The cat lung strip as an in vitro preparation of peripheral airways: a comparison of beta-adrenoceptor agonists, autacoids and anaphylactic challenge on the lung strip and trachea. (1/57)

1 A new in vitro preparation, the isolated lung strip of the cat, is described for investigating the direct effect of drugs on the smooth muscle of the peripheral airways of the lung. The preparation comprises a thin strip of lung parenchyma which can be mounted in a conventional organ bath for isometric tension recording. Its pharmacological responses have been characterized and compared with the isolated tracheal preparation of the cat. 2 The lung strip exhibited an intrinsic tone which was relaxed by catecholamines, aminophylline and flufenamate. It was contracted strongly by histamine, prostaglandin F2alpha, acetylcholine, compound 48/80, potassium depolarizing solution and alternating current field stimulation. In contrast, the cat trachea was unresponsive to histamine and prostaglandin F2alpha and did not exhibit an intrinsic tone. 3 (-)-Isoprenaline and (-)-adrenaline were much more potent in relaxing the lung strip than the trachea. The potency order of relaxation responses to isoprenaline, adrenaline and (+/-)-noradrenaline in the lung strip was isoprenaline greater than adrenaline greater than noradrenaline but in the trachea was isoprenaline greater than noradrenaline greater than or equal to adrenaline. 4 beta2-Adrenoceptor selective agonists salbutamol and terbutaline were more potent in the lung strip than the trachea, suggesting beta2-adrenoceptors predominated in the lung strip. Propranolol was equipotent in inhibiting isoprenaline relexations of the lung strip and trachea, whereas practolol was much less effective in inhibiting lung strip than trachea, further supporting a predominance of beta2-adrenoceptors in lung strip and beta1-adrenoceptors in trachea. 5 Strong Schultz-Dale type contractions were elicited in both lung strips and trachea by Ascaris lumbricoides antigen in actively sensitized cats. The initial phase of the contractile response of the lung strip following challenge was shown to be due to histamine release and was absent in the trachea. The delayed phase of the contraction which took several minutes to develop in both the mepyramine-treated lung strip and trachea was not due to prostaglandins E1, F2alpha or bradykinin, the probable mediator being slow reacting substance of anaphylaxis (SRS-A). 6 It is concluded that the isolated lung strip of the cat is useful as an in vitro model for investigating the effect of drugs on the smooth muscle of the peripheral airways of the lungs.  (+info)

Slow reacting substance as a preformed mediator from human lung. (2/57)

Homogenates from human lung contained a preformed slow reacting substance (pSRS). The pattern of contraction on the guinea-pig ileum by pSRS was indistinguishable from that of SRS-A. The activity of pSRS could not be attributed to the presence of K+, Na+, Ca2+ and Mg2+ ions, or any prostaglandin including PGF2 or its 15-oxo derivative. As with SRS-A, pSRS could be absorbed onto Amberlite XAD-2 and silicic acid. Both were eluted from the former with 80 per cent ethanol and from the latter with a mixture of ethanol, ammonia and water. Both pSRS and SRS-A were resistant to the action of NaOH whereas their activities were destroyed by boiling in HCl. Arylsulphatase II B destroyed the activities of both pSRS and SRS-A. An antagonist of SRS-A, FPL55712, inhibited the action of pSRS at comparable concentrations to that of SRS-A. These experiments suggest that pSRS and SRS-A are identical. Thus SRS joins histamine and ECF-A as a preformed mediator. Although SRS was present in a preformed state the amount of material extractable was more than doubled by the anaphylactic reaction. The extraction of slow reacting substance from human lung without apparent requirement for antigen or antibody points to a possible role of this mediator in inflammatory reactions evoked by mechanisms independent of IgE and other tissue-sensitizing antibodies.  (+info)

Changes in renal autacoids in aged human hypertensives. (3/57)

