1 We studied the effects of endothelium-derived relaxing factor (EDRF), bovine retractor penis muscle inhibitory factor and sodium nitroprusside, three stimulants ofguanylate cyclase, on the in vitro aggregation of washed human platelets. 2 Platelet aggregation induced either by collagen or by the thromboxane A2 analogue U46619 was inhibited by all three agents. 3 The anti-aggregatory effect of each agent was inhibited by haemoglobin. 4 The anti-aggregatory effect of EDRF was potentiated by superoxide dismutase. 5 These findings are discussed in relation to a potential role for EDRF in haemostasis.
For terrestrial animals and plants, a fundamental cost of living is water vapor lost to the atmosphere during exchange of metabolic gases. Here, by bringing together previously developed models for specific taxa, we integrate properties common to all terrestrial gas exchangers into a universal model of water loss. The model predicts that water loss scales to gas exchange with an exponent of 1 and that the amount of water lost per unit of gas exchanged depends on several factors: the surface temperature of the respiratory system near the outside of the organism, the gas consumed (oxygen or carbon dioxide), the steepness of the gradients for gas and vapor, and the transport mode (convective or diffusive). Model predictions were largely confirmed by data on 202 species in five taxa-insects, birds, bird eggs, mammals, and plants-spanning nine orders of magnitude in rate of gas exchange. Discrepancies between model predictions and data seemed to arise from biologically interesting violations of model assumptions, which emphasizes how poorly we understand gas exchange in some taxa. The universal model provides a unified conceptual framework for analyzing exchangeassociated water losses across taxa with radically different metabolic and exchange systems.ll terrestrial animals and plants exchange O 2 and CO 2 with the atmosphere and thereby incur costs in the currency of water vapor (1-4). The inevitability of water loss stems from universal characteristics of terrestriality-(i) adequate gas exchange requires large surface areas of high-conductance tissues, usually invaginated; (ii) high-conductance tissues saturate internal exchange spaces with water vapor; and (iii) those surfaces must be ventilated by the atmosphere, at least intermittently. Consequently, water vapor tends to escape into surrounding drier air. Terrestrial organisms-here defined to include air-breathing marine mammals-thus face a gas-water tradeoff in which higher rates of gas exchange give higher rates of water loss. For individual organisms, this tradeoff shapes patterns of ventilation and behavior. For populations and species, the tradeoff influences diverse phenomena, including the evolution of hibernation, dormancy, and diapause (5-8), the evolution of nasal physiology in vertebrate homeotherms (9-11), and the evolution and ecology of plants with different modes of carbon fixation (C3, C4, and CAM) (12). In general, the severity of the tradeoff for any species will depend on the fraction of total water lost through the gas-exchange system, which in turn is related to the temperature and aridity of its habitat (13).The diversity of gas-exchange systems among taxa has spawned a large set of models for predicting respiratory and stomatal water losses (14-21). Although the models are all quite similar, they have failed to provide unification and generality as a group, because each uses different terminology and is built on taxonspecific details. Broader conceptualization of the problem may give insight into how diverse organisms function across biome...
Acute coronary syndrome (ACS) describes the range of myocardial ischemic states that includes unstable angina, non-ST elevated myocardial infarction (MI), or ST-elevated MI. ACS is associated with substantial morbidity and mortality and places a large financial burden on the health care system. The diagnosis of ACS begins with a thorough clinical assessment of a patient's presenting symptoms, electrocardiogram, and cardiac troponin levels as well as a review of past medical history. Early risk stratification can assist clinicians in determining whether an early invasive management strategy or an initial conservative strategy should be pursued and can help determine appropriate pharmacologic therapies. Key components in the management of ACS include coronary revascularization when indicated; prompt initiation of dual antiplatelet therapy and anticoagulation; and consideration of adjuvant agents including  blockers, inhibitors of the renin angiotensin system, and HmG-coenzyme A reductase inhibitors. It is essential for clinicians to take an individualized approach to treatment and consider long-term safety and efficacy when managing patients with a history of ACS after hospital discharge. The term myocardial infarction (MI) is used when there is evidence of myocardial necrosis in the setting of acute myocardial ischemia. STEMI is differentiated from NSTEMI by the presence of persistent ECG findings of ST segment elevation. 3In recent years, progress has been made in the management of ACS, particularly related to optimizing pharmacotherapy. 2,3 Family physicians care for patients presenting with ACS in office as well as emergency settings and play an important role in both acute and long-term management of such patients. In this article, we review the topic of ACS with particular emphasis on initial management and use of the newer medications. Specific coronary interventions performed by the cardiologist (eg, stents or balloon angioplasty) are beyond the scope of this review. Scope of the ProblemCoronary heart disease (CHD) is responsible for more than half of all cardiovascular events in individuals less than 75 years of age. The prevalence of This article was externally peer reviewed.
