Disseminated arterial calcification and enhanced myogenic response are associated with abcc6 deficiency in a mouse model of pseudoxanthoma elasticum.

OBJECTIVE: Pseudoxanthoma elasticum is an inherited metabolic disorder resulting from ABCC6 gene mutations. It is characterized by progressive calcification and fragmentation of elastic fibers in the skin, retina, and the arterial wall. Despite calcium accumulation in the arteries of patients with pseudoxanthoma elasticum, functional consequences remain unknown. In the present study, we investigated arterial structure and function in Abcc6(-/-) mice, a model of the human disease. APPROACH AND RESULTS: Arterial calcium accumulation was evaluated using alizarin red stain and atomic absorption spectrometry. Expression of genes involved in osteochondrogenic differentiation was measured by polymerase chain reaction. Elastic arterial properties were evaluated by carotid echotracking. Vascular reactivity was evaluated using wire and pressure myography and remodeling using histomorphometry. Arterial calcium accumulation was 1.5- to 2-fold higher in Abcc6(-/-) than in wild-type mice. Calcium accumulated locally leading to punctuate pattern. Old Abcc6(-/-) arteries expressed markers of both osteogenic (Runx2, osteopontin) and chondrogenic lineage (Sox9, type II collagen). Abcc6(-/-) arteries displayed slight increase in arterial stiffness and vasoconstrictor tone in vitro tended to be higher in response to phenylephrine and thromboxane A2. Pressure-induced (myogenic) tone was significantly higher in Abcc6(-/-) arteries than in wild type. Arterial blood pressure was not significantly changed in Abcc6(-/-), despite higher variability. CONCLUSIONS: Scattered arterial calcium depositions are probably a result of osteochondrogenic transdifferentiation of vascular cells. Lower elasticity and increased myogenic tone without major changes in agonist-dependent contraction evidenced in aged Abcc6(-/-) mice suggest a reduced control of local blood flow, which in turn may alter vascular homeostasis in the long term.

A Simple Questionnaire as a First-Step Tool to Detect Specific Frailty Profiles: The Lorraine Frailty-Profiling Screening Scale.

OBJECTIVES: To propose a simple frailty screening tool able to identify frailty profiles. DESIGN: Cross-sectional observational study. SETTING: Participants were recruited in 3 different clinical settings: a primary care outpatient clinic (RURAL population, N=591), a geriatric day clinic (DAY-CLINIC population, N=76) and healthy volunteers (URBAN population, N=147). PARTICIPANTS: A total of 817 older adults (>70 years old) living at home were included. INTERVENTION: A 9-item questionnaire (Lorraine Frailty Profiling Screening Scale, LoFProSS), constructed by an experts' working group, was administered to participants by health professionals. MEASUREMENTS: A Multiple Correspondence Analysis (MCA) followed by a hierarchical clustering of the results of the MCA performed in each population was conducted to identify participant profiles based on their answers to LoFProSS. A response pattern algorithm was resultantly identified in the RURAL (main) population and subsequently applied to the URBAN and DAY-CLINIC populations and, in these populations, the two classification methods were compared. Finally, clinically-relevant profiles were generated and compared for their ability to similarly classify subjects. RESULTS: The response pattern differed between the 3 sub-populations for all 9 items, revealing significant intergroup differences (1.2±1.4 positive responses for URBAN vs. 2.1±1.3 for RURAL vs. 3.1±2.1 for DAY-CLINIC, all p<0.05). Five clusters were highlighted in the main RURAL population: "non-frail", "hospitalizations", "physical problems", "social isolation" and "behavioral", with similar clusters highlighted in the remaining two populations. Identification of the response pattern algorithm in the RURAL population yielded a second classification approach, with 83% of tested participants classified in the same cluster using the 2 different approaches. Three clinically-relevant profiles ("non-frail" profile, "physical frailty and diseases" profile and "cognitive-psychological frailty" profile) were subsequently generated from the 5 clusters. A similar double classification approach as above was applied to these 3 profiles revealing a very high percentage (95.6%) of similar profile classifications using both methods. CONCLUSION: The present results demonstrate the ability of LoFProSS to highlight 3 frailty-related profiles, in a consistent manner, among different older populations living at home. Such scale could represent an added value as a simple frailty screening tool for accelerated and better-targeted investigations and interventions.

