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Effect of drugs on the synthesis of noradrenaline in guinea‐pig vas deferens
Author(s) -
BOADLEBIBER MARGARET C.,
ROTH R. H.
Publication year - 1972
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1972.tb06894.x
Subject(s) - reserpine , vas deferens , tyrosine , endocrinology , incubation , medicine , catecholamine , chemistry , tyrosine hydroxylase , guinea pig , pteridine , biology , dopamine , biochemistry , enzyme
Summary1 . Reserpine in vitro (10 −5 m ) caused a profound inhibition (>85%) of the formation of both 14 C‐catecholamine ( 14 C‐CA) and 14 C‐dihydroxyphenylalanine ( 14 C‐DOPA) (in the presence of the amino acid decarboxylase inhibitor brocresine) from 14 C‐tyrosine in guinea‐pig vas deferens. The magnitude of the inhibition was similar for both 14 C‐CA and 14 C‐DOPA suggesting that the inhibition occurred primarily at the tyrosine hydroxylase step. 2 . One hour after in vivo treatment with reserpine (1 mg/kg) when tissue stores of noradrenaline (NA) were depleted by 50%, there was a significant inhibition of the formation of 14 C‐DOPA. Twenty‐four hours after such treatment, when endogenous NA could no longer be detected, synthesis of 14 C‐DOPA was indistinguishable from untreated controls. However a 45% inhibition of 14 C‐DOPA synthesis from 14 C‐tyrosine could be produced in tissues which had been depleted of NA for 24 h or 48 h by the addition of reserpine, 10 −5 m , to the incubation medium. 3 . Addition of pteridine cofactor, 2‐amino‐6,7,‐dimethyl‐4‐hydroxy‐5,6,7,8‐tetrahydropteridine, to the incubation medium in a concentration of 5 × 10 −3 m enhanced the formation of both 14 C‐CA and 14 C‐DOPA from 14 C‐tyrosine in guinea‐pig vas deferens. In 52 m m KCl Krebs‐Henseleit medium 14 C‐CA formation increased from 2·58 ± 0·20 (nmol/g)/h to 6·35 ± 0·47 (nmol/g)/h whilst 14 C‐DOPA formation increased from 5·04 ± 0·88 (nmol/g)/h to 11·29 ± 0·59 (nmol/g)/h. 4 . Pteridine cofactor (5 × 10 −3 m ) did not reverse the inhibition of 14 C‐DOPA formation seen with reserpine (10 −5 m ) in previously untreated tissues or in vasa deferentia from animals pretreated with reserpine 1 mg/kg for 24 hours. However, the inhibition did disappear in the presence of pteridine cofactor when treatment with reserpine was prolonged to 48 h and included two doses of reserpine of 2 mg/kg. 5 . Tyramine (5·8 × 10 −5 m ) and bretylium (10 −5 m ) in vitro inhibited the formation of 14 C‐CA and 14 C‐DOPA from 14 C‐tyrosine to the same extent in guinea‐pig vas deferens again indicating that their major site of action is on tyrosine hydroxylase. The inhibitory effects were reversed by pteridine cofactor. 6 . Synthesis of 14 C‐NA from 14 C‐tyrosine in calf splenic nerve was not increased by incubating the tissue in 52 m m KCl‐Krebs‐Henseleit solution.