Antidepressants and the risk of arrhythmia in elderly affected by a previous cardiovascular disease: a real-life investigation from Italy.

PURPOSE: The study aimed to fill existing knowledge gaps on the safety of antidepressant drugs (ADs) by estimating the risk of hospitalization for arrhythmia associated with use of selective serotonin reuptake inhibitors (SSRIs) and newer atypical ADs (NAAs) among elderly with previous cardiovascular (CV) events. METHODS: The cohort was composed by 199,569 individuals aged ≥ 65 years from five Italian healthcare territorial units who were discharged for cardiovascular outcomes in the years 2008-2010. The 17,277 patients who experienced hospital admission for arrhythmia during follow-up were included as cases. Odds of current ADs use among cases (i.e., 14 days before hospital admission) was compared with (i) odds of current use of 1:5 matched controls (between-patients case-control) and with (ii) odds of previous use during 1:5 matched control periods (within-patient case-crossover). The risk of arrhythmia associated with ADs current use was modelled fitting a conditional logistic regression. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. RESULTS: Current users of SSRIs and NAAs were at increased risk of arrhythmia with case-control odds ratios (OR) of 1.37 (95% confidence interval, CI 1.18 to 1.58) and 1.41 (1.16 to 1.71) and case-crossover OR of 1.48 (1.20 to 1.81) and 1.72 (1.31 to 2.27). An increased risk of arrhythmia was associated with current use of trazodone (NAA) consistently in case-control and case-crossover designs. CONCLUSIONS: Evidence that current use of SSRIs and NAAs is associated to an increased risk of arrhythmia among elderly with CV disease was consistently supplied by two observational approaches.

Does seawater acidification affect survival, growth and shell integrity in bivalve juveniles?

Anthropogenic emissions of carbon dioxide are leading to decreases in pH and changes in the carbonate chemistry of seawater. Ocean acidification may negatively affect the ability of marine organisms to produce calcareous structures while also influencing their physiological responses and growth. The aim of this study was to evaluate the effects of reduced pH on the survival, growth and shell integrity of juveniles of two marine bivalves from the Northern Adriatic sea: the Mediterranean mussel Mytilus galloprovincialis and the striped venus clam Chamelea gallina. An outdoor flow-through plant was set up and two pH levels (natural seawater pH as a control, pH 7.4 as the treatment) were tested in long-term experiments. Mortality was low throughout the first experiment for both mussels and clams, but a significant increase, which was sensibly higher in clams, was observed at the end of the experiment (6 months). Significant decreases in the live weight (-26%) and, surprisingly, in the shell length (-5%) were observed in treated clams, but not in mussels. In the controls of both species, no shell damage was ever recorded; in the treated mussels and clams, damage proceeded via different modes and to different extents. The severity of shell injuries was maximal in the mussels after just 3 months of exposure to a reduced pH, whereas it progressively increased in clams until the end of the experiment. In shells of both species, the damaged area increased throughout the experiment, peaking at 35% in mussels and 11% in clams. The shell thickness of the treated and control animals significantly decreased after 3 months in clams and after 6 months in mussels. In the second experiment (3 months), only juvenile mussels were exposed to a reduced pH. After 3 months, the mussels at a natural pH level or pH 7.4 did not differ in their survival, shell length or live weight. Conversely, shell damage was clearly visible in the treated mussels from the 1st month onward. Monitoring the chemistry of seawater carbonates always showed aragonite undersaturation at 7.4 pH, whereas calcite undersaturation occurred in only 37% of the measurements. The present study highlighted the contrasting effects of acidification in two bivalve species living in the same region, although not exactly in the same habitat.

Analysis and improvement of organizational models for the management of patients with type 2 diabetes mellitus: a case study in north-east Italy.