Effects of lean and fat mass on bone mineral density and arterial stiffness in elderly men.

SUMMARY: The role of body composition on arterial stiffness and osteoporosis remains unclear, especially in the elderly male population. Our results indicate that elderly men with high lean mass and low fat mass exhibit the best arterial and bone profile with the lowest arterial stiffness and the highest bone mineral density. INTRODUCTION: The aim of this study was to evaluate the influence of fat and lean mass on both arterial stiffness and bone mass density (BMD) in elderly men. METHODS: This study was performed in 169 French males over 60 years old. Aortic stiffness was assessed by carotid/femoral pulse wave velocity (PWV). BMD and body composition were determined with a dual-energy X-ray absorptiometry device in the lumbar spine L1-L4, femoral neck, and total body. RESULTS: Lean mass was positively correlated with the three T scores accounting for 11.6%, 26.6%, and 12.2% of the variability in the lumbar spine L1-L4, femoral neck, and total body BMD T scores, respectively. Fat mass had no effect on BMD. However, fat mass was positively correlated with aortic PWV, accounting for 9.8% of its variability. Lean mass was not a determinant of PWV. Hypertension, diabetes, and dyslipidemia were associated with higher PWV but had no effect on BMD. CONCLUSIONS: In males from a general population over 60 years of age, bone and arterial aging are differently influenced by lean and fat mass. Our results indicate that elderly men with high lean mass and low fat mass exhibit the best arterial and bone profile with the lowest arterial stiffness and the highest BMD.

Effect of urban waste compost application on soil near-saturated hydraulic conductivity.

Compost application tends to increase soil fertility and is likely to modify soil hydrodynamic properties by acting on soil structural porosity. Two composts, a municipal solid waste compost (MSW) and a co-compost of green wastes and sewage sludge (SGW), have been applied every other year for 6 yr to cultivated plots located on a silt loam soil in the Parisian Basin, France. Four soil zones were defined in the topsoil after plowing: the plowpan located at the base of the plowed layer, compacted (Delta) or noncompacted (Gamma) zones located within the plowed layer, and interfurrows created by plowing and containing a large quantity of crop residues together with the recently-applied compost. To assess the effect of compost application on the near-saturated soil hydraulic conductivity, infiltration rates were measured using a tension disc infiltrometer at three water pressure potentials -0.6, -0.2, and -0.05 kPa in the various zones of the soil profile. Compost addition decreased K((sat)) in the interfurrows after plowing by almost one order of magnitude with average values of 5.6 x 10(-5) m.s(-1) in the MSW plot and 4.1 x 10(-5) m.s(-1) in the SGW plot, against 2.2 x 10(-4) m.s(-1) in the control plot. This effect had disappeared 6 mo after plowing when the average K((sat)) in the control plot had decreased to 1.9 x 10(-5) m.s(-1) while that in the compost-amended plots remained stable.

Influence of Thoracic Aortic Inflammation and Calcifications on Arterial Stiffness and Cardiac Function in Older Subjects.

