When inappropriate for salt status, the mineralocorticoid aldosterone induces cardiac and renal injury. Autonomous overproduction of aldosterone from the adrenal zona glomerulosa (ZG) is also the most frequent cause of secondary hypertension. Yet, the etiology of nontumorigenic primary hyperaldosteronism caused by bilateral idiopathic hyperaldosteronism remains unknown. Here, we show that genetic deletion of TWIK-related acid-sensitive K (TASK)-1 and TASK-3 channels removes an important background K current that results in a marked depolarization of ZG cell membrane potential. Although TASK channel deletion mice (TASK −/− ) adjust urinary Na excretion and aldosterone production to match Na intake, they produce more aldosterone than control mice across the range of Na intake. Overproduction of aldosterone is not the result of enhanced activity of the renin–angiotensin system because circulating renin concentrations remain either unchanged or lower than those of control mice at each level of Na intake. In addition, TASK −/− mice fail to suppress aldosterone production in response to dietary Na loading. Autonomous aldosterone production is also demonstrated by the failure of an angiotensin type 1 receptor blocker, candesartan, to normalize aldosterone production to control levels in TASK −/− mice. Thus, TASK −/− channel knockout mice exhibit the hallmarks of primary hyperaldosteronism. Our studies establish an animal model of nontumorigenic primary hyperaldosteronism and identify TASK channels as a possible therapeutic target for primary hyperaldosteronism.

T-type Ca(2+) channels encoded by voltage-gated Ca(2+) channel (Ca(v)) 3.1, 3.2, and 3.3 genes play important physiological roles and serve as therapeutic targets for neurological and cardiovascular disorders. Currently there is no selective T-channel blocker. To screen for such a blocker, we developed three stable cell lines expressing human recombinant Ca(v)3.1, 3.2, or 3.3 channels and then examined their usefulness in high throughput screens. All three cell lines displayed an increase in intracellular Ca(2+) in response to changes in extracellular Ca(2+) as detected with Ca(2+)-sensitive dyes using a fluorometric imaging plate reader (FLIPR [Molecular Devices, Sunnyvale, CA] or FlexStation [Molecular Devices]). The signal-to-noise ratio was 2-4. Co-expression of Ca(v)3.2 with a mouse leak K(+) channel, which by virtue of being open at rest hyperpolarizes the cell membrane, blocked the fluorescent signal. Co-addition of KCl to these cells induced a Ca(2+) signal that was similar to that observed in the cell line expressing Ca(v)3.2 alone. These results confirm that the detection of intracellular Ca(2+) increase in cells expressing Ca(v)3.2 alone results from Ca(2+) entry through channels that are open at the resting membrane potential of each cell line (i.e., window currents). Testing known drugs on Ca(v)3 channels showed that block could be reliably detected using the FlexStation assay, FLIPR assay, or voltage clamp recordings using the IonWorks HT system (Molecular Devices). These results support the use of the FLIPR window current assay for primary drug screening and high throughput patch recordings for secondary screening of novel T-channel blockers.

Depressed myofilament Ca2+ sensitivity contributes to the negative inotropic effects of isoflurane and halothane but not sevoflurane. The decrease in the Ca2+ transient is either responsible for or contributory to the negative inotropic effects of all three anesthetics and is either primarily the result of a decrease in fractional release (isoflurane and sevoflurane) or primarily the result of a decrease in SR Ca2+ content (halothane).

Objective —To devise, implement and evaluate a medication adherence support service by community pharmacists for elderly patients living at home and at risk of non‐adherence. Method — Six community pharmacists identified patients who were 65 years of age and older, prescribed four or more regular medicines and living alone. A random sample of patients was visited at home and assessed for adherence‐related problems using a structured interview. The pharmacist then drew up an action plan in conjunction with the patient and general practitioner (GP), and returned for a second home visit, where the revised regime was delivered and explained. A self‐reported adherence questionnaire was also administered. After two months an independent researcher visited the patients at home to assess progress. Setting — Six community pharmacies in the city of Leeds, UK, and patients' homes. Key findings — A total of 143 patients were recruited and 441 medicine‐related problems were identified. Of these, 241 (55 per cent) required the provision of information and advice, 106 (24 per cent) required consultation with the GP and 86 (20 per cent) required changes in the presentation of the medicines. The median number of regular prescribed medicines fell from six to five (P<0.001). Overall, there was a reduction in the number of patients with one or more problems from 94 per cent to 58 per cent (P<0.001). The proportion of patients who reported non‐adherence fell from 38 per cent to 14 per cent (P<0.001). Conclusion — This study shows that community pharmacists can target patients at risk of medication non‐adherence and, using a structured approach, identify problems and implement solutions. The pharmacy patient medication record is an underutilised tool for identifying patients with adherence problems. The software needs enhancing to enable pharmacists to maximise their use of these records in adherence support. An adherence support programme needs to take more account of intentional non‐adherence and should be closely linked with the rest of the primary health care team.

Halothane has been shown to affect several membrane currents in cardiac tissue including the L‐type calcium current (ICa), sodium current and a variety of potassium currents. However, little is known about the effects of halothane on the transient outward K+ current (Ito). Single ventricular myocytes from rat hearts were voltage clamped using the whole cell patch configuration and an EGTA‐containing pipette solution to record the Ca2+‐independent, 4‐aminopyridine sensitive component of Ito. 300 μM Cd2+ or 10 μM nifedipine was used to block ICa. At +80 mV, Ito (peak current minus current at the end of the pulse) was 1.8±0.2 nA under control conditions which was reduced to 1.3±0.2 nA by 1 mM halothane (P<0.001, mean±s.e.mean, n=9). The inhibition of Ito by halothane was concentration‐dependent (K0.5, 1.1±0.2 mM). One mM halothane led to a 16 mV shift in the steady‐state inactivation curve towards negative membrane potentials (P=0.005, n=8) but had no significant effect on the activation‐voltage relationship (P=0.724). One mM halothane also increased the rate of inactivation of Ito; the dominant time constant of inactivation was reduced from 14±1 to 9±1 ms (P=0.017, mean±s.e.mean, n=6). These data show that halothane reduced Ito; 0.3 mM, close to the MAC50 value for halothane, inhibited the current by 15% and as such, the inhibition of Ito will be relevant to the clinical situation. Halothane induced a shift in the steady‐state inactivation curve and accelerated the inactivation process of Ito which could be responsible for its inhibitory effect. Due to the differential transmural expression of Ito in ventricular tissue, inhibition of Ito would reduce the transmural dispersion of refractoriness which could contribute to the arrhythmogenic properties of halothane. British Journal of Pharmacology (2000) 131, 223–230; doi: