No abstract

The TASK subfamily of two pore domain potassium channels (K2P) gives rise to leak potassium currents, which contribute to the resting membrane potential of many neurons and regulate their excitability. K2P channels are highly regulated by phosphorylation and by G protein-mediated pathways. In this study, we show that protein kinase C (PKC) inhibits recombinant TASK3 channels. Inhibition by PKC is blocked by the PKC inhibitors bisindolylmaleimide 1 hydrochloride (BIM) and 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (Gö 6976). Gene-silencing experiments with a validated small interfering RNA sequence against PKC␣ ablates the effect of PKC. PKC acts directly on hTASK3 channels to phosphorylate an identified amino acid in the C terminus region (Thr341), thereby reducing channel current. PKC also inhibits mTASK3 channels despite their having a quite different C-terminal structure to hTASK3 channels. Activation of M 3 muscarinic receptors inhibits both hTASK3 channels expressed in tsA-201 cells and standing outward potassium current (IK SO ) in mouse cerebellar granule neurons through the activation of the G protein G␣ q , because both effects are abolished by the selective G␣ q antagonist YM-254890 (J Biol Chem 279: 47438 -47445, 2004). This inhibition is not directly transduced through activation of PKC because inhibition persists in mutated PKC-insensitive hTASK3 channels. Instead, inhibition seems to occur through a direct action of G␣ q on the channel. Nevertheless, preactivation of PKC blocks muscarinic inhibition of both TASK3 channels and IK SO . Our results suggest that activation of PKC (via phospholipase C) has a role in opposing inhibition after M 3 receptor activation rather than transducing it and may act as a negative regulator of G protein modulation to prevent prolonged current inhibition.

BackgroundClinical trials indicate that the use of fixed-dose combinations (FDCs) is associated with a higher level of treatment adherence and prolonged blood pressure (BP) control. The aim of this study was to document the safety and effectiveness of the FDC olmesartan/amlodipine/hydrochlorothiazide in patients with essential hypertension in clinical practice.MethodsThis multicenter, prospective, 24-week, noninterventional study enrolled 5,831 patients from primary care offices in Germany and Austria. Inclusion criteria were a diagnosis of essential hypertension and newly initiated treatment with the FDC.ResultsThe mean age of patients was 63.5 years, almost 50% of patients had a time since diagnosis of essential hypertension of over 5 years, and approximately 70% of patients had at least one cardiovascular risk factor, including 29.4% of patients with diabetes mellitus. Following approximately 24 weeks of treatment, the mean reduction in systolic/diastolic BP was 29.0/14.0 mmHg, a BP response was observed by 94.2% of patients, and a target BP of <140/90 mmHg was attained in 67.5% of patients. At least one adverse drug reaction (ADR) was experienced by 1.2% of patients, with the most common being peripheral edema. Subanalyses demonstrated that the following factors did not have a significant influence on the ADR rate: age (<65 years versus ≥65 years), diabetes mellitus (no/yes), cardiovascular risk (low/high), and concomitant medication (no/yes).ConclusionThis study demonstrates that in clinical practice, treatment with the three-drug combination as an FDC tablet resulted in a very high proportion of patients with a BP response and control, accompanied by a very low rate of ADRs.

The higher concentration of insulin in U300 results in a distinct pharmacokinetic and pharmacodynamic profile. U300 has a longer duration of action than U100 and plasma insulin exposure is less variable. Both insulin formulations exhibit a similar efficacy and safety profile, but importantly, U300 is associated with less body weight gain and a lower incidence of hypoglycaemic events.