1. In isolated heart muscle preparations, selective removal of the endocardium results in a characteristic and unusual negative inotropic effect. Possible mechanisms for this effect were investigated in this study. 2. In endocardium-intact preparations of ferret papillary muscle, 8-bromo-cyclic GMP, sodium nitroprusside, atrial natriuretic peptide (ANP) and substance P each induced changes in contractile behaviour similar to selective endocardial removal, and each significantly elevated myocardial cyclic GMP levels. Substance P failed to elevate myocardial cyclic GMP levels following removal of endocardium or in the presence of haemoglobin, suggesting that it may act by releasing endothelium-derived relaxing factor (EDRF) from endocardium. However, there was no change in myocardial cyclic GMP levels following endocardium removal alone. 3. In cascade bioassay experiments, it was confirmed that porcine cultured endocardial cells released an unstable humoral agent whose effects on an endothelium-denuded pig coronary artery were indistinguishable from EDRF. 4. The negative inotropic effects of endocardium removal were reversed in bioassay experiments where an endocardium-denuded papillary muscle was exposed to the effluent from a column of porcine cultured endocardial cells on microcarrier beads. This demonstrates for the first time the release of a 'contraction prolonging factor' from endocardium, the tonic release of which would explain the negative inotropic effect of endocardium removal. 5. It is concluded that elevation of ferret papillary muscle cyclic GMP (as for example with EDRF) produces changes in contractile performance similar to those induced by endocardium removal. We also demonstrate that superfused porcine cultured endocardial cells release a humoral agent (provisionally named 'endocardin') which causes reversal of the changes in mechanical properties seen after endocardial removal.
The effects of valvular endothelial cell (VlvEC) paracrine signaling on VIC phenotype and nodule formation were tested using a co-culture platform with physiologically relevant matrix elasticities and diffusion distance. 100μm thin poly(ethylene glycol) (PEG) hydrogels of 3 to 27 kPa Young’s moduli were fabricated in transwell inserts. VICs were cultured on the gels, as VIC phenotype is known to change significantly within this range, while VlvECs lined the underside of the membrane. Co-culture with VlvECs significantly reduced VIC activation to the myofibroblast phenotype on all gels with the largest percent decrease on the 3 kPa gels (~70%), while stiffer gels resulted in approximately 20–30% decrease. Additionally, VlvECs significantly reduced αSMA protein expression (~2 fold lower) on both 3 and 27 kPa gels, as well as the number (~2 fold lower) of nodules formed on the 27kPa gels. Effects of VlvECs were prevented when nitric oxide (NO) release was inhibited with L-NAME, suggesting that VlvEC produced NO inhibits VIC activation. Withdrawal of L-NAME after 3, 5, and 7 days with restoration of VlvEC NO production for 2 additional days led to a partial reversal of VIC activation (~25% decrease). A potential mechanism by which VlvEC produced NO reduced VIC activation was studied by inhibiting initial and mid-stage cGMP pathway molecules. Inhibition of soluble guanylyl cyclase (sGC) with ODQ or protein kinase G (PKG) with RBrcGMP or stimulation of Rho kinase (ROCK) with LPA, abolished VlvEC effects on VIC activation. This work contributes substantially to the understanding of the valve endothelium’s role in preventing VIC functions associated with aortic valve stenosis initiation and progression.
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