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Protein kinase C (PKC)-beta and other PKC isozymes have been implicated in the loss of endothelial barrier function in diabetic microangiopathy. The effects of a PKC-beta-specific inhibitor, LY379196, on hyperpermeability responses to high-glucose, angiotensin II, alpha-thrombin and endothelin-1 were evaluated using an in vitro model of human pulmonary artery endothelial cell monolayers. LY379196 attenuated the increase in transendothelial albumin flux induced by glucose 40 mM (e.g. 411+/-160% [high-glucose] vs. 167+37% [high-glucose+LY379196], P

Accepted for publication 26 June 2003 . . . . . . . . . . . . . . . . . . . . . . . R educing the incidence and slowing the progression of diabetes related microvascular complications remains a difficult challenge. In the case of diabetic retinopathy, tight glucose and blood pressure control are difficult to achieve and maintain in practice, yet still only provide partial protection against sight threatening complications in the lifetime of a person with diabetes. More than 250 000 patients every year develop sight threatening diabetic retinopathy in the United States alone, often despite good compliance with antidiabetic and antihypertensive treatments. Furthermore, the morbidity and healthcare costs associated with diabetic retinopathy are likely to escalate as the prevalence of type 2 diabetes increases and as patients with diabetes live longer. For example, the effectiveness of cholesterol lowering drugs and angiotensin converting enzyme (ACE) inhibitors in preventing macrovascular (mostly coronary heart disease) deaths, as well as the wider use of renal replacement therapy, means that patients with diabetes related complications are more likely to survive to experience the distress of failing visual acuity as a result of retinopathy. Thus, as well as improving systems for eye screening and detection of retinopathy, new therapeutic strategies are urgently needed as an adjunct to existing treatments—glucose and blood pressure reduction, photocoagulation and vitreous surgical techniques—to improve visual outcomes for patients with diabetes.

To compare the metabolic and vascular effects of two sulphonylureas (SU), gliclazide (specific for the pancreatic [SUR1] receptor) and glimepiride (a nonspecific agent that also binds to vascular and cardiac [SUR2] receptors), during chronic administration in metformin-treated patients with Type 2 diabetes (T2DM).A randomized, double-blind, crossover study of gliclazide 80 mg BID and glimepiride 2 mg OD, each for 4 weeks as add-on therapy to metformin, with a 4-week washout period. Patients attended four study mornings after first dose and 4 weeks' SU treatment for measurements of arterial distensibility (Ax), pressor responsiveness to i.v. angiotensin II (ANGII), and cutaneous microvascular vasodilator responses to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP).Glycaemic responses were similar (e.g. serum fructosamine was 315 vs 329 micro mol l-1 after 4 weeks), and there was no change in augmentation index during treatment with either SU (9.1 vs 9.8 mmHg after 4 weeks [95% confidence interval -8.1, 10.5]). Similarly, there were no differences between treatments in pressor responsiveness (e.g. PD10[dose of agonist required to increase mean BP by 10 mmHg] for ANGII was 1.37 vs 1.68 ng kg-1 min-1[-4.3, 6.9]) or cutaneous microvascular vasodilator responses (peak ACh response 68 +/- 36 vs 63 +/- 34 perfusion units [-82.7, 79.1]).There is no evidence that SUR1-specific and nonspecific SUs have differential effects on arterial distensibility, endothelial function or vasodilator mechanisms in metformin-treated patients with T2DM.

Microalbuminuria (defined as an albumin-creatinine ratio of 10-25 mg/mmol on the first-morning urine sample, or an albumin excretion rate of 20-200 microg/min on a timed collection) is present in 20-30% of all patients with type 2 diabetes, and is especially common in those with hypertension, endothelial dysfunction and other features of insulin resistance. Although microalbuminuria is predictive of worsening microvascular disease in the kidney (5-10% per year progress to overt diabetic nephropathy), an increased albumin excretion rate (AER) reflects a generalized abnormality of vascular function and is associated with 2-4-fold increases in cardiovascular and all-cause mortality. The extent to which microalbuminuria is a risk factor independent of other variables in type 2 diabetes, e.g. blood pressure and smoking, has been highlighted by recent cohort studies, e.g. the Heart Outcome Prevention Evaluation study and the Wisconsin Epidemiological Study of Diabetic Retinopathy. In the former study, for example, microalbuminuria at baseline increased the adjusted relative risks (RR) of a major cardiovascular event (RR 1.83), all-cause death (RR 2.09) and hospitalization for heart failure (RR 3.23) in both diabetic and non-diabetic subjects. These studies also highlighted that AER is a continuous risk factor, and that levels of AER below the arbitrary threshold for defining microalbuminuria are associated with relatively increased cardiovascular risk. Similarly, microalbuminuria affects 10-15% of middle-aged non-diabetics and is associated with coronary, peripheral and cerebral vascular complications. Detection of microalbuminuria, especially in type 2 diabetes, signifies the need to intensify blood pressure control as part of a multiple risk factor intervention strategy in a high-risk group. As hypertensive patients with type 2 diabetes are frequently treated by more than one antihypertensive agent, ACE inhibitors and low-dose diuretics are preferably recommended in order to provide sufficient blood pressure control and target organ protection.