PURPOSE: The study aimed to establish whether the organization for the management of type 2 diabetes mellitus at 9 diabetic units (DUs), in 5 neighboring local health authorities (LHAs), was able to (a) comply with the organizational model prescribed by specific regional standards; (b) ensure adequate clinical management of diabetic patients; (c) assess whether the relationship between primary care physicians (PCPs) and diabetologists (SDs) was instrumental to the needs of patients; (d) optimize specialist treatment at the DUs; (e) optimize drug management; and (f) check whether organizational changes led to variations in clinical results. METHODS: This 6-stage study analyzed procedures, precoded actions, and recordable processes. Stage (1) Defining clinical and organizational endpoints; (2) Drafting flowcharts to describe the actions and work procedures implemented within each LHA; (3) Comparing the flowcharts with the data obtained from related literature; (4) Establishing a protocol shared with PCPs for the management and treatment of patients with type 2 diabetes; (5) Changing the procedures at the DUs; and (6) Evaluating the results. The data were assessed before and after establishing a shared protocol for SDs and PCPs (year 2009 vs 2011). RESULTS: The study shows inconsistencies in the organization of work in the 5 LHAs; however, collaboration with PCPs has guaranteed: (a) unchanged hemoglobin A1C values before and after applying the protocol; (b) a percentage increase in the number of patients with type 2 diabetes who were identified thanks to these protocols; (c) an increase in the use of biguanides compared to the preprotocol period; and (d) no change in the number of patients hospitalized because of acute complications from type 2 diabetes mellitus. CONCLUSIONS: This study confirms how adequate collaboration between SDs and PCPs keeps the risk of complications stable. Nevertheless, shared protocols and clearly defined roles are required.

Variaciones hematológicas postoperatorias endermolipectomía / Postoperative hematological variations in dermolipectomy

La tétrada deformante de la pared abdominal está constituida por la obesidad, la distensión abdominal, la gravidez y la diástasis muscular. Nos planteamos como objetivo de nuestro trabajo el demostrar la variación que sufren el hematocrito y la hemoglobina con relación al porcentaje del peso corporal total que representan los colgajos dermograsos extirpados en una dermolipectomía abdominal, tomando como parámetro los valores obtenidos a las 24 horas de la cirugía y a los7 días de postoperatorio. Diseñamos un estudio prospectivo observacional en el que analizamos 93 pacientes operados entre el 1 de agosto del2007 y el 31 de diciembre de 2008. Las variables analizadas fueron las modificaciones sufridas por el hematocrito y la hemoglobina en relación al tanto por ciento de peso corporal total que representan los colgajos extirpados. El promedio de descenso del hematocrito a las 24 horas de la intervención fue del 6,19 % y el de la hemoglobina a las 24 horas de la intervención fue de1,9 gr/l; los valores a los 7 días de postoperatorio fueron de 3,84% y 1,25 gr/l respectivamente. Como conclusión, destacamos la necesidad de comprender la importancia de una correcta preparación prequirúrgica de los pacientes que se van a someter a una dermolipectomía abdominal, para evitar complicaciones en el postoperatorio inmediato y tardío, mejorando así su selección para disminuirla morbilidad de esta intervención quirúrgica (AU)

The deforming tetrad of the abdominal wall is formed byobesity, abdominal distension, gravidity and muscle diastases. Our objective is to show the variation of the hematocrit and hemoglobin in relation to the percentage of the total bodymass that represents the fatty skin folds extirpated in a dermolipectomy, having as parameter the one obtained 24 hours after surgery and at 7 postoperative day. We design an observational prospective study on 93 patients who underwent an abdominal dermolipectomy between august 1st 2007 and december 31st 2008.Analyzed variables were hematocrit and hemoglobin variations related to the percentage of total body mass that represents the skin folds extirpated. The average decrease of the hematocrit 24 hours after surgery was 6,19% and the hemoglobin 1,9gr/l; 7 days later were 3,84% and 1,25gr/l respectively. As a conclusion, we remark the importance of a correct presurgical care of the patients to avoid immediate and distant postoperative complications in abdominal dermolipectomy, improving selection to diminish morbidity (AU)

Benefit of statins in daily practice? A six-year retrospective observational study.