BACKGROUND: Vascular aging is accompanied by gradual remodeling affecting both arterial and cardiac structure and mechanical properties. Hypertension is suggested to exert pro-inflammatory actions enhancing arterial stiffness. OBJECTIVE: To determine the influence of thoracic aortic inflammation and calcifications on arterial stiffness and cardiac function in hypertensive and normotensive older subjects. DESIGN: A prospective study. SETTING: An acute geriatrics ward of the University Hospital of Nancy in France. SUBJECTS: Thirty individuals ≥ 65 years were examined, including 15 hypertensive subjects and 15 controls well-matched for age and sex. MEASUREMENTS: Applanation tonometry was used to measure aortic pulse wave velocity (AoPWV) and carotid/brachial pulse pressure amplification (PPA). Left ventricular parameters were measured with magnetic resonance imaging. Local thoracic aortic inflammation and calcification were measured by 18 F-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Biomarkers of low-grade inflammation were also quantified. RESULTS: AoPWV was higher in elderly hypertensive subjects comparatively to normotensive controls (15.5±5.3 vs. 11.9±2.5, p=0.046), and hypertensives had a higher calcification volume. In the overall population, calcifications of the thoracic descending aorta and inflammation of the ascending aorta accounted for respectively 18.1% (p=0.01) and 9.6% (p=0.07) of AoPWV variation. Individuals with high levels of calcifications and/or inflammation had higher AoPWV (p=0.003). Inflammation had a negative effect on PPA explaining 13.8% of its variation (p<0.05). CONCLUSION: This study highlights the importance of local ascending aortic inflammation as a potential major actor in the determination of PPA while calcifications and hypertension are more linked to AoPWV. Assessment of PPA in the very elderly could provide complementary information to improve diagnostic and therapeutic strategies targeting ascending aortic inflammation.

Preventive and chronic mineralocorticoid receptor antagonism is highly beneficial in obese SHHF rats.

BACKGROUND AND PURPOSE: Mineralocorticoid receptor (MR) activation contributes to heart failure (HF) progression. Its overactivity in obesity is thought to accelerate cardiac remodelling and HF development. Given that MR antagonists (MRA) are beneficial in chronic HF patients, we hypothesized that early MRA treatment may target obesity-related disorders and consequently delay the development of HF. EXPERIMENTAL APPROACH: Twenty spontaneously hypertensive HF dyslipidaemic obese SHHF(cp/cp) rats and 18 non-dyslipidaemic lean SHHF(+/+) controls underwent regular monitoring for their metabolic and cardiovascular phenotypes with or without MRA treatment [eplerenone (eple), 100 mg∙kg(-1) ∙day(-1) ] from 1.5 to 12.5 months of age. KEY RESULTS: Eleven months of eple treatment in obese rats (SHHF(cp/cp) eple) reduced the obesity-related metabolic disorders observed in untreated SHHF(cp/cp) rats by reducing weight gain, triglycerides and total cholesterol levels and by preserving adiponectinaemia. The MRA treatment predominantly preserved diastolic and systolic functions in obese rats by alleviating the eccentric cardiac hypertrophy observed in untreated SHHF(cp/cp) animals and preserving ejection fraction (70 ± 1 vs. 59 ± 1%). The MRA also improved survival independently of these pressure effects. CONCLUSION AND IMPLICATIONS: Early chronic eple treatment resulted in a delay in cardiac remodelling and HF onset in both SHHF(+/+) and SHHF(cp/cp) rats, whereas SHHF(cp/cp) rats further benefited from the MRA treatment through a reduction in their obesity and dyslipidaemia. These findings suggest that preventive MRA therapy may provide greater benefits in obese patients with additional risk factors of developing cardiovascular complications.

Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats.

OBJECTIVES: Because the synthesis of aldosterone is mainly modulated by angiotensin II through type I receptor stimulation and because converting enzyme inhibition (CEI) does not modify aortic extracellular matrix in old normotensive rats, the aim of the present study was to determine whether inhibition of aldosterone formation was able to prevent aortic fibrosis in old Sprague-Dawley normotensive rats. BACKGROUND: We have previously shown that long-term aldosterone antagonism prevents the age-related increase in aortic collagen accumulation in young spontaneously hypertensive rats, independent of blood pressure changes. In contrast, we reported that the positive effects of CEI in the prevention of aortic collagen accumulation were related to the inhibition of angiotensin II actions on angiotensin II type I receptors. METHODS: For this purpose, we studied the histomorphometric and stiffness (echo-tracking technique) changes of an eight-week treatment with the aldosterone antagonist spironolactone by comparison with placebo. RESULTS: At the end of treatment, spironolactone in conscious animals did not change intra-arterial blood pressure, aortic and carotid wall thickness, and cardiac weight. Cardiac collagen density and, to a lesser extent, carotid collagen and elastin densities and contents were significantly decreased in association with an increase of carotid distensibility. CONCLUSIONS: These results show that in old normotensive rats, spironolactone can markedly prevent cardiac and, to a lesser extent, arterial fibrosis and improve arterial stiffness, despite a lack of hypotensive effect.

