Positive Chronotropic Responses Research Articles

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Pacemaker activity in the insect (T. molitor) heart: role of the sarcoplasmic reticulum

The electrophysiological properties of the myogenic cardiac cells of insects have been analyzed, but the mechanisms that regulate the pacemaker activity have not been elucidated yet. In mammalian pacemaker cells, different types of membrane ion channels seem to be sequentially activated, perhaps in a cooperative fashion with the current generated by Ca(2+) extrusion mediated by the electrogenic Na(+)/Ca(2+) exchanger, which is sustained by the diastolic sarcoplasmic reticulum (SR) Ca(2+) release. The objective of the present work was to investigate the role of the SR function on the basal beating rate (BR), and BR modulation by extracellular Ca(2+) concentration ([Ca(2+)](o)) and neurotransmitters in the in situ dorsal vessel (heart) of the mealworm beetle Tenebrio molitor. The main observations were as follows: 1) basal BR was reduced by 50% by inhibition of SR function, but not affected by perfusion with CsCl or ZD7288; 2) spontaneous activity was abolished by Cd(2+); 3) a robust positive chronotropic response could be elicited to serotonin (5-HT), but not to norepinephrine or carbamylcholine; 4) SR inhibition abolished the sustained chronotropic stimulation by [Ca(2+)](o) elevation and by 5-HT, while the latter was unaffected by CsCl. It is concluded that, in T. molitor heart, BR is markedly, but not exclusively, dependent on the SR function, and that BR control and modulation by both [Ca(2+)](o) and 5-HT requires a functional SR.

Evidence from agonist and antagonist studies to suggest that the beta1-adrenoceptors subserving the positive inotropic and chronotropic responses of the heart do not belong to two separate subgroups.

The positive inotropic and chronotropic responses of guinea-pig isolated left and right atria to 17 sympathomimetic amines were examined under conditions selected to control the pharmacological environment. Each agonist was compared with (--)-isoprenaline as the reference by constructing dose-response curves. Equiactive molar concentration ratios relative to (--)-isoprenaline were calculated at the EC50 for rate and tension responses. Statistical analysis revealed that (--)-noradrenaline and (+/-)-alpha-methylnoradrenaline were tension selective whereas (+/-)-alpha-ethylisoprenaline and N-methyldopamine were rate selective relative to (--)-isoprenaline. However, no structural trends emerged. The rank order of potency varied slightly between rate and tension, but an analysis of the regression and correlation coefficients indicated respectively that the equiactive molar concentration ratios and the rank orders could be considered identical on rate and tension. Antagonism of the (--)-isoprenaline-induced rate and tension responses by acebutolol, atenolol, practolol and propranolol was assessed from the pA2 values which were almost identical for both parameters with each antagnosti. It is concluded that the beta1-adrenoceptors mediating the positive inotropic and chronotropic responses do not warrant subdivision into two separate groups.

Inotropic and chronotropic effects of 4-(4'-n-butylaniline)-7,8- dimethoxy-5H-pyrimido[5,4-b]indole in guinea-pig atria.

Cardiotonic effect of 4-(4'-n-butylaniline)-7,8-dimethoxy- 5H-pyrimido[5,4-b]indole (B11) was investigated in isolated cardiac tissue preparations. The action of this agent on force of contraction, beating frequency and cyclic nucleotide phosphodiesterase (PDE) activity was studied. Amrinone was used for comparison. B11 produced concentration-dependent (5 x 10(6)-1 x 10(-4)M) positive inotropic and positive chronotropic responses in guinea-pig atrial tissues. The potency of B11 was greater than that of amrinone. The cardiotonic effects of B11 were not modified by beta-adrenoceptor blockade. Carbachol inhibited the positive inotropic effect of B11. The activity of B11 was increased in desensitized left atrial tissues. B11 inhibited the activities of PDE isoenzymes (type I, II, IV and V) from dog heart ventricle and PDE type IV from guinea-pig heart ventricle nonselectively. It is concluded that B11 possesses potent positive inotropic activity in guinea-pig atria, and the effect is probably mediated by a non-selective inhibition of PDE activity.

Cardioregulatory properties of indoramin in the rat.