This observational retrospective study analysed the association of adherence to statins with the achievement of a target total cholesterol level (CL, <200mg/dl), and any association of adherence with the time to first hospital admission for coronary event in hypercholesterolemic patients treated with statins, in one Italian Local Health Authority between 1998 and 2003. The study population consisted of 3516 patients who were prescribed statins and for whom full cholesterol results were available. After three months of treatment, there were significant reductions in CL (p<0.001) in the three treatment groups stratified by adherence (good adherents -24%, poor adherents -22%, and nonadherents -14%). Patients more likely to achieve the target CL were older, male and more adherent to the statins. The risk of first hospitalization was associated positively with increased age and male gender. Patients with co-treatments were more likely to be hospitalized. Surprisingly, better adherence to statin treatment increased the risk of hospitalization.

Resource consumption and costs of treating pain in patients affected by cancer in a district of northeast Italy.

WHO declared that pain is a relevant problem in public health and that opioids are the gold standard therapy for the treatment of moderate to severe pain. The present retrospective, epidemiological, observational study is aimed to evaluate resource consumption therapy in patients treated with opioids and died with a diagnosis of cancer in Treviso, a district in northeast Italy. For the monetisation of resource consumed, the Italian National Health Service perspective was adopted. For each patient, resource monetized were drugs (opioids, NSAIDs and adjuvants), hospitalizations with cancer diagnosis, diagnostic examinations and laboratory tests. All databases were linked in order to obtain patient profile of resource consumption. A total of 935 patients were included in the study. The incident opioid prescribed were for 60% morphine, 37% fentanyl, and 2.5% buprenorphine. The average length of treatment with opioids was 105+/-73 days. Of the patients included in the study, 79% received an anti-inflammatory drug (traditional NSAIDs and/or COX2 inhibitors), while 21% of patients treated with opioids never had an anti-inflammatory reimbursed prescription during the observation period. The average length of anti-inflammatory treatment was 133+/-83 days. For the vast majority of prescribed anti-inflammatory drugs, the received daily dose (RDD) was widely greater then the defined daily dose (DDD) before and during treatment with opioids, while for opioids the RDD was in line with the revised DDD for fentanyl, and less than the DDD for morphine and buprenorphine. The total daily cost per patient before the first prescription of opioids was euro 11.36 while after the first prescription of opioids, it increased to euro 21.12. This study confirms the under utilization of opioids in Italy both in terms of dosages and length of therapy.

Utilisation Pattern of Nonspecific Nonsteroidal Anti-Inflammatory Drugs and COX-2 Inhibitors in a Local Health Service Unit in Northeast Italy.

BACKGROUND AND OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed widely in Italy. They include nonspecific NSAIDs (NS-NSAIDs) and the newly marketed cyclo-oxygenase (COX)-2 specific inhibitors (COXIBs) celecoxib and rofecoxib. The objective of this study was to describe the prescribing patterns for NS-NSAIDs and COXIBs in a local Italian area, analysing an administrative database. PATIENTS AND METHODS: We extracted from the database information on subjects who had received at least one reimbursed prescription of an NSAID during the period between 1 January 2001 and 31 December 2001, including age, sex, patient identification code, Anatomical Therapeutic Chemical (ATC) classification system code, strength, formulation, number of packs prescribed, prescription date, and prescription of gastroprotective agents (GPAs) on the same day as the prescription of the NSAID. On the basis of the type of NSAID received, we divided the patients into five cohorts: oral NS-NSAIDs only during the observed year, injectable NS-NSAIDs only, celecoxib only, rofecoxib only, and a combination. For descriptive purposes, we defined three age groups: <40 years, 40-64 years, and >64 years. The duration of exposure to NSAID therapy was calculated using the most commonly prescribed dose for the different drugs. Subjects receiving >/=30 doses per year were defined as "regular users". Analyses included mean age, mean duration of exposure, percentage of regular users, and percentage of GPAs co-prescribed in the different cohorts. RESULTS: NSAIDs were prescribed to 62 059 subjects from a resident population of 365 321 inhabitants; 43.8% received oral NS-NSAIDs only, 22.6% injectable NS-NSAIDs only, 7.2% celecoxib only, 5.2% rofecoxib only, and 22% different regimens of different types of NSAIDs. The mean duration of treatment increased with age in all cohorts; the mean age was 56 years in the NS-NSAID cohort, 61 years in the celecoxib cohort, and 62 years in the rofecoxib cohort (p = 0.01, COXIBs vs NS-NSAIDs). The mean duration of therapy was 11.4 days/year for injectable NS-NSAIDs, 43.8 days/year for rofecoxib, 50.5 days/year for oral NS-NSAIDs, and 53.7 days/year for celecoxib. Fifty-four percent of subjects in the oral NS-NSAID cohort were regular users versus 64% in the rofecoxib and 70% in the celecoxib groups (p = 0.001, COXIBs vs NS-NSAIDs). Co-prescription with GPAs was 9.5% for NS-NSAIDs, 8.4% for rofecoxib, and 7.7% for celecoxib. CONCLUSIONS: Analysis of an administrative database in Italy showed a trend suggesting that COXIBs are prescribed to an older population and for a longer period of time than NS-NSAIDs, and that their use is less frequently associated with GPAs.

