A State-of-Art Review of the Vicious Circle of Sleep Disorders, Diabetes and Neurodegeneration Involving Metabolism and Microbiota Alterations.

In the context of neurodegenerative disorders, cognitive decline is frequently reported in older population. Recently, numerous metabolic pathways have been implicated in neurodegeneration, including signaling disruption of insulin and other glucose-regulating hormones. In fact, Alzheimer's disease has now been considered as "type-3 diabetes". In this review, we tried to clarify the role of sleep impairment as the third major player in the complex relationship between metabolic and neurodegenerative diseases. Altered sleep may trigger or perpetuate these vicious mechanisms, leading to the development of both dementia and type 2 diabetes mellitus. Finally, we analyzed these reciprocal interactions considering the emerging role of the gut microbiota in modulating the same processes. Conditions of dysbiosis have been linked to circadian rhythm disruption, metabolic alterations, and release of neurotoxic products, all contributing to neurodegeneration. In a future prospective, gut microbiota could provide a major contribution in explaining the tangled relationship between sleep disorders, dementia and diabetes.

Dietary nitrate prevents progression of carotid subclinical atherosclerosis through blood pressure-independent mechanisms in patients with or at risk of type 2 diabetes mellitus.

AIMS: To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, vs. placebo/doxazosin, to control for blood pressure (BP). METHODS: A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial had carotid imaging. Patients with hypertension and with/at risk of type 2 diabetes were randomized to active nitrate-containing beetroot juice or placebo nitrate-depleted juice, and spironolactone or doxazosin. Vascular ultrasound for carotid diameter (CD, mm) and intima-media thickness (CIMT, mm) was performed at baseline, 3- and 6-months. Carotid local stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph) and carotid lumen area. Data were analysed by modified intention to treat and using mixed-model effect, adjusted for confounders. RESULTS: In total, 93 subjects had a baseline evaluation and 86% had follow-up data. No statistical interactions occurred between the juice and drug arms and BP was similar between the juices and between the drugs. Nitrate-containing vs. placebo juice significantly lowered CIMT (-0.06 [95% confidence interval -0.12, -0.01], P = .034), an overall difference of ~8% relative to baseline; but had no effect on CD or CS. Doxazosin appeared to reduce CS from baseline (-0.34 [-0.62, -0.06]) however, no difference was detected vs. spironolactone (-0.15 [-0.46, 0.16]). No differences were detected between spironolactone or doxazosin on CIMT and CD. CONCLUSIONS: Our results show that 6 months' intervention with dietary nitrate influences vascular remodelling, but not carotid stiffness or diameter. Neither spironolactone nor doxazosin had a BP-independent effect on carotid structure and function.

Effects of Antithrombotic Agents on Ophthalmological Outcomes, Cardiovascular Risk, and Mortality in Hypertensive Patients with Retinal Vein Occlusion: An Exploratory Retrospective Study.

Background and objectives: Because few data are available, the aim of this study is to analyze the effects of antithrombotic agents (ATAs) on visual function and long-term risk of cardiovascular events and mortality in hypertensive patients with retinal vein occlusion (RVO). Materials and methods: Hypertensive patients with RVO were consecutively selected from 2008 to 2012 and followed for a median of 8.7 years. Ophthalmologists evaluated and treated RVO complications, and best-corrected visual acuity (BCVA) was checked at each visit during the first one year of follow-up. Survival analysis was conducted on the rate of the composite endpoint of all-cause deaths or non-fatal cardiovascular events. Results: Retrospectively, we collected data from 80 patients (age 68 ± 12 years, 39 males). Central and branch RVO was present in 41 and 39 patients, respectively, and 56 patients started ATAs (50 antiplatelet drugs, 6 warfarin, and 2 low-molecular weight heparin). Average BCVA of the cohort did not change significantly during one-year of follow-up. The only predictor of BCVA was the baseline BCVA value. There was a reduction in proportion and severity of macular edema and an increase in the cumulative proportion of retinal vein patency reestablishment during the follow-up, independent of treatment. ATAs had no effects on one-year BCVA, intraocular complications, or the composite endpoint rate. Conclusions: In this exploratory study, ATAs had no effect on BCVA during the first one year of follow-up and on the composite endpoint during the long-term follow-up. Further prospective studies need to be conducted with an accurate standardization of the intraocular and antithrombotic treatment to define the positive or negative role of ATAs in hypertensive patients with RVO.