The antihypertensive action of the competitive alpha-adrenoceptor antagonist indoramin is not accompanied by reflex tachycardia in animals or man. The possibility that the established local anaesthetic property of indoramin is involved in its cardioinhibitory action has been investigated. Indoramin evoked a dose-dependent bradycardia in anaesthetized/pithed rats. The decrease in heart rate was slightly greater than that evoked in anaesthetized intact animals suggesting that indoramin had a direct action on the heart. Reflex tachycardia was simulated in pithed rats be increasing the frequency of cardiac nerve stimulation from 0.3 to 1 Hz. Indoramin and the local anaesthetic agents, lignocaine and procaine, reduced the positive chronotropic response without markedly altering the basal rate. The response curves were parallel. In contrast, phentolamine decreased the positive chronotropic response, but only at high doses which were associated with a marked decrease in the basal rate. Thymoxamine and prazosin had so significant effects on the chronotropic response. These experiments suggest that the cardioregulatory action of indoramin is attributable to its local anaesthetic property had this action further distinguishes it from the other alpha-adrenoceptor antagonists tested.

Catecholamine uptake blockade in anaesthetized dogs: influence on cardiovascular responses.

The effects of differential and combined catecholamine uptake antagonism on cardiovascular responses of anaesthetized dogs to isoprenaline, noradrenaline, and electrical stimulation of the left ansa subclavia nerve have been studied. Uptake1 inhibition by cocaine HCl (5 mg kg-1 and 1 mg kg-1 every 45 min) enhanced responses to noradrenaline (0.1 to 2.0 micrograms kg-1 i.v.) and sympathetic nerve stimulation (1 to 20 Hz), but did not affect those to isoprenaline. Uptake2 inhibition by metanephrine (40 micrograms kg-1 min-1) enhanced cardiac responses to isoprenaline (0.05 to 1.0 microgram kg-1 i.v.), but did not significantly alter those to noradrenaline or nerve stimulation. Responses to all agonist interventions were increased by the combined administration of cocaine and metanephrine. Cocaine preferentially enhanced the positive chronotropic cardiac response to noradrenaline, but metanephrine did not differentiate between heart rate and contractility. These results have been discussed in the light of the mechanism of drug action involved.

Cardiac reactivity in rats with acute renal failure.

Cardiac reactivity has been determined in rats with acute renal failure (ARF) induced by either bilateral nephrectomy or intramuscular glycerol injection. Rats with bilateral nephrectomy showed reduced chronotropic responses to cervical sympathetic stimulation but no appreciable alteration in the chronotropic responses to vagal stimulation. By contrast, we have previously noted that rats with glycerol-induced ARF show diminished chronotropic responses to stimulation of both nerves. The negative chronotropic and inotropic responses to carbachol in isolated atria from both nephrectomized and glycerol-injected rats were not significantly different from their respective controls. In both models of ARF the atrial positive chronotropic responses to isoprenaline were significantly decreased whilst positive inotropic responses were not significantly different from controls. The results indicate that the cause of the reduced chronotropic response to vagal stimulation observed in glycerol-injected rats is of presynaptic origin whilst the reduced chronotropic response to cervical sympathetic stimulation noted in both models of ARF may be due to an impaired postsynaptic response.

The Effects of Opioid Peptides on Cardiovascular Function and Sympathetic Neurotransmission in Rats