[The metabolic syndrome in hypertensive black population of South Algeria]. / Le syndrome métabolique chez les hypertendus de la population noire du sud algérien.

INTRODUCTION: The metabolic syndrome is a risk factor for cardiovascular diseases. It exposes to two main complications: cardiovascular diseases and type II diabetes. This risk is higher among women. It causes a high cardiovascular mortality. OBJECTIVES: Assess the prevalence of the metabolic syndrome (MS) among our black hypertensive population. Study of the distribution of the different criteria in the cluster. Search cardiovascular complications. MATERIALS AND METHODS: This longitudinal study that was carried out included one thousand five hundred and fifty subjects of both sexes from black and white populations aged 40 and older, living in the Algerian Sahara and reviewed after six years of decline. The control consisted of filling a questionnaire oriented on civil status, in addition to a clinical examination, including morphometry, measurement of blood pressure performed with validated electronic device (OMRON 705 CP). Also, a biological check-up was done (glycemy, HDL, cholesterol). A univariate and multivariate analysis have been carried out. All calculations and statistical analyzes are processed by the SPSS 17.0 and Epi Info6 software. RESULTS: The MS frequency is 20.8%, more frequent among women than among men, with a significant difference (28.4% versus 15.1%, P<0.001). We found out a difference between black and white populations in terms of obesity (37.6% versus 31.1%), hypertension (60.6% versus 55.0%), diabetes (25.2% versus 19.2%) or other metabolic syndrome criteria. The most frequent complications according to decreasing frequency are: hospitalization for cardiovascular diseases 8.9%, stroke 6.3%, heart failure 5.8%, myocardial infarction 3.6%. The mortality rate is 14.7% among the blacks and 11.3% among the whites without difference. The survival rate of the population is influenced by the MS and by a non-checked blood pressure by an antihypertensive treatment. CONCLUSION: The MS is highly prevailing among hypertensive black population, and significantly higher among women. The ranking of the cluster elements frequency shows clearly the specifities of our population. It is necessary to elaborate an adequate strategy to prevent such cardiovascular morbidity and mortality.

Angiotensin II type 1 receptor-153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects.

OBJECTIVES: Arterial stiffness is associated with excess morbidity and mortality, independently of other cardiovascular risk factors. Age is the main determinant responsible for arterial wall changes leading to arterial stiffening. Environmental and genetic factors may however influence the magnitude of the effects of age on large artery stiffness. DESIGN AND METHODS: The present study assessed whether or not the relationship between age and aortic stiffness was influenced by genetic variants of angiotensinogen (AGT 174T/M, 235M/T), angiotensin converting enzyme (ACE I/D), angiotensin II type 1 receptor (AT1 1166A/C, -153A/G) and aldosterone synthase (CYP11B2 -344T/C). This study was realized in 441 untreated hypertensive subjects of European origin (aged 18-74 years). Aortic stiffness was assessed by carotid-femoral pulse wave velocity (PWV). RESULTS: Carriers of the angiotensin II type 1 receptor -153G allele showed a steeper age/PWV relationship than the AT1 -153AA subjects. The effect of the AT1 -153A/G polymorphism on aortic stiffness became apparent after the age of 55 years. In subjects with the AT1 1166C allele, the relationship age/PWV is shifted upward, indicating higher values of aortic stiffness at any age compared to the AT1 1166AA patients. Carriers of both the AT1 1166C and -153G alleles presented the additive effects of these 2 genotypes on aortic stiffness. Angiotensinogen, ACE and CYP11B2 genotypes did not influence the effects of age on PWV. CONCLUSIONS: AT1 receptor genotypes could influence arterial ageing in hypertensive subjects. These results also show that the association between genotypes and arterial stiffness may manifest itself later in life.