Aims To evaluate the short-term and 1-year outcomes of an intensive very-lowcalorie diet (VLCD) on metabolic and cardiovascular variables in obese patients with Type 2 diabetes (T2DM) and symptomatic hyperglycaemia despite combination oral anti-diabetic therapy ± insulin, and to assess patient acceptability and the feasibility of administering VLCD treatment to this subgroup of patients in a routine practice setting. Methods Forty obese patients with T2DM (22 M, mean age 52 years, body mass index (BMI) 40 kg/m 2 , duration of T2DM 6.1 years) and symptomatic hyperglycaemia despite combination oral therapy ( n = 26) or insulin + metformin ( n = 14) received 8 weeks of VLCD therapy (750 kcal/day) followed by standard diet and exercise advice at 2–3-month intervals up to 1 year. Insulin was discontinued at the start of the VLCD, and anti-diabetic therapy was adjusted individually throughout the study, including (re)commencement of insulin as required. Results Immediate improvements in symptoms and early weight loss reinforced good compliance and patient satisfaction. After 8 weeks of VLCD, body weight and BMI had fallen significantly: 119 ± 19–107 ± 18 kg and 40.6–36.6 kg/m 2 , respectively, with favourable reductions in serum total cholesterol (5.9–4.9 m M ), blood pressure (10/6 mmHg) and fructosamine (386 ± 73–346 ± 49 µ M ) (equates to an HbA 1c reduction of approximately 1%). Sustained improvements were evident after 1 year, with minimal weight regain, e.g. mean body weight 109 ± 18 kg and BMI 37 ± 4 kg/m 2 . Glycaemic control tended to deteriorate after 1 year. Conclusions The absence of a control group is a major limitation, but the results indicate that 8 weeks of VLCD treatment may be effective and well tolerated in symptomatic obese patients with T2DM in secondary failure, producing sustained cardiovascular and metabolic improvements after 1 year. VLCD therapy is a treatment option that deserves greater consideration in this difficult-to-treat patient population. Diabet. Med. 20, 319–324 (2003)

We previously reported that proinflammatory mediator bradykinin (BK) induces cyclooxygenase (COX)-2 expression in human airway smooth muscle (HASM), but the mechanism is unknown in any biological system. Here, we studied the role of specific protein kinase C (PKC) isozyme(s) in COX-2 expression. Among the eight PKC isozymes present in HASM cells, the Ca2+-independent PKC-delta and -epsilon and the Ca2+-dependent PKC-alpha and -betaI were translocated to the nucleus upon BK stimulation. BK-induced COX-2 expression and prostaglandin E2 (PGE2) accumulation were mimicked by the direct PKC activator phorbol 12-myristate 13-acetate (PMA) and inhibited by the broad spectrum PKC inhibitor bisindolylmaleimide I. However, the selective Ca2+-dependent PKC isozyme inhibitor Go 6976 had no effect. Furthermore, the membrane-permeable calcium chelator BAPTA-AM had no effect on BK-induced COX-2 expression and COX activity despite its inhibition of PGE2 accumulation, suggesting the involvement of Ca2+-independent PKC isozymes. Rottlerin, a PKC-delta inhibitor, also had no effect, likely implicating PKC-epsilon. BK-stimulated transcriptional activation of a COX-2 promoter reporter construct was enhanced by overexpression of wild-type PKC-epsilon and abolished by a dominant negative PKC-epsilon, but it was not affected by wild-type or dominant negative PKC-alpha or -delta. Collectively, our results demonstrate that PKC-e mediates BK-induced COX-2 expression in HASM cells.

Diabetes is associated with considerably higher risks of developing peripheral arterial disease (PAD) which, when it occurs, is more severe and progresses more rapidly than in nondiabetics. Early detection of PAD in the diabetic patient is therefore important, but may be complicated by the presence of neuropathy and calcification of the arteries such that ischaemic symptoms are not felt by the patient and ankle pressures are not reduced. Toe pressures are an alternative diagnostic tool in these patients. Good glycaemic control, while an essential part of diabetes management, does not appear to bring more than modest benefits in preventing the peripheral vascular complications of diabetes. Therefore, attention to other risk factors is needed. Treatment with the phosphodiesterase III inhibitor, cilostazol, has been shown to improve walking distances significantly in diabetes patients with intermittent claudication and also appears to improve plasma lipid profiles. Further, cilostazol has an antiplatelet action, which may prove to be of benefit in diabetes because hyperglycaemia is associated with increased platelet aggregability. Revascularization in diabetes patients with critical leg ischaemia is complex and associated with poorer outcomes than in non-diabetes patients. While surgical revascularization has better patency rates, in patients at high risk of surgical complications, percutaneous transluminal angioplasty may be a better option.

Intermittent claudication (IC) is a common, debilitating symptom of atherosclerotic peripheral arterial disease. There are two therapeutic objectives in patients with IC: relief of symptoms and secondary prevention of acute thrombotic complications. Among patients with Fontaine stage II disease, surgical revascularization for symptom relief is reserved for those in whom exercise/lifestyle modification and medical therapy has failed. To improve exercise tolerance in IC requires favourable alteration in the oxygen supply/demand relationship in the lower limb. Following the largest ever clinical trials programme in patients with IC, cilostazol, a phosophodiesterase III inhibitor, has been licensed for symptom relief in the UK. In double-blind, randomized, placebo-controlled trials involving over 2000 patients, cilostazol 100 mg b.d. produced significant and sustained improvements in pain-free and maximal walking distances as well as improved subjective assessments of quality of life. In particular, comparative studies with pentoxifylline (oxpentifylline) showed that cilostazol had significantly greater effects on functional outcome and exhibited good patient tolerance.

Objectives: the tissue renin-angiotensin system (RAS), which plays an important role in vascular structure and function, is regulated in part by an insertion-deletion polymorphism of the angiotensin converting enzyme (ACE) gene. We hypothesised that ACE genotype might affect rate of AAA expansion via modulating long-term structural changes associated with RAS activation. Methods: fifty-eight patients (50 M, mean age 70 years, mean initial aneurysm size 4.3 cm) with current or previous AAA and serial (>3) annual ultrasound measurements of antero-posterior AAA size provided a sample of leucocyte DNA for ACE genotyping. AAA expansion rate (cm per year) for individual subjects was calculated by linear regression. Results: median AAA expansion rate was 0.28 cm/year (range 0–1.8 cm/year), and the genotype distribution included DD ( n =14), DI ( n =29) and II ( n =15). Corresponding median AAA expansion rates for each of the three genetic subgroups were 0.22, 0.32 and 0.30 cm/year, respectively ( p =0.6, nonparametric). Conclusions: the wide inter-individual variability in AAA expansion rate is likely to reflect complex genetic and environmental interactions, but the lack of any relationship with ACE genotype suggests that differences in vascular ACE activity in aortic tissue are not major determinants of the variability in rate of AAA dilatation.

Protein kinase C (PKC) is a family of multifunctional isozymes that plays an important role in the regulation of intracellular insulin signal transduction in various insulin-sensitive tissues. This article highlights current understanding on the mechanism of PKC-induced insulin resistance in skeletal muscle, a major target site for insulin-mediated glucose disposal. Initial, apparently contradictory findings on the role of PKC on insulin action can be explained on the basis that certain PKC isoforms (e.g., -zeta and -lambda) have been identified as downstream targets of PI3-kinase activation, while DAG-sensitive PKCs (e.g., -theta; and -epsilon) have negative regulatory effects on insulin signaling. Hence, pharmacological therapies targeting specific PKC isoforms could enhance insulin action and improve glycemic control in patients with impaired glucose tolerance and overt diabetes.

Peripheral and pulmonary oedema has emerged as the most common drug-related side effect of rosiglitazone in clinical practice, but the underlying mechanisms are not clear. Fluid retention and changes in vascular tone could contribute to oedema formation, but the interpretation of clinical and in vivo studies is particularly difficult and the direct effects of thiazolidinediones on endothelial barrier function have not been previously reported.Human pulmonary artery endothelial cells were seeded and grown on 0.4 microm collagen-coated filters to form a tight monolayer (transendothelial electrical resistance 9-11 ohms.cm(-2) after 2-3 days). Transendothelial albumin flux (expressed as the percentage clearance of albumin relative to control) was measured using Evans blue-labelled albumin after exposure to rosiglitazone 1-100 micromol/l for 1 h to 48 h, and after removal of drug from the monolayer.Incubation of pulmonary artery endothelial cells with rosiglitazone for 4 h produced immediate concentration-dependent increases in transendothelial albumin flux: e.g., relative to control (100%), 113%+/-13% (1 micromol/l), 215%+/-37% (10 micromol/l, p=0.01) and 461%+/-96% (100 micromol/l, p=0.002) (n=12). There was no effect after 1 h. The acute hyperpermeability response to rosiglitazone, maximal after 4 h, was fully reversible after washing the monolayer. After incubation for 24 to 48 h the effect of rosiglitazone on pulmonary endothelial permeability tended to subside: e.g., 210%+/-59% (24 h) for rosiglitazone 100 micromol/l (p=0.06).Exposure to high-therapeutic concentrations of rosiglitazone causes a reversible fourfold increase in pulmonary endothelial permeability which could be clinically relevant especially at higher doses and at times of peak plasma drug concentration.

Malignant insulinomas are very rare endocrine tumours with a variable clinical course. We describe a 51-year-old man who had two large insulinomas resected from the body of the pancreas and 19 years later, having again become symptomatic, was found to have hepatic metastases. Medical treatment with diazoxide and octreotide failed to control his symptoms, but repeated hepatic embolization effected both symptomatic and biochemical improvements for a further 5 years. When symptoms recurred but further embolization failed to control his symptoms the hepatic metastases were treated by outpatient percutaneous radio-frequency ablation. He remains symptom-free 18 months later and levels of insulin and pro-insulin have nearly normalized. The survival, with liver metastases, for 27 years in a man with a malignant insulinoma has not been described previously. Malignant insulinoma may follow a rather indolent course and symptoms respond well to locally destructive therapies. Hepatic embolization is less traumatic than hepatic lobe resection and radio-frequency ablation offers an alternative if vascular access to the tumour is no longer possible.

Protein kinase C (PKC) is a family of multifunctional isoenzymes, activated by diacylglycerols (DAGs), which play a central role in signal transduction and intracellular crosstalk by phosphorylating at serine/threonine residues an array of substrates, including cell-surface receptors, enzymes, contractile proteins, transcription factors and other kinases. Individual isozymes vary in their pattern of tissue and subcellular distribution, function and Ca2+/phospholipid cofactor requirements, and in diabetes there is widespread activation of the DAG-PKC pathway in metabolic, cardiovascular and renal tissues. In liver, muscle and adipose tissue, PKC isozymes have been implicated both as mediators and inhibitors of insulin action. Activation of DAG-sensitive PKC isoforms, such as PKC-theta and PKC-epsilon, down-regulates insulin receptor signalling and could be an important biochemical mechanism linking dysregulated lipid metabolism and insulin resistance in muscle. On the other hand, atypical PKC isozymes, such as PKC-zeta and PKC-lambda, have been identified as downstream targets of PI-3-kinase involved in insulin-stimulated glucose uptake, especially in adipocytes. Glucose-induced de novo synthesis of (palmitate-rich) DAG and sustained isozyme-selective PKC activation (especially but not exclusively PKC-beta) has been strongly implicated in the pathogenesis of diabetic microangiopathy and macroangiopathy through a host of undesirable effects on endothelial function, VSM contractility and growth, angiogenesis, gene transcription (in part by MAP-kinase activation) and vascular permeability. Interventions that increase DAG metabolism (e. g. vitamin E) and/or inhibit PKC isozymes (e. g. the beta-selective inhibitor LY333531) ameliorate the biochemical and functional consequences of DAG-PKC activation in experimental diabetes, for example improving retinal blood flow and albuminuria in parallel with reductions in membrane-associated PKC isozyme activities. Thus, a greater understanding of the functional diversity and pathophysiological regulation of PKC isozymes is likely to have important clinical and therapeutic benefits.

