Strength Of Cardiac Contraction Research Articles

Nanodomain cAMP signalling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.

3', 5'-cyclic adenosine monophosphate (cAMP) mediates the effects of sympathetic stimulation on the rate and strength of cardiac contraction. Beyond this pivotal role, in cardiac myocytes cAMP also orchestrates a diverse array of reactions to various stimuli. To ensure specificity of response, the cAMP signaling pathway is intricately organized into multiple, spatially confined, subcellular domains, each governing a distinct cellular function. In this review, we describe the molecular components of the cAMP signalling pathway, how they organized are inside the intracellular space and how they achieve exquisite regulation of signalling within nanometer-size domains. We delineate the key experimental findings that lead to the current model of compartmentalised cAMP signaling and we offer an overview of our present understanding of how cAMP nanodomains are structured and regulated within cardiac myocytes. Furthermore, we discuss how compartmentalized cAMP signaling is affected in cardiac disease and consider the potential therapeutic opportunities arising from understanding such organization. By exploiting the nuances of compartmentalized cAMP signaling, novel and more effective therapeutic strategies for managing cardiac conditions may emerge. Finally, we highlight the unresolved questions and hurdles that must be addressed to translate these insights into interventions that may benefit patients.

Beta-adrenergic receptors gene polymorphisms are associated with cardiac contractility and blood pressure variability.

Beta-adrenergic receptors (beta-ARs) play a pivotal role in the cardiovascular regulation. In the human heart beta1- and beta2-ARs dominate in atria as well as in ventricle influencing heart rate and myocardial contractility. Some single nucleotide polymorphisms (SNPs) of beta-ARs might influence cardiovascular function. However, the influence of beta-AR genes SNPs on hemodynamic parameters at rest and their reactivity under stress is still not well known. We aimed to explore the associations between four selected beta-ARs gene polymorphisms and selected cardiovascular measures in eighty-seven young healthy subjects. While in beta1-AR polymorphism rs1801252 no significant association was observed, second beta1-AR polymorphism rs1801253 was associated with decreased cardiac output and cardiac index during all phases and with decreased flow time corrected and ejection time index at rest and during mental arithmetics. Polymorphism rs1042713 in beta2-AR was associated with alterations in blood pressure variability at rest and during head-up-tilt, while rs1042714 was associated predominantly with decreased parameters of cardiac contractility at rest and during mental arithmetics. We conclude that complex analysis of various cardiovascular characteristics related to the strength of cardiac contraction and blood pressure variability can reveal subtle differences in cardiovascular sympathetic nervous control associated with beta-ARs polymorphisms.

Getting help from Frank and Starling (and Coats and Bowditch) to augment blood flow in heat-stressed older adults.

Otto Frank and Ernest Starling are credited with the first observations that led to Starling's law of the heart, namely that the strength of cardiac contraction during systole is proportional to end-diastolic volume, or the amount of stretch on the myocardial muscle cells during diastole. This article is protected by copyright. All rights reserved

Minimal model for calcium alternans due to SR release refractoriness.

In the heart, rapid pacing rates may induce alternations in the strength of cardiac contraction, termed pulsus alternans. Often, this is due to an instability in the dynamics of the intracellular calcium concentration, whose transients become larger and smaller at consecutive beats. This alternation has been linked experimentally and theoretically to two different mechanisms: an instability due to (1) a strong dependence of calcium release on sarcoplasmic reticulum (SR) load, together with a slow calcium reuptake into the SR or (2) to SR release refractoriness, due to a slow recovery of the ryanodine receptors (RyR2) from inactivation. The relationship between calcium alternans and refractoriness of the RyR2 has been more elusive than the corresponding SR Ca load mechanism. To study the former, we reduce a general calcium model, which mimics the deterministic evolution of a calcium release unit, to its most basic elements. We show that calcium alternans can be understood using a simple nonlinear equation for calcium concentration at the dyadic space, coupled to a relaxation equation for the number of recovered RyR2s. Depending on the number of RyR2s that are recovered at the beginning of a stimulation, the increase in calcium concentration may pass, or not, over an excitability threshold that limits the occurrence of a large calcium transient. When the recovery of the RyR2 is slow, this produces naturally a period doubling bifurcation, resulting in calcium alternans. We then study the effects of inactivation, calcium diffusion, and release conductance for the onset of alternans. We find that the development of alternans requires a well-defined value of diffusion while it is less sensitive to the values of inactivation or release conductance.