Pharmacological characterization of endothelial cell nitric oxide synthase inhibitors in isolated rabbit aorta.

Different receptors mediating the release of endothelium-derived nitric oxide (EDNO) have been identified at endothelial level. In the present study we aimed to characterise, on rabbit aorta by means of pharmacological tools, the generation of EDNO by receptors located on endothelial cell membrane (M3, P2u, P2y) and by direct activation of Ca2+ entry into the endothelial cell. Four vasodilating drugs were tested (acetylcholine, UTP, A23187 and 2-methyl-thio-ATP); they were active only if the endothelial layer was intact, suggesting that they act through endothelial receptors. The effect of different nitric oxide synthase (NOS) inhibitors (0.1 mM: L- and D-NAME, L-NMMA, L-NIO and 7-NI) was investigated on NO-mediated relaxation induced by the relaxants in vessels with intact endothelium. NOS inhibitors differently affected relaxation mediated by the vasoactive drugs in isolated rabbit aorta. Reversibility of the inhibition by using a fixed concentration of L-arginine (0.1 mM) was different depending on the relaxing drug and NOS-inhibitor. The data obtained support the coexistence in aortic vessel of more than one endothelial cell NOS isoform, each provided with different receptor coupling.

Effect of duration of ampullary gallstone obstruction on severity of lesions of acute pancreatitis.

BACKGROUND: This study was done to determine the effects of duration of obstruction on severity of lesions in patients with acute pancreatitis of biliary origin. STUDY DESIGN: This case controlled study used patient data collected prospectively on protocol during a 27-year period in a university teaching hospital. We studied a group of 97 patients with acute pancreatitis, all with an impacted stone at the ampulla of Vater at exploration (Group Ob), and a control group of 49 patients with acute gallstone pancreatitis who experienced spontaneous ampullary disobstruction within 24 hours from the onset of symptoms and who showed a patent ampulla at exploration (Group Cont). Duration of obstruction was defined as the time elapsed between the onset of symptoms and exploration in Group Ob, and from the onset of symptoms until the appearance of signs of ampullary disobstruction in Group Cont. Severity of disease in both groups was determined by the appearance of the pancreas at exploration. Patients in Group Ob were divided into three subgroups according to duration of obstruction: under 24 hours, 25 to 48 hours, and more than 48 hours. RESULTS: The incidence of severe pancreatic lesions was higher in Group Ob than in Group Cont (19.7 percent compared to 6.1 percent, p < .01). Mean duration of obstruction was also significantly longer in Group Ob than in Group Cont (42.4 hours compared to 10.6 hours). In the subgroups of patients whose obstruction lasted under 48 hours, the incidence of severe lesions was low: in the 24 hours or fewer group, severe lesions were observed in 8.1 percent (3 of 37); and in the 25 to 48 hours group, the incidence was 10.6 percent (5 of 47). Neither subgroup differed significantly from Group Cont (6.1 percent, 3 of 49). When duration of obstruction exceeded 48 hours, however, frequency of severe lesions increased significantly to 84.6 percent (11 of 13) (p < .001). CONCLUSIONS: The findings in this study suggest that duration of ampullary obstruction is a major factor determining the severity of pancreatic lesions: severe pancreatic lesions are rare in patients whose obstruction lasts not more than 48 hours. In contrast, pancreatic necrosis develops in nearly all patients with obstruction beyond 48 hours. It may be safe to treat patients conservatively during the first day of the illness. If obstruction is not resolved by the second day, endoscopic retrograde cholangiopancreatography or surgical intervention must be carried out.

