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1.
Acta Pharmacol Sin ; 22(6): 541-8, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11747762

ABSTRACT

AIM: To evaluate the acute effects of tezosentan, a new dual parenteral endothelin receptor antagonist, on hemodynamics in a rat model of chronic heart failure (CHF), and further investigated if the combination of tezosentan with the angiotensin converting enzyme (ACE) inhibitor, enalapril, had additive hemodynamic effect. METHODS: Hemodynamics was measured in rats with CHF, induced by ligation of the left coronary artery. RESULTS: At 3 to 5 weeks after myocardial infarction, rats developed CHF. This was evidenced by a marked increase in left ventricular end-diastolic pressure (LVEDP) with mean values of 23 to 26 mmHg, by a 30 % to 40 % reduction in left ventricular dp/dt(max) and by a more than 10 % decrease in mean arterial pressure (MAP) as compared to sham-operated rats. In CHF rats, acute intravenous administration of either tezosentan (10 mg . kg) or enalapril (1 mg . kg) markedly decreased MAP and LVEDP, without affecting heart rate or dp/dtmax. Tezosentan had additive effects on MAP and LVEDP when given with enalapril compared with tezosentan (P < 0.05) or enalapril (P < 0.05) alone. There were no significant changes in heart rate and dp/dtmax with the combination treatment compared with tezosentan- or enalapril-treated CHF rats. CONCLUSION: Acute intravenous tezosentan improves cardiac hemodynamics and decreases LVEDP and afterload (MAP) without changes in heart rate and cardiac contractility dp/dtmax) in CHF rats. These favorable effects of tezosentan are similar to those of enalapril. Furthermore, the benefits of tezosentan are apparent in addition to ACE inhibition. Thus, tezosentan could be a useful therapeutic agent in the acute treatment of heart failure.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Enalapril/pharmacology , Endothelin Receptor Antagonists , Heart Failure/physiopathology , Pyridines/pharmacology , Tetrazoles/pharmacology , Animals , Blood Pressure/drug effects , Drug Synergism , Heart Rate/drug effects , Hemodynamics/drug effects , Male , Myocardial Infarction/physiopathology , Rats , Rats, Wistar
2.
Neuron ; 32(3): 477-88, 2001 Nov 08.
Article in English | MEDLINE | ID: mdl-11709158

ABSTRACT

In the spinal cord dorsal horn, excitatory sensory fibers terminate adjacent to interneuron terminals. Here, we show that kainate (KA) receptor activation triggered action potential-independent release of GABA and glycine from dorsal horn interneurons. This release was transient, because KA receptors desensitized, and it required Na+ entry and Ca2+ channel activation. KA modulated evoked inhibitory transmission in a dose-dependent, biphasic manner, with suppression being more prominent. In recordings from isolated neuron pairs, this suppression required GABA(B) receptor activation, suggesting that KA-triggered GABA release activated presynaptic GABA(B) autoreceptors. Finally, glutamate released from sensory fibers caused a KA and GABA(B) receptor-dependent suppression of inhibitory transmission in spinal slices. Thus, we show how presynaptic KA receptors are linked to changes in GABA/glycine release and highlight a novel role for these receptors in regulating sensory transmission.


Subject(s)
Glycine/metabolism , Posterior Horn Cells/metabolism , Presynaptic Terminals/metabolism , Receptors, Kainic Acid/physiology , gamma-Aminobutyric Acid/metabolism , Action Potentials/drug effects , Action Potentials/physiology , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Excitatory Amino Acid Agonists/pharmacology , Ion Channel Gating/drug effects , Ion Channel Gating/physiology , Kainic Acid/pharmacology , Male , Posterior Horn Cells/drug effects , Presynaptic Terminals/drug effects , Rats , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/metabolism
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