Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2

Cardiac atrial natriuretic peptide (ANP) locally counteracts cardiac hypertrophy via the guanylyl cyclase-A (GC-A) receptor and cGMP production, but the downstream signalling pathways are unknown. Here, we examined the influence of ANP on β-adrenergic versus Angiotensin II (Ang II)-dependent (Gs vs. Gαq mediated) modulation of Ca2+i-handling in cardiomyocytes and of hypertrophy in intact hearts. L-type Ca2+ currents and Ca2+i transients in adult isolated murine ventricular myocytes were studied by voltage-clamp recordings and fluorescence microscopy. ANP suppressed Ang II-stimulated Ca2+ currents and transients, but had no effect on isoproterenol stimulation. Ang II suppression by ANP was abolished in cardiomyocytes of mice deficient in GC-A, in cyclic GMP-dependent protein kinase I (PKG I) or in the regulator of G protein signalling (RGS) 2, a target of PKG I. Cardiac hypertrophy in response to exogenous Ang II was significantly exacerbated in mice with conditional, cardiomyocyte-restricted GC-A deletion (CM GC-A KO). This was concomitant to increased activation of the Ca2+/calmodulin-dependent prohypertrophic signal transducer CaMKII. In contrast, β-adrenoreceptor-induced hypertrophy was not enhanced in CM GC-A KO mice. Lastly, while the stimulatory effects of Ang II on Ca2+-handling were absent in myocytes of mice deficient in TRPC3/TRPC6, the effects of isoproterenol were unchanged. Our data demonstrate a direct myocardial role for ANP/GC-A/cGMP to antagonize the Ca2+i-dependent hypertrophic growth response to Ang II, but not to β-adrenergic stimulation. The selectivity of this interaction is determined by PKG I and RGS2-dependent modulation of Ang II/AT1 signalling. Furthermore, they strengthen published observations in neonatal cardiomyocytes showing that TRPC3/TRPC6 channels are essential for Ang II, but not for β-adrenergic Ca2+i-stimulation in adult myocytes

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Indoor biocide concentrations after application of biocidal aerosol sprays: Abstract Number 3905 at Conference "Environment and Health". Bridging South, North, East and West. Basel, Switzerland, August 19-23, 2013

Fulltext: Biocidal sprays are frequently used by consumers in indoor areas to control pests.To obtain data on indoor contaminations, different insecticide aerosol sprays were applied in furnished model rooms (40 m³). On the one hand, the sprays were used according to the manufacturers' instructions (spraying for about 10-20 sec), and on the other hand under worst-case conditions (spraying for 2 min). Within two weeks, four spray applications with correct use and three worst-case applications were performed. Indoor air was collected a) during the spraying process, b) 2-4 h after spraying (in case of correct use the room was ventilated for 30 min), and c) about two weeks after the last application. The applied sprays contained i) tetramethrin/d-phenothrin (0.15 g/0.15 g), ii) pyrethrum extract/PBO (0.25 g/1g), and iii) chlorpyrifos/bioallethrin/PBO (0.5 g/0.15 g/n.s.) per 100 g spray. During spraying, concentrations of biocides in the air (mean values from 3 or 4 measurements) ranged from 100-1020 µg/m³ for correct use (290-6020 µg/m³ for worst case). Highest concentrations of 2510 µg/m³ (10340 µg/m³) were measured for the synergist PBO. Two to four h after application, concentrations of the active ingredients in the indoor air were down to 0.1-0.8% (1-11% for worst case). Three weeks after the last application, concentrations between 0.02-1 µg/m³ were measured for both scenarios. To determine the surface load, pads of filter paper were placed horizontally at different positions in the room. The amounts of active ingredients were determined at different times (after first and last applications and about two weeks later). Concentrations varied from 10-480 ng/cm² (70-5700 ng/cm² for worst case) for biocides and from 300-2260 ng/cm² (1000-16500 ng/cm² for worst case) for PBO. After 2 weeks, bioallethrin had been degraded, the other biocide concentrations were down to 10-40% (40-70% for worst case). The PBO value remained constant over time