Nonexocytotic noradrenaline release and ventricular fibrillation in ischemic rat hearts

Kurz, Thomas; Offner, Bertram; Schreieck, Jürgen; Richardt, Gert; Tölg, Ralph; Schömig, Albert

doi:10.1007/bf00169382

Cited by 29 publications

(29 citation statements)

References 13 publications

(12 reference statements)

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“…20,23,24 Most recently, we found that the attenuation of NE overflow after ischemia/reperfusion resulted in a marked improvement in postischemic cardiac dysfunction in isolated rat hearts. 33 Several investigations have also indicated that there is a direct correlation between NE release and the severity of reperfusion arrhythmia in postischemic guinea pig, 23 rat, 43 and mouse 44 hearts. Furthermore, it has been demonstrated that increased plasma NE levels in patients with asymptomatic left ventricular dysfunction appear to predict all-cause and cardiovascular mortality and the development of clinical events related to the onset of heart failure or acute ischemic syndromes.…”

Section: Discussionmentioning

confidence: 99%

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

et al. 2005

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Background-Endothelin (ET)-1 and norepinephrine (NE) are involved in myocardial ischemia/reperfusion injury. We investigated the role of ET-1 in ischemia/reperfusion-induced NE overflow and cardiac dysfunction using a selective ET A receptor antagonist (ABT-627), a selective ET B receptor antagonist (A-192621), and the spotting lethal (sl) rat, which carries a naturally occurring deletion in the ET B receptor gene. Methods and Results-According to the Langendorff technique, isolated hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. In Sprague-Dawley rat hearts, ischemia/reperfusion-induced cardiac dysfunctions such as decreased left ventricular developed pressure and coronary flow and increased left ventricular end-diastolic pressure were worsened by treatment with A-192621. This agent enhanced excessive NE overflow in the coronary effluent from the postischemic heart. In contrast, treatment with ABT-627, in the absence or presence of A-192621, significantly improved postischemic cardiac dysfunction and markedly suppressed NE overflow to the same extent. Postischemic cardiac dysfunction and NE overflow in the heart of ET B receptor-deficient homozygous (sl/sl) rats were highly observed compared with cases in wild-type rats, and exaggerated responses to ischemia/reperfusion in sl/sl rats were abolished by ABT-627 treatment. Exogenously applied ET-1 produced severe cardiac dysfunction and a significant increase in NE overflow in a dose-dependent manner, but these responses were markedly suppressed in the presence of 5-N-ethyl-N-isopropyl-amiloride, an inhibitor of the Na ϩ /H ϩ exchanger (NHE). Conclusions-Pharmacological blockade or genetic deficiency of ET B receptors is detrimental to the postischemic heart, and exaggerated cardiac pathology under the above conditions is mediated by ET A receptor activation. ET A /NHEmediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.

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Section: Discussionmentioning

confidence: 99%

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

et al. 2005

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“…Postischemic reperfusion is associated with high levels of NE release into the coronary perfusate caused by reversal of the NE transporter (NET) under ischemic conditions (carrier-mediated NE release) (9,20). The experimental protocol utilized in the present study (30-min global ischemia) has been shown to result in carrier-mediated NE release (6).…”

Section: [ 3 H]ne Uptake In Cardiac Synaptosomesmentioning

confidence: 99%

A highly potent peptide analgesic that protects against ischemia-reperfusion-induced myocardial stunning

