Sudden cardiac death, genes, and arrhythmogenesis : consideration of new population and mechanistic approaches from a national heart, lung, and blood institute workshop, part I.

Malignant ventricular arrhythmias are the leading mechanism of death in patients with acute and chronic cardiac pathologies. The extent to which inherited mutations and polymorphic variation in genes determining arrhythmogenic mechanisms affect these patients remains unknown, but based on recent population studies, this risk appears significant, deserving much greater investigation. This report summarizes a National Heart, Lung, and Blood Institute workshop that considered sources of genetic variation that may contribute to sudden cardiac death in common cardiac diseases. Evidence on arrhythmogenic mechanisms in recent population studies suggests a significant portion of the risk of sudden cardiac death in such broad populations may be unrelated to traditional risk factors for predisposing conditions such as atherosclerosis, hypertension, and diabetes and instead may involve unrecognized genetic and environmental interactions that influence arrhythmic susceptibility more directly. Additional population and genetic studies directed at discovering the sources of inherited molecular risk that are most directly linked to arrhythmia initiation and propagation, in addition to studies on previously well-described risk factors, would appear to have considerable potential for reducing premature cardiovascular mortality.

Sudden cardiac death, genes, and arrhythmogenesis: consideration of new population and mechanistic approaches from a National Heart, Lung, and Blood Institute workshop, Part II.

This is Part II of a 2-part article dealing with malignant ventricular arrhythmias, which are the leading mechanism of death in common cardiac diseases. Genetic population studies directed at discovering common proximal sources of inherited molecular risk most directly linked to arrhythmia initiation and propagation would appear to have considerable potential in helping reduce cardiovascular mortality.

Effect of epinephrine and other lipolytic agents on intracellular lipolysis and lipoprotein lipase activity in 3T3-L1 adipocytes.

3T3-L1 adipocytes were used to test the hypothesis that hormone-sensitive lipolysis and lipoprotein lipase activity might be regulated in a reciprocal manner. Intracellular lipolysis was stimulated by catecholamine, dibutyryl cAMP, and ACTH, but not by glucagon. The effects of epinephrine on lipolysis were blocked by the beta-antagonist propanolol but not by the alpha-antagonist phentolamine. Hormone-stimulated lipolysis was not changed by acute (45 min) or chronic (2 days) treatment of the cells with insulin whereas the latter treatment augmented lipoprotein lipase activity about fivefold. Epinephrine did not affect the lipoprotein lipase activity of insulin-stimulated cells. Withdrawal of glucose from the medium decreased lipoprotein lipase activity and the effect of epinephrine on lipolysis. Effects of lipolytic agents on activity of lipoprotein lipase were variable and concentration-dependent. Lipoprotein lipase activity was decreased only by concentrations of epinephrine greater than those inducing maximal intracellular lipolysis, and the decrease in activity occurred about 30 min after the increase in glycerol release. There seems to be no relationship between the level of activity of lipoprotein lipase and the maximal rate of hormone-stimulated lipolysis in 3T3-L1 cells. Unlike in adipose tissue and adipocytes of rats, hormone-stimulated lipolysis and lipoprotein lipase activity in murine 3T3-L1 adipocytes appear to be regulated independently.

Regulation of mammary and adipose tissue lipoprotein lipase and blood triacylglycerol in rats during late pregnancy. Effect of prostaglandins.

The effects of several prostaglandins on lipoprotein lipase activity of mammary gland and adipose tissue and serum triacylglycerol were studied during late pregnancy in rats. Prostaglandins were injected twice daily for 2 days before and once on the day of analysis. In rats pregnant 20 days, prostaglandin F(2alpha) (PGF(2alpha)) increased the activity of lipoprotein lipase in mammary gland fourfold, reduced the activity in adipose tissue about 60%, and decreased serum concentration of triacylglycerol 50%. PGF(2alpha) also reduced serum concentration of progesterone 90% and increased that of prolactin fivefold, but had no effect on serum concentrations of either immuno-reactive insulin or 17beta-estradiol. Injections of 13,14-dihydro-15-keto PGF(2alpha), a metabolite of PGF(2alpha), had similar effects in rats pregnant 20 days, whereas prostaglandins E(1) and E(2) did not. In rats pregnant 16 days, PGF(2alpha) did not affect lipoprotein lipase activity in the tissues or the concentration of triacylglycerol and prolactin in serum, although it decreased serum progesterone 80%.2-Br-alpha-ergocryptine prevented the increase in serum prolactin in response to PGF(2alpha), but did not alter the effect of PGF(2alpha) on lipoprotein lipase activity or serum triacylglycerol. Progesterone completely blocked the effects of PGF(2alpha) on lipoprotein lipase activity and serum triacylglycerol and prolactin concentrations. These findings indicate that the changes in lipoprotein lipase activity and serum triacylglycerol in PGF(2alpha)-treated rats are probably related to the inhibitory action of PGF(2alpha) on progesterone secretion. They also suggest that endogenous F prostaglandins may play a role in the regulation of lipoprotein lipase activity in mammary gland and adipose tissue near parturition.