Inhibition of platelet activation by MM-706, a stable carbacyclin analog, in the conscious rat.

A new stable analog of carbacyclin, 13,14-dihydro-15,16,17,18,19,20-hexanor-14-(1-hydroxycyclohexyl) carbacyclin, identified as MM-706, was investigated in vivo in the conscious rat. MM-706 as single bolus (200 micrograms/kg, equivalent to 546 nmol/kg) prevented the reduction of circulating platelets induced by adenosine diphosphate (ADP) (1 mumol/kg as IV bolus). 2. A similar effect on free platelet numbers also was observed with iloprost (20 and 200 micrograms/kg IV bolus). However, MM-706 did not induce any significant variation of mean arterial blood pressure (MABP) or heart rate, unlike iloprost, which reduced MABP within 10 min of administration. 3. In conclusion, MM-706 is effective in interfering with in vivo platelet activation induced by ADP without influencing other cardiovascular parameters, such as arterial pressure and heart rate.

P2X-purinoceptors in the heart: actions of ATP and UTP.

Positive inotropic effects of ATP and UTP (1 microM - 1mM) were studied in isolated rat and guinea pig cardiac tissues. The potency order obtained was ATP>UTP in both species, suggesting possible interaction with P2X-purinoceptors. Binding studies using [(3)H]alpha,beta-methylene ATP as marker of P2X-purinoceptors revealed two receptor sites: one high-, the other low-affinity, in atria and ventricles from rat and guinea pig. Both ATP and UTP were found to bind high-affinity sites of [(3)H]alpha,beta-methylene ATP. The effects of various calcium inhibitors such as nifedipine, dantrolene, ryanodine and TMB-8 on positive inotropic effects induced by ATP and UTP were also studied. The results suggest that ATP and UTP may increase inotropism by interaction with P2X-purinoceptors by means of a calcium-dependent mechanism.

Prolonged inhibition of nitric oxide synthesis in Yoshida hyperlipidemic rat: aorta functional and structural properties.

To test whether inhibition of nitric oxide synthesis, associated with high levels of plasmatic lipids, can induce atherosclerotic lesions and phenotypic changes in smooth muscle cell composition in the aortic wall of an atherosclerotic-resistant species such as the rat, an inbred strain of hyperlipidemic Pittsburgh Yoshida rat was subjected to prolonged treatment (2 months) with the nitric oxide-synthase inhibitor L omega-nitro-arginine-methyl ester or with L-arginine. The two types of in vivo treatments were not able to modify in vitro aortic endothelium-mediated relaxation induced by acetylcholine or calcium-ionophore A-23187, the endothelium-independent sodium nitrite relaxation and the contractile response to serotonin. Histology and lipid infiltration of vascular specimens showed that L omega-nitro-arginine-methyl ester in vivo treatment did not induce any significant change in the aortic wall. Monoclonal antibodies to myosin isoforms and immunofluorescence procedures revealed the presence of an immature smooth muscle cell subpopulation in aortic specimens from saline-treated Pittsburgh Yoshida rats, whose expansion has been related in other species to atherogenesis. This peculiar cell phenotype disappeared in our animal model after prolonged L omega-nitro-arginine-methyl ester treatment. These data indicate that, despite interference with endothelium-mediated nitric oxide synthesis, atherosclerosis does not develop in this animal model and furnish for the first time a biological justification for atherogenesis resistance of rat, i.e., the lack of activation of an immature aortic smooth muscle cell population which in atherosclerosis-prone species is involved in lesion formation.