The aging process determines several modifications of the kidney, that, however, do not provoke any dysfunction in normal conditions. But in the elderly--in the presence of stressful situations and particularly when adrenergic activation is present--the kidney is more vulnerable than in the young, and renal failure may arise. Variations typical of the aging kidney are accelerated when hypertension overlaps the physiological renal process, because both senescence and hypertension weight on the same structures, i.e. glomeruli. We studied renal hemodynamic adaptation capacity both in the healthy elderly and in patients affected by isolated systolic hypertension, in an acute experiment which requires the application of a mental stress-induced adrenergic activation. In hypertensive patients we have already demonstrated a total lack of renal adaptation capacity. In fact, while the elderly normotensives react with a prolonged and pronounced vasoconstriction, in those with isolated systolic hypertension, adrenergic activation induces a passive renal vasodilation and glomerular hyperfiltration. The anomalous adaptation capacity of renal hemodynamics is probably due to an impairment in the paracrine response of renal vasculature. Indeed in the hypertensive elderly, unlike in the normotensive one, no variations of autacoid production occur during the adrenergic activation. Following on from this, pattients affected by isolated systolic hypertension passively suffer the many hypertensive peaks which characterize their every day life. The altered renal autoregulation of the elderly with isolated systolic hypertension may explain the accelerated glomerulosclerosis and the greater incidence of renal damage and end-stage renal disease which characterize this condition. These aspects underline the primary role of the antihypertensive treatment of isolated systolic hypertension, not only for the prevention of cardiovascular mortality but also of renal damage and/or end-stage renal disease.  (+info)

Mechanisms in anti-inflammation and resolution: the role of lipoxins and aspirin-triggered lipoxins. (4/57)

Multicellular host responses to infection, injury or inflammatory stimuli lead to the formation of a broad range of chemical mediators by the host. The integrated response of the host is essential to health and disease; thus it is important to achieve a more complete understanding of the molecular and cellular events governing the formation and actions of endogenous mediators of resolution that appear to control the duration of inflammation. Lipoxins are trihydroxytetraene-containing lipid mediators that can be formed during cell-cell interactions and are predominantly counterregulators of some well-known mediators of inflammation. Since this circuit of lipoxin formation and action appears to be of physiological relevance for the resolution of inflammation, therapeutic modalities targeted at this system are likely to have fewer unwanted side effects than other candidates and current anti-inflammatory therapies. Here, we present an overview of the recent knowledge about the biosynthesis and bioactions of these anti-inflammatory lipid mediators.  (+info)

Selective inhibition of the renal angiotensin type 2 receptor increases blood pressure in conscious rats. (5/57)

The angiotensin II type 2 (AT(2)) receptor is present in rat kidney; however, its function is not well understood. The purpose of this study was to evaluate the role of the AT(2) receptor in blood pressure (BP) regulation. The effects of selective inhibition of the renal AT(2) receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) were examined in conscious uninephrectomized rats. Oligodeoxynucleotides (AS-ODN or scrambled [S-ODN]) were infused directly into the renal interstitial space by using an osmotic pump at 1 microL/h for 7 days. Texas red-labeled AS-ODN was distributed in renal tubules in the infused but not the contralateral kidney of normal rats. Continuous renal interstitial infusion of the AS-ODN, but not S-ODN, caused a significant (P<0.01) increase in BP 1 to 5 days after the initiation of the infusion. AS-ODN-treated rats experienced an increase in systolic BP from 109+/-4 to 130+/-4 mm Hg (n=8, P<0.01), whereas S-ODN-treated (n=8) and vehicle-treated (n=8) rats did not show any significant change in BP. On day 5 of the oligodeoxynucleotide infusion, AS-ODN-treated rats exhibited a greater pressor response to systemic angiotensin II infusion (30 ng/kg per hour) than did S-ODN-treated rats (P<0.01). Renal interstitial fluid cGMP decreased from 11.9+/-0.8 to 3.6+/-0.5 pmol/mL (P<0.001), and bradykinin decreased from 0.05+/-0.05 to 0.18+/-0.03 ng/mL (P<0.001) in response to AS-ODN, but they were not significantly changed in response to S-ODN. To evaluate the effects of AS-ODN and S-ODN on AT(2) receptor expression, Western Blot analysis was performed on treated kidneys. Kidneys treated with AS-ODN had approximately 40% less expression of AT(2) receptor than did kidneys treated with S-ODN or vehicle (P<0.05). These results suggest that AS-ODN directed selectively against the renal AT(2) receptor decreased receptor expression and caused an increase in BP. We conclude that the renal AT(2) receptor plays an important role in the regulation of BP via a bradykinin/cGMP vasodilator signaling cascade.  (+info)

Formation of slow-reacting substance by guinea pig immunoglobulins. (6/57)

The capacity of guinea pig antibodies to mediate the antigen-induced release of slow-reacting substance (SRS) in the rat peritoneal cavity is restricted to IgG2 and, to a lesser extent, to IgG1 populations of immunoglobulin. IgM and homocytotropic antibody of the reaginic type lacked this activity. The process was partially blocked by previous decomplementation of the rats, was not affected by previous reduction of the circulating leukocytes, and was partially suppressed by previous depletion of circulating platelets with an antiserum to rat platelets.  (+info)