Abstract The haemodynamic effects of three opioid receptor agonists, with some preferential activity on δ-, μ- and κ-receptors were investigated in anaesthetized and pithed rats, and effects on sympathetic neurotransmission were also investigated in pithed rats. In anaesthetized rats, d-Ala2-d-Leu5-enkephalin (DADLE) (a predominantly δ-receptor agonist, 10 μg kg−1), glyol (μ, 0·5 mg kg−1) and R,S-N-C2-N-methyl-3,4,dichloro-phenylacetamido-2-C3-carboxy phenylethyl-pyrrolidine (ICI 204448) (·, 0·1 mg kg−1) by intravenous administration transiently decreased heart rate from 462 ± 12 to 432 ± 14, 460 ± 12 to 448 ± 13 and 460 ± 12 to 448 ± 11 beats min−1, respectively, and mean arterial blood pressure from 142 ± 6 to 111 ± 9, 141 ± 6 to 122 ± 5 and 148 ± 7 to 121 ± 6 mmHg, respectively. The effects of DADLE, but not those of glyol or ICI 204448, were blocked by M8008, a δ-receptor antagonist. In pithed rats, none of the opioid agonists had any significant effects on heart rate or mean arterial blood pressure; however, acetylcholine significantly reduced both heart rate and mean arterial blood pressure. All three opioid agonists reduced the positive chronotropic response to thoracic (C7-T2) spinal cord stimulation in pithed rats, by 17 ± 4,30 ± 2 and 20 ± 10% for DADLE, glyol and ICI 204448, respectively. This compared with a 48 ± 15% reduction with clonidine (5 μ kg−1). This effect of DADLE was almost abolished by M8008. It is concluded that the haemodynamic effects of the opioid agonists studied are mediated via actions on the central nervous system and that a decrease in sympathetic neurotransmission may account for, at least in part, the bradycardia produced by opioid agonists in intact anaesthetized rats. It seems that the sympathetic nervous system is unlikely to be involved in the arrhythmogenic effects of opioid peptides.

Sympathomimetic actions of methylenedioxymethamphetamine in rat and rabbit isolated cardiovascular tissues.

The aim of this study was to investigate the actions of methylenedioxymethamphetamine (MDMA) in several isolated cardiovascular tissues. In spontaneously beating rat atria, concentration-dependent positive chronotropic responses to MDMA and amphetamine were blocked by the neuronal-uptake inhibitor desipramine (1 microM) and the beta-adrenoceptor antagonist propranolol (1 microM). In atria incubated with [3H]noradrenaline to label transmitter stores, 10 microM MDMA and 1 microM amphetamine increased the resting outflow of radioactivity, while 1 microM desipramine had no effect on resting outflow. The MDMA- and amphetamine-induced release of radioactivity were blocked by 1 microM desipramine. MDMA, amphetamine and desipramine each enhanced the electrical stimulation-induced (2 Hz, 30-s train) release of radioactivity; the enhancing effects of MDMA and amphetamine were blocked by 1 microM desipramine. In rat isolated perfused hearts, MDMA (1 and 10 microM) increased heart rate by a similar amount to the increase caused by noradrenaline (10 and 50 nM). MDMA also induced dysrhythmias in 7 out of 11 rat isolated perfused heart preparations. In rabbit isolated perfused and superfused ear arteries preloaded with [3H]noradrenaline, MDMA increased the resting release of radioactivity by 230 +/- 18% (n = 6) of control resting release; the increase was accompanied by a rise in perfusion pressure of 17 +/- 7 mmHg (n = 6). MDMA also facilitated the vasoconstrictor responses to noradrenaline (3-9 ng) and perivascular nerve stimulation (1-5 Hz, 10-s train). MDMA-induced vasoconstriction and the facilitation of vasoconstrictor responses to noradrenaline and electrical stimulation were blocked by 1 microM desipramine.(ABSTRACT TRUNCATED AT 250 WORDS)

Fractalkine in human inflammatory cardiomyopathy

BackgroundCardiac inflammation is important for the prognosis of patients with inflammatory cardiomyopathy (CMi), but the mechanisms leading to it are not fully elucidated.ObjectiveTo study the role of fractalkine (CX3CL1) in...