Effects of N omega-nitro-L-arginine methyl ester on benzodiazepine binding in some limbic areas of hyperlipidaemic rats.

Quantitative autoradiography techniques were used to evaluate the chronic effects of the potent nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester, on the binding pattern of [3H]flunitrazepam (benzodiazepine agonist) in some behaviorally key limbic areas of the genetic hyperlipidaemic Pittsburg Yoshida rat. Administration of this potent synthase inhibitor was capable of supplying higher and moderately higher binding levels in the basolateral amygdala nucleus (+52%) and in the oriens-pyramidalis CA1 hippocampus layer (+38%), respectively. When we tested for the binding changes in the presence of GABA (principal benzodiazepine modulator) we noticed that a physiological concentration (20 microM) of this inhibitory neurotransmitter was sufficient to induce notable changes in other limbic areas. In fact, lower binding values (-65%) were reported for the bed nucleus of stria terminalis whereas moderately higher values (+38%) were obtained for the radiatum-lacunosum molecular CA1 hippocampus layer. From the saturation studies, it was possible to observe that the major receptor variations provoked by the potent synthase inhibitor were not only due to changes in the total number of binding sites because there were variations, as in the case of the basolateral amygdala nucleus, that were instead due to differences in the affinity binding state. These results provide evidences of a GABAergic-nitric oxide synthase inhibitor interaction that might also be involved in the regulation of convulsive, anxiolytic, and aggressive behaviors that are modulated at the benzodiazepine site.

Characterization of in vitro relaxant mechanisms in erectile tissue from rabbits of different ages.

In the present study we investigated the in vitro relaxant response of erectile tissue obtained from rabbits of different ages (3, 7 and 24 months) in order to detect the progression with age of cavernosal activity in response to substances acting via endothelium-dependent or -independent mechanisms. Noradrenaline induced a concentration-dependent contraction (0.1 microM-3 mM), with an increase in the contractility in the 24-month-old group. Acetylcholine produced a concentration-dependent relaxant effect in the three age groups, with a reduction of the maximal relaxant effect in older animals. ATP (10 microM-1 mM) and adenosine (10 microM-1 mM) induced a concentration-dependent relaxant effect that was higher in the older group. The presence of the NO2-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) (0.1 mM) or of the P2-purinoceptor antagonist suramin did not affect ATP relaxation. Relaxation induced by sodium nitrite and nifedipine was reduced in older animals. In conclusion, aging selectively alters the in vitro responsiveness of rabbit erectile tissue. Purinergic system remains more active despite a decrease in the maximal endothelial cholinergic activity and the direct smooth muscle relaxant component.

Chronic treatment with cyclosporine A in New Zealand rabbit: aortic and erectile tissue alterations.

Transplanted patients frequently present erectile impotence. In order to test any interference by cyclosporine A (CsA), which is commonly used in the post-transplantation management, we investigated the in vitro contractile and relaxant responses of corpus cavernosum and aorta from rabbits chronically treated with CsA. Male New Zealand White rabbits 6 months of age were treated with CsA (25 mg/kg per day s.c.) or solvent (corn oil) for 3 weeks. Descending thoracic aorta and erectile tissue were studied in vitro at the end of treatment. Isometric tension was recorded. In thoracic aorta, noradrenaline (0.1-30 mM) induced a concentration-dependent contraction with no difference between the two groups. Acetylcholine (30 nM-3 mM) produced relaxation (52 +/- 4% at 1 mM) that was significantly reduced in comparison to controls (67 +/- 4%, P < 0.05). ATP (3-10 mM) relaxation was not significantly different (maximal 78 +/- 10% and 62 +/- 12% in CsA-treated and controls). The relaxation produced by sodium nitrite was reduced in CsA-treated rabbits (at 10 mM and 0.1 mM concentrations). In erectile tissue, no significant variation in the response of isolated erectile tissue to the above drugs was observed between CsA-treated and control animals. These data indicate that chronic treatment with CsA in rabbits, despite alteration of the in vitro response of thoracic aorta, does not directly influence the function of penile tissue with relaxants.

