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Abstract #26880 Published in IGR 12-3
Pharmacology of pre-versus postsynaptic A(2)-adrenoceptors
Hein L; Gilsbach R; Haubold M; Albarran-Juarez J; Schneider JBasic and Clinical Pharmacology and Toxicology 2010; 107: 42-43
(alpha)(2)-adrenoceptors mediate important functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. The aim of the present study was to determine in transgenic mouse models, which receptor functions are mediated via presynaptic (alpha)(2)-adrenoceptors in adrenergic neurons versus postsynaptic (alpha)(2)-adrenoceptors in nonadrenergic neurons or other cell types. Only few functions previously ascribed to (alpha)(2)-adrenoceptors were mediated by receptors on adrenergic neurons, including feedback inhibition of norepinephrine release from sympathetic nerves and spontaneous locomotor activity. Other agonist effects including analgesia, hypothermia, sedation and anesthetic-sparing were mediated by (alpha)(2)-receptors in non-adrenergic cells. In the cardiovascular system, (alpha)(2)-adrenoceptors in adrenergic cells mediated only a minor part of the bradycardic and hypotensive effects of the (alpha)(2)-agonist medetomidine. After chronic pressure overload as induced by transverse aortic constriction in mice, these receptors were desensitized and did not reduce norepinephrine spillover, cardiac dysfunction, hypertrophy or fibrosis. Among the (alpha)(2)-adrenoceptors, the a2B-subtype is unique as it is essentially required for placenta vascular development and for perinatal adaptation and survival. Ablation of (alpha)(2B)-expression led to early postnatal respiratory failure due to a defect in alveolar maturation and increased mesenchymal proliferation in the lung. Activation of pulmonary epithelial (alpha) (2B)-adrenoceptors suppressed expression of sonic hedgehog and its receptor patched. Inhibition of sonic hedgehog signaling by the smoothened antagonist cyclopamine partially rescued perinatal lethality and the associated pulmonary phenotype. In conclusion, both pre- and postsynaptic (alpha)(2)-adrenoceptors are mediators of adrenergic physiology and pharmacology.
L. Hein. University of Freiburg, Department of Pharmacology, FreiburgGermany.
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
3.8 Pharmacology (Part of: 3 Laboratory methods)