Heart failure in the elderly: A geriatric syndrome. Picture of the modern situation.

Among the older patients' cohort, the aetiology of heart failure is peculiar and differs in many ways from the younger one, both in its epidemiology, diagnostic work-up and clinical presentation. Focusing on this population, we could assume that heart failure is a real geriatric syndrome, characterized by several features, which coexist with other comorbidities and require specific and targeted cares. It is therefore necessary to examine the global burden of heart failure and the patient's history rather than the causal cardiomyopathy - frequently more than one in the elderly - facing with the condition, bearing in mind the quality of life even before its duration.

Long-Term Renal and Cardiac Outcomes after Stenting in Patients with Resistant Hypertension and Atherosclerotic Renal Artery Stenosis.

BACKGROUND/AIMS: Atherosclerotic renal artery stenosis (ARAS) is frequently detected in patients with resistant hypertension (RHTN), but the evidence supporting the utility of renal revascularization in these patients is limited. This prospective, observational study investigates the outcomes of renal stenting in patients with RHTN and hemodynamically significant ARAS. METHODS: Fifty-four patients with RHTN were selected because of angiographic evidence of ARAS >70% and were followed for 4 years after renal stenting. Renal function and echocardiographic variables were assessed at baseline and during follow-up. RESULTS: Blood pressure decreased rapidly after renal stenting and was normalized in 67% of patients at six months, with significant reduction in the number of antihypertensive drugs. Creatinine clearance increased in 39% of patients, decreased in 52%, and remained stable in the remaining 9%, with an average value that had a nonsignificant decrease during follow-up. Urinary albumin excretion did not change throughout the study. After 4 years, left ventricular (LV) wall thickness and concentric geometry decreased significantly and variables of LV diastolic function improved. CONCLUSION: In patients with RHTN, stenting of hemodynamically significant ARAS decreases blood pressure, preserves renal function in a substantial proportion of patients, and improves LV structure and function, suggesting the opportunity for timely identification of ARAS in these patients.

COVID-19 Accelerated Cognitive Decline in Elderly Patients with Pre-Existing Dementia Followed up in an Outpatient Memory Care Facility.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) may affect the cognitive function and activities of daily living (ADL) of elderly patients. This study aimed to establish the COVID-19 effect on cognitive decline and the velocity of cognitive function and ADL changes in elderly patients with dementia followed up in an outpatient memory care facility. METHODS: In total, 111 consecutive patients (age 82 ± 5 years, 32% males) with a baseline visit before infection were divided into those who had or did not have COVID-19. Cognitive decline was defined as a five-point loss of Mini-Mental State Examination (MMSE) score and ADL comprising basic and instrumental ADL indexes (BADL and IADL, respectively). COVID-19 effect on cognitive decline was weighted for confounding variables by the propensity score, whereas the effect on change in the MMSE score and ADL indexes was analyzed using multivariate mixed-effect linear regression. RESULTS: COVID-19 occurred in 31 patients and a cognitive decline in 44. Cognitive decline was about three and a half times more frequent in patients who had COVID-19 (weighted hazard ratio 3.56, 95% confidence interval 1.50-8.59, p = 0.004). The MMSE score lowered on average by 1.7 points/year, independently of COVID-19, but it lowered twice faster in those who had COVID-19 (3.3 vs. 1.7 points/year, respectively, p < 0.050). BADL and IADL indexes lowered on average less than 1 point/year, independently of COVID-19 occurrence. Patients who had COVID-19 had a higher incidence of new institutionalization than those who did not have the disease (45% versus 20%, p = 0.016, respectively). CONCLUSIONS: COVID-19 had a significant impact on cognitive decline and accelerated MMSE reduction in elderly patients with dementia.

Polyphenols Rich Diets and Risk of Type 2 Diabetes.

Type 2 diabetes is an increasing health concern worldwide. Both genetic and environmental risk factors as improper dietary habits or physical inactivity are known to be crucial in the pathogenesis of type 2 diabetes. Polyphenols are a group of plant-derived compounds with anti-inflammatory and antioxidant properties that are associated with a low prevalence of metabolic conditions characterized by insulin resistance, including obesity, diabetes, and hypertension. Moreover, there is now full awareness that foods that are rich in phytochemicals and polyphenols could play an important role in preserving human cardiovascular health and substantial clinical evidence indicates that regular dietary consumption of such foods affects favorably carbohydrate metabolism. This review briefly summarizes the evidence relating dietary patterns rich in polyphenols with glucose metabolism and highlights the potential benefits of these compounds in the prevention of type 2 diabetes.

Plasma Lipoprotein(a) Levels as Determinants of Arterial Stiffening in Hypertension.

Previous studies have shown that plasma lipoprotein(a) (Lp(a)) plays an important role in the development of hypertensive organ damage. The aim of the present study was to investigate the relationship of Lp(a) with markers of arterial stiffening in hypertension. In 138 essential hypertensive patients free of diabetes, renal failure and cardiovascular complications, we measured plasma lipids and assessed vascular stiffness through the use of pulse wave analysis and calculation of the brachial augmentation index (AIx), and measured the pulse wave velocity (PWV). Plasma Lp(a) levels were significantly and directly related to both AIx (r = 0.490; p < 0.001) and PWV (r = 0.212; p = 0.013). Multiple regression analysis showed that AIx was independently correlated with age, C-reactive protein, and plasma Lp(a) (beta 0.326; p < 0.001), while PWV was independently and directly correlated with age, and inversely with HDL, but not with plasma Lp(a). Logistic regression indicated that plasma Lp(a) could predict an AIx value above the median for the distribution (p = 0.026). Thus, in a highly selective group of patients with hypertension, plasma Lp(a) levels were significantly and directly related to markers of vascular stiffening. Because of the relevance of vascular stiffening to cardiovascular risk, the reduction of Lp(a) levels might be beneficial for cardiovascular protection in patients with hypertension.

Dulaglutide reduces binge episodes in type 2 diabetic patients with binge eating disorder: A pilot study.

AIMS: Binge eating disorder (BED) is the most common eating disorder in the United States and Europe and is associated with obesity and type 2 diabetes (T2D). Presence and severity of BED have been associated with worse metabolic control and greater BMI in T2D patients. Glucagon Like Peptide-1 (GLP1) receptors are present in central nervous system areas involved in appetite regulation and treatment with GLP-1 receptor agonists modulates appetite and reward-related brain areas in humans. We evaluated the effects of treatment with dulaglutide on eating behavior in T2D outpatients with BED. METHODS: This was a pilot open label, prospective controlled study. Inclusion criteria were: Age ≤65, HbA1c between 7.5 and 9% on metformin therapy alone, normal renal function and diagnosis of BED. Patients were randomly assigned to receive either Dulaglutide 1,5 mg/sett or Gliclazide 60 mg for 12 weeks. We evaluated baseline binge eating scale score (BES), weight, BMI, percentage fat mass, HbA1c and their changes after treatment. A multivariate linear regression model was used to verify the association between Δ BES from baseline with Δ Hba1c and variation of anthropometric parameters after treatment. RESULTS: After 12 weeks patients treated with dulaglutide had grater reduction of binge eating behaviour (p < 0.0001), body weight (p < 0,0001), BMI (p < 0.0001), percentage fat mass (p < 0.0001) and HbA1c (p = 0.009) than patients treated with gliclazide. Reduction in BES was associated with reduction in body weight (p < 0.0001) and HbA1c (p = 0.033). CONCLUSION: Dulaglutide treatment reduces binge eating behaviour in T2D patients with BED.

