Cataract formation is prevented by administration of verapamil to diabetic rats

The purpose of the present study was to examine the effects on cataractogenesis of daily sc administration of the Ca2+ antagonist drug verapamil to diabetic rats. Streptozotocin-induced diabetic rats were given verapamil half-way through the 8-week experimental period or during the full 8 weeks of diabetes. Verapamil administration had no effect on the high blood glucose values, low circulating insulin levels, or elevated triglyceride and cholesterol concentrations in the diabetic rats. Untreated diabetic rats had a 90% incidence of cataracts. Four weeks of verapamil administration reduced this incidence to 41%, and a full 8 weeks of drug treatment further lowered the incidence to 20%. Diltiazem, another Ca2+ antagonist, lowered the incidence of cataracts in the diabetic rats to a similar extent. Verapamil administration to the diabetic animals also partially protected against the presence of retinal microangiopathy in the diabetic animals. Lenticular hydration and lipid accumulation were only indirectly related to cataractogenesis in the diabetic rats and its protection by verapamil treatment. Lenticular electrolyte imbalance, particularly Ca2+, in the diabetic animals was closely correlated with cataract formation, and verapamil significantly reduced the alterations in these ion concentrations. The present results demonstrate the efficacy of verapamil as a protective agent against cataractogenesis and some retinal damage in diabetic animals. Most importantly, this occurs in the absence of any change in the glycemic status of the diabetic animals. The findings strongly support a role for lenticular Ca2+ imbalance in cataract development in diabetes and provide initial evidence to suggest its clinical use in the diabetic population at risk for blindness.     

Effect of Oxygen Free Radicals on Cardiac Contractile Activity and Sarcolemmal Na(+)-Ca(2+) Exchange

BACKGROUND: Although oxygen free radicals have been shown to induce myocardial cell damage and cardiac dysfunction, the exact mechanism by which these radicals affect the heart function is not clear. Since the occurrence of intracellular Ca(2+) overload is critical in the genesis of cellular damage and cardiac dysfunction, and since the sarcolemmal Na(+)-Ca(2+) exchange is intimately involved in Ca(2+) movements in myocardium, this study was undertaken to examine the effects of oxygen free radicals on the relationship between changes in cardiac contractile force development and sarcolemmal Na(+)-Ca(2+) exchange activity. METHODS AND RESULTS: Isolated rat hearts were perfused with a medium containing xanthine plus xanthine oxidase for different times, and changes in contractile force as well as sarcolemmal Na(+)-(2+) exchange activity were monitored. Perfusion of the heart with xanthine plus xanthine oxidase resulted in a transient increase followed by a marked decrease in contractile activity; the resting tension was markedly increased. The xanthine plus xanthine oxidase-induced depression in developed tension, rate of contraction, and rate of relaxation, except the transient increase in contractile activity, was prevented by the addition of catalase, but not by superoxide dismutase, in the perfusion medium. A time-dependent depression in sarcolemmal Na(+)-Ca(2+) was also evident upon perfusing the heart with xanthine plus xanthine oxidase. This depression in Na(+)-dependent Ca(2+) uptake was associated with a decrease in the maximal velocity of reaction without any changes in the affinity of Na(+)-Ca(2+) exchanger for Ca(2+). The presence of catalase, unlike superoxide dismutase, prevented the decrease in sarcolemmal Na(+)-Ca(2+) exchange activity in hearts perfused with xanthine plus xanthine oxidase. CONCLUSIONS: The results support the view that a depression in the sarcolemmal Na(+)-Ca(2+) exchange activity may contribute to the occurrence of intracellular Ca(2+) overload and subsequent decrease in contractile activity. Furthermore, these actions of xanthine plus xanthine oxidase in the whole heart appear to be a consequence of H(2)O(2) production rather than the generation of superoxide radicals.     

Effect of beta-Adrenoceptor Antagonists on Phospholipid N-Methylation Activities of Cardiac Sarcolemma

BACKGROUND: Some beta-adrenoceptor antagonists exert a negative inotropic action by affecting Ca(2+) fluxes in the myocardial cell as a consequence of their interaction with sarcolemmal and sarcoplasmic reticular membranes. This action may be caused by their effects on the chemicophysical properties of membranes phospholipids. Because phosphatidylethanolamine (PE) N-methylation can influence the chemicophysical properties of membranes, these agents may affect PE N-methylation. This study was undertaken to examine the effects of propranolol, acebutolol, and atenolol on PE-N-methylation in rat heart sarcolemma (SL). METHODS AND RESULTS: Sarcolemmal membrane was isolated from rat hearts by the hypotonic shock LiBr method. Incorporation of radiolabeled methyl groups from S-adenosyl-l-methionine was assayed at three catalytic sites involved in the PE N-methylation reaction in the presence and absence of these drugs. A biphasic effect of propranolol at site I was noted; low concentrations (10(-8) M) were inhibitor. Acebutolol (10(-9)-10(-3) M) depressed methyl group incorporation in SL at site II in a dose-dependent manner, whereas atenolol showed no effect. Propranolol also exerted a biphasic effect on sarcoplasmic reticular (SR) methylation at site I, whereas acebutolol depressed the SR enzyme activity at site II and atenolol had no effect. The mitochondrial methyltransferase activities at sites I, II, and III were unaltered by any of these drugs. CONCLUSIONS: It is suggested that propranolol and acebutolol alter SL and SR PE N-methyltransferase activity at site I and site II, respectively, either by affecting the enzyme directly or by changing the physiochemical properties of the membrane.     