Reduced Binding of the M-Domain of Cardiac Myosin Binding Protein C to Actin Impairs the Ability of the Heart to Respond to Chronic Stress

Cardiac myosin binding protein C (cMyBP-C) is a sarcomeric protein that regulates cross bridge cycling to control timing and strength of cardiac contraction. However, the molecular mechanisms by which cMyBP-C influences cross bridge cycling are incompletely understood. The M-domain of cMyBP-C can interact with actin and myosin, and phosphorylation of cMyBP-C in response to β-adrenergic stimulation during cardiac stress diminishes its affinity for both.In this study we determined the functional relevance of cMyBP-C binding to actin on cardiac function. Binding of cMyBP-C to actin can activate the thin filament and we hypothesize that dissociation of cMyBP-C from actin is essential for cardiac relaxation. To test our hypothesis, we created a transgenic mouse model with a mutation in the M-domain of cMyBP-C (E330K) that reduced binding affinity for actin in vitro. We then used echocardiography and pressure-volume recordings to assess cardiac function under sedentary and stress conditions.Both systolic function (e.g. stroke volume, ejection fraction and maximal rate of pressure development (+dP/dt)) and diastolic function (e.g. –dP/dt, isovolumetric relaxation time, E/A) were normal in E330K-Tg mice under sedentary conditions. Acute β-adrenergic stimulation with isoprenaline also led to normal increases in both contractility and relaxation in E330K-Tg mice. However, chronic cardiac stress by increasing preload to the heart by aortocaval fistula was fatal to all E330K-Tg mice within 10 days after surgery.Our results demonstrate that reduced interaction between the M-domain of cMyBP-C and actin did not impair cardiac function in E330K-Tg mice under sedentary conditions, but that this interaction may be essential for the heart to cope with chronic volume overload.This work is supported by NIH HL-080367 and AHA 15POST25700403.

Alcohol consumption in women and the elderly : When does it induce heart failure?

The association between alcohol consumption and the etiology and prognosis of cardiovascular diseases has been the focus of attention and also the subject of controversial discussions for many years. This is particularly true for heart failure, which can be induced by coronary artery disease (CAD), arterial hypertension, atrial and ventricular arrhythmias and cardiomyopathies. Acute effects of high doses of alcohol can lead to impairment of the cardiac contraction strength with rhythm disturbances (holiday heart syndrome), transient ischemic attacks and in rare cases to sudden cardiac death. The chronic effects of high alcohol consumption include in particular, ventricular dysfunction, chronic rhythm disturbances, alcoholic cardiomyopathy and CAD. In contrast, light to moderate consumption of alcohol is associated with a reduced risk of CAD and ischemic stroke; however, even moderate alcohol drinking is associated with a greater risk for atrial fibrillation. The unfavorable effects of alcohol occur at much lower levels of acute or chronic consumption in women than in men. In the elderly just as in young people, a moderate alcohol consumption is associated with a lower risk of heart failure.

The calcium-frequency response in the rat ventricular myocyte: an experimental and modelling study.

