Contribution of IK,ADO to the negative dromotropic effect of adenosine

Martynyuk, Anatoly E.; Seubert, Christoph N.; Zima, Aleksey V.; Morey, Timothy E.; Belardinelli, Luiz; Lin, Guilan; Cucchiara, Roy F.; Dennis, Donn M.

doi:10.1007/s00395-002-0349-8

Cited by 9 publications

(8 citation statements)

References 22 publications

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“…There is considerable scope for this, for example in determining the functional consequences for AVN activity of two I K components rather than one, and also (through comparative experiments on rabbit and guineapig AVN cells) the consequences of the presence/absence of an I to . Furthermore, whilst recent studies of adenosine have combined data from the guinea-pig heart with data from isolated rabbit AVN cells [26,27,45], adenosine has been shown to produce species-dependent effects on atrio-ventricular conduction [9]. Data from the two species have been combined because 'AV nodal cells have only been successfully isolated from rabbit heart', whilst 'the AV nodal effects of adenosine in guinea-pigs are more similar to those in humans' [27].…”

Section: Implications Limitations and Conclusionmentioning

confidence: 95%

“…Furthermore, whilst recent studies of adenosine have combined data from the guinea-pig heart with data from isolated rabbit AVN cells [26,27,45], adenosine has been shown to produce species-dependent effects on atrio-ventricular conduction [9]. Data from the two species have been combined because 'AV nodal cells have only been successfully isolated from rabbit heart', whilst 'the AV nodal effects of adenosine in guinea-pigs are more similar to those in humans' [27]. Thus, the availability of a guinea-pig single cell AVN preparation may facilitate and extend cellular electrophysiological investigations of adenosine on this region of the heart, and may also be of value in studying other receptor-mediated responses.…”

Section: Implications Limitations and Conclusionmentioning

confidence: 98%

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Characteristics of single cells isolated from the atrioventricular node of the adult guinea-pig heart.

Yuill¹,

Hancox²

2002

Pfl�gers Archiv European Journal of Physiology

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To date, data regarding the cellular electrophysiology of the atrioventricular node (AVN) have derived from AVN cells isolated from the rabbit heart. The aim of this study was to characterise for the first time the electrophysiological properties of single cells isolated from the AVN of the guinea-pig heart. Cells were isolated from the AVN region by a combination of enzymatic and mechanical dispersion. Mean (+/-SEM) cell dimensions were 110.8+/-2.3 microm in length by 11.4+/-1.3 micro m in width (n=76 cells). Electrophysiological recordings were made using the whole-cell patch-clamp technique at 37 degrees C. Mean cell capacitance was 25.1+/-0.9 pF (n=43) and mean cell input resistance was 1,377+/-178 Muomega (n=21). Spontaneously active cells exhibited action potentials characteristic of cardiac pacemaker tissue. Under whole-cell voltage clamp, the mean 'zero current' potential was -39.7+/-4.1 mV (n=21). Voltage commands of 500 ms duration to a range of test potentials from a holding potential of -40 mV revealed a number of distinct current components. At potentials positive to -40 mV an early inward current was observed that exhibited a bell-shaped current voltage (I-V) relation, typical of L-type calcium current. A delayed outward current that increased progressively with test potential magnitude was also observed. Analysis of the outward current 'tails' on repolarisation to -40 mV showed this to be comprised of two components with half-maximal activation voltages of -17.2+/-1.8 mV, and +27.1+/-3.6 mV (n=13). 'Transient outward' current appeared absent from guinea-pig AVN cells. Hyperpolarising test pulses activated net inward current, for which three components could be observed: a barium-sensitive (100 microM Ba(2+)) inwardly rectifying current evident at the start of the voltage command and prominent at potentials negative to the diastolic potential range; a time-dependent, hyperpolarisation-activated current, and a residual background current. On repolarisation to -40 mV, a large inward current spike typical of cardiac Na current was observed in some cells. Notably, the following electrophysiological characteristics of guinea-pig AVN cells are distinct from those characteristics previously reported for the rabbit AVN: (1) an absence of transient outward current, (2) the presence of two components of delayed outward current, and (3) the presence of a Ba(2+)-sensitive inwardly rectifying current at negative voltages. The guinea-pig AVN isolated cell preparation may be valuable in providing additional insights into the cellular electrophysiology of this important region of the heart.

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Section: Implications Limitations and Conclusionmentioning

confidence: 95%

Section: Implications Limitations and Conclusionmentioning

confidence: 98%

Characteristics of single cells isolated from the atrioventricular node of the adult guinea-pig heart.

Yuill¹,

Hancox²

2002

Pfl�gers Archiv European Journal of Physiology

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“…Furthermore, the negative dromotropic effect of adenosine is not diminished in vivo in mice lacking I K,ACh (35), so I K,ACh is probably not involved in this pathway. In fact, work in guinea pig and rabbit AV nodal cells indicates that adenosine mediates its negative dromotropic effects at concentrations smaller than 2 M (which are probably reached in normoxia) rather via activation of a potassium current with delayed rectifying properties [guinea pig AV nodal cells (22)]. Taken together, these findings may suggest that A 1 AR couple to different ion channels with different efficiency, using different G proteins as signal transductors.…”

