On the relation between contraction and prostaglandin release in rabbit mesenteric blood vessels (original) (raw)
Related papers
British Journal of Pharmacology, 1982
1 The actions of prostaglandin F2a (PGF2J) and noradrenaline on contraction and 45Ca exchange have been studied in rat mesenteric arteries. 2 PGF2,, and noradrenaline contracted rat isolated mesenteric artery preparations to about the same extent. The PGF2,,-stimulated contractions, unlike those produced by noradrenaline, were completely inhibited in calcium-free physiological solution. 3 The calcium entry blocking drugs, cinnarizine and flunarizine, had little effect on the resting exchange of calcium in the arterial smooth muscle, but inhibited PGF2U-stimulated contractions and 45Ca uptake to a similar extent. 4 Flunarizine was about 7 fold more potent as an inhibitor of noradrenalinethan of PGF2,,mediated contraction and 45Ca uptake and this ratio was about 50 for cinnarizine. 5 EGTA (1.25 mM) produced a relaxation of noradrenaline and PGF2,,-induced maximal contractions. Measured over the first 2 min of EGTA contact, the rate of relaxation was much faster in noradrenaline than in PGF2,z-stimulated preparations.
European Journal of Pharmacology, 1993
Subthreshold concentrations of endothelin-1 potentiated the norepinephrine-induced contraction in isometrically mounted rings of the rabbit aorta. Pretreatment with endothelin-1 (0.1 nM) for 10 minutes increased the sensitivity of the aortic rings to norepinephrine without affecting the maximal contraction. This amplification was unaffected by removal of the endothelium but was prevented by the protein kinase C inhibitors staurosporine (0.01 microM) and calphostin C (0.1 microM). Pretreatment of the aortic rings for 24 hours with phorbol 12-myristate 13-acetate (0.1 microM) also abolished the potentiation. Norepinephrine-induced contraction was potentiated by pretreating with phorbol 12-myristate 13-acetate (10 nM) and by increasing the concentration of K+ in the bath solution from 4.6 to 8.6 mM. The potentiation of the norepinephrine-induced contraction by endothelin-1 (0.1 nM) or by phorbol 12-myristate 13-acetate (10 nM) was not associated with an increase in norepinephrine-induced 45Ca2+ uptake or influx, whereas the potentiation due to an increase in the concentration of K+ in the bath solution from 4.6 to 8.6 mM was associated with an increase in norepinephrine-induced 45Ca2+ uptake. We conclude that endothelin-1 potentiation of the norepinephrine-induced contraction occurs in the absence of changes in stimulated Ca2+ entry and is endothelium independent. It is probable that endothelin-1 increases the sensitivity of the contractile apparatus to Ca2+ by activating protein kinase C-dependent mechanisms.
Mechanism of Action of Angiotensin II on Excitation-Contraction Coupling in the Rat Portal Vein
British Journal of Pharmacology, 1982
The action of angiotensin II (At II) has been studied on the electrical and mechanical activity of the vascular smooth muscle of the rat portal vein. 2 At low concentrations (between 5 x 10l0 and 10-9 M) At II induces an acceleration of spontaneous action potential (AP) discharge without change in the resting membrane potential. The frequency and size of the associated contractions are simultaneously augmented. Under these conditions the size of the spikes is not affected, thus suggesting that At II triggers the release of Ca2+ from internal stores. 3 The increase in AP discharge rate produced by low concentrations of At II results from an acceleration of the pacemaker potential. Furthermore, in the presence of 10mM tetraethylammonium (TEA), there is an acceleration of the repolarizing phase of AP. 4 Ouabain (10-3 M) inhibits the increase in rhythmic activity induced by low concentrations of At II (in the presence of 1OmM TEA), thus suggesting that the Na-K pump is directly or indirectly involved in this action of the peptide. 5 At higher concentrations, At II produces a concentration-dependent depolarization with an EC50 of 1.2 x 10-8M and a maximum of 10-7M. The associated contraction has an EC50 of 3.3 x 10-8 Mand a maximum of 3 x 10-7 M. 6 Ouabain (3 x 10-3 M) depolarizes the cell membrane. Under these conditions, At II (10-7 M) has a slight depolarizing effect, but it still produces a large tonic contraction. 7 It is concluded, that At II acts on different steps of excitation-contraction coupling, depending on the concentration. At low levels, the peptide mainly accelerates spike discharge, through a mechanism involving the Na-K pump. At higher concentrations, At II depolarizes the cell membrane. The contraction is then activated by the influx of Ca2+ due to secondary AP discharge and the release of Ca2+ from intracellular stores. Pharmacomechanical coupling has an important role in the triggering of contractions both at high and at low concentrations of At II.