The role of ambulatory blood pressure (ABP) monitoring in the assessment of mild/borderline hypertension (BHT) is unclear. The aim of this study was to test the hypothesis that measurement of ABP in borderline hypertensives differentiates patients with true mild hypertension from those with isolated clinic hypertension (raised office BP but normal ABP) and that a raised ABP identifies a subgroup who are more likely to progress to and require treatment over 1 year. Consecutive untreated patients with BHT (n = 127, 44 +/- 13 years, 45% male) were divided into two groups according to awake ABP: Group 1 (normal ABPor = 136/86, n = 48), and Group 2 (abnormal ABP136/86, n = 79). Left ventricular mass index (LVMI) was greater (116 +/- 30 vs 101 +/- 25 g/m2, p0.01) and the proportion of patients with an increased LVMI was significantly higher (34% vs 17%, p = 0.05) in Group 2. During 1 year of follow-up, significantly more patients in Group 2 (34%) required antihypertensive treatment compared with Group 1 (8%, p = 0.01). ABP monitoring usefully discriminates between patients with true BHT and those with isolated clinic hypertension. An elevated awake ABP on initial assessment is associated with a higher LVMI and a greater likelihood of progression to moderate hypertension requiring pharmacological treatment.

Angiotensin II (ANGII) increases insulin sensitivity in diabetic and non-diabetic subjects, even at subpressor doses, and because there is 'crosstalk' between ANGII and insulin-signaling pathways the underlying mechanism may not be due solely to changes in regional blood flow. A series of experimental studies was undertaken to evaluate the effects of ANGII on glucose and lipid metabolism in vivo and in vitro. Groups of fructose-fed, insulin-resistant Sprague-Dawley (SD) rats were pre-treated with 0.3 mg/kg per day of the AT(1)-receptor antagonist L-158 809 (n=16), or vehicle (n=16), by oral gavage. This was prior to an oral glucose tolerance test (day 5) and measurement of the effects of ANGII infusion (20 ng/kg per min i.v. for 3 h) on whole-body insulin sensitivity using the insulin suppression test (day 7). The effect of ANGII infusion on total triglyceride secretion rate (TGSR) was evaluated in normal SD rats pretreated for 7 days with L-158 809 (n=12) or vehicle (n=12). AT(1)- and AT(2)- receptor mRNA expression and [(3)H]2-deoxyglucose uptake were assessed in cultured L6 myoblasts. Short-term treatment with L-158 809 had no effect on glucose tolerance or fasting triglyceride levels in fructose-fed rats. ANGII infusion had no effect on insulin sensitivity in fructose-fed rats pretreated with vehicle (steady-state plasma glucose (SSPG) values 8.1+/-1.6 vs 8. 4+/-0.4 mmol/l), but pretreatment with L-158 809 resulted in ANGII having a modest insulin antagonist effect in this insulin-resistant model (SSPG values 9.6+/-0.3 vs 7.1+/-0.6, P

The most common cause of leg swelling is oedema, but expansion of all or part of a limb may be due to an increase in any tissue component (muscle, fat, blood, etc). A correct diagnosis requires consideration of whether the swelling is acute or chronic, symmetrical or asymmetrical, localised or generalised, and congenital or acquired. Chronic swelling, particularly if asymmetrical, is usually a sign of chronic oedema arising from venous or lymphatic disease, whereas symmetrical lower limb swelling suggests a systemic or more central cause of oedema, such as heart failure or nephrotic syndrome. Oedema develops when the rate of capillary filtration (lymph formation) exceeds lymphatic drainage, either because of increased capillary filtration, inadequate lymphatic flow, or both. Extracellular fluid volume is controlled prinicpally by the lymphatic system, which normally compensates for increases in capillary filtration. Most oedemas arise because filtration overwhelms the lymph drainage system. Increased capillary filtration may occur because of raised venous pressure, hypoalbuminaemia, or increased capillary permeability due to local inflammation. The two main causes of a swollen lower limb are deep vein thrombosis and lymphoedema (a failure of the lymph drainage system). This article concentrates on deep vein thrombosis and next week's article on lymphoedema. #### Causes of swelling of lower limb ##### Acute ##### Chronic ###### Congenital vascular abnormalities ###### Venous disease ###### Lymphoedema ###### Other Thrombosis usually develops as a result of venous stasis or slow flowing blood around venous valve sinuses; extension of the primary thrombus occurs within or between the deep and superficial veins of the leg and the propagating clot causes venous obstruction, damage …