Sustained virologic response to direct-acting antiviral agents predicts better outcomes in hepatitis C virus-infected patients: A retrospective study.

BACKGROUND: Direct-acting antiviral agents (DAAs) are extremely effective in eradicating hepatitis C virus (HCV) in chronically infected patients. However, the protective role of the sustained virologic response (SVR) achieved by second- and third-generation DAAs against the onset of hepatocellular carcinoma (HCC) and mortality is less well established. AIM: To examine the occurrence of HCC or death from any cause in a retrospective-prospective study of patients treated with DAAs. METHODS: Patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy. The study was conducted in 380 patients (age: 60 ± 13 years, 224 males, 32% with cirrhosis) treated with DAAs with or without SVR (95/5%), with a median follow up of 58 wk (interquartile range: 38-117). The baseline anthropometric features, HCV viral load, severity of liver disease, presence of extra-hepatic complications, coinfection with HIV and/or HBV, alcohol consumption, previous interferon use, alpha-fetoprotein levels, and renal function were considered to be confounders. RESULTS: The incidence rate of HCC in patients with and without SVR was 1.3 and 59 per 100 person-years, respectively (incidence rate ratio: 44, 95%CI: 15-136, P < 0.001). Considering the combined endpoint of HCC or death from any cause, the hazard ratio (HR) for the SVR patients was 0.070 (95%CI: 0.025-0.194, P < 0.001). Other independent predictors of HCC or death were low HCV viremia (HR: 0.808, P = 0.030), low platelet count (HR: 0.910, P = 0.041), and presence of mixed cryoglobulinemia (HR: 3.460, P = 0.044). Considering SVR in a multi-state model, the independent predictors of SVR achievement were absence of cirrhosis (HR: 0.521, P < 0.001) and high platelet count (HR: 1.019, P = 0.026). Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR (HR: 5.982, P = 0.028 and HR: 5.633, P = 0.047, respectively). CONCLUSION: DAA treatment is effective in inducing SVR and protecting against HCC or death. A residual risk of HCC persists in patients with advanced liver disease or with complications, such as mixed cryoglobulinemia or renal failure.

Pre-Procedural Statin Use Is Associated with Improved Long-Term Survival and Reduced Major Cardiovascular Events in Patients Undergoing Carotid Artery Stenting: A Retrospective Study.

Carotid artery stenting (CAS) is a minimal invasive procedure used to resolve carotid occlusion that can be affected by peri-procedural complications. Statin use before CAS has shown to reduce peri-procedural risk and improve survival, though time-dependent cofactors that influence mortality has not been considered. The aim of this study was to evaluate long-term survival of patients who undergo CAS considering new occurred major adverse cardiovascular event (MACE) as time-dependent cofactor. In this study, 171 high cardiovascular risk patients (age 72 ± 8 years, 125 males) were enrolled after CAS procedure and were followed for a median of 8.4 years. Death occurred in 44% of patients with a mean time to death of 69 ± 39 months and MACE in 34% with a mean time of 35 ± 42 months. In patients who used or not statins at baseline, death occurred in 33% and 65%, respectively (p < 0.001). Survival analysis showed that statin use reduced risk of death (hazard ratio HR 0.36, 95% confidence interval CI 0.23⁻0.58, p < 0.0001). Including MACE as time-dependent variable did not change beneficial effects of statins. Additionally, statin use was associated with a protective effect on MACE (HR 0.48, 95% CI 0.27⁻0.85, p = 0.012); particularly, the prevalence of stroke was reduced by 59% (p = 0.018). In multivariate analysis, effects of statins were independent of demographic and anthropometric variables, prevalence of cardiovascular risk factors, renal function, antiplatelet use, and MACE occurrence. In conclusion, use of statins before CAS procedure is associated with increased long-term survival and reduced MACE occurrence. This evidence supports the hypothesis that statin use before CAS might be beneficial in high risk patients.