Section: Av Nodal Conduction Delaymentioning

confidence: 99%

Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A₁ adenosine receptor

Kirchhof

Fabritz²,

Fortmüller³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor. Am J Physiol Heart Circ Physiol 285: H145-H153, 2003. First published March 13, 2003 10.1152/ ajpheart.01036.2002To investigate whether altered function of adenosine receptors could contribute to sinus node or atrioventricular (AV) nodal dysfunction in conscious mammals, we studied transgenic (TG) mice with cardiac-specific overexpression of the A 1 adenosine receptor (A1AR). A Holter ECG was recorded in seven freely moving littermate pairs of mice during normal activity, exercise (5 min of swimming), and 1 h after exercise. TG mice had lower maximal heart rates (HR) than wild-type (WT) mice (normal activity: 437 Ϯ 18 vs. 522 Ϯ 24 beats/min, P Ͻ 0.05; exercise: 650 Ϯ 13 vs. 765 Ϯ 28 beats/min, P Ͻ 0.05; 1 h after exercise: 588 Ϯ 18 vs. 720 Ϯ 12 beats/min, P Ͻ 0.05; all values are means Ϯ SE). Mean HR was lower during exercise (589 Ϯ 16 vs. 698 Ϯ 34 beats/min, P Ͻ 0.05) and after exercise (495 Ϯ 16 vs. 592 Ϯ 27 beats/min, P Ͻ 0.05). Minimal HR was not different between genotypes. HR variability (SD of RR intervals) was reduced by 30% (P Ͻ 0.05) in TG compared with WT mice. Pertussis toxin (n ϭ 4 pairs, 150 g/kg ip) reversed bradycardia after 48 h. TG mice showed first-degree AV nodal block (PQ interval: 42 Ϯ 2 vs. 37 Ϯ 2 ms, P Ͻ 0.05), which was diminished but not abolished by pertussis toxin. Isolated Langendorffperfused TG hearts developed spontaneous atrial arrhythmias (3 of 6 TG mice vs. 0 of 9 WT mice, P Ͻ 0.05). In conclusion, A 1AR regulate sinus nodal and AV nodal function in the mammalian heart in vivo. Enhanced expression of A 1AR causes sinus nodal and AV nodal dysfunction and supraventricular arrhythmias. heart rate regulation; autonomous nervous system; heart rate variability; sinus node dysfunction; atrioventricular block; atrial fibrillation

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“…The substrate of this phenomenon remains to be clarified, although complex interaction among different electrophysiological and molecular mechanisms is likely to be involved. These include a direct effect on the activation of the inward rectifier potassium current I(K, Ado), which produces hyperpolarization and depression in AV-conduction, 76 and an indirect effect of antagonism on catecholaminestimulated adenylate cyclase activity, which occurs through coupling with guanosine triphosphate-binding inhibitory proteins.…”

Section: Probability Of Success (%)mentioning

confidence: 99%

Heart rate is a predictor of success in the treatment of adults with symptomatic paroxysmal supraventricular tachycardia

Ballo

Bernabò

Faraguti

2004

European Heart Journal

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Aims To analyse whether heart rate may affect the efficacy of adenosine, verapamil and carotid sinus massage in terminating symptomatic episodes of paroxysmal supraventricular tachycardia (PSVT) in adults. Methods and results The study population was selected among 175 adult patients, affected by symptomatic PSVT. One hundred and six of them were considered eligible for the study. Each subject received one of the following treatments: verapamil, 5 mg intravenously (IV) in 5-10 min, followed by 1-5 lg/kg/min; adenosine, 6 mg IV, followed by 12 mg IV after 2-3 min; carotid sinus massage. Adenosine and verapamil were similarly effective in terminating PSVT (74.4% vs 81.8%, P ¼ 0:45). The efficacy of carotid sinus massage was significantly lower in comparison with the other two groups (32.4%, P ¼ 0:00032 vs adenosine and P ¼ 0:000044 vs verapamil group). At logistic regression, PSVT rate showed a positive association with the percentage of sinus rhythm restoration in the group who received adenosine (P ¼ 0:0004). The probability of success in resolving the tachycardia following treatment with adenosine was >75% for heart rates over 166 beats per minute (bpm), but rapidly decreased at lower frequencies, reducing to 25% at 138 bpm. In the verapamil group, PSVT rate was negatively related to the percentage of sinus rhythm restoration (P ¼ 0:018). The probability of success in terminating PSVT following administration of verapamil was >75% for heart rates lower than 186 bpm, but tended to decrease at faster rates, reducing to 25% at 241 bpm. No significant effects of heart rate were observed in the carotid sinus massage group (P ¼ 0:17). The probability curves obtained in the adenosine and verapamil group crossed at a point corresponding to 173 bpm, which may represent a cut-off value to predict which treatment could ensure higher rate of success. Conclusions Heart rate predicts restoration of sinus rhythm in adult subjects with symptomatic episodes of PSVT treated with adenosine and verapamil. Adenosine is highly effective in PSVT characterised by fast rates, whereas the efficacy of verapamil is increased in patients with low-frequency PSVT.

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Contribution of IK,ADO to the negative dromotropic effect of adenosine

Abstract: I(K,ADO) contributes significantly to the negative dromotropic effect of adenosine, but predominantly at relatively high concentrations of the nucleoside.

Cited by 9 publications

References 22 publications

Characteristics of single cells isolated from the atrioventricular node of the adult guinea-pig heart.

Characteristics of single cells isolated from the atrioventricular node of the adult guinea-pig heart.

Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A₁ adenosine receptor

Heart rate is a predictor of success in the treatment of adults with symptomatic paroxysmal supraventricular tachycardia

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