Role of CGRP and GABA in the hypotensive effect of intrathecally administered anandamide to anesthetized rats.
In urethane-anesthetized rats the intrathecal (i.t.) injection of 100 nmol anandamide produced a hypotensive effect (-19.3+/-1.6 mm Hg; n=6) that was mimicked by i.t. administration of 0.25 nmol calcitonin gene-related peptide (CGRP; -26.2+/-1.8 mm Hg, n=4). Both effects were antagonized either by the CGRP receptor antagonist CGRP(8-37) (5 nmol; i.t.) or by the gamma-aminobutyric acid (GABA)(A) receptor antagonist bicuculline (8.8 nmol, i.t) or by the GABA(B) receptor antagonist 2-hydroxy saclofen (110 nmol; i.t.). On the contrary, blockade of spinal CGRP receptors by CGRP(8-37) did not modify the hypotensive response to either the GABA(A)-receptor agonist muscimol (8.8 nmol; i.t.) or the GABA(B)-receptor agonist baclofen (100 nmol; i.t). This result suggests a unidirectional effect of CGRP on the GABAergic system. The response to anandamide remained unaltered after acute inhibition of nitric oxide (NO) synthase activity by either i.t. (1 micromol) or i.v. (10 mg/kg) injection of N(G)-nitro-L-arginine methyl ester (L-NAME), but increased significantly after long-term L-NAME administration (70 mg/kg/day; four weeks; p.o.), thus suggesting compensatory changes in cardiovascular homeostasis. It is proposed that the hypotensive effect of anandamide in urethane-anesthetized rats could involve the release of CGRP followed by the release of GABA in the spinal cord. NO does not appear to have a direct participation in the spinal mechanisms involved in the decrease of the blood pressure caused by anandamide.
Cátedra de Farmacología, Facultad de Farmacia y Bioquímica (Universidad de Buenos Aires), Junín 956, 5o piso, 1113 Buenos Aires, Argentina.
María del Carmen
Mdel C
García
Edda
E
Adler-Graschinsky
Stella Maris
SM
Celuch
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D001418:Baclofen / Q000008:administration & dosage / Q000494:pharmacology; D048588:Benzoxazines; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002211:Capsaicin / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D007275:Injections, Intravenous; D007278:Injections, Spinal; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000819:agonists / Q000502:physiology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000959:Antihypertensive Agents; D001095:Arachidonic Acids; D048588:Benzoxazines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D018755:GABA Agonists; D018756:GABA Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010446:Peptide Fragments; D053284:Polyunsaturated Alkamides; D018015:Receptors, Calcitonin Gene-Related Peptide; C058636:calcitonin gene-related peptide (8-37); D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D019001:Nitric Oxide Synthase; D001418:Baclofen; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; C078814:anandamide; D019331:NG-Nitroarginine Methyl Ester; D001640:Bicuculline