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Kinetic studies of the spasmogenic effects of serotonin and isolates from Byrsonima crassifolia leaves on rat fundus

Author

Ezra Béjar, University of the Pacific

Date of Award

1991

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Graduate School

First Advisor

Marvin H. Malone

First Committee Member

James W. Blankenship

Second Committee Member

David S. Fries

Third Committee Member

Paul H. Gross

Fourth Committee Member

H.D. [?]

Fifth Committee Member

Harry H. S. Fong

Abstract

Leaf and bark extracts of a Mexican medicinal plant, Byrsonima crassifolia (Malpighiaceae), exhibited spasmogenic effects on isolated rat fundus and biphasic effects on jejunum and ileum. Preliminary evaluations using rat fundus in Krebs solution indicated that the activity of a 2% acetic acid extract of eaves (HOAcE) could be split into two types: (i) high-efficacy, low-potency, n-butanol-extracted, pargyline- and 1-(1-naphtylpiperazine) (1-NP)-sensitive, atropine-insensitive activity, and (ii) low-efficacy, high-potency, ethyl acetate-extracted, pargyline-insensitive, atropine- and 1-NP-sensitive activity. HOAcE lacked muscarinic and nicotinic effects on rat jejunum and frog rectus abdominis. Serotonin (5-HT) and HOAcE curves in fundus were parallel and 5-HT potency was 6,037 times that of HOAcE (95% confidence limits: 4,624-7,852). The pD₂ (affinity constant) for 5-HT was 7.96 (7.92-8.00) with pargyline added to the medium. 5-HT receptor-interaction kinetics using cholinergics and 5-HT agonists and antagonists was carried out. 1-NP competitively antagonized 5-HT. The 5-HT, antagonist s-(-)propranolol did not significantly antagonize 5-HT. The 5-HT₂ blocker ketanserin noncompetitively antagonized 5-HT and α-Me-5-HT (pD'2 = 5.6 and 6.7, respectively). The 5-HT₃ antagonist MDL-72222 inactivated only a small proportion of receptors (pD'2 = 6.46). Atropine did not significantly modify the curve of 5-HT while fluoxetine noncompetitively antagonized 5-HT (pD'2 = 5.8). 5-HT and α-Me-5-HT curves were biphasic indicating two receptor interactions (high and low affinity). High-affinity pD₂ values for six different 5-HT agonists and 1-NP on rat fundus correlate well with reported rat brain (radioligand binding) pKd values at the 5-HT_1C receptor (r = 0.94). Large scale extraction and fractionation of a methanol extract of leaves yielded two peaks of activity (Peak 1, lipophilic; Peak 2, polar). Peak 1 contained Compounds 1 to 7 (C1-C7); Peak 2 included C8-C15. Compound 1, C2, C3, C4, C10 and C11 were inactive while C8, C12 and C13 showed equivocal effects. Compound 5, C6, C7, C9, C14, C15, quercetin and gallic acid were active. Potencies were: C5 > C6 > C7 = quercetin > C9 > gallic acid. Efficacy (IA) was: C15 ≥ C14 > gallic acid > C9 > C5 > C7 > quercetin > C6. Compound 9 and its aglycone quercetin were partial agonists (C9 IA = 70%, pD₂ = 6.35; quercetin IA = 60%, pD₂ = 6.58). Compound 9 noncompetitively antagonized 5-HT (pD'2 = 6.10), while quercetin did not. Compound 14 and C15, the most active compounds, had similar response curves but these curves were not parallel to 5-HT. Spasmogenic ED₅₀ values for C14 = 0.76 (0.38-1.54) μg/mL and C15 = 0.76 (0.41-1.42) μg/mL. Gram for gram 5-HT was 181 x C14 and 182 x C15.

Pages

274

Recommended Citation

Béjar, Ezra. (1991). Kinetic studies of the spasmogenic effects of serotonin and isolates from Byrsonima crassifolia leaves on rat fundus. University of the Pacific, Dissertation - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/507