Insulin sensitivity in patients with primary aldosteronism: a follow-up study.

CONTEXT: The relationship between aldosterone and glucose metabolism is poorly understood, and there is substantial disparity among findings of studies that have examined glucose tolerance and insulin sensitivity in patients with primary aldosteronism. OBJECTIVE: The objective of the study was to determine the outcome of glucose tolerance and insulin sensitivity in patients with primary aldosteronism after treatment. DESIGN: This was a prospective study of patients who received a diagnosis of primary aldosteronism and were followed up for an average period of 5.7 yr (range, 3-9 yr). SETTING: The study was conducted at a university referral center. PATIENTS: A consecutive sample of 47 patients with tumoral or idiopathic aldosteronism was followed up after either surgical or medical treatment. Patients with primary aldosteronism were compared with 247 patients with essential hypertension with the same severity and duration of disease and 102 normotensive subjects. MAIN OUTCOME MEASURES: Short- and long-term changes in glucose tolerance and insulin sensitivity were measured. RESULTS: After adjustment for age, gender, and body mass index, patients with primary aldosteronism had greater homeostasis model assessment index (P < 0.05) and plasma insulin response to an oral glucose load (P < 0.05) and lower quantitative insulin sensitivity check index (P < 0.01) than normotensive controls. Changes in insulin sensitivity were significantly greater in essential hypertension than primary aldosteronism, and this difference was confirmed by assessment with the hyperinsulinemic-euglycemic clamp (P < 0.01). Treatment of primary aldosteronism decreased blood pressure significantly, and during the initial 6 months of follow-up, parameters of insulin sensitivity were restored to normal. Analysis of subsequent follow-up showed nonsignificant changes in glucose metabolism parameters in both adrenalectomized and spironolactone-treated patients. CONCLUSIONS: Insulin resistance is present in patients with tumoral and idiopathic aldosteronism, but the defect appears less severe than in patients with essential hypertension. Treatment with surgery or aldosterone antagonists restores rapidly and persistently normal sensitivity to insulin.

New risk factors for atherosclerosis in hypertension: focus on the prothrombotic state and lipoprotein(a).

Although adequate control of blood pressure is of basic importance in cardiovascular prevention in hypertensive patients, correction of additional risk factors is an integral part of their management. In addition to classical risk factors, epidemiological research has identified a number of other conditions that might significantly contribute to cardiovascular risk in the general population and might achieve specific relevance in patients with high blood pressure. In fact, more than 20% of patients with premature cardiovascular events do not have any of the traditional risk factors and, although effective intervention on blood pressure and additional risk factors has significantly reduced cardiovascular morbidity and mortality, the contribution to stroke, coronary artery disease and renal failure is still unacceptably high. Evaluation of new risk factors may further expand our capacity to predict atherothrombotic events when these factors are included along with the traditional ones in the assessment of global cardiovascular risk in hypertensive patients. Because it could be anticipated that the role of these novel factors will become increasingly evident in the future, researchers with an interest in hypertension and physicians dealing with problems related to cardiovascular prevention should give them appropriate consideration. This review summarizes the basic biology and clinical evidence of two emerging risk factors that are reciprocally related and contribute to the development and progression of organ damage in hypertension: the prothrombotic state and lipoprotein(a).

Cellular mechanisms of insulin resistance in rats with fructose-induced hypertension.