In the majority of species, including humans, increased heart rate increases cardiac contractility. This change is known as the force-frequency response (FFR). The majority of mammals have a positive force-frequency relationship (FFR). In rat the FFR is controversial. We derive a species- and temperature-specific data-driven model of the rat ventricular myocyte. As a measure of the FFR, we test the effects of changes in frequency and extracellular calcium on the calcium-frequency response (CFR) in our model and three altered models. The results show a biphasic peak calcium-frequency response, due to biphasic behaviour of the ryanodine receptor and the combined effect of the rapid calmodulin buffer and the frequency-dependent increase in diastolic calcium. Alterations to the model reveal that inclusion of Ca(2+) /calmodulin-dependent protein kinase II (CAMKII)-mediated L-type channel and transient outward K(+) current activity enhances the positive magnitude calcium-frequency response, and the absence of CAMKII-mediated increase in activity of the sarco/endoplasmic reticulum Ca(2+) -ATPase induces a negative magnitude calcium-frequency response. An increase in heart rate affects the strength of cardiac contraction by altering the Ca(2+) transient as a response to physiological demands. This is described by the force-frequency response (FFR), a change in developed force with pacing frequency. The majority of mammals, including humans, have a positive FFR, and cardiac contraction strength increases with heart rate. However, the rat and mouse are exceptions, with the majority of studies reporting a negative FFR, while others report either a biphasic or a positive FFR. Understanding the differences in the FFR between humans and rats is fundamental to interpreting rat-based experimental findings in the context of human physiology. We have developed a novel model of rat ventricular electrophysiology and calcium dynamics, derived predominantly from experimental data recorded under physiological conditions. As a measure of FFR, we tested the effects of changes in stimulation frequency and extracellular calcium concentration on the simulated Ca(2+) transient characteristics and showed a biphasic peak calcium-frequency relationship, consistent with recent observations of a shift from negative to positive FFR when approaching the rat physiological frequency range. We tested the hypotheses that (1) inhibition of Ca(2+) /calmodulin-dependent protein kinase II (CAMKII)-mediated increase in sarco/endoplasmic reticulum Ca(2+) -ATPase (SERCA) activity, (2) CAMKII modulation of SERCA, L-type channel and transient outward K(+) current activity and (3) Na(+) /K(+) pump dynamics play a significant role in the rat FFR. The results reveal a major role for CAMKII modulation of SERCA in the peak Ca(2+) -frequency response, driven most significantly by the cytosolic calcium buffering system and changes in diastolic Ca(2+) .

Cardiac troponin I phosphorylation and the force–length relationship

Cardiac troponin I phosphorylation and the force–length relationship

Action of La3+ on the systems providing contractility of vertebrate myocardium

The inotropic action of La3+ on frog myocardium was studied with taking into account of its effect on mitochondria of cardiomyocytes (CM). It has been established that in the range of studied concentrations (0.2-6 mM), La3+ decreases dose-dependently the strength of cardiac contractions (by 3.3-92.2 %). In parallel experiments on isolated rat heart mitochondria (RHM), La3+ at a concentration of 25 microM has been shown to cause swelling of non-energized and energized mitochondria in isotonic medium with 125 mM NH4NO3 and in hypotonic medium with 25 mM CH3COOK. The study of oxidative processes in mitochondria with aid of polarographic method of measurement of oxygen concentration has shown that La3+ at concentrations of 50 and 100 microM increases the oxygen consumption rate by mitochondria in the state 2. However, La3+ does not decrease the respiration rate of isolated mitochondria in the state 3, as this takes place in the case of use of Cd2+ or at the Ca(2+)-overloading of mitochondria. The rate of endogenous respiration of isolated mitochondria in the medium with La3+ was higher than in control, which implies its effect on ion permeability of the inner membrane. The data obtained in this work indicate that the La(3+)-produced decrease of the contractility of cardiac muscle is not only due to the direct blocking effect on the potential-controlled Ca2+ channels, but is also mediated by its unspecific action on the CM mitochondria. This action is manifested in acceleration of the energy-dependent K+ transport in matrix and in an increase of ion permeability of the inner mitochondrial membrane (IMM).