The actions of Paf-acether (platelet-activating factor) on guinea-pig isolated heart preparations.

Paf-acether (platelet-activating factor) is a phospholipid capable of stimulating platelets to release their granular contents and cause platelet aggregation. When Paf-acether was administered to isolated heart preparations from normal guinea-pigs there was a significant concentration-dependent reduction in coronary flow and contractile force. The high concentration of Paf-acether was equally effective in reducing these cardiac parameters in the presence of atropine. The non-acetylated Paf-acether analogue, 2-lyso Paf-acether, the enantiomer, and a closely related phospholipid 1, alpha-lysophosphatidylcholine palmitoyl, did not affect coronary flow and contractile force, indicating the specificity of Paf-acether. These data demonstrate a potent effect of Paf-acether on cardiac function. Whether or not these effects are direct or mediated through generation of endogenous mediators remains to be established.

Inhibitory effects of BAY u3405 on prostanoid-induced contractions in human isolated bronchial and pulmonary arterial muscle preparations.

1. The thromboxane-mimetic, U46619, was a more potent contractile agonist than prostaglandin D2 (PGD2), PGF2 alpha or histamine in human isolated bronchial and pulmonary arterial muscle preparations. 2. Human isolated proximal bronchial muscles were less sensitive to contractile agents than distal bronchial preparations. However, the former tissues developed a greater contractile force (Emax) when compared with results obtained in the latter tissues. 3. BAY u3405 attenuated the contractions induced by U46619, PGF2 alpha and PGD2 in both human isolated bronchial and pulmonary arterial muscle preparations. 4. BAY u3405 did not alter histamine concentration-effect curves nor the relaxation induced by Butaprost (TR4979) in human isolated bronchial muscle preparations. In addition BAY u3405 did not modify the relaxation induced by PGI2 in isolated pulmonary arterial muscle preparations. 5. The contractions induced by different prostaglandins were blocked by BAY u3405, suggesting a common functional site for these agents found both on human bronchial and pulmonary arterial muscles.

Anaphylactic bronchoconstriction in BP2 mice: interactions between serotonin and acetylcholine.

1. Immunized BP2 mice developed an acute bronchoconstriction in vivo and airway muscle contraction in vitro in response to ovalbumin (OA) and these contractions were dose dependent. 2. Methysergide or atropine inhibited OA-induced bronchoconstriction in vivo and airway muscle contraction in vitro. 3. Neostigmine potentiated the OA-induced bronchoconstriction in vivo and airway muscle contraction in vitro of BP2 mice. This potentiation was markedly reduced by the administration of methysergide or atropine and when the two antagonists were administered together, the responses were completely inhibited. 4. Neostigmine also potentiated the serotonin (5-HT)- and acetylcholine (ACh)-induced bronchoconstriction and this potentiation was significantly reversed by atropine. 5. These results indicate that OA provokes a bronchoconstriction in immunized BP2 mice by stimulating the release of 5-HT, which in turn acts via the cholinergic mediator, ACh.

Degradation of acetylcholine in human airways: role of butyrylcholinesterase.

1. Neostigmine and BW284C51 induced concentration-dependent contractions in human isolated bronchial preparations whereas tetraisopropylpyrophosphoramide (iso-OMPA) was inactive on airway resting tone. 2. Neostigmine (0.1 microM) or iso-OMPA (100 microM) increased acetylcholine sensitivity in human isolated bronchial preparations but did not alter methacholine or carbachol concentration-effect curves. 3. In the presence of iso-OMPA (10 microM) the bronchial rings were more sensitive to neostigmine. The pD2 values were, control: 6.05 +/- 0.15 and treated: 6.91 +/- 0.14. 4. Neostigmine or iso-OMPA retarded the degradation of acetylcholine when this substrate was exogenously added to human isolated airways. A marked reduction of acetylcholine degradation was observed in the presence of both inhibitors. Exogenous butyrylcholine degradation was prevented by iso-OMPA (10 microM) but not by neostigmine (0.1 microM). 5. These results suggest the presence of butyrylcholinesterase activity in human bronchial muscle and this enzyme may co-regulate the degradation of acetylcholine in this tissue.