BACKGROUND: Feeding a high-fructose diet induces hypertension and insulin-resistance in Sprague-Dawley rats. METHODS: To investigate whether insulin receptors contribute to abnormal glucose metabolism and whether their regulation is differentially regulated in different tissues, we evaluated the glycemic and insulinemic response to an oral glucose load, insulin receptor binding, and insulin receptor messengerRNA (mRNA) levels in tissues of rats that were fed either standard rat chow or a diet containing 66% fructose for 2 weeks. RESULTS: Blood pressure and plasma triglycerides increased significantly in the fructose-fed rats, whereas body weight, fasting plasma glucose, and plasma insulin did not differ significantly from controls. Plasma glucose and insulin responses to oral glucose were significantly greater in fructose-fed than in control rats. Insulin receptor-binding characteristics were determined by an in situ autoradiographic technique associated with computerized microdensitometry. The insulin receptor number was significantly lower in both skeletal muscle and liver of fructose-fed rats as compared to controls, whereas no difference was observed in the kidney. No significant differences were found in binding affinity. Insulin receptor mRNA levels were determined by slot-blot hybridization with a cRNA probe encoding the 5' end of the rat insulin receptor cDNA. Consistent with binding data, mRNA levels were significantly lower in skeletal muscle and liver of fructose-fed rats as compared to controls, but not in the kidney. CONCLUSIONS: Decreased number of insulin receptors occurring at the level of gene expression is present in skeletal muscle and liver of fructose-fed rats and might contribute to insulin resistance in this model.

Insulin receptors and renal sodium handling in hypertensive fructose-fed rats.

BACKGROUND: Insulin resistance and hypertension are present in Sprague-Dawley rats fed a fructose-enriched diet. In these rats, insulin might elevate blood pressure via an antinatriuretic action. METHODS: To investigate the sodium-insulin interaction in fructose-fed rats, we compared insulin sensitivity, insulin receptor binding, and insulin receptor mRNA levels in the kidney and skeletal muscle of rats that were fed standard rat chow or a fructose-enriched diet (66%) with either low (0.07%), normal (0.3%), or high (7.5%) NaCl concentrations for 3 weeks. RESULTS: Systolic blood pressure increased in the fructose-fed rats receiving the normal and high-salt diet, but not the low-salt diet. When the rats were fed the low-salt diet, the rate of glucose infusion required to maintain euglycemia during a hyperinsulinemic clamp and insulin receptor number and mRNA levels in skeletal muscle were lower in fructose-fed than control rats. High-salt diet decreased significantly the rate of glucose disposal during the clamp and muscular insulin receptor number and mRNA levels in control, but not fructose-fed rats. During the low-salt diet, renal insulin receptor number and mRNA levels were comparable in fructose-fed and control rats and hyperinsulinemia had comparable acute antinatriuretic effects in the two groups; when the rats were maintained on the high-salt diet, the expected decrease in renal insulin receptor number and mRNA levels occurred in control but not fructose-fed rats and, consistent with this finding, the antinatriuretic response to hyperinsulinemia was blunted only in controls. An inverse relationship between dietary NaCl content and renal insulin receptor mRNA levels was observed in control but not fructose-fed rats. CONCLUSION: Fructose-fed rats appear to have lost the feedback mechanism that limits insulin-induced sodium retention through a down-regulation of the renal insulin receptor when the dietary NaCl content is increased. This abnormality might possibly contribute to the elevation of blood pressure in these rats.

Rho-kinase inhibition blunts renal vasoconstriction induced by distinct signaling pathways in vivo.

In addition to intracellular calcium, which activates myosin light chain (MLC) kinase, MLC phosphorylation and hence contraction is importantly regulated by MLC phosphatase (MLCP). Recent evidence suggests that distinct signaling cascades of vasoactive hormones interact with the Rho/Rho kinase (ROK) pathway, affecting the activity of MLCP. The present study measured the impact of ROK inhibition on vascular F-actin distribution and on vasoconstriction induced by activation/inhibition of distinct signaling pathways in vivo in the microcirculation of the split hydronephrotic rat kidney. Local application of the ROK inhibitors Y-27632 or HA-1077 induced marked dilation of pre- and postglomerular vessels. Activation of phospholipase C with the endothelin ET B agonist IRL 1620, inhibition of soluble guanylyl cyclase with 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), or inhibition of adenylyl cyclase with the adenosine A1 agonist N6-cyclopentyladenosine (CPA) reduced glomerular blood flow (GBF) by about 50% through vasoconstriction at different vascular levels. ROK inhibition with Y-27632 or HA-1077, but not protein kinase C inhibition with Ro 31-8220, blunted ET B-induced vasoconstriction. Furthermore, the reduction of GBF and of vascular diameters in response to ODQ or CPA were abolished by pretreatment with Y-27632. ROK inhibitors prevented constriction of preglomerular vessels and of efferent arterioles with equal effectiveness. Confocal microscopy demonstrated that Y-27632 did not change F-actin content and distribution in renal vessels. The results suggest that ROK inhibition might be considered as a potent treatment of renal vasoconstriction, because it interferes with constriction induced by distinct signaling pathways in renal vessels without affecting F-actin structure.

