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Activation of histamine H3-receptors inhibits carrier-mediated norepinephrine release during protracted myocardial ischemia. Comparison with adenosine A1-receptors and alpha2-adrenoceptors.
- Source :
-
Circulation research [Circ Res] 1996 Mar; Vol. 78 (3), pp. 475-81. - Publication Year :
- 1996
-
Abstract
- We previously showed that prejunctional histamine H3-receptors downregulate norepinephrine exocytosis, which is markedly enhanced in early myocardial ischemia. In the present study, we investigated whether H3-receptors modulate nonexocytotic norepinephrine release during protracted myocardial ischemia. In this setting, decreased pH(i) in sympathetic nerve endings sequentially leads to a compensatory activation of the Na+-H+ antiporter (NHE), accumulation of intracellular Na+, reversal of the neuronal uptake of norepinephrine, and thus carrier-mediated release of norepinephrine. Accordingly, norepinephrine overflow from isolated guinea pig hearts undergoing 20-minute global ischemia and 45-minute reperfusion was attenuated approximately 80% by desipramine (10 nmol/L) and 70% by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA, 10 micromol/L), inhibitors of norepinephrine uptake and NHE, respectively. The H3-receptor agonist imetit (0.1 micromol/L) decreased carrier-mediated norepinephrine release by approximately 50%. This effect was blocked by the H3-receptor antagonist thioperamide (0.3 micromol/L), indicating that H-receptor activation inhibits carrier-mediated norepinephrine release. At lower concentrations, imetit (10 nmol/L) or EIPA (3 micromol/L) did not inhibit carrier-mediated norepinephrine release. However, a 25% inhibition occurred with imetit (10 nmol/L) and EIPA (3 micromol/L) combined. This synergism suggests an association between H-receptors and NHE. Conceivably, activation of H-receptors may lead to inhibition of NHE. In fact, alpha2-adrenoceptor activation, which is known to stimulate NHE, enhanced norepinephrine release, whereas alpha2-adrenoceptor blockade attenuated it. Furthermore, activation of adenosine A1-receptors markedly attenuated norepinephrine release, whereas their inhibition potentiated it. Because norepinephrine directly correlated with the severity of reperfusion arrhythmia and imetit reduced the incidence of ventricular fibrillation by 50%, our findings with H-receptor agonists may further the development of novel pharmacological means to reduce reperfusion arrhythmias in the clinical setting.
- Subjects :
- Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-2 Receptor Antagonists
Animals
Arrhythmias, Cardiac etiology
Arrhythmias, Cardiac metabolism
Guinea Pigs
Histamine metabolism
Histamine Agonists pharmacology
In Vitro Techniques
Ligands
Male
Myocardial Reperfusion Injury complications
Myocardial Reperfusion Injury metabolism
Neurotransmitter Uptake Inhibitors pharmacology
Purinergic P1 Receptor Agonists
Myocardial Ischemia metabolism
Myocardium metabolism
Norepinephrine metabolism
Receptors, Adrenergic, alpha-2 metabolism
Receptors, Histamine H3 metabolism
Receptors, Purinergic P1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0009-7330
- Volume :
- 78
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 8593706
- Full Text :
- https://doi.org/10.1161/01.res.78.3.475