Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with type 1 or type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here, we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in an LDLR −/− mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR −/− mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied by a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction in CVD risk.

Left ventricular hypertrophy is an independent cardiovascular risk factor. In hypertensives, the pattern of hypertrophy is influenced by central haemodynamic characteristics. Central haemodynamics may also determine physiological differences in left ventricular structure and predispose to particular responses of the left ventricle to pathological increases in load. M-mode echocardiography was used to measure left ventricular diastolic dimension and to estimate left ventricular mass index, relative wall thickness and stroke volume in 159 healthy volunteers aged between 19 and 74 years. Tonometric sphygmography was used to estimate augmentation index, central end-systolic and mean arterial blood pressure. Effective arterial elastance was calculated as the ratio of end-systolic pressure to stroke volume. Left ventricular mass index and relative wall thickness were adjusted for variation in age, sex and blood pressure before analyses. Left ventricular diastolic dimension exhibited significant inverse correlations with both effective arterial elastance ( r =-0.72, P < 0.0001) and augmentation index ( r =-0.23, P = 0.004). Adjusted left ventricular mass index was inversely correlated with effective arterial elastance ( r =-0.35, P < 0.0001), but no correlation was observed between left ventricular mass index and augmentation index ( r = 0.04). Adjusted relative wall thickness correlated with increasing effective arterial elastance ( r = 0.32, P < 0.0001) and augmentation index ( r = 0.18, P = 0.02). Relative wall thickness ( r = 0.34, P < 0.0001), but not left ventricular mass index, correlated with age. Higher elastance and augmentation correlates with relatively smaller left ventricular cavity size but larger relative wall thickness. Age-related changes in left ventricular afterload may affect relative wall thickness more significantly than left ventricular mass index and may contribute to a particular change in left ventricular geometry with age.

Increased left ventricular (LV) mass is associated with increased cardiovascular morbidity and mortality. LV mass is commonly estimated from echocardiography according to the Penn or ASE (American Society of Echocardiography) conventions. No formal statistical test of agreement between these methods has been published. Therefore we compared M-mode echocardiographic LV mass estimates by the Penn and ASE methods in a normal adult population. M-mode echocardiographic tracings were obtained in 169 healthy volunteers and used to calculate LV mass using the Penn and ASE methods. Median values of the estimates were similar [Penn, 126 g (interquartile range 96–170 g); ASE, 129 g (105–164 g); P = 0.08] and were highly intercorrelated ( r = 0.98, P < 0.0001). However, the Bland–Altman analysis of agreement revealed significant inconsistencies between Penn and ASE LV mass values. The difference between Penn and ASE values was correlated significantly with heart size ( P < 0.0001), such that, for small hearts, the Penn LV mass was lower than the ASE LV mass; in contrast, for large hearts, Penn estimates were greater than ASE values. In the upper 5% of the LV mass distribution, the median value for the Penn LV mass index was 132.4 g/m 2 , compared with 116.5 g/m 2 for ASE values (2 P = 0.017). Thus the two most common methods of echocardiographic estimation of LV mass differ significantly at the upper and lower ends of the heart size distribution. These results have important implications for both cardiac research and clinical evaluation.

1. As mineralocorticoid and adrenocorticoid activity are both under the diurnal control of adrenocorticotropic hormone secretion, we aimed to evaluate whether the normal circadian rhythm of cortisol and aldosterone secretion was suppressed by inhaled corticosteroid therapy. 2. Ten normotensive patients with mild–moderate asthma, mean age 24.0 (S.D. 9.8) years and mean arterial pressure 90.7 (9.8) mmHg, were studied in a double-blind, randomized crossover design comparing placebo with fluticasone propionate, 1000 ; μ g administered twice daily at 08:00 ;h and 20:00 ;h. After 5 days of repeated dosing at steady state, measurements were made of plasma cortisol and aldosterone at midnight and 08:00 ;h. 3. With placebo there was a significant ( P < 0.05) difference between cortisol values at 08:00 ;h (588.6±83.8 ;nmol/l) and midnight (109.6±35.0 ;nmol/l), whereas after treatment with fluticasone propionate there was no significant difference between levels at 08:00 ;h (143.3±57.4 ;nmol/l) and midnight (64.3±22.3 ;nmol/l). For cortisol at 08:00 ;h there was also a significant ( P < 0.05) difference between placebo and fluticasone propionate. The same pattern was observed for aldosterone. Plasma aldosterone levels at 08:00 ;h after treatment with placebo (129.6±30.9 ;nmol/l) were significantly different ( P < 0.05) to those seen at midnight (40.4±6.2 ;nmol/l). After treatment with fluticasone propionate, there was no significant difference between levels at midnight (55.4±11.7 ;nmol/l) and 08:00 ;h (64.8±12.7 ;nmol/l). 4. These results show that inhaled corticosteroid therapy abolishes the circadian rhythm of aldosterone and cortisol secretion. This may have possible implications for patients taking inhaled corticosteroids in terms of the beneficial cardiac effects of suppressing early morning aldosterone.

