HIV vaccine preparedness studies in the organization for economic co-operation and development (OECD) countries

HIV vaccine development remains an urgent priority. This article is a systematic review of HIV vaccine preparedness studies in the high-income 30 Organization for Economic Co-operation and Development countries, to identify factors important for HIV vaccine trial development in injection drug users (IDU), men who have sex with men (MSM), and women at heterosexual risk (WAHR) across these countries. Of 27 articles we identified, willingness to participate (WTP) was assessed in eight studies involving IDU, 11 involving MSM, and one involving WAHR. WTP ranged in IDU at 41-86%, MSM at 23-94%, and in WAHR, it was at 81%. Studies reported recruitment of high-risk individuals. Retention was assessed in eight studies involving IDU, five involving MSM, and three involving WAHR. IDU were retained at a range of 3-98%, MSM at 70-95% and WAHR at 67-92%. This review provides an in-depth summary of HIV vaccine preparedness studies that were conducted in the Organization for Economic Co-operation and Development countries.     

Inhibitory profile of SEA0400 [2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline] assessed on the cardiac Na+-Ca2+ exchanger, NCX1.1

SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline) has recently been described as a potent and selective inhibitor of Na(+)-Ca(2+) exchange in cardiac, neuronal, and renal preparations. The inhibitory effects of SEA0400 were investigated on the cloned cardiac Na(+)-Ca(2+) exchanger, NCX1.1, expressed in Xenopus laevis oocytes to gain insight into its inhibitory mechanism. Na(+)-Ca(2+) exchange currents were measured using the giant excised patch technique using conditions to evaluate both inward and outward currents. SEA0400 inhibited outward Na(+)-Ca(2+) exchange currents with high affinity (IC(50) = 78 +/- 15 and 23 +/- 4 nM for peak and steady-state currents, respectively). Considerably less inhibitory potency (i.e., micromolar) was observed for inward currents. The inhibitory profile was reexamined after proteolytic treatment of excised patches with alpha-chymotrypsin, a procedure that eliminates ionic regulatory mechanisms. After this treatment, an IC(50) value of 1.2 +/- 0.6 microM was estimated for outward currents, whereas inward currents became almost insensitive to SEA0400. The inhibitory effects of SEA0400 on outward exchange currents were evident at both high and low concentrations of regulatory Ca(2+), although distinct features were noted. SEA0400 accelerated the inactivation rate of outward currents. Based on paired pulse experiments, SEA0400 altered the recovery of exchangers from the Na(+)(i)-dependent inactive state, particularly at higher regulatory Ca(2+)(i) concentrations. Finally, the inhibitory potency of SEA0400 was strongly dependent on the intracellular Na(+) concentration. Our data confirm that SEA0400 is the most potent inhibitor of the cardiac Na(+)-Ca(2+) exchanger described to date and provide a reasonable explanation for its apparent transport mode selectivity.     

Status of myocardial antioxidants in ischemia-reperfusion injury

BACKGROUND: Myocardial ischemia-reperfusion represents a clinically relevant problem associated with thrombolysis, angioplasty and coronary bypass surgery. Injury of myocardium due to ischemia-reperfusion includes cardiac contractile dysfunction, arrhythmias as well as irreversible myocyte damage. These changes are considered to be the consequence of imbalance between the formation of oxidants and the availability of endogenous antioxidants in the heart. OBSERVATIONS: An increase in the formation of reactive oxygen species during ischemia-reperfusion and the adverse effects of oxyradicals on myocardium have now been well established by both direct and indirect measurements. Although several experimental studies as well as clinical trials have demonstrated the cardioprotective effects of antioxidants, some studies have failed to substantiate the results. Nonetheless, it is becoming evident that some of the endogenous antioxidants such as glutathione peroxidase, superoxide dismutase, and catalase act as a primary defense mechanism whereas the others including vitamin E may play a secondary role for attenuating the ischemia-reperfusion injury. The importance of various endogenous antioxidants in suppressing oxidative stress is evident from the depression in their activities and the inhibition of cardiac alterations which they produce during ischemia-reperfusion injury. The effects of an antioxidant thiol containing compound, N-acetylcysteine, and ischemic preconditioning were shown to be similar in preventing changes in the ischemic-reperfused hearts. CONCLUSIONS: The available evidence support the role of oxidative stress in ischemia-reperfusion injury and emphasize the importance of antioxidant mechanisms in cardioprotection.     

Inotropic responses to isoproterenol in congestive heart failure subsequent to myocardial infarction in rats

It is well known that the positive inotropic effect of catecholamines is mediated through the activation of adrenergic receptors and the formation of cyclic adenosine monophosphate (AMP) in the cardiac cell. Although attenuated responses of failing hearts to catecholamines are commonly seen in patients and experimental animals with coronary artery disease, their mechanisms are poorly understood. To examine the status of beta-adrenergic receptors and postadrenergic receptor mechanisms in congestive heart failure due to myocardial infarction, the left coronary artery in rats was ligated for 4 and 8 weeks before studying the hemodynamic and biochemical changes due to isoproterenol, a beta-adrenoceptor agonist, or forskolin, a postreceptor agonist. Isolated perfused rat heart preparations were also used for studying changes in contractile function and cyclic AMP content. The hemodynamic actions and changes in the left ventricular cyclic AMP content in the experimental animals were depressed, not only in response to isoproterenol but also to forskolin. The density of beta-adrenoceptors was also decreased in the failing myocardium. In isolated perfused hearts from the 8-week experimental animals, isoproterenol-induced as well as forskolin-induced increases in both contractile force and cyclic AMP content in the left ventricle were depressed. These data suggest that defects in both beta-adrenergic receptor and postreceptor sites may be involved in attenuating the response of infarcted hearts to catecholamines.     

Phospholipid N-methylation as a Signal Transduction Mechanism in Normal and Failing Hearts

The phospholipid N-methylation pathway comprises of three successive N-terminal methylations of phosphatidylethanolamine where S-adenosyl-L-methionine acts as the physiological donor. Under optimal conditions in cardiac membranes, the catalytic sites I, II, and III of methyltransferase have been identified which are responsible for the synthesis of the major product, phosphatidyl-N-monomethylethanolamine, phosphatidyl-N,N-dimethylethanolamine, and phosphatidylcholine, respectively. The characterization of the phosphatidylethanolamineN-methyltransferase system has shown that each of the catalytic sites exhibits different biochemical properties. The phospholipid N-methylation pathway has also been observed to regulate heart function by inducing localized structural, compositional, and functional changes in cardiac membranes under different pathological conditions of chronic nature. This review deals with the phosphatidylethanolamine N-methylation–mediated signal transduction mechanism involving modification of the Ca2+-transporting activities of the sarcolemmal and sarcoplasmic reticular membranes of the cardiomyocyte. In this regard, special attention is given to the status of this pathway and its relevance for the functioning of membrane-related Ca2+-transport systems in heart dysfunction due to different cardiac pathologies, such as diabetes-induced cardiomyopathy, catecholamine-induced cardiomyopathy, genetically linked cardiomyopathy, and adriamycin-induced cardiomyopathy. In addition, changes in phosphatidylethanolamine N-methylation in heart dysfunction due to cardiac hypertrophy, Ca2+-paradox hearts, and ischemic-reperfused hearts have been described. It is suggested that an increase in phosphatidylethanolamine N-methylation activity may play an adaptive role, whereas a depression may contribute towards contractile dysfunction. This revised version was published online in July 2006 with corrections to the Cover Date.     