Tissue-specific expression of human lipoprotein lipase in the vascular system affects vascular reactivity in transgenic mice. (7/57)

1. The role of smooth muscle-derived lipoprotein lipase (LPL) that translocates to the endothelium surface on vascular dysfunction during atherogenesis is unclear. Thus, the role of vascular LPL on blood vessel reactivity was assessed in transgenic mice that specifically express human LPL in the circulatory system. 2. Aortic free fatty acids (FFAs) were increased by 69% in the transgenic mice expressing human LPL in aortic smooth muscle cells (L2LPL) compared with their non-transgenic littermates (L2). 3. Contractility to KCl was increased by 33% in aortae of L2LPL mice. Maximal contraction to phenylephrine (PE) was comparable in L2 and L2LPL animals, while the frequency of tonus oscillation to PE increased by 104% in L2LPL mice. 4. In L2LPL animals, *NO mediated relaxation to acetylcholine (ACh) and ATP was reduced by 47 and 32%, respectively. In contrast, endothelium-independent relaxation to sodium nitroprusside (SNP) was not different in both groups tested. 5. ATP-initiated Ca(2+) elevation that triggers *NO formation was increased by 41% in single aortic endothelial cells freshly isolated from L2LPL animals. 6. In aortae from L2LPL mice an increased *O(2)(-) release occurred that was normalized by removing the endothelium and by the NAD(P)H oxidase inhibitor DPI and the PKC inhibitor GF109203X. 7. The reduced ACh-induced relaxation in L2LPL animals was normalized in the presence of SOD, indicating that the reduced relaxation is due, at least in part, to enhanced *NO scavenging by *O(2)(-). 8. These data suggest that despite normal lipoprotein levels increased LPL-mediated FFAs loading initiates vascular dysfunction via PKC-mediated activation of endothelial NAD(P)H oxidase. Thus, vascular LPL activity might represent a primary risk factor for atherosclerosis independently from cholesterol/LDL levels.  (+info)

EDHF, but not NO or prostaglandins, is critical to evoke a conducted dilation upon ACh in hamster arterioles. (8/57)

Vasomotor reactions upon focal stimulation of arterioles have been shown to be conducted along the vascular wall. Such a conduction, which is assumed to reflect the spread of electrical signals, may contribute to coordination of responses within a vascular segment. We aimed to identify which endothelial autacoid(s) act as mediators of the local and conducted dilator responses, respectively. To this end, arterioles in the hamster cremaster microcirculation were locally stimulated with endothelium-dependent [acetylcholine (ACh)] or endothelium-independent dilators [sodium nitroprusside (SNP)], and the resulting changes in diameter were measured using a videomicroscopy technique at the site of application and up to 1.4 mm upstream at distant sites. Experiments were also performed after blockade of nitric oxide (NO) synthase, cyclooxygenase, P-450 monooxygenase, or K(+) channels. Dilations upon ACh (71 +/- 3%) were conducted rapidly (<1 s) to upstream sites (at 1.4 mm: 37 +/- 5%). Although the NO donor SNP induced a similar local dilation (71 +/- 7%), this response was not conducted. Maximal amplitudes of ACh-induced dilations were not attenuated after inhibition of NO synthase and cyclooxygenase at the local and remote sites. However, additional treatment with a P-450 monooxygenase blocker (sulfaphenazole) strongly attenuated the local response (from 62 +/- 9 to 17 +/- 5%) and abrogated dilations at distant sites (at 0.67 mm: from 23 +/- 4% to 4 +/- 3%). Likewise, 17-octadecynoic acid strongly attenuated local and remote responses. Blockers of Ca(2+)-dependent K(+) channels (charybdotoxin or iberiotoxin) attenuated dilations at the local and remote sites after focal application at the ACh stimulation site. In marked contrast, treatment of the upstream site with these blockers was without any effect. We conclude that upon local stimulation with ACh, a cytochrome P-450 monooxygenase product is generated that induces local dilation via the activation of Ca(2+)-dependent K(+) channels and initiates conduction of the dilation. In contrast to the local site, neither activation of these K(+) channels nor the synthesis of NO or prostaglandins is necessary to dilate the arterioles at remote, distant sites. This suggests that endothelium-derived hyperpolarizing factor serves as an important mediator to initiate conducted dilations and, by doing so, may act as a key player in the coordination of arteriolar behavior in the microcirculatory network.  (+info)

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