Effects of beta 2-adrenoceptor agonists on anti-IgE-induced contraction and smooth muscle reactivity in human airways.

1. The beta 2-adrenoceptor agonists, salbutamol, salmeterol and RP 58802 relaxed basal tone of human isolated bronchial smooth muscle. Salmeterol- and RP 58802-induced relaxations persisted for more than 4 h when the medium was constantly renewed after treatment. 2. Salbutamol, salmeterol and RP 58802 reversed histamine-induced contractions in human airways (pD2 values: 6.15 +/- 0.21, 6.00 +/- 0.19 and 6.56 +/- 0.12, respectively). 3. Anti-IgE-induced contractions were significantly inhibited immediately after pretreatment of preparations with beta 2-adrenoceptor agonists (10 microM). However, when tissues were treated with beta 2-agonists and then washed for a period of 4 h, salmeterol was the only agonist which significantly inhibited the anti-IgE response. 4. Histamine response curves were shifted to the right immediately after pretreatment of tissues with the beta 2-adrenoceptor agonists (10 microM; 20 min), but maximal contractions were not affected. After a 4 h washing period, the histamine curves were not significantly different from controls. Concentration-effect curves to acetylcholine (ACh) or leukotriene C4 (LTC4) were not significantly modified after beta 2-agonist pretreatment. 5. These results suggest that beta 2-adrenoceptor agonists may prevent anti-IgE-induced contraction by inhibition of mediator release rather than alterations of those mechanisms involved in airway smooth muscle contraction.

M1 and M3 muscarinic receptors in human pulmonary arteries.

1. Acetylcholine (ACh) and the M1 agonists (McN-A-343 or PD142505) relaxed human isolated pulmonary arteries which were pre-contracted with noradrenaline (10 microM). In preparations where the endothelium had been removed ACh induced a contractile response whereas the M1 agonists (McN-A-343 or PD142505) had no effect. 2. ACh- and McN-A-343-induced relaxations were abolished after treatment of endothelium-intact preparations with the drug combination NG-nitro-L-arginine (L-NOARG: 0.1 mM) and indomethacin (1.7 microM). 3. The affinity (pKB value) for pirenzepine was higher in human pulmonary arteries when tissues were relaxed with McN-A-343 as compared with ACh (pKB values, 7.71 +/- 0.30 (n = 4) and 6.68 +/- 0.15 (n = 8), respectively). In addition, the affinity for pFHHSiD against McN-A-343- and ACh-induced relaxations was 6.86 +/- 0.13 (n = 3) and 7.35 +/- 0.11 (n = 9) respectively. 4. The low affinities for methoctramine in human isolated pulmonary arteries with the endothelium either intact or removed, suggested the lack of involvement of M2 and M4 receptors in the Ach responses. 5. Phenoxybenzamine (3 microM: 30 min) abolished both ACh contraction and relaxation in human pulmonary artery. The ACh contraction was present when the phenoxybenzamine treatment was preceded by incubation with pFHHSiD (2 microM) but not with pirenzepine (1 microM). In addition, the ACh relaxation was present when preparations were treated with either pFHHSiD (2 microM) or pirenzepine (1 microM), before exposure to phenoxybenzamine. 6. These results in human isolated pulmonary arteries support the notion that only M3 receptors, on smooth muscle, mediate the ACh-induced contraction whereas M3 and M1 receptors are involved in the endothelium-dependent ACh-induced relaxation.

Prostanoid receptors involved in the relaxation of human bronchial preparations.