Heparin: pharmacological potentials from atherosclerosis to asthma.

1. Heparin belongs to a family of polysaccharide species, whose best known property is, undoubtedly, anticoagulant activity. However, heparin has many other pharmacological effects, particularly on the cardiovascular system. 2. The therapeutic use of chronically inhaled heparin has been suggested as prophylaxis in atherosclerosis. 3. Heparin, physiologically stored in mast cells of the respiratory system, has also been recently studied in the prevention of immunological and non-immunological asthmatic attacks. 4. Experimental findings and new hypotheses of heparin action in asthma and atherosclerosis are discussed.

Pharmacological properties of MM-706, a new prostacyclin derivative.

1. In human platelet-rich plasma, platelet aggregation induced in vitro by collagen (10 micrograms/ml) or thrombin (50 mU/ml) was dose-dependently inhibited by increasing concentrations of prostacyclin or of the new derivative (+/-)(5E)-13,14-didehydro-omega-hexanor(1-hydroxycyclo hexyl)-9a- carbaprostacyclin (MM-706) with an IC50 of 20-50 nM and 250-500 nM, respectively. In human platelets loaded with fura-2, the intracellular rise of [Ca2+] induced by thrombin was dose-dependently inhibited by MM-706 with an approximate IC50 of 100 microM. 2. In rabbit isolated femoral artery, MM-706 (10 nM-10 microM) was completely ineffective in relaxing the vessel, which was different to prostacyclin which was able to relax vessels at the same concentrations. 3. In in vitro guinea-pig ileum, prostacyclin produced a contractile effect in the concentration range 1 nM-10 microM, but the derivative MM-706 was ineffective at the same concentrations. Preventive addition of MM-706 did not inhibit prostacyclin contraction. 4. On isolated guinea-pig tracheal preparation, prostacyclin induced a concentration-dependent contraction but the new compound MM-706 showed a lower activity, in the concentration range 10 nM-10 microM. The activity of prostacyclin was not affected by the contemporary presence of MM-706. 5. It is concluded that MM-706 is a prostacyclin analogue with antiaggregating properties but without evident effects on smooth muscle of different regions.

Endothelial nucleotide-mediated aorta relaxation in aged Watanabe heritable hyperlipidemic rabbits.

We investigated the activity of muscarinic and purinergic endothelial receptors during atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbit aorta. Experiments were performed on isolated thoracic aorta from WHHL rabbits aged 1 and 2.5 years. The relaxant response to acetylcholine (ACh) was progressively reduced with aging, being almost completely abolished in 2.5-year-old rabbits. The relaxant effect of ATP was not affected by the P2-purinoceptor antagonist suramin, thus excluding any involvement of relaxant P2y purinoceptors in both considered ages. The pyrimidine UTP, acting on nucleotide (P2U) receptors, produced concentration-dependent relaxation in 1-year-old WHHL rabbit aorta only in the presence of endothelium; relaxation was reduced in older animals. In 1-year-old WHHL rabbits, the endothelium-dependent relaxant effect of UTP was not antagonized by suramin, but was by the inhibitors of nitric oxide (NO) effect, methylene blue (MB) and L-NG-nitroarginine methyl ester (L-NAME), suggesting involvement of NO in the UTP-mediated relaxation. Morphological data from electron microscopy observations indicated the presence of typical atherosclerotic lesions and extensive dystrophic changes in endothelial cells, gradually evolving at 1 and 2.5 years of age. The present data suggest that progressive atherosclerosis differentially affects the activity of endothelial receptors: The most precociously altered is the P2y-purinoceptor, followed by an impairment of the muscarinic and finally of the P2U-purinoceptor.