Individuals homozygous for the autosomal recessive disorder CF are known to have low blood pressure, thought to be caused by greatly increased sweat salt loss. We examined whether carriers of the CF gene also have low blood pressure. Our pilot studies had suggested an effect limited to females, leading to 2 further studies in white females. In the first, blood pressure was measured in 232 known CF mutation carriers and compared with 246 mutation-negative control subjects. The carriers showed a significantly lower rate of increase in systolic blood pressure with age than the controls, especially after age 50 (3.5% per decade compared with 5.4% per decade, P =0.010). In a small substudy, sweat sodium and chloride levels were highest in those CF carriers with the lowest blood pressures. In the second study, CF carrier status was investigated in 563 normotensive females and in 607 women with essential hypertension diagnosed to test whether a lower incidence of carriers in the hypertensives suggested a protective effect. Twenty-five of the normotensives (4.4%) were carriers compared with 21 (3.5%) of the hypertensive group ( P =0.45). Older CF carrier females had lower systolic and diastolic pressures than matched control subjects, with a tendency for blood pressure to increase less with age. This could result in significant reduction in stroke and heart disease. The effect on blood pressure is insufficient to prevent hypertension, though it remains conceivable that the severity might be ameliorated in carriers.
In this study the effect of post-treatment with rolipram, an inhibitor of cAMP phosphodiesterase, on neuronal damage following global ischemia was evaluated. Global cerebral ischemia was induced in male Wistar rats by four-vessel occlusion for 20 minutes. Rolipram was administered 6 hours after onset of ischemia and thereafter the following 7 days daily once at a dose of 0.3 or 3.0 mg/kg intraperitoneally. Four weeks after ischemia the amount of intact neurons in the hippocampus and in the striatum was assessed following perfusion fixation. The ischemia-induced neuronal damage in the CA1 sector of the hippocampus and in the striatum was reduced by rolipram at either dose. The present results show that treatment with rolipram reduces ischemic neuronal damage at a therapeutic window of 6 hours.
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The congenital long QT syndrome (LQTS) is characterized by a prolonged QT interval on the surface electrocardiogram and an increased risk of recurrent syncope and sudden cardiac death. Mutations in seven genes have been identified as the molecular basis of LQTS. β‐blockers are the treatment of choice to reduce cardiac symptoms. However, long‐term follow‐up of genotyped families with LQTS has been rarely reported. We have clinically followed a four‐generation family with LQTS being treated with β ‐ blocker therapy over a period of 23 years. Seven family members were carriers of two amino acid alterations in cis (V254M‐V417M) in the cardiac potassium channel gene KCNQ1 . Voltage‐clamp recordings of mutant KCNQ1 protein in Xenopus oocytes showed that only the V254M mutation reduced the I Ks current and that the effect of the V417M variant was negligible. The family exhibited the complete clinical spectrum of the disease, from asymptomatic patients to victims of sudden death before β‐blocker therapy. There was no significant reduction in QTc (556 ± 40 ms ½ before therapy, 494 ± 20 ms ½ during 17 years of treatment; n = 5 individuals). Of nine family members, one female died suddenly before treatment, three females of the second generation were asymptomatic, and four individuals of the third and fourth generation were symptomatic. All mutation carriers were treated with β‐blockers and remained asymptomatic for a follow‐up up to 23 years. Long‐term follow‐up of a LQT1 family with a common mutation (V254M) being on β‐blocker therapy was effective and safe. This study underscores the importance of long‐term follow‐up in families with specific LQT mutations to provide valuable information for clinicians for an appropriate antiarrhythmic treatment.
Possible structural and functional similarities between the channel part, CF 0 , of chloroplast ATPase (CF 0 CF 1 ) and ion channels permeable to monovalent cations were investigated using high‐affinity toxins mainly targeted against voltage‐sensitive K + channels. In particular, the effect of the K + ‐channel blocker α‐dendrotoxin and the crude scorpion venom of Leiurus quinquestriatus hebraeus (LQ venom) on ATP synthesis in thylakoid membranes and in CF 0 CF 1 ‐containing liposomes was characterised. α‐dendrotoxin (K i ∼ 5.05 μM) and the LQ venom (K i ∼ 1.55 μg/ml) specifically inhibited ATP synthesis in thylakoid membranes and in CF 0 CF 1 ‐containing liposomes. Our results show that α‐dendrotoxin and peptides of the LQ venom with an apparent molecular mass of about 4.0 kDa, probably isoforms of charybdotoxin, specifically bind to CF 0 CF 1 . This binding was reversible and induced a high leak conductance for H + through CF 0 . The Ca 2+ ‐dependent ATPase activity of the isolated soluble part of CF 0 CF 1 (CF 1 ) was completely inhibited by 1 μM α‐dendrotoxin, while the crude LQ venom, at concentrations up to 10 μg/ml, had no affect on ATPase activity. The concentration dependence of the inhibition by α‐dendrotoxin indicates that approximately 2 mol α‐dendrotoxin bind/mol CF 0 CF 1 and 1 mol α‐dendrotoxin/mol CF 1 . Known inhibitors of H + ‐flow‐through CF 0 acted in the presence of α‐dendrotoxin synergistically. Dicyclohexylcarbodiimide and venturicidin, in contrast to their known effect of blocking H + ‐flow‐through CF 0 , increased the leak conductance through CF 0 in the presence of α‐dendrotoxin drastically. This uncoupling effect indicates that their normal mode of blocking is a secondary effect. Binding of the inhibitors to their respective sites apparently does not affect the proton pathway in CF 0 , but induces a conformation which closes the channel part for H + . Protein sequence comparison between the known binding site of charybdotoxin in the shaker K + channel from Drosophila [MacKinnon, R. & Heginbotham, L. (1990) Neuron 5 , 767–771] and the choroplast ATPase showed that subunit III reveals a significant similarity (64%) in parts of its sequence (Gln28–Leu53) to the helix 5 and helix 6 (S5‐S6) linker region (Ala413–Cys462; the charybdotoxin‐binding site) of the shaker K + channel. According to secondary‐structure predictions, the homologous sequences in subunit III and the shaker K + channel represent putative hydrophilic loops connecting two transmembrane α‐helices. Apparently the shaker K + channel and subunit III share significant topological features in these hydrophilic loops which may be part of the respective channel entrance.
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