Stimulation of Na+ transport across the toad urinary bladder by p-chloromercuribenzene sulfonate.

The sulfhydryl reagent p-chloromercuribenzene sulfonate increased the ISC across substrate-replete toad urinary bladder when applied to the mucosal (apical) surface. This increase was accounted for by an increased mucosal to serosal net flux of Na+. In the absence of substrate, the rise in ISC was accompanied by an irreversible increase in tissue conductance which was not apparent in the replete preparation. These findings suggest that p-chloromercuribenzene sulfonate may be useful in marking mucosal functions associated with the Na+ transport apparatus.

Effects of aldosterone on Na+ transport in the toad bladder. I. Glycolysis and lactate production under aerobic conditions.

Previous studies indicated that aldosterone enhances active Na+ transport, glycolysis, lactate production and respiration of the toad bladder. Evidence was also presented that the changes in glycolysis and lactate production were secondary to the changes in active Na+ transport. Further analysis of the relationships between metabolism and Na+ transport was undertaken with the aid of two inhibitors of pyruvate metabolism, oxythiamine and phenylpyruvate. These inhibitors prevented the aldosterone-induced increase in oxidation of [6-(14)C] glucose but had little effect on the increase in lactate production. In contrast, the effect on Na+ transport (i.e., Isc) was completely inhibited by oxythiamine plus phenylpyruvate with glucose as substrate. The effect on Na+ transport, however, was obtained with the by-pass substrates, oxaloacetate plus beta-hydroxybutyrate, in the presence of these inhibitors. These results implied that steroidal enhancement of lactate production and Na+ transport were independent effects. To evaluate whether an increase in Na+ transport, per se would augment lactate production, the responses were evaluated under conditions of an imposed Na+ gradient (mucosal Na+ = 5mM; serosal Na+ 110 mM). Addition of NaCl to the mucosal media evoked the same increase in Isc as the addition of aldosterone; both additions increased Isc more than two-fold. Aldosterone reduced lactate production under these conditions while the re-addition of NaCl had no effect on lactate formation. These results are consistent with an action of aldosterone on pathways involved in oxidative energy metabolism, and suggest that the activation of glycolysis may be a function of the net balance between energy production and utilization.

Effects of aldosterone on Na+ transport in the toad bladder. II. The anaerobic response.

The action of aldosterone on active Na+ transport was assessed under aerobic and anaerobic conditions in the isolated urinary bladder of the toad, Bufo marinus. Aldosterone augmented the short-circuit current (Isc) under rigorous anaerobiosis. Four lines of evidence indicate that the increase in anaerobic Isc does not represent an equivalent increase in active Na+ transport: 1. Net Na transport, determined by isotopic fluxes, was the same in the aldosterone-treated and control quarter-bladders, and significantly greater than the simultaneously measured Isc-2. Amiloride, an inhibitor of the apical entry of Na+, did not reduce the steroid-dependent increase in the anaerobic Isc-3. Substitution of choline for Na+ in the mucosal medium reduced the magnitude of the anaerobic Isc values but did not eliminate the effect of aldosterone. 4. Addition of ouabain, a potent inhibitor of the Na+ pump, partially inhibited the effect of aldosterone on the anerobic Isc but a significant hormonal increment remained. The source of the anaerobic Isc was not identified; an effort was made, however, to determine the dependence of this current on glycolysis. During anaerobiosis, aldosterone increased the integral Isc by 42% but did not alter lactate production. These results suggest that the steroid-dependent increase in the anaerobic Isc may involve effects on permeability properties of the epithelium rather than on active transport systems.