Usefulness of Hemodynamic Sensors for Physiologic Cardiac Pacing in Heart Failure Patients

The rate adaptive sensors applied to cardiac pacing should respond as promptly as the normal sinus node with an highly specific and sensitive detection of the need of increasing heart rate. Sensors operating alone may not provide optimal heart responsiveness: central venous pH sensing, variations in the oxygen content of mixed venous blood, QT interval, breathing rate and pulmonary minute ventilation monitored by thoracic impedance variations, activity sensors. Using sensors that have different attributes but that work in a complementary manners offers distinct advantages. However, complicated sensors interactions may occur. Hemodynamic sensors detect changes in the hemodynamic performances of the heart, which partially depends on the autonomic nervous system-induced inotropic regulation of myocardial fibers. Specific hemodynamic sensors have been designed to measure different expression of the cardiac contraction strength: Peak Endocardial Acceleration (PEA), Closed Loop Stimulation (CLS) and TransValvular Impedance (TVI), guided by intraventricular impedance variations. Rate-responsive pacing is just one of the potential applications of hemodynamic sensors in implantable pacemakers. Other issues discussed in the paper include: hemodynamic monitoring for the optimal programmation and follow up of patients with cardiac resynchronization therapy; hemodynamic deterioration impact of tachyarrhythmias; hemodynamic upper rate limit control; monitoring and prevention of vasovagal malignant syncopes.

A random cycle length approach for assessment of myocardial contraction in isolated rabbit myocardium.

It is well known that the strength of cardiac contraction is dependent on the cycle length, evidenced by the force-frequency relationship (FFR) and the existence of postrest potentiation (PRP). Because the contractile strength of the steady-state FFR and force-interval relationship involve instant intrinsic responses to cycle length as well as slower acting components such as posttranslational modification-based mechanisms, it remains unclear how cycle length intrinsically affects cardiac contraction and relaxation. To dissect the impact of cycle length changes from slower acting signaling components associated with persisting changes in cycle length, we developed a novel technique/protocol to study cycle length-dependent effects on cardiac function; twitch contractions of right ventricular rabbit trabeculae at different cycle lengths were randomized around a steady-state frequency. Patterns of cycle lengths that resulted in changes in force and/or relaxation times can now be identified and analyzed. Using this novel protocol, taking under 10 min to complete, we found that the duration of the cycle length before a twitch contraction ("primary" cycle length) positively correlated with force. In sharp contrast, the cycle length one ("secondary") or two ("tertiary") beats before the analyzed twitch correlated negatively with force. Using this protocol, we can quantify the intrinsic effect of cycle length on contractile strength while avoiding rundown and lengthiness that are often complications of FFR and PRP assessments. The data show that the history of up to three cycle lengths before a contraction influences myocardial contractility and that primary cycle length affects cardiac twitch dynamics in the opposite direction from secondary/tertiary cycle lengths.

T-channels and Na+,Ca2+-exchangers as components of the Ca2+-system of regulation of activity of the heart myocardium of the frog Rana temporaria

