Potentiation of the effects of dopamine in the rabbit isolated splenic artery by 3-isobutyl-1-methylxanthine or forskolin.
Dopamine relaxes precontracted rabbit isolated splenic arteries via stimulation of dopamine DA1 receptors on the smooth muscle. However, in many preparations, the effect of dopamine is small. In an attempt to increase the effectiveness of dopamine and thus increase the proportion of usable preparations, we have examined the effects, on the sensitivity of dopamine, of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the adenylate cyclase stimulant forskolin. In tissues pretreated with phenoxybenzamine, and in the presence of propranolol, IBMX (1 mumol/l) or forskolin (0.01 mumol/l) produced a small increase in the sensitivity to dopamine in otherwise insensitive preparations. The maximum relaxation of U-46619-induced tone produced by dopamine was increased to around 50%. However, after treatment with higher concentrations of IBMX (10 mumol/l) or forskolin (0.1 mumol/l), previously insensitive preparations relaxed readily to dopamine with EC50 values in the range 1-3 mumol/l. Similarly, in spontaneously dopamine-sensitive preparations IBMX (1 mumol/l) or forskolin (0.01 mumol/l) produced only a 2-3-fold parallel shift to the left in the dopamine concentration-effect curves. However, higher concentrations of IBMX (10 mumol/l) or forskolin (0.1 mumol/l) produced 10-20-fold parallel shifts to the left in dopamine concentration-effect curves. Higher concentrations of IBMX (100 mumol/l) or forskolin (1 mumol/l) abolished the ability of the spasmogen to contract the preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
Clark
K L
KL
Department of Cardiovascular Pharmacology, Glaxo Group Research Ltd., Ware, Hertfordshire, England, UK.
Drew
G M
GM
Hilditch
A
A
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D019806:Cromakalim; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D010276:Parasympatholytics / Q000494:pharmacology; D058914:Purinergic Antagonists; D011688:Purinones / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011817:Rabbits; D013157:Splenic Artery / Q000502:physiology*; D013806:Theophylline / Q000031:analogs & derivatives*
D001578:Benzopyrans; D010276:Parasympatholytics; D058914:Purinergic Antagonists; D011688:Purinones; D011758:Pyrroles; D019806:Cromakalim; D005576:Colforsin; D013806:Theophylline; D000262:Adenylyl Cyclases; C011145:zaprinast; D015056:1-Methyl-3-isobutylxanthine; D004298:Dopamine