RyR2(R 4496C) Expression Induces Sinoatrial Node Dysfunction

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an arrhythmogenic disease characterized by stress-triggered syncope and sudden death. While ventricular tachycardia appears only during stress conditions, CPVT patients manifest basal sino-atrial node (SAN) dysfunction, but the underlying mechanism remains unknown. We investigated Ca2+ handling on SAN from transgenic mice expressing the CPVT ryanodine receptor R4496C mutation (RyR2R4496C) and on their wild type (WT) littermates. A 2-fold increase of Ca2+ spark frequency in RyRR4496C SAN cells was recorded in basal conditions during the diastolic periods. beta-adrenergic stimulation with 20 nM isoproterenol, multiplied by ∼10-fold the occurrence of Ca2+ sparks and Ca2+ waves. Spontaneous [Ca2+]i transients recorded by confocal microscope in isolated SAN from RyR2R4496C mice presented a slower beating rate than WT SAN and an impaired positive chronotropic response to beta-adrenergic stimulation. Moreover, isoproterenol induced the appearance of [Ca2+]i transients and action potentials pauses in 75% of RyR2R4496C SAN cells. Caffeine experiments showed that the sarcoplasmic reticulum (SR) Ca2+ load was significantly reduced in the RyR2R4496C SAN cells. In vivo telemetric recordings of electrocardiograms (ECG) identified atrial and junctional escape beats overcoming sinus pauses in RyR2R4496C mice following isoproterenol injection consistent with the pauses recorded in isolated SAN. Similar ECGs were observed in CPVT patients during exercise testing, validating the animal model. We conclude that the increased activity of the RyR2R4496C SAN cells during diastolic periods unloads the SR with Ca2+, participating in SAN dysfunction in CPVT.

To the Editor—Biological Pacemakers Exhibit Positive Chronotropic Response to Emotional Arousal

To the Editor—Biological Pacemakers Exhibit Positive Chronotropic Response to Emotional Arousal

Biological pacemakers in canines exhibit positive chronotropic response to emotional arousal

Biological pacemakers based on the HCN2 channel isoform respond to beta-adrenergic and muscarinic stimulation, suggesting a capacity to respond to autonomic input. The purpose of this study was to investigate autonomic response to emotional arousal in canines implanted with murine HCN2-based biological pacemakers using gene therapy. An electronic pacemaker was implanted with its lead in the right ventricular apical endocardium (VVI 35 bpm). An adenoviral HCN2/GFP construct (Ad-HCN2, n = 7) or saline (control, n = 5) was injected into the left bundle branch on day 2 after radiofrequency ablation of the atrioventricular node to induce complete atrioventricular block. Emotional arousal was achieved by presenting food following an overnight fast. Autonomic control was evaluated with Poincaré plots of R-R(N) against R-R(N+1) intervals to characterize heart rate variability (HRV) and with continuous RR interval assessment via 24-hour ambulatory ECG. The 24-hour ECG and Poincaré plot shape were analyzed. During day 1 after biological pacemaker implantation, Poincaré HRV parameters and RR intervals were unchanged with food presentation. However, on day 7, food presentation was accompanied by an increase in HRV (SD1, p < 0.07, and SD2, p < 0.05) and shortening of RR interval (P < .05) in dogs with Ad-HCN2 but not in controls. This is the first demonstration that biological pacemakers are capable of responding to natural arousal stimuli to elicit appropriate chronotropic responses, a potential advantage over electronic pacemakers.

Alpha-adrenergic responsiveness in rat isolated perfused heart after abdominal aortic coarctation.

Chronic isoproterenol pre-treatment, a well-known model of compensatory hypertrophy associated with cardiac beta-adrenoceptor desensitization, enhances the inotropic response to phenylephrine in rat isolated perfused hearts, supporting the hypothesis that myocardial alpha-adrenoceptor stimulation contributes to the maintenance of myocardial performance in situations in which cardiac beta-adrenoceptor function is compromised. To further corroborate this hypothesis, the effects of abdominal aortic coarctation on cardiac alpha-adrenergic responsiveness were investigated in Langendorff heart preparations. Abdominal aortic coarctation causes cardiac hypertrophy (21%) as shown by a significant increase in the ratio of ventricular dry weight to bodyweight. In preparations from hypertrophied rats, both maximum increases in left ventricular systolic pressure and heart rate elicited by isoproterenol (10(-12) to 10(-4) M) were significantly reduced (the isoproterenol concentration producing 50% of the maximum positive inotropic and chronotropic responses was enhanced almost 21- and 2-fold, respectively). However, the positive inotropic response to phenylephrine (10(-12) to 10(-4) M) remained unaffected following abdominal aortic coarctation, when compared with sham-operated rats. In preparations from both groups, phenylephrine infusion did not induce significant changes in heart rate. These results show that although abdominal aortic stenosis induced desensitization of cardiac beta-adrenoceptors, it did not enhance cardiac alpha-adrenoceptor responsiveness. This suggests that such an enhancement depends on the experimental model used to induce cardiac hypertrophy associated with desensitization of cardiac beta-adrenoceptors.

