GABAA receptor-mediated positive inotropism in guinea-pig isolated left atria: evidence for the involvement of capsaicin-sensitive nerves.
1. Isolated left atria from reserpine-pretreated guinea-pigs, electrically driven (3 Hz) in the presence of atropine (1 microM), phentolamine (0.3 microM) and propranolol (1 microM), responded to a train of stimuli (10 Hz for 2.5s) with a delayed neurogenic positive inotropic response which was insensitive to hexamethonium (10 microM) but abolished by either tetrodotoxin (1 microM), omega-conotoxin (0.1 microM), in vitro capsaicin desensitization or desensitization to calcitonin gene-related peptide (CGRP). 2. In these experimental conditions, gamma-aminobutyric acid (GABA) produced a concentration-related (10 microM-1 mM) positive inotropic response similar to that produced by electrical field stimulation. The effect of GABA was competitively antagonized by bicuculline methiodide (10 microM), a GABAA receptor antagonist. 3. The selective GABAA receptor agonists, muscimol and homotaurine mimicked the positive inotropic effect of GABA while baclofen, the selective GABAB receptor agonist, did not. 4. The action of GABA (1 mM) was abolished by either tetrodotoxin (1 microM), omega-conotoxin (0.1 microM), in vitro capsaicin desensitization or desensitization to CGRP, while it was unaffected by hexamethonium. In contrast, the inotropic response to CGRP was unaffected by tetrodotoxin, omega-conotoxin, bicuculline methiodide, hexamethonium or in vitro capsaicin desensitization, but was abolished by CGRP desensitization. 5. In the spontaneously beating guinea-pig right atrium, GABA (1 microM) produced a small and transient positive chronotropic effect that was no longer observed after in vitro desensitization with capsaicin (1 microM). 6. In the guinea-pig isolated perfused heart from reserpine-pretreated animals (with atropine, phentolamine and propranolol in the perfusion medium), GABA (1 microM) produced a transient tachycardia and a small increase in coronary flow. Both capsaicin (1 microM) and CGRP (1 microM) produced marked tachycardias and increases in coronary flow. After exposure to capsaicin (1 microM), no effect of GABA could be detected. 7. We conclude that, in the guinea-pig heart, GABAA receptors, presumably located on the preterminal region of capsaicin-sensitive sensory nerves, initiate a conducted impulse (since it is tetrodotoxin-sensitive) which leads to transmitter release (endogenous CGRP-like material) by activation of omega-conotoxin-sensitive, voltage-sensitive calcium channels and a functional response.
Maggi
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Pharmacology Department, Research Laboratories, A. Menarini Pharmaceuticals, Florence, Italy.
Giuliani
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Manzini
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Meli
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D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin / Q000494:pharmacology*; D004558:Electric Stimulation; D018756:GABA Antagonists; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009118:Muscimol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D009479:Neuropeptides / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology*; D013654:Taurine / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018756:GABA Antagonists; D009479:Neuropeptides; D011963:Receptors, GABA-A; D013654:Taurine; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; C001355:tramiprosate; D001418:Baclofen; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D001640:Bicuculline