Adults with diabetes have an annual mortality of about 5.4% (double the rate for non-diabetic adults), and their life expectancy is decreased on average by 5-10 years. Although the increased death rate is mainly due to cardiovascular disease, deaths from non-cardiovascular causes are also increased. A diagnosis of diabetes immediately increases the risk of developing various clinical complications that are largely irreversible and due to microvascular or macrovascular disease. Duration of diabetes is an important factor in the pathogenesis of complications, but other risk factors—for example, hypertension, cigarette smoking, and hypercholesterolaemia—interact with diabetes to affect the clinical course of microangiopathy and macroangiopathy. View this table: Vascular complications of diabetes View this table: Risk of morbidity associated with all types of diabetes mellitus A continuous relation exists between glycaemic control and the incidence and progression of microvascular complications. Hypertension and smoking also have an adverse effect on microvascular outcomes. In the diabetes control and complications trial—a landmark study in type 1 diabetes—the number of clinically important microvascular endpoints was reduced by 34-76% in patients allocated to intensive insulin (that is, a 10% mean reduction in glycated haemoglobin (HbA1c) concentration from 8.0% to 7.2%). However, these patients also had more hypoglycaemic episodes. Similarly, in the UK prospective diabetes study of patients with type 2 diabetes, an intensive glucose control policy that lowered glycated haemoglobin concentrations by an average of 0.9% compared with conventional treatment (median HbA1c 7.0% v 7.9%) resulted in a 25% reduction in the overall microvascular complication rate. It was estimated that for every 1% reduction in HbA1c concentration there is a 35% reduction in microvascular disease. Relation between glycaemic control (HbA1c) and risk of progression of microvascular complications (retinopathy) and severe hypoglycaemia in patients with type 1 diabetes. Data from the diabetes control and complications trial. Dotted lines represent 95% confidence …

Recent international guidelines on the detection, clinical assessment and management of patients with hypertension have highlighted a number of themes that should be incorporated into routine clinical practice. First, although antihypertensive therapy is having a major impact on reducing the incidence of coronary heart disease, cerebrovascular disease and heart failure, community surveys show that most hypertensive patients remain untreated or have suboptimal blood pressure control. Second, the guidelines have emphasised the importance of making an overall assessment of individual patients to gauge their absolute risk of a cardiovascular event; risk factors include not only blood pressure but also target organ damage, the presence of coexisting symptomatic vascular disease and the number of associated cardiovascular risk factors. Patients at the highest risk, especially those with diabetes, the elderly and patients with target organ damage, merit vigorous antihypertensive therapy, and such patients often require treatment with more than one drug to achieve target levels of blood pressure (< 135/80 mm Hg). An additional important theme in recent guidelines has been a move towards using lower dosages and therapies that provide 24-hour blood pressure control with once-daily administration. Since diuretics have been reaffirmed as evidence-based first-line therapy in a broad spectrum of patients with hypertension, especially the elderly, a new lower dosage sustained release formulation of indapamide has been developed (indapamide SR 1.5 mg). Recent multicentre European clinical trials have defined the efficacy and tolerability of indapamide SR 1.5 mg, both relative to other antihypertensive drugs and in key subgroups of patients. Indapamide SR 1.5 mg has an antihypertensive effect, maintained throughout the 24-hour administration interval, equivalent to that of immediate release indapamide 2.5 mg, but the new formulation has even less effect on circulating K+ levels. Indapamide SR 1.5 mg is at least as effective as amlodipine or hydrochlorothiazide. In patients with left ventricular hypertrophy (LVH), a comparative study of indapamide SR 1.5 mg and enalapril (the LIVE study) used a rigorous unique study design with blinded reading of echocardiograms to show that after 1 year the ACE inhibitor had no significant effect on LVH regression, whereas indapamide SR 1.5 mg produced significant reductions in left ventricular mass index. Diuretic-based therapy for hypertension has been reaffirmed in international guidelines as effective first-line therapy, especially in the elderly and patients with LVH. Indapamide SR 1.5 mg shows an improved efficacy-tolerability profile, with impressive 24-hour effects on blood pressure, important ancillary properties with regard to LVH and cardiovascular protection.

Protein kinase C (PKC) is implicated in the regulation of smooth muscle contractility and growth. We have previously described the pattern of isoform expression of PKC in canine airway smooth muscle. This study identified the isoforms present in human cultured airway smooth muscle cells and also addressed the question of whether mitogenesis in these cells is associated with changes in a specific isoform, PKC-zeta. Western blot analysis revealed the presence of PKC-alpha, -betaI, and -betaII of the conventional group; PKC-delta, -theta, -epsilon, and -eta of the novel group; and PKC-zeta, -mu, and -iota of the atypical group. There was a significant increase in density of the Western blot for PKC-zeta in cells proliferating in response to 10% fetal bovine serum (FBS) to 372 +/- 115% of control values (P0.05; n = 3 patients) in the cytosolic fraction. Platelet-derived growth factor (PDGF) produced increases in PKC-zeta in both the cytosolic and membrane fractions to 210 +/- 49 and 443 +/- 227%, respectively, of control values (P0.05; n = 4 patients). There was no change in expression of PKC-alpha, -betaI, -betaII, -theta, -epsilon, -eta, -delta, or -iota in response to the same stimuli. PGE2 (1 microM) added to the cells 30 min before PDGF reduced incorporation of [3H]thymidine from 5,580 +/- 633 (SE) to 3, 980 +/- 126 dpm (P0.05; n = 3 patients) and, in addition, reduced expression of PKC-zeta in the membrane fraction as determined by Western blotting from 266 +/- 66 to 110 +/- 4% of control values (P0.05; n = 3 patients). PKC-zeta activity in stimulated cells (10% FBS), as assessed by immunoprecipitation and phosphorylation of glycogen synthase peptide, was approximately 3-fold greater than that in unstimulated cells, and the amount of PKC-zeta protein correlated with isoenzyme activity (r2 = 0.91; P0.02; n = 4 patients). In conclusion, this study 1) provides the first description of which isoforms of PKC are present in human cultured airway smooth muscle cells and 2) shows that proliferation of these cells is associated with upregulation of PKC-zeta. Whether activation of PKC-zeta is a primary or secondary event in airway smooth muscle cell proliferation remains to be determined.

Aims To assess the duration and consistency of the pharmacological activity of the dihydropyridine calcium antagonist drug, lacidipine. Methods Eight healthy normotensive young males participated in a double-blind randomised crossover comparison of single and multiple doses (for 2 weeks) of lacidipine and placebo. The calcium antagonist effects were quantified at 2, 6 and 24 h post dose by the extent of the attenuation of the pressor responses to the intravenous administration of the vasoconstrictors angiotensin II and noradrenaline. Results After 2 weeks of treatment, lacidipine consistently and significantly attenuated the pressor responses to both agents at 2 h post dose. At 6 and 24 h post dose there was a significant and progressive decline in the effectiveness of lacidipine in attenuating the pressor responses and for the response to angiotensin II there was no statistically significant effect at either 6 or 24 h post dose. Conclusions These results indicate that there is an obvious ‘peak’ in the pharmacological activity of lacidipine at about 2 h post dose and that this activity is not fully and consistently maintained throughout 24 h.

Sulphonylureas have remained the mainstay of oral therapy for type 2 (non-insulin-dependent) diabetes mellitus (NIDDM). They stimulate insulin release from pancreatic beta cells. Pharmacokinetic differences between the various sulphonylureas are of clinical importance in terms of the time to onset of action, timing of drug administration in relation to food intake, magnitude and duration of the glucose-lowering effect and the risk of serious hypoglycaemia. Recent studies with improved analytical sensitivity have shown that the elimination half-life of glibenclamide is longer than previously thought and that 2 metabolites of glibenclamide have significant hypoglycaemic activity. Furthermore, single dose studies in healthy volunteers using an integrated pharmacokinetic-pharmacodynamic model have identified clear concentration-effect relationships for both glibenclamide and its metabolites after oral and intravenous administration. Under multiple dose conditions, kinetic-dynamic relations have been identified with shorter-acting drugs in dosages that give discontinuous sulphonylurea exposure. However, at continuous exposure, i.e. sustained 24-hour therapeutic concentrations in plasma, there is evidence indicating the development of tolerance, which may be caused by downregulation of beta cell sensitivity. As more sophisticated concentration-effect studies appear, it has become evident that currently recommended maximum daily doses of many sulphonylureas are too high.

1. Resistance to insulin-mediated glucose transport and metabolism has been identified as a primary mechanism in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) and as a target for drug development. The aetiology of insulin resistance is likely to be multifactorial, but the present review focuses on candidate post-receptor mechanisms of insulin resistance, particularly protein kinase C (PKC), and the metabolic and genetic significance of beta3-adrenoceptors (beta3-AR) in adipose tissue. 2. Multiple lines of evidence suggest that isoform-selective activation of PKC phosphorylates and down-regulates one or more substrates involved in glucose transport and metabolism (e.g. glycogen synthase and the insulin receptor) and recent studies have shown increased expression of calcium-independent isozymes (PKC-epsilon and PKC-theta) in the membrane fraction of skeletal muscle in fructose- and fat-fed rat models of insulin resistance. In addition, there is separate evidence that glucose-induced PKC activation plays an important role in the micro- and macrovascular complications of diabetes. 3. New pharmacological approaches to NIDDM and obesity have focused on insulin-sensitizing agents (e.g. troglitazone), beta3-AR agonists, anti-lipolytic drugs (e.g. the adenosine A1 receptor agonist GR79236) and selective inhibitors of PKC isoforms (e.g. the inhibitor of PKC-beta LY333531). Experimental studies with GR79236 show that this drug ameliorates the hypertriglyceridaemia induced by fructose feeding and that the reduction in fatty acid levels is associated with secondary improvements in glucose tolerance. 4. Recent insights into the pathogenesis of NIDDM and its associated complications have been used to develop a range of new therapeutic agents that are currently showing promise in clinical and preclinical development.

SUMMARY 1. The recognition of the role of insulin resistance in disease states and the recent development of new drugs that modify insulin-dependent metabolism has led to increased use of the euglycaemic hyperinsulinaemic clamp to measure in vivo insulin sensitivity, but several key aspects of the technique are poorly documented in the literature. 2. We have evaluated the reproducibility and intersubject variation of measurements of insulin sensitivity in groups of insulin-sensitive and insulin-resistant subjects and assessed the effects of hand warming on haemodynamic and metabolic responses. 3. Subjects participated in one of two protocols: (i) 18 healthy male volunteers and 18 patients with hypertension and glucose intolerance were clamped on two occasions, 1 week apart with measurements of insulin sensitivity (M) derived after 120 and 180 min of hyperinsulinaemia; and (ii) six healthy volunteers were clamped on one occasion with simultaneous sampling of antecubital and ‘arterialized’ (dorsal hand) venous blood for comparison of plasma glucose concentrations and oxygen saturation and a further six volunteers were clamped on two occasions with and without the use of hand warming. 4. Measurements of M derived after 120 min (M120) and 180 min (M180) of hyperinsulinaemia were reproducible: the coefficients of repeatability (mg/kg per min) of M120 and M180 were 1.0 and 0.9 for volunteers and 1.0 and 1.0 for the patient group, respectively. The intersubject variation in insulin stimulus was high: coefficients of variation for M180 were 22% for volunteers compared with 38% for the patient group. In volunteers compared with the patient group, hand warming significantly increased venous oxygen saturations (95 ± 2 vs 79 ± 18%, respectively) and glucose concentrations (5.2 ± 0.2 vs 4.5 ± 0.4 mmol/L, respectively) and measurements of M were significantly higher using arterialized compared with antecubital venous blood. However, local hand warming was associated with systemic vasodilatation: blood pressure decreased (e.g. 6mmHg diastolic; P < 0.05) with a compensatory increase in heart rate (8 b.p.m.). 5. In conclusion, clamps of 120 and 180 min duration yielded measurements of M that were reproducible. The technique is much more robust when used in the context of a crossover design because of the significant (20–40%) intersubject variation in M, even among apparently homogeneous male volunteers. Hand warming effectively arterializes venous blood and gives significantly higher M values, but induces systemic vasodilatation, which may confound measurements of M.

