High temperature oxidation of higher manganese silicides

publishedVersio

Comparison between Alpha-1 Adrenoceptor-Mediated and Beta Adrenoceptor-Mediated Inotropic Components Elicited by Norepinephrine in Failing Human Ventricular Muscle 1

ABSTRACT The purpose of our study was to investigate the inotropic response to the endogenous agonist norepinephrine mediated through alpha-1 adrenoceptors and to compare this response to that mediated through beta-adrenoceptors in failing human ventricular myocardium. We studied ex vivo the inotropic effect of norepinephrine in isometrically contracting trabecular myocardium from both ventricles of explanted hearts. By studying influence of appropriate adrenoceptor blockers, qualitative characteristics of the inotropic response and sensitivity of the inotropic response to cholinergic stimulation, it was revealed that norepinephrine evoked both alpha-1 and beta adrenoceptor-mediated inotropic effects in failing human ventricle myocardium. Quantitatively the inotropic responses to norepinephrine varied markedly between preparations, but the mean responses elicited through the respective adrenoceptor systems were of comparable magnitude. Concomitant stimulation of alpha-1 and beta adrenoceptors by norepinephrine alone revealed a contribution of an alpha-1 adrenoceptor-mediated component to the final and unopposed inotropic response. Differential sensitivity of the two adrenoceptor systems to norepinephrine depending on etiology of heart failure and possibly also thyroid status was observed. It is concluded that norepinephrine evokes an alpha-1 adrenoceptor-mediated inotropic effect comparable to that evoked through the beta adrenoceptors in failing human ventricular myocardium, and that this alpha-1 adrenoceptor-mediated inotropic effect may be of functional importance. The catecholamine-induced increase in contractile force in mammalian myocardium is mainly due to activation of beta adrenoceptors. The existence of myocardial alpha-1 adrenoceptors mediating positive inotropic effects is, however, now well established In the failing human heart where the beta-1 adrenoceptor mediated inotropic response is attenuated, it has been difficult to demonstrate an alpha-1 adrenoceptor-mediated inotropic effect of functional significance (e.g.

Agents increasing cyclic GMP amplify 5-HT4-elicited positive inotropic response in failing rat cardiac ventricle

Activation of 5-HT4 receptors in failing ventricles elicits a cAMP-dependent positive inotropic response which is mainly limited by the cGMP-inhibitable phosphodiesterase (PDE) 3. However, PDE4 plays an additional role which is demasked by PDE3 inhibition. The objective of this study was to evaluate the effect of cGMP generated by particulate and soluble guanylyl cyclase (GC) on the 5-HT4-mediated inotropic response. Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats, exhibiting heart failure 6 weeks after surgery. Contractility was measured in left ventricular preparations. Cyclic GMP was measured by EIA. In ventricular preparations, ANP or BNP displayed no impact on 5-HT4-mediated inotropic response. However, CNP increased the 5-HT4-mediated inotropic response as well as the β1-adrenoceptor (β1-AR)-mediated response to a similar extent as PDE3 inhibition by cilostamide. Pretreatment with cilostamide eliminated the effect of CNP. Inhibition of nitric oxide (NO) synthase and soluble GC by l-NAME and ODQ, respectively, attenuated the 5-HT4-mediated inotropic response, whereas the NO donor Sin-1 increased this response. The effects were absent during PDE3 inhibition, suggesting cGMP-dependent inhibition of PDE3. However, in contrast to the effects on the 5-HT4 response, Sin-1 inhibited whereas l-NAME and ODQ enhanced the β1-AR-mediated inotropic response. cGMP generated both by particulate (NPR-B) and soluble GC increases the 5-HT4-mediated inotropic response in failing hearts, probably through inhibition of PDE3. β1-AR and 5-HT4 receptor signalling are subject to opposite regulatory control by cGMP generated by soluble GC in failing hearts. Thus, cGMP from different sources is functionally compartmented, giving differential regulation of different Gs-coupled receptors

New benzodiazepine and Z-hypnotic users and disability pension: an eight-year nationwide observational follow-up study