Mechanisms of bradykinin-induced contraction of the guinea-pig gallbladder in vitro
British Journal of Pharmacology, 1995
The mechanisms underlying bradykinin (BK)-mediated contractions in strips of guinea-pig gallbladder (GPG) were examined by use of selective bradykinin (BK) receptor agonists and antagonists. 2 Addition of BK and related kinins (0.1 pM-10 uM) after 2 h of equilibration of the preparation caused graded contractions characterized by two distinct phases: high affinity (0.1 pM-1 nM) and low affinity (3 nM-ILM). The rank order of potency for the first phase (mean ECM,, pM) was: BK (1.36) = Hyp3-BK (1.44) = Lys-BK (1.54)> Tyr8-BK (2.72)> Met-Lys-BK (4.30). The rank order of potency for the second phase (mean ECm, nM, at concentration producing 50% of the contraction caused by 80 mM KCl) was: Hyp3-BK (8.95)> Met-Lys-BK (12.78)> Tyr8-BK (33.75)> Lys-BK (60.92)> BK (77.35). The contractile responses (g of tension) to 3 gM of BK (the highest concentration tested) were: Hyp3-BK, 1.76 ± 0.09; BK, 1.65 ± 0.12; Lys-BK, 1.45 ± 0.13; Tyr8-BK, 1.36 ± 0.15 and Met-Lys-BK, 1.36 ± 0.15. The selective B1 agonist, des-Arg9-BK, caused only a weak contraction with maximal response (0.21 ± 0.05 g), which corresponded to approximately 10% of that induced by BK. 3 BK-induced contraction in GPG was inhibited by indomethacin (3 JiM) or ibuprofen (30 JM), and was partially reduced by phenidone (30 gM), but was not affected by atropine (1 JM), nicardipine (1 gM), Ca2+-free medium plus EGTA, dazoxiben (30 nM), L-655,240 (10 nM, a selective receptor antagonist of thromboxane A2), MK-571 (0.1 ILM, a selective leukotriene D4 receptor antagonist), tetrodotoxin (0.3gM), CP 96,345 (0.3 tM, a NK1 receptor antagonist), mepyramine (1 tM), glibenclamide (1 gM), H-7 (3 gLM), staurosporine (100 nM), or phorbol 12-myristate 13-acetate (1 gM). However, BK-induced contractions in GPG maintained in Ca2'-free medium were markedly attenuated by ryanodine (10lM). 4 Prostaglandin E2, prostaglandin F2,, or U46619 (0.1 nM to 100IM), caused concentration-dependent contractions in GPG with mean ECms of 3.1 tM; 1.7 gM and 0.47 nM and maximal responses of 1.36 0.15; 1.32 ± 0.20 and 0.96 ± 0.09 g, respectively. 5 The selective B2 receptor antagonists, Hoe 140, NPC 17731 and NPC 17761 (0.01-1 .M), caused concentration-dependent displacements to the right of the contractile concentration-response curve for BK. The selective B1 receptor antagonist, des-Arg9-[Leu8]-BK (1 LM), did not affect BK-induced GPG contraction. 6 These data suggest that both high and low affinity BK responses in GPG are mediated by activation of B2 receptors, and that BK-mediated contraction in GPG depends on the release of intracellular Ca21 sources sensitive to ryanodine. In addition, BK-induced contraction in GPG is mediated by release of proinflammatory eicosanoid(s) derived from the cyclo-oxygenase pathway from arachidonic acid metabolism unrelated to thromboxane A2, and seems not to be coupled to activation of a protein kinase C-dependent mechanism.