Defective membrane systems in dystrophic skeletal muscle of the UM-X7.1 strain of genetically myopathic hamster.

1. The function of mitochondria, sarcotubular membranes (heavy microsomes), sarcolemma and myofibrils from the hind-leg skeletal muscle of about 60- and 150-day-old normal and myopathic (UM-X7.1) hamsters was examined. 2. The mitochondrial calcium uptake as well as mitochondrial phosphorylation and respiratory rates were lower in 60-day-old myopathic skeletal muscle, unlike 150-day-old myopathic animals, when pyruvate-malate and glutamate-malate were used as substrates. However, mitochondria from 150-day-old myopathic animals showed depressed glutamate-dependent respiratory and phosphorylation rates and succinate-supported initial rate of calcium uptake. 3. The microsomal calcium-uptake, but not calcium-binding, and Ca2+-stimulated adenosine triphosphatase (ATPase) activity of the 150-day-old myopathic skeletal muscle were lower than the control values. Although microsomal calcium-binding, calcium-uptake and ATPase activities of the 60-day-old myopathic muscle were not depressed significantly, the initial rate of calcium uptake was less than the control. 4. The sarcolemmal Ca2+-ATPase, but not Mg2+-ATPase or Na+ +K+-ATPase, activity was higher in 60-day-old myopathic muscle whereas the activities of all these enzymes from 150-day-old myopathic animals were higher than the control. On the other hand, the Na+ +K+-ATPase activities from 60- and 150-day-old myopathic animals were inhibited by ouabain to a lesser extent in comparison with the respective control values. 5. The myofibrillar Ca2+-ATPase and Mg2+-ATPase activities as well as inhibition of Mg2+-ATPase due to Na+ and K+ in myopathic muscle were no different from the control values. 6. The results reported here give further support to the view that different membrane systems of the dystrophic muscle are defective.     

Antilipolytic activity of a novel partial A1 adenosine receptor agonist devoid of cardiovascular effects: comparison with nicotinic acid

Elevated lipolysis and circulating free fatty acid (FFA) levels have been linked to the pathogenesis of insulin resistance. A1 adenosine receptor agonists are potent inhibitors of lipolysis. Several A1 agonists have been tested as potential antilipolytic agents; however, their effect on the cardiovascular system remains a potential problem for development of these agents as drugs. In the present study, we report that CVT-3619 [(2-{6-[((1R,2R)-2-hydroxycyclopentyl) amino] purin9-yl} (4S,5 S,2R,3R)5-[(2fluorophenylthio) methyl] oxolane-3,4-diol)], a novel partial A1 receptor agonist, significantly reduces circulating FFA levels without any effect on heart rate and blood pressure in awake rats. Rats were implanted with indwelling arterial and venous cannulas to obtain serial blood samples, record arterial pressure, and administer drug. CVT-3619 decreased FFA levels in a dose-dependent manner at doses from 1 up to 10 mg/kg. The FFA-lowering effect was blocked by the A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine. Triglyceride (TG) levels were also significantly reduced by CVT-3619 treatment in the absence and presence of Triton. Tachyphylaxis of the antilipolytic effect of CVT-3619 (1 mg/kg i.v. bolus) was not observed with three consecutive treatments. An acute reduction of FFA by CVT-3619 was not followed by a rebound increase of FFA as seen with nicotinic acid. The potency of insulin to decrease lipolysis was increased 4-fold (p < 0.01) in the presence of CVT-3619 (0.5 mg/kg). In summary, CVT-3619 is an orally bioavailable A1 agonist that lowers circulating FFA and TG levels by inhibiting lipolysis. CVT-3619 has antilipolytic effects at doses that do not elicit cardiovascular effects.     