Subcellular changes during cardiac hypertrophy and heart failure due to bacterial endocarditis

Summary Rabbits were catheterized and injected with saline (uninfected) orStreptococcus viridans (infected) to study the time course of changes in heart function, ultrastructure, membrane systems, myofibrils, and myocardial cations, cyclic AMP, norepinephrine and high energy phosphate contents. Myocardial hypertrophy in both infected and uninfected animals was found to follow increased activity of sympathetic nervous system as indicated by increased heart rate as well as norepinephrine and cyclic AMP contents. The decrease in sarcolemmal Na⁺–K⁺ ATPase activity was associated with contractile failure and preceded the observed decrease in myocardial K⁺ and increase in Na⁺ contents. The decrease in sarcolemmal Ca²⁺ binding activity may contribute in decreasing calcium entry and explain decreased myocardial Ca²⁺ contents and contractile activity; these changes were also accompanied by decreased microsomal calcium binding as well as depressed mitochondrial RCI. Depression in mitochondrial oxidative phosphorylation activity was found to result in declining high energy phosphate stores. Decreases in sarcolemmal, mitochondrial and myofibrillar ATPase activities as well as sarcolemmal adenylate cyclase activity were observed in late stages of bacterial endocarditis, at which time extensive myocardial cell damage was also apparent. These observations suggest that myocardial hypertrophy due to bacterial endocarditis may be a consequence of elevated levels of cyclic AMP whereas subsequent heart failure and cell damage in this disease may be due to defects in different membrane systems accompanied by a myocardial calcium deficiency.

---

Subzelluläre Änderungen des hypertrophierten und insuffizienten Herzens bei bakterieller Endokarditis

Zusammenfassung Bei katheterisierten Kaninchen wurde Streptococcus viridans bzw. Kochsalzlösung (bei Kontrolltieren) injiziert und der Zeitverlauf der Veränderungen in der Herzaktion der myokardialen Ultrastruktur (Membransysteme, Myofibrillen) sowie dem Gehalt an Kationen, zyklischem AMP, Noradrenalin und energiereichem Phosphat verfolgt. Sowohl bei in infizierten als auch bei den nichtinfizierten Tieren ergab sich, daß die Myokardhypertrophie einer verstärkten Aktivität des sympathischen Nervensystems folgt, wie aus der Steigerung der Herzfrequenz sowie des Gehaltes an Noradrenalin- und zyklischem AMP hervorging. Der Rückgang in der Aktivität der sarkolemmalen Na⁺–Ka⁺-ATPase-Aktivität war von kontraktilem Versagen begleitet und ging einem Abfall des myokardialen K⁺-Gehalts und einem Anstieg des Na⁺-Gehalts voraus. Die Minderung der sarkolemmalen Ca²⁺-Bindungsaktivität könnte zu einem Rückgang der Ca²⁺-Aufnahme beitragen und die Minderung des myokardialen Ca²⁺-Gehaltes und der kontraktilen Aktivität erklären. Diese Veränderungen waren auch von einer reduzierten mikrosomalen Ca²⁺-Bindung und von einer verminderten mitochondrialen RCI begleitet. Eine reduzierte Aktivität der oxidativen Phosphorylierung in den Mitochondrien bewirkte einen Rückgang der Vorräte an energiereichem Phosphat. Ein Abfall der sarkolemmalen, mitochondrialen und myofibrillären ATPase-Aktivität und der sarkolemmalen Adenylatcyclase wurde in späteren Stadien der bakteriellen Endokarditis beobachtet, in denen auch ausgedehnte Zellschädigungen vorlagen. Diese Beobachtungen lassen vermuten, daß die myokardiale Hypertrophie bei bakterieller Endokarditis Folge eines erhöhten Spiegels an zyklischem AMP ist, während das nachfolgende Herzversagen und die Zellschädigung bei dieser Erkrankung auf Defekte verschiedener Membransysteme-begleitet von myokardialem Ca²⁺-Defizit-bezogen werden kann.

---

---

Paper, presented at the Erwin Riesch Symposium, Tübingen, April 3–7, 1979

---

With 1 figure and 3 tables

---

Supported by the Manitoba Heart Foundation.

---

Visiting Professor supported by the Canadian Heart Foundation.     

Cardiovascular effects of acebutolol following coronary artery occlusion and reperfusion in anaesthetized dog.

