No abstract

1. Carbohydrate and lipid metabolism and the capacity to perform prolonged submaximal physical exercise were studied in six young healthy subjects treated in a randomized double-blind fashion for 2 days with either placebo, the non-selective beta-adrenoceptor antagonist propranolol (80 mg b.i.d.) or the cardioselective agent metoprolol (100 mg b.i.d.). On day 3, 1 h after the last dose, the subjects exercised for 30 min periods followed up 10 min rest up to the point of exhaustion. 2. The capacity to perform exercise was decreased with both beta-adrenoceptor antagonists. However, at an equal degree of beta 1-adrenoceptor blockade, all subjects could exercise for a longer period of time on the cardioselective agent as compared with the non-selective drug. 3. Blood glucose levels decreased during exercise irrespective of the type of treatment, but the attenuation occurred most rapidly on propranolol. At exhaustion the average non-esterified fatty acid levels had increased 256% on placebo, 148% on metoprolol and 65% on propranolol. A significant positive correlation was found between changes in non-esterified fatty acid levels during exercise and total working time. It is concluded that beta-adrenoceptor blockade diminishes the capacity for prolonged sub-maximal exercise at least in part by reducing the availability of substrates to the working muscles.

Three zinc ion dependent oligonucleotide based artificial nucleases (OBANs) have been synthesized. These consist of 2'-O-methyloligoribonucleosides connected to 5-amino-2,9-dimethylphenanthroline via a urea function to a linker extending either from C-5 of deoxyuridine or from the 2'-position of uridine moieties. Both types of linkers are placed centrally in the modified sequence and in addition one OBAN carries the C-5 modified dU as an additional nucleoside unit at the 5'-end. All three OBANs are shown to cleave target oligoribonucleotides selectively. The target RNA's are varied to form differently sized bulges (0-5 nucleotides (nt)) and the different OBANs have different preferences for which sizes are preferentially cleaved. The OBAN with the centrally positioned C-5 linked zinc chelate preferentially cleaves 3 and 4-nt bulges, the OBAN with the 2'-linked chelate has a preference for slightly smaller bulges and the OBAN with a 5'-end chelate is more efficient the larger the bulge is. In addition the OBAN with the centrally positioned C-5 linked zinc chelate is shown to be a real enzyme, capable of turnover of substrate and displaying Michaelis-Menten behaviour. The main differences in efficiency of cleavage between the different OBAN-RNA substrate combinations are likely to be due to proximity factors i.e. the positioning of a catalytic group relative to cleaved phosphodiester functions. The model systems investigated partially display the importance of catalytic group positioning and should be useful in future development of more efficient OBANs.

Two new zinc ion dependent oligonucleotide based artificial nucleases (OBAN's) have been synthesized. These consist of 2'-O-methyl modified RNA oligomers conjugated to 5-amino-2,9-dimethylphenanthroline (neocuproine)via a urea linker. OBAN 4 carries the catalytic group on a linker extending from the C-4 of an internal cytosine moiety. OBAN 5 has two neocuproine units attached, each to linkers extending from the C-5 position of uridine moieties, one placed internally and the other at the at the 5'-end of the oligonucleotide. The key step in the synthesis of the OBAN systems is conjugation of the catalytic group to the respective amino linkers of the modified oligonucleotides. This is achieved by first converting the 5-amino-2,9-dimethylphenanthroline to the phenylcarbamate. The reaction of this neocuproine phenylcarbamate with the oligonucleotide carrying one or two primary aliphatic amines in aqueous buffer (at pH 8.5) leads to nearly quantitative formation of the urea-linked conjugates. Both OBAN systems were found to cleave RNA in the bulged out regions formed from the non-complementary part of the target sequences, in the presence of Zn(II) ions. Differences in efficiency between these and previously reported systems are discussed.

The inducibility of ventricular arrhythmias is high in patients with bifascicular block and of the same magnitude in patients with and without a history of syncope. Clinical events during follow-up were not predicted by programmed ventricular stimulation in either of the two groups. The finding of inducible ventricular arrhythmia in patients with bifascicular block should therefore be interpreted with caution.