1. Iloprost and cicaprost (IP-receptor agonists) induced relaxations in the histamine- (50 microM) contracted human bronchial preparations (pD2 values, 6.63+/-0.12 and 6.86+/-0.08; Emax values, 90+/-04 and 65+/-08% of the papaverine response for iloprost (n=6) and cicaprost (n=3), respectively). 2. Prostaglandin E2 (PGE2) and misoprostol (EP-receptor agonist) relaxed the histamine-contracted human bronchial preparations (pD2 values, 7.13+/-0.07 and 6.33+/-0.28; Emax values, 67+/-04 and 57+/-08% of the papaverine response for PGE2 (n=14) and misoprostol (n=4), respectively). In addition, both relaxations were inhibited by AH6809 (DP/EP1/EP2-receptor antagonist; 3 microM; n=5-6). 3. The PGE2-induced relaxations of human bronchial preparations were not modified by treatment with AH23848B (TP/EP4-receptor antagonist; 30 microM; n=4). 4. The contracted human bronchial preparations were significantly relaxed by prostaglandin D2 (PGD2) or by BW245C a DP-receptor agonist. However, these responses did not exceed 40% of the relaxation induced by papaverine. In addition, the relaxations induced by PGD2 were significantly inhibited by treatment with a DP-receptor antagonist BWA868C (0.1 microM; n=3). 5. These data suggest that the relaxation of human isolated bronchial preparations induced by prostanoids involved IP-, EP2- and to a lesser extent DP-receptors but not EP4-receptor.

Prostanoid receptors involved in the relaxation of human pulmonary vessels.

1. To characterize the prostanoid receptors on human pulmonary smooth muscle involved in vasodilatations, isolated arteries and veins were contracted with norepinephrine (10 microM) and vessels were subsequently challenged with different prostanoid-receptor agonists in the absence or presence of selective antagonists. 2. Prostaglandin D2 (PGD2) and the selective DP-receptor agonist, BW245C, induced relaxations in the contracted human pulmonary venous preparations. The pD2 values were: 6.88+/-0.11 (n=17) and 7.31+/-0.12 (n=5), respectively. The relaxant responses induced by PGD2 were reduced by the selective DP-receptor antagonist, BWA868C, and the estimated pA2 value was 7.84+/-0.16 (n=4). PGD2 and BW245C did not relax contracted human pulmonary arteries. 3. The selective IP-receptor agonists, iloprost and cicaprost, both induced relaxations in the contracted human vascular preparations. The pD2 values for iloprost were: 7.84+/-0.08 (n=6) and 8.25+/-0.06 (n=4) and for cicaprost: 8.06+/-0.12 (n=5) and 8.11+/-0.09 (n=5) in arteries and veins respectively. 4. Prostaglandin E2 (PGE2) and the EP2/EP3-receptor agonist, misoprostol, partially relaxed the contracted venous preparations and the pD2 values were: 8.10+/-0.15 (n=15) and 6.24+/-0.33 (n=3), respectively. These relaxations suggest the presence of an EP receptor in the human pulmonary veins. The contracted human pulmonary arteries did not relax when challenged with PGE2. 5. In human pulmonary venous preparations, the PGE2-induced relaxations were neither modified by treatment with TP/EP4-receptor antagonist, AH23848B (10 and 30 microM, n=6), nor by the DP/EP1/EP2-receptor antagonist, AH6809 (3 microM, n=6). 6. These data suggest that the relaxation induced by prostanoids involved DP-, IP-receptors and to a lesser extent an EP-receptor on human pulmonary venous smooth muscle. In contrast, only the IP-receptor is involved in the prostanoid induced relaxations on human pulmonary arterial smooth muscle.

Response and sensitivity of guinea-pig airway muscle preparations to 5-hydroxytryptamine during ontogenesis.

Responsiveness (g mm-2) and sensitivity (pD2 value) to 5-hydroxytryptamine (5-HT) were markedly reduced in isolated tracheal and bronchial tissues from guinea-pigs during ontogenesis. Responsiveness of the trachea to 5-HT was depressed much more than that to histamine. Airway preparations from young guinea-pigs of either sex always contracted when exposed to 5-HT, an effect that was blocked by methysergide. Airway muscle preparations from old animals exhibited a wide range of responses to 5-HT, namely, no effect, relaxation or contraction. The contractile effect of 5-HT in tracheal and bronchial preparations from old animals was always blocked by methysergide, whereas, the relaxant effect was not. These results indicate that there are significant alterations in the response to 5-HT receptor stimulation in airway muscle preparations from guinea-pigs during ontogenesis.