Soong

Zhao

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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We recently discovered an opioid peptide analgesic, 2′,6′-dimethyltyrosine (Dmt)-d-Arg-Phe-Lys-NH2([Dmt1]DALDA), that can protect against ischemia-induced myocardial stunning. In buffer-perfused hearts, 30-min global ischemia followed by reperfusion resulted in a significant increase in norepinephrine (NE) overflow immediately upon reperfusion and significant decline in contractile force (45%). Pretreatment with [Dmt1]DALDA before ischemia completely abolished myocardial stunning and significantly reduced NE overflow (68%). In contrast, pretreatment with morphine before ischemia only provided brief protection against myocardial stunning and no reduction in NE overflow. [Dmt1]DALDA inhibited [3H]NE uptake into cardiac synaptosomes in vitro (IC50 = 3.9 μM), whereas morphine had no effect. Surprisingly, protection against myocardial stunning was apparent even when hearts were perfused with [Dmt1]DALDA only upon reperfusion, whereas reperfusion with morphine had no effect. Binding studies with [3H][Dmt1]DALDA revealed no high-affinity specific binding in cardiac membranes, suggesting that the cardioprotective actions of [Dmt1]DALDA are not mediated via opioid receptors. These findings suggest that [Dmt1]DALDA is a potent analgesic that may be useful for myocardial stunning resulting from cardiac interventions or myocardial ischemia.

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“…In recent years, the finding has been established that myocardial ischemia leads to local-metabolic, nonexocytotic noradrenaline release, which contributes to the generation of arrhythmias (Schömig et al 1984(Schömig et al , 1986Dietz et al 1989;Kurz et al 1995). This concept implies that noradrenaline displays an arrhythmogenic action by stimulating adrenergic receptors, and thus it can be concluded that adrenoceptor antagonists protect against arrhythmias evoked by ischemia.…”

Section: Introductionmentioning

confidence: 99%

Influence of alpha- and beta-adrenoceptor antagonists on ventricular fibrillation in ischemic rat hearts

Tölg

Kurz

Ungerer³

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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Although it is generally accepted that adrenergic influences contribute to arrhythmias during myocardial ischemia, it is still a matter of debate whether these arrhythmogenic effects are mediated via alpha- or beta-adrenergic receptors and which particular receptor subtype is involved. Controversial results may be due to ancillary properties of the adrenergic receptor antagonists used to resolve this question. Therefore, we compared the influence of various, structurally different alpha- and beta-adrenoceptor blocking agents on the occurrence of ventricular fibrillation in rat isolated hearts. Regional ischemia was induced by ligature of the left coronary artery and ECG was monitored over 30 min of coronary occlusion. Myocardial ischemia precipitated ventricular fibrillation in a well reproducible manner with an incidence of about 80% in control hearts. Racemic propranolol (0.1-1 micromol/l) concentration-relatedly reduced the incidence of ventricular fibrillation from 71% in controls to 10%, whereas the beta-adrenoceptor blocking agents atenolol (10 micromol/l) and timolol (1 micromol/l) did not influence the occurrence of arrhythmias. Moreover, both stereoisomers of propranolol were equipotent in suppressing ischemia-induced ventricular fibrillation, indicating an action of propranolol independent of its beta-adrenoceptor blocking properties. Unselective antagonism of alpha-adrenoceptors by phentolamine decreased the incidence of ventricular fibrillation from 90% to 58% at 0.1 micromol/l and totally suppressed ventricular fibrillation at 1 micromol/l. The alpha1-selective antagonists prazosin and HEAT concentration-dependently (0.1-10 micromol/l) reduced the incidence of ventricular fibrillation from 83% to 0%, whereas the alpha2-selective antagonist RX 821002 revealed no antiarrhythmic effect. Furthermore, subtype specific antagonism of alpha1A-adrenoceptors by WB 4101 clearly reduced the occurrence of ventricular fibrillation in a concentration-dependent manner (0.01-1 micromol/l) from 66% to 17%. Conversely, CEC, known to block the alpha1B-adrenoceptor subtype, possessed no antifibrillatory effect. In conclusion, the contribution of catecholamines to ischemia-induced arrhythmias in rat isolated heart is primarily mediated via WB 4101-sensitive alpha1-adrenergic activation. Beta- and alpha2-adrenoceptor blockade did not affect ventricular fibrillation in this model. The antifibrillatory action of propranolol was rather due to ancillary properties of this agent.

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Nonexocytotic noradrenaline release and ventricular fibrillation in ischemic rat hearts

Cited by 29 publications

References 13 publications

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

A highly potent peptide analgesic that protects against ischemia-reperfusion-induced myocardial stunning

Influence of alpha- and beta-adrenoceptor antagonists on ventricular fibrillation in ischemic rat hearts

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