachycardia (MAT) of 184 beats/min, confirmed by electrocardiogram. Echocardiographic findings were consistent with DCM, with an ejection fraction of 20%. Thus, she was initially diagnosed with acute heart failure due to DCM with coexistent MAT. Tachycardia persisted despite cardioversion attempts and treatment with multiple anti-arrhythmic drugs. Consequently, she rapidly progressed to cardiogenic shock and respiratory decompensation, which required intubation and an intra-aortic balloon pump support. Moreover, the undiagnosed Graves' disease, lack of suspicion, and postponed analysis of thyroid function tests led to a delayed diagnosis of TS. Amiodarone, which was initiated for MAT, unexpectedly ameliorated thyrotoxicosis, resulting in a euthyroid state and the patient’s significantly improved condition and cardiac function. She was discharged on day 40. Finally, she underwent total thyroidectomy; thyroid pathology was consisting with Graves' disease. Her postoperative course was uneventful. Conclusions Herein, we describe a case of delayed diagnosis of dilated thyrotoxic cardiomyopathy with coexistent MAT. The patient required intensive care due to the catastrophic sequelae and was successfully treated with amiodarone. This is the first case report of TS-associated MAT and highlights the clinical importance of high suspicion of TS in de novo heart failure with any tachyarrhythmia or DCM of unknown etiology and the potential effects of short-term amiodarone administration in the treatment of TS.