Evidence that the histamine sensitivity and responsiveness of guinea-pig isolated trachea are modulated by epithelial prostaglandin E2 production.

1. Guinea-pig isolated tracheal preparations in which the epithelium had been removed exhibited a greater contractile response to histamine (intact: 1.91 +/- 0.12 g; n = 6 and rubbed: 2.76 +/- 0.15 g; n = 11; P less than 0.001). The histamine sensitivity (pD2 value) of these preparations was also significantly greater (intact: 4.80 +/- 0.04 and rubbed: 5.40 +/- 0.08; P less than 0.01). 2. Indomethacin suppressed the basal tone of both intact and rubbed preparations but was more effective in the former tissues (intact: -0.70 +/- 0.14 g; n = 22 and rubbed: -0.17 +/- 0.05 g; n = 12; P less than 0.02). 3. Arachidonic acid (AA; 10 microM) suppressed the basal tone of intact tissues but contracted such preparations following indomethacin treatment (1.7 microM; 30 min). However, in rubbed tissues AA (10 microM) induced a contraction which was attenuated following indomethacin treatment. 4. Prostaglandin E2 (PGE2; 0.01 and 0.1 microM) suppressed the basal tone of intact preparations and always evoked contraction of rubbed tissues. Following indomethacin treatment PGE2 (0.01 and 0.1 microM) generally evoked spasm of intact and rubbed tissues while at higher concentrations (1 microM) relaxant effects were observed. 5. Removal of the epithelium did not alter the relaxant effect of PGE2 (pD2 value) on histamine (50 microM)-contracted tissues (intact: 6.86 +/- 0.08 and rubbed: 7.10 +/- 0.3; n = 4; P greater than 0.1). 6. In rubbed preparations treated with indomethacin, PGE2 (0.01 and 0.1 microM) evoked spasm. However, when added to preparations contracted with 5 microM histamine, PGE2 always caused relaxation. 7. The release of immunoreactive PGE2 by rubbed preparations during histamine and/or AA stimulation was significantly less than that produced by intact stimulated tissues. 8. Exogenous PGE2 (0.01-1 microM) decreased the maximal response and sensitivity of rubbed tracheal preparations to histamine. 9. These results suggest that release of an epithelial derived cyclo-oxygenase product, namely PGE2, may regulate basal tone, histamine response and sensitivity of the guinea-pig isolated trachea.

Leukotriene receptors on human pulmonary vascular endothelium.

1. Cysteinyl-leukotrienes cause contractions and/or relaxations of human isolated pulmonary vascular preparations. Although, the localization and nature of the receptors through which these effects are mediated have not been fully characterized, some effects are indirect and not mediated via the well-described LT1 receptor. 2. In human pulmonary veins (HPV) with an intact endothelium, leukotriene D4 (LTD4) induced contraction above basal tone. This response was observed at lower concentrations of LTD4 in the presence of nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NOARG). Contractions (in the absence and presence of L-NOARG) were partially blocked by the LT1 antagonists (MK 571 and ICI 198615). 3. LTD4 relaxed HPV previously contracted with noradrenaline. This relaxation was potentiated by LT1 antagonists, but was abolished by removal of the endothelium. LTD4 also relaxed human pulmonary arteries (HPA) precontracted with noradrenaline but this effect was not modified by LT1 antagonists. 4. The results suggest that contraction of endothelium-intact HPV by LTD4 is partially mediated via LT1 receptors. Further, in endothelium-intact HPV, this contraction was opposed by a relaxation induced by LTD4, dependent on the release of nitric oxide, which was mediated, at least in part, via a non-LT1 receptor. In addition, LTD4 relaxation on contracted HPA was not mediated by LT1 receptors. 5. The mechanical effects of LTD4 on human pulmonary vasculature are complex and involve both direct and indirect mechanisms mediated via at least two types of cysteinyl-leukotriene receptors.