Earlier we have shown that regulation of rhythm and strength of the frog heart contractions, mediated by transmitters of the autonomic nervous system, is of the Ca2+-dependent character. In the present work, we studied chronoand inotropic effect of verapamil—an inhibitor of Ca2+-channels of the L-type, of nickel chloride-an inhibitor of Ca2+—channels of the T-type and of Na+,Ca2+exchangers as well as of adrenaline and acetylcholine (ACh) after nickel chloride. It has been found that the intracardially administered NiCh2 at a dose of 0.01 μg/kg produced a sharp fall of amplitude of action potential (AP) and an almost twofold deceleration of heart rate (HR). The intracardiac administration of NiCh2 (0.01 μg/kg) on the background of action of verapamil (6 mg/kg, i/m) led as soon as after 3 min to even more prominent HR deceleration and to further fall of the AP amplitude by more than 50% as compared with norm. An intracardiac administration of adrenaline (0.5 mg/kg) partly restored the cardiac activity. However, preservation of the myocardium electrical activity in such animals was brief and its duration did not exceed several minutes. Administration of Ni2+ on the background of acetylcholine (3.6 mg/kg) led to almost complete cessation of cardiac activity. As soon as 3 min after injection of this agent the HR decreased to 2 contractions/min. On electrograms (EG), the 10-fold fall of the AP amplitude was recorded. To elucidate role of extraand intracellular Ca2+ in regulation of strength of heart contractions, isometric contraction of myocardium preparations was studied in response to action of NiCl2 (10–200 μM), verapamil (70 μM), adrenaline (5 μM), and acetylcholine (0.2 μM) after NiCl2. It has been found that Ni2+ causes a dose-dependent increase of the muscle contraction amplitude. Minimal change of the contraction amplitude (on average, by 14.9% as compared with control) was recorded at a Ni2+ concentration of 100 μM. An increase of Ni2+ in the sample to 200 μM increased the cardiac contraction strength, on average, by 41%. The negative inotropic action of verapamil was essentially reduced by 100 μM Ni2+. Adrenaline added to the sample after Ni2+ produced stimulating effect on the cardiac muscle, with an almost twofold rise of the contraction amplitude. ACh (0.2 μM) decreased the cardiac contraction amplitude, on average, by 56.3%, whereas Ni2+ (200 μM) administered after ACh not only restored, but also stimulated partly the myocardial work. Within several parts of percent there was an increase of such isometric contraction parameters as amplitude of the effort developed by muscle, maximal rate, maximal acceleration, time of semirise and semifall. The obtained experimental results indicate that the functional activity of the frog pacemaker and contractile cardiomyocytes is regulated by Ca2+-dependent mechanisms. Structure of these mechanisms includes the potential-controlled Land T-channels of the plasma membrane as well as Na+,Ca2-exchangers characteristic exclusively of contractile cardiomyocytes. The existence of these differences seems to be due to the cardiomyocyte morphological peculiarities that appeared in evolution at the stage of the functional cell specialization.

Ca 2+ Signaling Domains Responsible For Cardiac Hypertrophy and Arrhythmias

See related articles, pages 514–521 and 522–530 Ca2+ activates and regulates multiple processes in every cell type. In the mammalian heart, cyclic fluctuations in cytosolic [Ca2+] induce and regulate the strength of cardiac contraction (termed “contractile” [Ca2+]). In addition, changes in Ca2+ appear to be centrally involved in normal and pathological signaling (termed “signaling” [Ca2+]) that regulates myocyte growth, hypertrophy, apoptosis, and necrosis.1 Whether or not contractile and signaling [Ca2+] are derived from common or distinct sources and are constrained to unique cellular microdomains is not established.2 What is clear is that cardiovascular diseases including hypertension and myocardial infarction are associated with alterations in contractile and possibly signaling [Ca2+] that are centrally involved in pathological cardiac hypertrophy, heart failure progression,1 and lethal cardiac arrhythmias.3 Defining the sources of signaling Ca2+ involved in the induction of pathological hypertrophy and the bases of dysregulated contractile [Ca2+] in cardiovascular disease should identify novel ways to treat heart disease. In this issue of Circulation Research , 2 independent reports address fundamental aspects of alterations in signaling and contractile [Ca2+]. Chiang et al4 have studied the idea that Ca2+ influx through voltage operated α1H (CaV3.2) T-type Ca2+ channels (TTCCs) is the source of the signaling [Ca2+] that activates the calcineurin (Cn)-NFAT (nuclear factor of activated T cells) signaling cascade and induces pathological cardiac hypertrophy in pressure overload. In a separate report, Terentyev et al5 explore the idea that microRNA (miR)-1, a muscle-specific microRNA that increases in abundance in cardiac disease,6 causes dysregulated contractile [Ca2+] and induces single cell arrhythmias. These 2 reports are provocative and, if independently confirmed, will have identified novel …

Role of acetylcholine in Ca2+-dependent regulation of functional activity of the frog Rana temporaria myocardium

To study role of acetylcholine (ACh) in Ca2+-dependent regulation of rhythm and strength of cardiac contractions in the frog Rana temporaria, we studied in parallel experiments the ACh chrono- and inotropic effects on the background of action of blockers of the potential-controlled Ca2+-channels, ryanodine and muscarine receptors. The obtained results indicate participation of acetylcholine in the Ca2+-dependent regulation of the rhythm and strength of the frog cardiac contractions.