The period between beta-blocker use and physical activity changes training heart rate behavior

The Brazilian Society of Cardiology (SBC) proposes that hypertensive subjects who use beta-blockers and practice physical exercises must have their training heart rate (HR) corrected due to the negative chronotropic effect of this drug. Nevertheless, if the physical activity is performed outside of plasmatic half-life, correction may not be necessary. This study investigated the exercise chronotropic response both inside and outside the beta-blocker plasmatic half-life. Nine subjects in use of atenolol or propranolol, and six controls, carried out three walking sessions in three days according to different schedules: EX2 (two hours after drug administration, at the plasmatic peak); EX11 (eleven hours after drug administration, at the end of plasmatic half-life); and EX23 (twenty-three hours after drug administration, outside the plasmatic half-life. The walking sessions were performed on an ergometric treadmill and HR was monitored by a heart rate monitor. During the exercises, mean HRs were 97.2, 108.4 and 109 for EX2, EX11 and EX23, respectively, with the value for EX2 statistically lower than the others (p&lt;0.05). There were no statistical differences in the control group (p&gt;0.05). The study concludes that the attenuation of the positive chronotropic response which occurs during exercise in subjects using beta-blockers, is less evident when the exercise is performed outside the plasmatic half-life of the drug.

Effects of β-Adrenergic Blocking Agents on Positive Chronotropic Responses to Exercise in Conscious Dogs

Effects of β-Adrenergic Blocking Agents on Positive Chronotropic Responses to Exercise in Conscious Dogs

Sympathetic control of heart rate in nNOS knockout mice

Inhibition of neuronal nitric oxide synthase (nNOS) in cardiac postganglionic sympathetic neurons leads to enhanced cardiac sympathetic responsiveness in normal animals, as well as in animal models of cardiovascular diseases. We used isolated atria from mice with selective genetic disruption of nNOS (nNOS(-/-)) and their wild-type littermates (WT) to investigate whether sympathetic heart rate (HR) responses were dependent on nNOS. Immunohistochemistry was initially used to determine the presence of nNOS in sympathetic [tyrosine hydroxylase (TH) immunoreactive] nerve terminals in the mouse sinoatrial node (SAN). After this, the effects of postganglionic sympathetic nerve stimulation (1-10 Hz) and bath-applied norepinephrine (NE; 10(-8)-10(-4) mol/l) on HR were examined in atria from nNOS(-/-) and WT mice. In the SAN region of WT mice, TH and nNOS immunoreactivity was virtually never colocalized in nerve fibers. nNOS(-/-) atria showed significantly reduced HR responses to sympathetic nerve activation and NE (P < 0.05). Similarly, the positive chronotropic response to the adenylate cyclase activator forskolin (10(-7)-10(-5) mol/l) was attenuated in nNOS(-/-) atria (P < 0.05). Constitutive NOS inhibition with L-nitroarginine (0.1 mmol/l) did not affect the sympathetic HR responses in nNOS(-/-) and WT atria. The paucity of nNOS in the sympathetic innervation of the mouse SAN, in addition to the attenuated HR responses to neuronal and applied NE, indicates that presynaptic sympathetic neuronal NO does not modulate neuronal NE release and SAN pacemaking in this species. It appears that genetic deletion of nNOS results in the inhibition of adrenergic-adenylate cyclase signaling within SAN myocytes.

Cardiac effects of L/N-type Ca 2+ channel blocker cilnidipine in anesthetized dogs

Cardiac effects of L/N-type Ca 2+ channel blocker cilnidipine were assessed using the halothane-anesthetized canine model. Cilnidipine (1 and 3 μg/kg, i.v.) lowered the mean blood pressure by − 5 and − 14 mm Hg, respectively, without affecting the heart rate or maximum upstroke velocity of left ventricular pressure. Isoproterenol or acetylcholine was intravenously injected to directly or indirectly induce the positive chronotropic responses, respectively. Cilnidipine hardly affected the isoproterenol-induced cardiac responses, but it attenuated the acetylcholine-induced reflex tachycardia to 63–78% of the pre-drug control level. These results suggest that clinically relevant doses of cilnidipine can directly attenuate the sympathetic tone.