Objective: To compare how newly initiated treatment with benzodiazepines, Z-hypnotics or both associates with the reception of disability pension among 40,661 individuals of a working age. Design: Prescription register study. Setting: Norwegian nationwide prescriptions socio-economic and disability status data. Methods: Cox regression analyses. Subjects: New benzodiazepine or Z-hypnotic users. Main outcome measure: Time to receive disability pension given benzodiazepine or Z-hypnotic use or both. Additional analyses focused on the benzodiazepine first redeemed. Results: Among new users 8.65% of Z-hypnotic users, 12.29% of benzodiazepines users and 13.96% of combined Z-hypnotic and benzodiazepine users became disability pensioners. Z-hypnotic users were weaker associated with becoming disability pensioners (HR = 0.78, CI: 0.73–0.84) and combined users were stronger associated (HR = 1.09, CI: 1.01–1.17), than benzodiazepine users. Women had higher risk than men for becoming disability pensioners. Higher age, lower education, previous drug use and psychiatrist as first prescriber were risk factors. Comparing first benzodiazepine redeemed; clonazepam initiators were stronger associated with becoming disability pensioners than diazepam initiators were (HR = 2.22, CI: 1.81–2.71). No differences between other benzodiazepine users were found. Conclusions: Adjusting for known risk factors gave lower risk for Z-hypnotic users compared to benzodiazepine users for receiving disability pension. Combined use increased the risk further. Clonazepam initiators are especially at risk. These findings may be helpful in prescribing situations to identify and guide individuals at risk for becoming disability pensioners

Mental Health and Disability Pension Onset: Changes in Consumption of Antianxiety and Hypnotic Drugs

Introduction: In Norway, disability pension (DP) has been more prevalent over the later years, with mental disorders being a frequent cause. Previous analyses have questioned whether receiving DP is beneficial for mental health by considering changes in antidepressant drug consumption. To explore this further, we examined changes in antianxiety and hypnotic drug consumption following DP onset. Methods: Based on national Norwegian register data, this retrospective study encompassed 8617 working-age individuals (25-50 years) who became DP during 2005 to 2013. We compared their benzodiazepines (BZD) and Z-hypnotic consumption 1 year pre- and postdisability pension onset. Results: About 80% of the individuals did not change their altogether benzodiazepine/Z-hypnotic consumption. Among individuals with an initial consumption ≤1 defined daily dose (DDD), 18.9% increased their consumption to above 1 DDD. Individuals in the age-group 45 to 50 versus 24 to 34 years had a lower risk of dose escalation (odds ratio [OR], 0.756, 95% confidence interval [CI]: 0.601-0.957). Individuals who used Z-hypnotics only had a higher risk of dose escalation compared to the joint benzodiazepine/Z-hypnotic user group (OR, 1.594, 95%CI: 1.284-1.970). Conclusion: In general, we cannot see that DP is associated with changes in benzodiazepine/Z-hypnotic consumption, but younger users and individuals using Z-hypnotics only had a greater risk of dose escalation compared to the older users and users with combined BZD and Z-hypnotic use

Gi Proteins Regulate Adenylyl Cyclase Activity Independent of Receptor Activation

Background and purpose Despite the view that only β2- as opposed to β1-adrenoceptors (βARs) couple to Gi, some data indicate that the β1AR-evoked inotropic response is also influenced by the inhibition of Gi. Therefore, we wanted to determine if Gi exerts tonic receptor-independent inhibition upon basal adenylyl cyclase (AC) activity in cardiomyocytes. Experimental approach We used the Gs-selective (R,R)- and the Gs- and Gi-activating (R,S)-fenoterol to selectively activate β2ARs (β1AR blockade present) in combination with Gi inactivation with pertussis toxin (PTX). We also determined the effect of PTX upon basal and forskolin-mediated responses. Contractility was measured ex vivo in left ventricular strips and cAMP accumulation was measured in isolated ventricular cardiomyocytes from adult Wistar rats. Key results PTX amplified both the (R,R)- and (R,S)-fenoterol-evoked maximal inotropic response and concentration-dependent increases in cAMP accumulation. The EC50 values of fenoterol matched published binding affinities. The PTX enhancement of the Gs-selective (R,R)-fenoterol-mediated responses suggests that Gi regulates AC activity independent of receptor coupling to Gi protein. Consistent with this hypothesis, forskolin-evoked cAMP accumulation was increased and inotropic responses to forskolin were potentiated by PTX treatment. In non-PTX-treated tissue, phosphodiesterase (PDE) 3 and 4 inhibition or removal of either constitutive muscarinic receptor activation of Gi with atropine or removal of constitutive adenosine receptor activation with CGS 15943 had no effect upon contractility. However, in PTX-treated tissue, PDE3 and 4 inhibition alone increased basal levels of cAMP and accordingly evoked a large inotropic response. Conclusions and implications Together, these data indicate that Gi exerts intrinsic receptor-independent inhibitory activity upon AC. We propose that PTX treatment shifts the balance of intrinsic Gi and Gs activity upon AC towards Gs, enhancing the effect of all cAMP-mediated inotropic agents