Vasodilatory and Electrophysiological Actions of 8-iso-Prostaglandin E2 in Porcine Coronary Artery
Journal of Pharmacology and Experimental Therapeutics, 2003
We examined the effects of several E-ring and F-ring isoprostanes on mechanical and electrophysiological activity in porcine coronary artery. Several isoprostanes evoked concentrationdependent contractions, with 8-iso PGE 2 being the most potent (-log EC 50 of 6.9±0.1): this excitatory effect has been described in detail elsewhere and was not examined further here. 8-iso PGE 2 evoked dose-dependent relaxations in tissues preconstricted with the TXA 2-agonist U46619 (10-6 M), with an EC 50 of 6.0±0.1 (n=5). 8-iso PGE 1 and 8-iso PGF 2$ also evoked relaxations (albeit with lower potency), while the other F-ring isoprostanes (8-iso PGF 1" , 8-iso PGF 1$ , and 8-iso PGF 2") were largely ineffective in this respect. The potency and efficacy of 8-iso PGE 2 in reversing tone were not dependent upon the concentration of U46619 used to preconstrict the tissues (10-8 to 10-6 M) , indicating a lack of U46619-induced functional antagonism of these responses. 8-iso PGE 2 was able to completely relax tissues which had been denuded of endothelium (as indicated by loss of responsiveness to bradykinin). 8-iso PGE 2-evoked relaxations were markedly reduced by elevating the K + equilibrium potential using 30 mM KCl, and abolished by 60 mM KCl; they were also sensitive to charybdotoxin (10-7 M) but not to 4-aminopyridine (1 mM). 8-iso PGE 2 also caused membrane hyperpolarization and augmentation of outward K + current. We conclude that 8-iso prostaglandin E 2 acts directly on the smooth muscle to increase K + conductance, leading to membrane hyperpolarization and vasodilation.
European Journal of Pharmacology, 1992
Angiotcnsin Ii, (AI@, 0.1 nM) incrc i;:cd ctmccntration dcpcndcntly the sensitivity of rabbit aortic rings to low mncontrations of noradrcnalinc. This was not asstxiatcd with increases in noractrcnalinc-induc~~i ,rsCa2 ' uptake or cftlux and was prcvcnted hy the pro&in kinasc C (PKC) inhibitors staurosporinc (0.01 PM) and calphostin C (0.1 PM). Prctrcatmcnt of the rings with PMA (phorhnl-ltmyristatc-l3-acetate, 0.1 and 1 gM, 24 h at 4°C) abolished the potcntiation phcnomcnon. WC conclude that All potcntintion of noradrenalinc-induced vascular lone may hc due la a PKC-mediated incrcasc in intracellular sensitivity of the cnnlmctilc apparatus lo Ca' ' .
European Journal of Pharmacology, 1982
In the isolated rat heart perfused with Krebs solution and prelabeled with [3H]noradrenaline, we examined the effect of prostaglandins (PG) 12, E2, 6-keto-PGF~,~ and their precursor, arachidonic acid, on the overflow of tritium elicited by potassium (K +) and by stimulation of cardiac sympathetic nerve plexus. Prostaglandins E2, 12 and arachidonic acid but not 6-keto-PGFt, ~ reduced K + and nerve stimulation-induced overflow of tritium. Administration of indomethacin, an inhibitor of cyclooxygenase, increased tritium overflow elicited by either K + or by nerve stimulation. During infusion of indomethacin, the inhibitory effect of both PGE 2 and PGI 2 on the K + or nerve stimulation:induced overflow of tritium remained unaltered. In contrast, the effect of arachidonic acid to reduce K + or nerve stimulation-induced overflow of tritium was abolished by indomethacin, indicating that the fatty acid inhibits release of tritium by its conversion to a product(s) of cyclooxygenase, presumably PGI 2 and PGE 2. These data suggest that prostaglandins, particularly PGI 2 and PGE 2 synthesized in the isolated rat heart act on prejunctional sites to modulate release of the adrenergic transmitter. PGE 2 PGI 2 Arachidonic acid Adrenergic transmission Indomethacin