Getting energy to where it is required is a problem in the failing heart

Getting energy to where it is required is a problem in the failing heart

Peculiarities of Ca2+-regulation of functional activity of myocardium of frog Rana temporaria

To elucidate role of intra- and extracellular Ca2+ in regulation of rhythm and strength of frog heart contractions, there were studied ECC and isometric contraction of myocardium preparations in response to verapamil, adrenaline, and blockers of alpha- and beta-adrenoreceptors. It has been shown that after an intramuscular injection of verapamil (6 mg/kg), bradycardia develops, the heart rate (HR) decreasing by 50-70 %. Further, the cardiac arrest occurred; however, administration to the animals of adrenaline (100 mg/kg) restored the cardiac rhythm for a short while. After an intramuscular injection of adrenaline at doses of 0.1-10 mg/kg, no essential changes were observed in the potential action amplitude and HR; an increase of the administered adrenalin concentration to 100 mg/kg was not accompanied by the cardiac rhythm stimulation, as this takes place in homoiothermal animals and human; on the contrary, an essential HR deceleration was revealed. Phentolamine (5 mg/kg) gradually decelerated HR rhythm by 32-45 %. The potential amplitude changed insignificantly. A subsequent intracardiac injection of adrenaline (100 mg/kg) on the background of block of alpha-adrenoreceptors produced acceleration of the rhythm (by 13-21%) and fall of the electrogram amplitude. These results can indicate that in the frog heart, phentolamine interacts predominanty with alpha-adrenoreceptors. An intracardiac administration of propranolol (1 mg/kg) to frogs promoted inhibition of beta-adrenergic receptors and produced a gradual cardiac rhythm deceleration. In experiments on assessment of verapamil effect on the character of contractions this preparation at a concentration of 150 microM was established to produce a significant dosedependent decrease of the contraction strength. A rise of verapamil concentration in the sample to 200 microM led to a decrease of the amplitude, on average, by 68-70 % and in individual preparations -- by 80-85 %; however, administration into the sample of adrenaline (10 microM) restored the cardiac contraction strength. Adrenaline (1 nM--100 microM) increased markedly the contraction amplitude. Phentolamine (10 microM) did not inhibit transmission of contractile signal to cardiomyocytes; this was manifested in that the contraction amplitude after addition of adrenaline (10 microM) into the sample was approximately the same as in the sample containing no phentolamine. Propranolol (10 microM) eliminated the stimulatory action of adrenaline (10 microM). The results of these experiments indicate that in the frog ventricular cardiomyocytes the main adrenaline acceptors are beta-adrenoreceptors.

Parasympathetic cardiac effects in sympathectomized rats

In adult sympathectomized rats the right and left vagus nerves exhibited asymmetric effects on heart rate and strength of cardiac contractions. After vagotomy, the heart rate and stroke volume remained high in sympathectomized rats, but returned to normal in intact animals. The sympathetic nervous system plays a role in postvagotomic tachycardia. Sympathectomized rats were characterized by higher reactivity of cardiac beta-adrenoceptors to propranolol compared to intact animals.

Blood magnesium concentration and dopamine or dobutamine infusion demand in patients during CABG (coronary artery bypass grafting) with normovolemic haemodilution.

