Influence of the nature of pre‐contraction on the responses to commonly employed vasodilator agents in rat‐isolated aortic rings

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Abstract
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 α1‐adrenoceptor agonist; St 587, a partial α1‐adrenoceptor stimulant; U46619 (U‐46), a thromboxane A2 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 Ca2+‐antagonist (selective l‐type calcium antagonist). The vasodilator activity of these compounds was quantified by their vasodilator potency value (pD2) and efficacy (Emax) obtained from their concentration–response curves.PhE (0.1, 0.3, 3 μm) 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 μm did not influence the response to FSK while it reduced the pD2 of SNP (8.6 ± 0.1 to 7.35 ± 0.1). Under these conditions, only the Emax of MCh was reduced (96.3 ± 4.3% to 43.3 ± 6.9%). U46 (0.18, 0.3, 1 μm) 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 μm 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 mm 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 μm 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 μm 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.