Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

Antidepressants are among the most commonly detected human pharmaceuticals in the aquatic environment. Since their mode of action is by modulating the neurotransmitters serotonin, dopamine, and norepinephrine, aquatic invertebrates who possess transporters and receptors sensitive to activation by these pharmaceuticals are potentially affected by them. We review the various types of antidepressants, their occurrence and concentrations in aquatic environments, and the actions of neurohormones modulated by antidepressants in molluscs and crustaceans. Recent studies on the effects of antidepressants on these two important groups show that molluscan reproductive and locomotory systems are affected by antidepressants at environmentally relevant concentrations. In particular, antidepressants affect spawning and larval release in bivalves and disrupt locomotion and reduce fecundity in snails. In crustaceans, antidepressants affect freshwater amphipod activity patterns, marine amphipod photo- and geotactic behavior, crayfish aggression, and daphnid reproduction and development. We note with interest the occurrence of non-monotonic dose responses curves in many studies on effects of antidepressants on aquatic animals, often with effects at low concentrations, but not at higher concentrations, and we suggest future experiments consider testing a broader range of concentrations. Furthermore, we consider invertebrate immune responses, genomic and transcriptomic sequencing of invertebrate genes, and the ever-present and overwhelming question of how contaminant mixtures could affect the action of neurohormones as topics for future study. In addressing the question, if antidepressants affect aquatic invertebrates at concentrations currently found in the environment, there is strong evidence to suggest the answer is yes. Furthermore, the examples highlighted in this review provide compelling evidence that the effects could be quite multifaceted across a variety of biological systems.

Serotonin (5-hydroxytryptamine, 5-HT) and its receptor ligands induce both oocyte maturation and spawning in zebra mussels (Dreissena polymorpha). The selective serotonin reuptake inhibitors (SSRIs) fluvoxamine ("Luvox"), fluoxetine ("Prozac"), and paroxetine ("Paxil") are commonly prescribed drugs for the treatment of depression in humans. They act to increase 5-HT neurotransmission by inhibiting reuptake transport proteins at synapses. I tested the efficacy of these drugs at inducing spawning in zebra mussels. All three compounds induced spawning in both sexes at concentrations lower than that for 5-HT itself. Fluvoxamine was particularly potent, inducing spawning in 100% of both sexes at 10-5 and 10-6 M. The concentration that induced a significant percentage of animals to spawn was as low as 10-9 M for males and and 10-7 M for females. The lowest concentration of fluvoxamine to induce spawning was 10-8 M for females (40%) and 10-10 M for males (20%). Gametes spawned in fluvoxamine (10-5 M and lower) were viable, and swimming trochophores were formed within 20 hours. Fluoxetine was also an effective spawning inducer, causing 100% of males to spawn at 5 x 10-6 M. The concentration of fluoxetine required to induce a significant percentage of spawning was as low as 5 x 10-8 M for males and 5 x 10-6 M for females. In both fluvoxamine and fluoxetine, more than 60% of the males spawned within the first hour of exposure. In contrast, paroxetine was a weak spawning inducer. At concentrations of 10-5 and 10-6 M it induced significant, but low (50% and 40%, respectively) percentages of males to spawn. Paroxetine did not induce significant spawning in females. Thus, fluvoxamine, fluoxetine, and paroxetine can induce spawning at low concentrations, and fluvoxamine is the most powerful spawning inducer in any bivalve. These may be useful agents for stimulating invertebrate serotonergic mechanisms without applying exogenous 5-HT, and they are potentially important in bivalve aquaculture. Moreover, these results suggest, for the first time, the presence of 5-HT reuptake transporters in bivalve molluscs.

The effects of antidepressants on wildlife are currently raising some concern because of an increased number of publications indicating biological effects at environmentally relevant concentrations (<100 ng/L). These results have been met with some scepticism because of the higher concentrations required to detect effects in some species and the perceived slowness to therapeutic effects recorded in humans and other vertebrates. Because their mode of action is thought to be by modulation of the neurotransmitters serotonin, dopamine, and norepinephrine, aquatic invertebrates that possess transporters and receptors sensitive to activation by these pharmaceuticals are potentially affected by them. The authors highlight studies on the effects of antidepressants, particularly on crustacean and molluskan groups, showing that they are susceptible to a wide variety of neuroendocrine disruptions at environmentally relevant concentrations. Interestingly, some effects observed in these species can be observed within minutes to hours of exposure. For example, exposure of amphipod crustaceans to several selective serotonin reuptake inhibitors can invoke changes in swimming behavior within hours. In mollusks, exposure to selective serotonin reuptake inhibitors can induce spawning in male and female mussels and foot detachment in snails within minutes of exposure. In the light of new studies indicating effects on the human brain from selective serotonin reuptake inhibitors using magnetic resonance imaging scans, the authors discuss possible reasons for the discrepancy in former results in relation to the read-across hypothesis, variation in biomarkers used, modes of uptake, phylogenetic distance, and the affinity to different targets and differential sensitivity to receptors. Environ Toxicol Chem 2016;35:794-798. #