Heterogeneity and prediction of hemodynamic responses to dobutamine in patients with septic shock

To establish the heterogeneity of hemodynamic responses to dobutamine in patients with septic shock and to identify the predictive factors of these hemodynamic responses. Prospective study. A total of 12 patients with septic shock in a tertiary medical intensive care unit. A 20-min dobutamine infusion at 5 microg.kg(-1).min(-1) with subsequent increments to 8, 12.6, and 20 microg.kg(-1).min(-1), on two consecutive days. Responses were dichotomized into changes in heart rate (HR) or stroke volume index (SVI) of >10% and < or =10% at the maximal dobutamine infusion. No differences were found in survival, Acute Physiology and Chronic Health Evaluation II score, maximal dobutamine doses, or pharmacokinetics of dobutamine between HR and SVI groups. In DeltaHR > 10% vs. DeltaHR < or = 10%, baseline HR was lower, and baseline mixed venous oxygen tension and saturation were higher. During dobutamine infusion, mean arterial pressure decreased in DeltaHR > 10%. Cardiac index and the systemic oxygen delivery index increased and the systemic vascular resistance index decreased at unchanged SVI. Pressure work index increased and the ratio of the diastolic to systolic aortic pressure time indices decreased but not to <0.6. In DeltaHR < or = 10%, systemic vascular resistance index and the ratio of the diastolic to systolic aortic pressure time indices decreased (but remained >0.6) without changes in SVI or cardiac index. Baseline hemodynamic and metabolic variables did not differ between SVI groups. In DeltaSVI > 10%, cardiac index increased with dobutamine, but Pao2 and the systemic oxygen delivery index decreased. In DeltaSVI < or = 10%, HR and the systemic oxygen delivery index increased; mean arterial pressure, left ventricular stroke work index, systemic vascular resistance index, and the ratio of the diastolic to systolic aortic pressure time indices decreased. Patients with a positive chronotropic response to dobutamine had lower baseline HR values, and a chronotropic rather than inotropic response predicted an increase in cardiac index and systemic oxygen delivery index. Incremental dosages of dobutamine did not compromise indirectly measured myocardial oxygen balance.

Changes in Atrium and Thoracic Aorta Reactivity to Adenosinergic and Adrenergic Agonists in Experimental Hyperhomocysteinemia

We prepared diet-induced hyperhomocysteinemia (hHcy) in adult male Wistar rats and investigated the effects of hHcy on the adenosinergic and adrenergic responses in vitro and in vivo. The responsiveness of right atria from hHcy rats to the negative chronotropic effects of adenosine (Ado) was found to be significantly greater in hHcy rats than in controls. The pD2 value and maximum effect of Ado were significantly increased in 12-week hHcy right atria when compared with those from age-matched controls. The vasodilatory effect of Ado on rat thoracic aorta was also increased in hHcy rats. In the presence of dipyridamole, an Ado uptake inhibitor, the negative chronotropic and vasodilatory effects of Ado were significantly potentiated in the hHcy rats much more than in the control rats. In anesthetized rats, Ado and dipyridamole, given as a rapid bolus into the femoral artery, led to reduction in mean blood pressure and heart rate. This effect was significantly pronounced in hHcy rats when compared with control animals. Otherwise, hHcy atria were found to have increased responsiveness to the positive chronotropic response to isoproterenol, an beta-adrenoceptor agonist. However, there were no significant differences between two groups in the vasoconstrictor effects to phenylephrine, an alpha-adrenoceptor agonist. On the basis of these results, we concluded that hHcy rats were significantly more sensitive to the negative chronotropic and vasorelaxant effects of Ado, possibly because of accelerated cellular Ado uptake and/or a change in Ado receptor-G protein system. This change may be related with the increased responsiveness to beta-adrenergic agonists in hHcy rats, and might contribute to the harmful cardiac effects of hHcy.