Depressed responsiveness of phospholipase C isoenzymes to phosphatidic acid in congestive heart failure

The cardiac sarcolemmal membrane cis -unsaturated fatty acid-sensitive phospholipase D hydrolyzes phosphatidylcholine to form phosphatidic acid. The functional significance of phosphatidic acid is indicated by its ability to increase [Ca(2+)](i)and augment cardiac contractile performance via the activation of phospholipase C. Accordingly, we tested the hypothesis that a defect occurs in the membrane level of phosphatidic acid and/or the responsiveness of cardiomyocytes to phosphatidic acid in congestive heart failure due to myocardial infarction. Myocardial infarction was produced in rats by ligation of the left coronary artery while sham-operated animals served as control. At 8 weeks after surgery, the experimental animals were at a stage of moderate congestive heart failure. Compared to sham controls, phosphatidic acid-mediated increase in [Ca(2+)](i), as determined by the fura 2-AM technique, was significantly reduced in failing cardiomyocytes. Immunoprecipitation of sarcolemmal phospholipase C isoenzymes using specific monoclonal antibodies revealed that the stimulation of phospholipase C gamma(1)and delta(1)phosphatidylinositol 4,5-bisphosphate hydrolyzing activities by phosphatidic acid was decreased in the failing heart. Although the activity of phospholipase C beta(1)in the failing heart was higher than the control, phosphatidic acid did not stimulate this isoform in control sarcolemma, and produced an inhibitory action in the failing heart preparation. Furthermore, the specific binding of phosphatidic acid to phospholipase C gamma(1)and delta(1)isoenzymes was decreased, whereas binding to phospholipase beta(1)was absent in the failing heart. A reduction in the intramembranal level of phosphatidic acid derived via cis -unsaturated fatty acid-sensitive phospholipase D was also seen in the failing heart. These findings suggest that a defect in phosphatidic acid-mediated signal pathway in sarcolemma may represent a novel mechanism of heart dysfunction in congestive heart failure.     

Gender Differences in Cardiac Dysfunction and Remodeling due to Volume Overload

BackgroundThis study examined the sex differences for hemodynamic and echocardiographic changes in hypertrophied and failing hearts induced by arteriovenous (AV) shunt.Methods and ResultsEchocardiographic and hemodynamic alterations were determined in male and female rats at 4 and 16 weeks after AV shunt. Ovariectomized females treated with estrogen for 16 weeks post-AV shunt were also used. Both genders developed cardiac hypertrophy at 4 and 16 weeks post-AV shunt; however, the increase in cardiac muscle mass was greater in females than males at 16 weeks. At 4 weeks post-AV shunt, increases in ventricular dimensions and left ventricular end-diastolic pressure (LVEDP) as well as a decrease in fractional shortening occurred in males only. Unlike the females, the rates of pressure development (+dP/dt) and decay (-dP/dt) were depressed and LVEDP increased in male rats at 16 weeks post-AV shunt. An increase in cardiac output was seen in both genders, but this was more marked in the males at 4 and 16 weeks post-AV shunt. Although mRNA levels for ACE were increased in both male and female rats at 4 and 16 weeks, mRNA levels for angiotensin II type 1 receptor were increased in males at 16 weeks only. Furthermore, increases in plasma catecholamines were elevated in males but were decreased or unchanged in females at 16 weeks of AV shunt. LV internal diameters as well as depressed fractional shortening occurred in males whereas increases in posterior wall thickness were seen in the female rats at 16 weeks of AV shunt. Ovariectomy resulted in depressed +dP/dt, -dP/dt, and fractional shortening, whereas a marked increase in cardiac output as well as increased LVEDP and LV internal diameters were observed at 16 weeks post-AV shunt. Although treatment with 17-β estradiol normalized ±dP/dt, LVEDP remained elevated.ConclusionGender differences in cardiac function may be due to differences in the type of cardiac remodeling as a consequence of AV shunt. Furthermore, estrogen appears to play an important role in preventing cardiac dysfunction and adverse ventricular remodeling in female rats.     

Dependence and Addiction During Chronic Opioid Therapy

The use of opioids for chronic noncancer pain has increased dramatically over the past 25?years in North America and has been accompanied by a major increase in opioid addiction and overdose deaths. The increase in opioid prescribing is multifactorial and partly reflects concerns about the effectiveness and safety of alternative medications, particularly the nonsteroidal anti-inflammatory drugs. However, much of the rise in opioid prescribing reflects the assertion, widely communicated to physicians in the 1990s, that the risks of dependence and addiction during chronic opioid therapy were low, predictable, and could be minimized by the use of controlled-release opioid formulations. In this narrative review, we offer a critical appraisal of the publications most frequently cited as evidence that the risk of addiction during chronic opioid therapy is low. We conclude that very few well-designed studies support the notion that opioid addiction is rare during chronic opioid therapy and that none can be readily generalized to present-day practice. Despite serious methodological limitations, these studies have been repeatedly mischaracterized as showing that the risk of addiction during chronic opioid therapy is rare. These studies are countered by a larger, more rigorous and contemporary body of evidence demonstrating that dependence and addiction are relatively common consequences of chronic opioid therapy, occurring in up to one-third of patients in some series.