British journal of pharmacology
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1. The mechanisms involved in bradykinin (BK)-induced oedema in the rat paw as well as the interactions between BK and several inflammatory mediators, have been investigated. 2. Intraplantar injection of BK (1 nmol/paw) in rats pretreated with captopril (5 mg kg-1, s.c.) caused a small amount of oedema formation (0.17 +/- 0.05 ml). ⋯ The B2 receptors are constitutive, but induction of expression of B, receptors seems to occur only after complete desensitization of the paw to BK. In addition, very low doses of inflammatory mediators markedly potentiate BK-induced paw oedema and can attenuate BK-induced paw oedema desensitization. Such mechanisms may be relevant for the manifestation of acute and chronic inflammatory processes.
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1. We have investigated whether glibenclamide, an inhibitor of ATP-sensitive potassium channels, influences the induction of the calcium-independent isoform of nitric oxide synthase (iNOS) in cultured J774.2 macrophages activated by bacterial endotoxin (E.coli lipopolysaccharide; LPS), as well as in the lung and aorta of rats with endotoxic shock. 2. Pretreatment of J774.2 macrophages with glibenclamide (10(-7) to 10(-5) M for 30 min) dose-dependently inhibited the accumulation of nitrite caused by LPS (1 microgram ml-1). ⋯ Treatment of LPS-rats with glibenclamide (1 mg kg-1, i.v. at 15 min prior to LPS, n = 5) did not significantly reduce the rise in plasma TNF alpha levels caused by endotoxin.9. Thus, glibenclamide inhibits the induction, but not the activity, of iNOS in vitro and in vivo. This inhibition of iNOS induction may contribute to the beneficial haemodynamic effects of glibenclamide in endotoxic shock.
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Comparative Study
Pharmacological characterization of noradrenaline-induced contractions of the porcine isolated palmar lateral vein and palmar common digital artery.
1. The aim of this study was to examine the pharmacological characteristics of alpha-adrenoceptor-mediated contractions in two porcine isolated blood vessels, the palmar lateral vein (PLV) and the palmar common digital artery (PCDA). This was carried out with noradrenaline used as the agonist throughout, and either phentolamine (non-selective alpha-adrenoceptor antagonist), prazosin and YM-12617 (selective alpha 1-adrenoceptor antagonists) or rauwolscine and CH-38083 (selective alpha 2-adrenoceptor antagonists). 2. ⋯ Phenoxybenzamine (0.3-3 microM, 60min exposure) produced a concentration-dependent reduction in the maximal response to noradrenaline which was more pronounced in the PCDA than the PLV. After a 60 min exposure to a combination of phenoxybenzamine (1 microM) and rauwolscine (1 microM), the remaining NA-induced contraction after washout was resistant to prazosin (0.1 microM) and sensitive to rauwolscine(1 microM) in both tissue preparations, indicating the existence of functional alpha2-adrenoceptors in both vessels.6. Evidence suggests that post-junctional alpha l- and alpha2-adrenoceptors contribute to noradrenaline-induced contractions in the PCDA and PLV, with the latter possessing a larger population of functional alpha2-adrenoceptors.
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Comparative Study
The relationship between density of alpha-adrenoceptor binding sites and contractile responses in several porcine isolated blood vessels.
1. The aim of this study was to investigate constrictor alpha-adrenoceptors in three isolated blood vessels of the pig, the thoracic aorta (TA), the splenic artery (SA) and marginal ear vein (MEV) and then compare the functional response with the densities of alpha 1- and alpha 2-adrenoceptor binding sites in these and several other porcine vascular tissues, palmar common digital artery (PCDA), palmar lateral vein (PLV) and ear artery (EA). 2. Noradrenaline (NA), phenylephrine (PE) and UK14304 (all at 0.03-10 microM) elicited concentration-dependent contractions in the TA and MEV, with a rank order of potency of UK14304 > NA > PE. ⋯ In saturation studies using [3H]-RX821002, all tissues produced single site saturation curves with no differences in the Kd values (range 1.31 +/- 2.16 nM) but the highest densities were found in the TA and MEV (545.3 +/- 36.2 and 531.0 +/- 40.9 fmol mg-1 respectively), followed by the PLV (418.4 +/- 39.4 fmol mg-1), then the EA (266.3 +/- 40.0 fmol mg-1), and low densities of [3H]-RX821002 binding being found in the PCDA and SA (155.9 +/- 18.1 and 117.5 +/- 19.3 fmol mg-1 respectively).8. The pattern of binding site distribution for alpha l- and alpha 2-adrenoceptors is in reasonable agreement with functional studies carried out in these porcine vascular tissues; the TA has the highest densities of alpha 1-and alpha2-adrenoceptors; in the SA and PCDA there is a predominance (although small) of alpha l-adrenoceptor binding sites, the reverse of which is observed both in the PLV and MEV (i.e. greater density of alpha2-adrenoceptor sites). Thus, it would appear that alpha 1- and alpha2-adrenoceptor densities play a role in the expression of functional responses via these receptor subtypes; although it is interesting to note that the SA did have a small density of alpha 2-adrenoceptor binding sites, no functional response was observed after alpha2-adrenoceptor activation.
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Comparative Study
Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction.
1. The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calcium-sensitizing and phosphodiesterase III (PDE III) inhibitory properties, were studied in conscious dogs in which heart failure had been induced by prolonged cardiac pacing in the presence of aortic constriction. These effects were compared with those in sham-operated dogs with essentially normal cardiac function. 2. ⋯ In the sham-operated dogs (group 2), only the higher dose (0.03 micromol kg-1)produced significant increases in LVSP (19%), + dP/dtmax (37%), and in dP/dt/P (32%). In dogs with heart failure (group 3) doses of 0.005, 0.01 and 0.03 micromol kg-1 levosimendan resulted in an improve mentin +dP/dtmax (26%, 38% and 49%), -dP/dtmax (20%, 25% and 38%) and in dP/dt/P (19%, 34%and 50%) and reduction in the elevated LVEDP (from 20 =/- 2.2 mmHg to 16 +/- 1.0, 10 +/- 1.3 and 9 +/- 1.0 mmHg, respectively).5. Levosimendan proved to be a potent cardiotonic drug at the doses used, and was approximately three times more effective under conditions of impaired left ventricular function than in normal hearts.