There are large ethnic differences in both the prevalence of diabetes and the pattern of clinical complications, especially diabetic nephropathy and coronary heart disease. The aim of this study was to compare ethnic differences in the prevalence of two important risk factors, hypertension and proteinuria, among 1845 consecutive patients with non-insulin-dependent diabetes mellitus (NIDDM) undergoing annual complications assessment. Using a well-established database and systematic methods of data collection, information on clinical, demographic and laboratory variables was compared among seven ethnic groups: Anglo-Celtic (n = 896), Italian (n = 246), Greek (n = 209), Arabic (n = 147), Chinese (n = 131), Indian (n = 115) and Aborigine (n = 101). The odds ratios (OR) for developing hypertension (relative to Anglo-Celtic subjects) were lower in all ethnic groups, especially Arabs (OR = 0.4), Indians (OR = 0.4) and Aborigines (OR = 0.6). By contrast, the odds ratios for proteinuria (relative to Anglo-Celts) were consistently higher in all ethnic groups, e.g. Arabs (OR = 3.0) and Aborigines (OR = 3.1), even after correction for age, duration of diabetes and glycaemic control. Thus, relative to Anglo-Celtic patients, other ethic groups are less likely to have hypertension and more likely to have proteinuria. These findings may have important implications for understanding the ethnic differences in onset and progression of diabetic nephropathy.

Nephropathy affects about one third of diabetic patients and its onset can be predicted almost a decade in advance by detecting small quantities of albumin in the urine (microalbuminuria). Thus, detection of proteinuria or microalbuminuria in diabetic patients carries important implications and merits intervention. Strategies for delaying the relentless progression of microalbuminuria to diabetic nephropathy and ultimately end-stage renal failure are focused on improving glycemic control and reducing blood pressure. Studies with beta-blockers, calcium antagonists, diuretics, and angiotensin-converting enzyme (ACE) inhibitors in hypertensive diabetics with microalbuminuria have shown a significant reduction in urinary albumin excretion rates (AER), with effective lowering of blood pressure. In a crossover study, we compared the effects of captopril versus indapamide as monotherapy for 12 weeks on AER and blood pressure in 31 diabetic patients with established microalbuminuria. The 2 drugs were equally effective in reducing AER (average reduction 30-40%) and had comparable antihypertensive effects.

1. The effects of 4 week treatment with rilmenidine or atenolol on tests of mental stress, dynamic exercise, autonomic function and psychometric tests were evaluated in a randomized, double-blind, placebo-controlled, cross-over study. 2. After a 4 week placebo run-in, 12 patients with essential hypertension (blood pressure [BP] 160/95 +/- 15/7 mmHg) received rilmenidine 1-2 mg day-1, and atenolol 50-100 mg day-1, each for 4 weeks, with a 4 week placebo wash-out between drug treatments. 3. Both agents produced a comparable reduction in supine and erect BP. During the mental arithmetic test, BP and heart rate (HR) responses were similar for rilmenidine and atenolol. 4. During bicycle exercise, the increase in HR was significantly greater after rilmenidine (+50 vs 41 beats min-1, P = 0.04). During recovery, the areas under the curve for diastolic BP (46,450 vs 51,400 mmHg s, P = 0.02) and HR (49,445 vs 63,597 beats min-1 s, P = 0.001) were significantly less with atenolol than rilmenidine. 5. Neither rilmenidine nor atenolol affected mental performance as judged by arithmetic and psychomotor tests. Physiological responses to autonomic function tests (deep breathing, facial immersion, isometric handgrip and cold pressor) were preserved with both drugs. The standing to lying ratio was higher on atenolol (P = 0.01) and Valsalva ratio was higher on rilmenidine (P = 0.03). 6. In conclusion, rilmenidine and atenolol exerted comparable antihypertensive effects both at rest and during mental and dynamic stress. Atenolol attenuated HR responses to dynamic exercise and the Valsalva manoeuvre; rilmenidine did not interfere with the physiological responses of BP and HR during autonomic function tests.