1 The effects of 5 mg/kg acebutolol given intravenously were investigated in anaesthetized dogs after (a) ligation of the left anterior descending coronary artery and (b) coronary reperfusion following 60 min of ligation of the anterior descending coronary artery. 2 Coronary artery ligation produced, after 4 to 6 h, persistent multiple ventricular ectopic beats and abnormalities of R and T waves and of the S-T segment. Administration of acebutolol, after the development of persistent ventricular arrhythmias, restored normal sinus rhythm within 5 min of injection. Electrocardiographic abnormalities were also reduced. 3 Coronary artery reperfusion (following 60 min of ligation) resulted in multiple ventricular ectopic beats, ventricular tachycardia and/or ventricular fibrillation. Pretreatment with acebutolol, 15 min before starting reperfusion, markedly reduced the arrhythmias. 4 Acebutolol did not affect peak inspiratory airway pressure. 5 Acebutolol produced significant bradycardia and slight, transient, hypotension. It was without effect on left ventricular systolic pressure, left ventricular end-diastolic pressure, cardiac output or pulmonary arterial pressure. 6 These results suggest beneficial effects of acebutolol in myocardial ischaemia and coronary reperfusion, without any significant risk of cardiodepression or bronchospasm.     

Heart sarcolemmal ATPase and calcium binding activities in rats fed a high cholesterol diet

ATPase and calcium binding activities were studied in sarcolemmal membranes from hearts of male rats fed either a control or 2% cholesterol diet for different time periods. Studies with isolated membrane revealed a significant increase in Na+-K+ ATPase activity, sialic acid content and ATP-independent calcium binding capacity in the presence of 1.25 mM CaCl2 in the 6 week cholesterol fed group. By 12 weeks, Na+-K+ ATPase, Mg2+-ATPase and Ca2+-ATPase activities as well as ATP-independent calcium binding in the presence of 0.05 mM CaCl2 were increased in membranes from cholesterol fed rats. A significant increase (P less than 0.05) in the sarcolemmal cholesterol/phospholipid molar ratio, which is an indicator of a decrease in membrane fluidity, was also noted in the 12 week cholesterol fed group. Concanavalin A, which is believed to decrease membrane fluidity, stimulated both Mg2+ and Ca2+-dependent ATPase activities and increased ATP-independent calcium binding in control sarcolemmal preparations and these changes resembled those observed in the sarcolemma from cholesterol fed rats. Since concanavalin A did not alter the activity of Na+-K+ ATPase, it appears that some of the observed differences in sarcolemmal activities upon cholesterol feeding did not correlate well with changes in membrane order. At 24 weeks, there was a generalized depression in the sarcolemmal ATPase activities of the cholesterol group; both Mg2+ ATPase and Ca2+ ATPase were significantly less than in control.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modification of cardiac sarcolemmal Na+-Ca2+ exchange by diltiazem and verapamil

Cardiac sarcolemmal membranes were isolated from the rat heart and their ability for Na+-Ca2+ exchange in the absence or presence of diltiazem and verapamil was examined. Maximal Ca2+ influx activity of membranes due to Na+-dependent reaction occurred within 3 min and was about 5 nmol Ca2+/mg protein. Diltiazem (0.1 to 10 microM) depressed the Ca2+ influx activity significantly whereas verapamil (0.1 to 10 microM) had no effect at initial stages of the reaction (10 to 20 sec). The inhibitory effect of diltiazem on Ca2+ influx was found to be of an uncompetitive nature. Sodium was found to cause a rapid Ca2+ efflux from the calcium loaded membrane vesicles; about 70% of the Ca2+ efflux activity was increased by 0.1 to 10 microM of verapamil and 10 microM of diltiazem significantly. The stimulatory effect of these agents on Ca2+ efflux was associated with a change in Ka value from 16 to 5 mM Na+. Both diltiazem (0.1-3 microM) and verapamil (0.1-10 microM) did not affect the membrane Na+-K+ ATPase activity, but diltiazem in high concentrations (10-30 microM) had an inhibitory action. Specific calcium channel blocking agents, nitrendipine and nifedipine, depressed sodium-dependent Ca2+-efflux activity. A beta-adrenoreceptor antagonist, propranolol, unlike acebutolol, increased sodium-induced Ca2+-influx at high concentrations (10-100 microM).(ABSTRACT TRUNCATED AT 250 WORDS)