1. The inhibitory effects of aspirin on platelet function in vitro have been shown to be both time (over 3 h) and concentration (1–10 μmol/l) dependent. 2. To determine if these effects occurred in vivo , four volunteers received intravenous infusions on four occasions, to give constant plasma aspirin concentrations of 0, 1, 2 and 4 μmol/l over 3 h. Infusions were performed at intervals of at least 2 weeks. 3. Before and during the infusions, blood was taken for assay of aspirin concentrations, and measurements of platelet aggregation in response to collagen, adenosine 5′-pyrophosphate and arachidonate. Thromboxane generation after stimulated platelet aggregation and whole-blood coagulation was also measured. 4. At each aspirin concentration, both platelet aggregation and thromboxane generation in response to collagen and arachidonate were inhibited progressively over the 3 h infusion period. Greatest inhibition was seen during the 4 μmol/l infusion, which produced maximal or near-maximal inhibition by the third hour. 5. Thromboxane generated during whole-blood coagulation was similarly inhibited in both a time- and concentration-dependent manner throughout all aspirin infusions. 6. The progressive nature of the inhibition of platelet function with these low aspirin concentrations may be due to either slow aspirin transport across the platelet membrane or delayed interaction with cyclo-oxygenase.

1. After a run-in period, six healthy, recumbent, water-loaded male subjects breathed through an inspiratory threshold load for 90 min. To correct for prolonged recumbency, a similar protocol was followed on a separate control day, but without an inspiratory load. 2. A negative intrathoracic pressure of at least 30 cmH 2 O was required to overcome the threshold load. 3. Urine was collected every 30 min and analysed for sodium concentration. 4. Plasma samples were collected every 30 min and analysed for atrial natriuretic peptide concentration. 5. The inspiratory load had no effect on urine volume, urinary sodium excretion or plasma atrial natriuretic peptide levels.

1. The aspirin concentrations previously reported to inhibit platelet aggregation in vitro (40–500 μmol/l) are much greater than those required in vivo in man (5 μmol/l). 2. Human platelet-rich plasma was incubated with buffer or various aspirin concentrations at 37°C for up to 4.5 h. Platelet aggregation and thromboxane generation were measured in response to collagen (0.4–6.3 μg/ml) and adenosine 5′-pyrophosphate (0.5–4 μmol/l). 3. The concentration of aspirin needed to inhibit platelet aggregation in response to a critical concentration of aggregating agent (lowest concentration to cause greater than 50% aggregation) was lower than that required for higher concentrations of aggregating agent. 4. With more prolonged incubation times with aspirin, lower concentrations of aspirin inhibited platelet aggregation. 5. Inhibition of platelet aggregation and thromboxane formation by 10 μmol/l aspirin was maximal by 90 min. There was progressive inhibition by 3 μmol/l aspirin during incubation for 270 min. By the end of this time there was also significant inhibition by 1 μmol/l aspirin. 6. The apparent discrepancy between inhibitory aspirin concentrations in vivo and those observed in vitro in previous studies appears to have been resolved by extending the incubation time of platelets with low aspirin concentrations, thus mimicking the conditions in vivo .

1. Blood pressure was controlled to the same extent whether propranolol or pindolol was given once or three times/day. 2. The anti-hypertensive action of β-receptor-blocking drugs persisted for 36–48 h when administration ceased.

1. The antidiuretic effects of oral therapy with benzothiadiazine and phthalimidine diuretics have been studied in seven patients with diabetes insipidus of pituitary origin. 2. The immediate and chronic phases of diuretic-induced antidiuresis differ in their characteristics. Immediate antidiuresis is closely related both to the saluretic action of the diuretics and to the level of fluid turnover prevailing before their administration. By contrast, the findings in four patients maintained on polythiazide or clorexolone for at least 4 years show that antidiuresis persists at a time when saluretic effects have ceased and there is no longer any detectable disturbance in body sodium metabolism. A change in mechanism of antidiuresis appears to occur with the passage of time. 3. There is a parallelism between the characteristics of the chronic antidiuretic and antihypertensive actions of diuretics. The mechanism of both effects remains obscure. 4. Despite uncertainty as to mechanism, diuretic therapy offers a reliable means of treating diabetes insipidus on a long-term basis. The only complication encountered was symptomless hypokalaemia which developed despite regular use of supplemental oral potassium. Combined administration of triamterene or amiloride with either polythiazide or clorexolone has been used with success as an alternative regime.