It is well known that magnesium (Mg) plays an essential role in cardiac protection. Mg has many beneficial effects on the myocardium and cardiac function, e.g. it improves contractility and reduces the number of cardiac arrhythmia episodes. The inotropically positive effects of Mg are interesting and worth stressing. High blood Mg concentration may result in an increase in cardiac contraction strength, which may be important for haemodynamic stabilization, and thus it is likely to decrease the demand for dopamine and dobutamine infusions. However, the exact determination of correlation between blood Mg concentrations and dopamine or dobutamine infusion demand is still unknown. The aim of the study was to assess the demand for dopamine or dobutamine infusion in relation to changes in blood magnesium concentrations in patients undergoing CABG (Coronary artery bypass graft) with extracorporeal circulation and normovolemic haemodilution. The study included 20 male patients, aged 53-70 (61.1 +/- 6.9) who underwent general anaesthesia and coronary artery bypass grafting (CABG) with extracorporeal circulation (ECC) and normovolemic haemodilution (NH) due to stable angina pectoris. The patients were retrospectively divided into three groups: A--patients who did not receive dopamine or dobutamine infusion, B--those receiving only D infusion in the doses dependent on their clinical state and C--those receiving DB infusion in the doses dependent on their clinical state. Mg was measured in 7 stages: 1) just before anaesthesia after the radial artery cannulation, 2) during normovolemic haemodilution and ECC, 3) immediately after surgery, 4) in the evening of the surgery day, 5) in the morning of the lst postoperative day, 6) in the evening of 1st postoperative day, 7) in the morning of the 2nd postoperative day. The spectrophotometric methods were used to determine Mg. The CABG procedure resulted in a decrease in Mg. Its level returned to normal in the evening of surgery day. The NH caused a similar Mg decrease in groups A, B and C, but these significantly low values of Mg were observed only in stage 2. There was no correlation between blood Mg concentrations and dopamine or dobutamine infusion demand. 1) The CABG procedure resulted in decreased blood magnesium concentrations. 2) The Mg changes do not correlate with dopamine or dobutamine infusion demand.

Nitric oxide inhibits the rate and strength of cardiac contractions in the lobster Homarus americanus by acting on the cardiac ganglion.

The lobster heart is synaptically driven by the cardiac ganglion, a spontaneously bursting neural network residing within the cardiac lumen. Here, we present evidence that nitric oxide (NO) plays an inhibitory role in lobster cardiac physiology. (1) NO decreases heartbeat frequency and amplitude. Decreased frequency is a direct consequence of a decreased ganglionic burst rate. Decreased amplitude is an indirect consequence of decreased burst frequency, attributable to the highly facilitating nature of the synapses between cardiac ganglion neurons and muscle fibers (although, during prolonged exposure to NO, amplitude recovers to the original level by a frequency-independent adaptation mechanism). NO does not alter burst duration, spikes per burst, heart muscle contractility, or amplitudes of synaptic potentials evoked by stimulating postganglionic motor nerves. Thus, NO acts on the ganglion, but not on heart muscle. (2) Two observations suggest that NO is produced within the lobster heart. First, immunoblot analysis shows that nitric oxide synthase (NOS) is strongly expressed in heart muscle relative to other muscles. Second, L-nitroarginine (L-NA), an NOS inhibitor, increases the rate of the heartbeat (opposite to the effects of NO). In contrast, the isolated ganglion is insensitive to L-NA, suggesting that heart muscle (but not the ganglion) produces endogenous NO. Basal heart rate varies from animal to animal, and L-NA has the greatest effect on the slowest hearts, presumably because these hearts are producing the most NO. Thus, because the musculature is a site of NOS expression, whereas the ganglion is the only intracardiac target of NO, we hypothesize that NO serves as an inhibitory retrograde transmitter.

Nitric Oxide Inhibits the Rate and Strength of Cardiac Contractions in the Lobster Homarus americanus by Acting on the Cardiac Ganglion

Nitric Oxide Inhibits the Rate and Strength of Cardiac Contractions in the Lobster Homarus americanus by Acting on the Cardiac Ganglion