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Influence of the nature of pre‐contraction on the responses to commonly employed vasodilator agents in rat‐isolated aortic rings
Author(s) -
Streefkerk Jörn O.,
Groot Annemieke A.,
Pfaffendorf Martin,
Zwieten Pieter A.
Publication year - 2002
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1046/j.1472-8206.2002.00107.x
Subject(s) - chemistry , vasodilation , sodium nitroprusside , phenylephrine , contraction (grammar) , medicine , endocrinology , agonist , pharmacology , adenylyl cyclase , forskolin , nitric oxide , receptor , biochemistry , blood pressure
The relaxing properties of vasodilator drugs in vitro may depend on the characteristics of the contractile state of the vessel investigated. Rat‐isolated thoracic aortas were exposed to different types of pre‐contraction. The following vasoconstrictor agents were used: phenylephrine (PhE), a selective α 1 ‐adrenoceptor agonist; St 587, a partial α 1 ‐adrenoceptor stimulant; U46619 (U‐46), a thromboxane A 2 agonist; and potassium ions causing receptor‐independent depolarization of the membrane. After pre‐contraction, various differential vasodilator drugs were investigated: methacholine (MCh, endothelium dependent), sodium nitroprusside (SNP, NO donor), forskolin (FSK, adenylyl cyclase stimulant) and nifedipine, a Ca 2+ ‐antagonist (selective l ‐type calcium antagonist). The vasodilator activity of these compounds was quantified by their vasodilator potency value (p D 2 ) and efficacy ( E max ) obtained from their concentration–response curves. PhE (0.1, 0.3, 3 μ m ) caused isometric responses of 4.8 ± 0.3, 6.5 ± 0.3 and 7.8 ± 0.5 mN, respectively. An increase of the PhE concentration from 0.1 to 3 μ m did not influence the response to FSK while it reduced the p D 2 of SNP (8.6 ± 0.1 to 7.35 ± 0.1). Under these conditions, only the E max of MCh was reduced (96.3 ± 4.3% to 43.3 ± 6.9%). U46 (0.18, 0.3, 1 μ m ) increased the contractile force by 7.4 ± 0.4, 8.8 ± 0.3 and 10.4 ± 0.3 mN, respectively. Increasing the concentration of U‐46 from 0.18 to 1 μ m affected only the efficacy of SNP (84 ± 4.4% to 17 ± 8.8%) and MCh (64.5 ± 12.3% to 0.0 ± 9.2%) and reduced the potency of FSK (7.91 ± 0.26 to 7.15 ± 0.10). The concentration of K + ‐ions from 25 to 30 and 40 m m increased the contractile force by 4.0 ± 0.4, 7.0 ± 0.5 and 10.8 ± 0.4 mN, respectively. The increase in [K + ] caused a potency decrease of FSK (7.1 ± 0.0 to 5.8 ± 0.0) whereas both efficacy and potency were reduced for SNP (95.6 ± 1.8% to 65.8 ± 1.9% and 8.7 ± 0.1 to 7.2 ± 0.1) and MCh (55.4 ± 3.5% to 24.5 ± 0.8% and 7.4 ± 0.3 to 6.1 ± 0.4). Inhibiting of the endothelial NO production by l ‐NAME 100 μ m resulted after pre‐contraction with PhE and potassium in comparable differences in properties for SNP. Pre‐contraction with St 587 1, 3, 10 and 30 μ m shows comparable results after nifedepine relaxation. The present experiments clearly demonstrate that the characteristics of the applied pre‐contraction strongly, but differentially influence both the potency and efficacy of various vasodilator drugs in vitro. Accordingly, in vitro characterization of vasodilator drugs should be performed under a carefully standardized protocol of pre‐contraction.