Since there appear to be important interactions between mechanisms of salt-sensitive and carbohydrate-sensitive hypertension, the goal of this study was to evaluate the effects of greatly reducing dietary salt intake and removal of one kidney (to increase salt sensitivity) on the hemodynamic and metabolic responses to carbohydrate-enriched diets in three different rat strains. All three strains of laboratory rat developed significant increases in fasting plasma insulin (1-2 fold, p0.03) and triglyceride (2-3 fold, p0.01) concentrations in response to fructose (or sucrose) enriched diets, irrespective of salt content. Blood pressure increased significantly in response to carbohydrate feeding in both Sprague-Dawley (S-D) and Dahl salt-sensitive rats, but not in Fischer 344 rats, and decreasing salt intake had no effect on the development of carbohydrate-induced hypertension: e.g., delta BP in S-D rats was +20 mmHg after the fructose-0.5% NaCl diet as compared with +19 mmHg after fructose-0.02% NaCl, and delta BP in Dahl salt-sensitive rats was +22 mmHg after fructose-0.02% NaCl. Finally, nephrectomy neither accentuated the degree of hypertension in fructose-fed S-D rats, nor increased blood pressure in fructose-fed Fischer 344 rats. These results emphasize the strain specific characteristics of carbohydrate-induced hypertension in rats, and indicate that the hemodynamic responses of different rat strains to dietary carbohydrate are not modified by either decreasing salt intake or removing one kidney.

The revised and updated second edition of An Introduction to Vascular Biology is broader in scope than its predecessor and more clinically oriented. The extent to which vascular biology and pathophysiology impacts upon clinical medicine is perfectly illustrated by the varied departmental affiliations of the four editors—haematology, rheumatology, obstetrics and vascular surgery. The book includes nineteen short, digestible chapters grouped under basic science, pathophysiology and clinical practice. Contributors include respected names such as Peter Weissberg, Patrick Vallance, Caroline Savage, Allun Hughes and John Tooke. Each chapter has a list of useful up-to-date references, but the illustrations would have benefited from a splash of colour (especially the clinical photographs and histological sections). The basic science section is comprehensive, with useful introductory chapters on topical subjects such as angiogenesis, vascular cell apoptosis, and the biology of wound healing. The whole area of angiogenesis is particularly relevant clinically. Sprouting of new blood vessels from existing vascular structures plays an important part in collateral vessel formation, tumour growth and tissue remodelling and regeneration. This chapter describes the regulation of endothelial cell migration and proliferation, with connective tissue expansion and the gradual creation of new vascular architecture. Numerous growth factors stimulate angiogenesis while other anti-angiogenic molecules inhibit new vessel formation. The basic science is outlined in a clinical context with reference to conditions in which therapeutic manipulation of angiogenic pathways has potential benefits. This might be achieved, for example, by gene therapy whereby DNA for a powerful angiogenic growth factor, VEGF, is administered locally in the leg or the heart to enhance new vessel formation in patients with critical ischaemia. Conversely, there is a rationale for inhibition of angiogenesis as a way to block tumour growth in primary or metastatic disease. The chapter on angiogenesis will appeal to many different clinical and research specialties. The section on pathophysiology also includes topical updates in fields that are rapidly changing—for example, the status of candidate genes for hypertension, the many aspects of endothelial dysfunction, and the growing importance of nitric oxide in health and disease. Imaging of the cardiovascular system has undergone enormous change over the past ten years, particularly with techniques such as spiral CT and MR. Alan Moody (radiologist) has written a chapter illustrating the versatility of these techniques not simply in arterial disease but also in assessing patients with venous disease and venous thrombosis. CT and MR angiography are becoming especially useful in the assessment of patients with carotid and renovascular disease. It is a pity that the images have not reproduced well, but in other respects the chapter is excellent. The third section becomes more focused on therapeutic strategies for improving symptoms and prognosis in patients with assorted vascular conditions, including the cardiovascular complications of diabetes, aortic aneurysms, pulmonary hypertension, and the different forms of vasculitis. Each of these chapters is well illustrated with simple, practical guides to diagnosis and treatment based on a clear understanding of the pathophysiological processes. Beverley Hunt and her co-editors have succeeded in putting together a collection of varied chapters in which the underlying structural and functional abnormalities in blood vessels are described scientifically in the context of clinical disorders. Individual chapters are easy to read and should provide helpful guidance to clinicians and those interested in the pathophysiological basis of vascular medicine.

There is evidence that the renin-angiotensin system may be involved in the metabolic as well as the cardiovascular features of diabetes and that pressor doses of angiotensin II (ANG II) increase insulin sensitivity in parallel with blood pressure (BP) in healthy subjects, but the effects of ANG II on insulin sensitivity have not been previously reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). In a randomized, double-blind, placebo-controlled, crossover study, 11 patients with NIDDM attended 3 study days to evaluate the effects of a 3-h infusion of subpressor and pressor doses of ANG II on whole body insulin sensitivity using the euglycemic hyperinsulinemic clamp. BP and heart rate were recorded, and blood samples were collected for serum insulin, C-peptide, potassium, catecholamines, plasma renin activity, and plasma ANG II concentrations. Plasma levels of ANG II (means ± SD) were 9 ± 4, 29 ± 9, and 168 ± 47 pmol/ml after placebo, low dose infusion, and high dose infusion, respectively. The higher dose of ANG II was associated with significant increases in BP (e.g., 18 mmHg systolic BP at 150 min) and plasma aldosterone. Whole body insulin sensitivity was 23.8 ± 12.7 mumol glucose.kg−1 · min−1 after placebo and 30.6 ± 12.7 and 27.2 ± 13.3 following low and high dose ANG II infusions, respectively (P < 0.05, analysis of variance). In summary, acute infusion of ANG II, with or without an increase in BP, increases insulin sensitivity in normotensive patients with NIDDM. The dissociation of metabolic and BP effects of ANG II suggests that hemodynamic alterations and redistribution of cardiac output might not be the sole underlying mechanism in patients with NIDDM.