Effects of angiotensin II, arginine vasopressin and tromboxane A2 in renal vascular bed: role of rho-kinase.

BACKGROUND: Angiotensin II (Ang II), arginine vasopressin (AVP) and tromboxane A(2) (TxA(2)) are dissimilar vasoconstrictors involved in regulating renal circulation. Whereas Ang II is primarily a physiological modulator, AVP and TxA(2) play important roles under pathological conditions. Previously, we have shown variable importance of intracellular Ca(2+) and protein kinase C for their mode of action (Ang II > AVP >U-46619), but the cell signalling via rho-associated kinase (ROK) is a common pathway. The aim of this study was to determine their sites of action in the renal vascular bed and the corresponding role of ROK at the microvascular level. METHODS: Glomerular blood flow (GBF) and luminal diameter of different vessels (10-70 micro m) were measured in the split hydronephrotic kidney of anaesthetized rats. The tissue bath concentration of Ang II, AVP or the TxA(2) agonist U-46619 was adjusted to reduce GBF by approximately 50%. The measurements were repeated after adding a sub-maximal dose of the ROK inhibitor Y-27632 into the bath. RESULTS: Ang II constricted all vessels significantly, the constriction being least in the proximal segment of the arcuate artery ( approximately 70 micro m). Significant constrictions due to AVP were found only in interlobular and arcuate arteries (20-70 micro m), but not in the afferent and efferent arterioles. U-46619 constricted only the arcuate artery (> or = 50 micro m). Y-27632 (10(-4) M) dilated all vessels significantly and increased GBF by 65%. Thereafter, effects of all agonists were severely attenuated. Control reductions in GBF could be obtained at higher concentrations of AVP (10-fold) and U-46619 (5-fold) and a lesser GBF reduction with Ang II (100-fold) without changes in the respective patterns of vascular constriction. CONCLUSIONS: Our data indicate that the agonists, in the order Ang II, AVP and TxA(2), constrict larger vessels within the renal vascular tree via activation of ROK. Therefore, ROK inhibitors may provide a therapeutic tool to antagonize pathological vasospasm of conduit vessels, which are resistant to other vasodilators.

The emerging risk factors for cardiovascular disease: a review of the epidemiologic evidence for lipoprotein(a), homocysteine, and fibrinogen.

Appropriate correction of cardiovascular risk factors is a mainstay of the treatment of patients that have developed or might develop cardiovascular disease. In addition to classical risk factors, such as hypertension, smoking, dyslipidemia, diabetes, obesity, and sedentary life, epidemiological research has identified a number of additional conditions that are associated with a greater risk of cardiovascular disease. In fact, a substantial percentage of patients who develop cardiovascular events do not have any of the classical risk factors. Over the past thirty years, effective intervention in the treatment of hypertension, dyslipidemia, and diabetes has reduced remarkably cardiovascular morbidity and mortality, but the incidence of coronary artery disease and stroke remains unacceptably high and cardiovascular diseases are still the leading cause of death in the Western world. New cardiovascular risk factors are likely to give substantial contribution to this scenario and it could be easily anticipated that this contribution will become more evident in the upcoming years. This is why physicians who operate in the field of cardiovascular medicine and deal with problems related to cardiovascular prevention should be aware of these emergent risk factors, evaluate them accurately in their patients, and treat them appropriately. This review will summarize the literature supporting the role of lipoprotein(a), homocysteine, and fibrinogen as cardiovascular risk factors.