Cardiovascular effects of the respiratory muscle metaboreflexes in dogs: rest and exercise.

In awake dogs, lactic acid was injected into the phrenic and deep circumflex iliac arteries to elicit the diaphragm and abdominal muscle metaboreflexes, respectively. At rest, injections into the phrenic or deep circumflex iliac arteries significantly increased mean arterial blood pressure 21 +/- 7% and reduced cardiac output 6 +/- 2% and blood flow to the hindlimbs 20 +/- 9%. Simultaneously, total systemic, hindlimb, and abdominal expiratory muscle vascular conductances were reduced. These cardiovascular responses were not accompanied by significant changes in the amplitude or timing of the diaphragm electromyogram. During treadmill exercise that increased cardiac output, hindlimb blood flow, and vascular conductance 159 +/- 106, 276 +/- 309, and 299 +/- 90% above resting values, lactic acid injected into the phrenic or deep circumflex iliac arteries also elicited pressor responses and reduced hindlimb blood flow and vascular conductance. Adrenergic receptor blockade at rest eliminated the cardiovascular effects of the respiratory muscle metaboreflex. We conclude that the cardiovascular effects of respiratory muscle metaboreflex activation are similar to those previously reported for limb muscles. When activated via metabolite production, the respiratory muscle metaboreflex may contribute to the increased sympathetic tone and redistribution of blood flow during exercise.     

Vasodilator actions of several N-nitroso compounds

Recent studies have shown that N-nitroso compounds can activate arterial guanylate cyclase and relax isolated arterial smooth muscle; however, the effects of these substances on the cardiovascular system in the anesthetized cat are unknown. The present study was undertaken to compare the effects of several nitrosoguanidines and a nitrosamine, N-nitrosodimethylamine, on arterial guanylate cyclase activity, isolated arterial smooth muscle tone, and systemic vascular resistance in the anesthetized cat. Intravenous injections and infusions of the nitrosoguanidines glyceryl trinitrate (GTN) and sodium nitroprusside (SNP) decreased systemic arterial pressure. During intravenous infusion of the nitrosoguanidines GTN and SNP, cardiac output was unchanged at the peak of the decrease in aortic pressure, indicating that the nitrosoguanidines GTN and SNP both reduced systemic vascular resistance. In addition, intraarterial injections of the nitrosoguanidines produced dose-dependent decreases in perfusion pressure in the feline mesenteric vascular bed perfused at constant flow. These substances were potent relaxants of isolated arterial smooth muscle and markedly activated arterial guanylate cyclase. In contrast, N-nitrosodimethylamine was devoid of vasodilator activity in vivo and exerted only minimal effects on isolated arterial smooth muscle tone or on arterial guanylate cyclase activity. The present data demonstrate a relationship between guanylate cyclase activation and arterial smooth muscle relaxation and suggest that the vasodilator effects on resistance vessels in vivo in response to selected N-nitroso compounds may involve such a mechanism. Although the significance of the presently reported cardiovascular responses to N-nitroso compounds is uncertain, N-nitroso compounds may represent a previously unrecognized class of substances which can be formed in the body and which possess marked vasodilator activity. It is possible that this vasodilator activity may involve the relaxation of vascular smooth muscle through activation of guanylate cyclase.     

Collateral damage: cardiovascular consequences of chronic sympathetic activation with human aging

Adult aging in humans is associated with marked and sustained increases in sympathetic nervous system (SNS) activity to several peripheral tissues, including the heart, the gut-liver circulation, and skeletal muscle. This chronic activation of the peripheral SNS likely is, at least in part, a primary response of the central nervous system to stimulate thermogenesis to prevent further fat storage in the face of increasing adiposity with aging. However, as has been proposed in obesity hypertension, this tonic activation of the peripheral SNS has a number of adverse secondary cardiovascular consequences. These include chronic reductions in leg blood flow and vascular conductance, increased tonic support of arterial blood pressure, reduced limb and systemic alpha-adrenergic vasoconstrictor responsiveness, impaired baroreflex buffering, large conduit artery hypertrophy, and decreased vascular and cardiac responsiveness to beta-adrenergic stimulation. These effects of chronic age-associated SNS activation on the structure and function of the cardiovascular system, in turn, may have important implications for the maintenance of physiological function and homeostasis, as well as the risk of developing clinical cardiovascular and metabolic diseases in middle-aged and older adults.     

Blood pressure modulation and cardiovascular protection by melatonin: potential mechanisms behind

The production of the pineal hormone melatonin is synchronized with day-night cycle via multisynaptic pathway including suprachiasmatic nucleus linking several physiological functions to diurnal cycle. The recent data indicate that impaired melatonin production is involved in several cardiovascular pathologies including hypertension and ischemic heart disease. However, the mechanisms of melatonin effect on cardiovascular system are still not completely understood. The activation of melatonin receptors on endothelial and vascular smooth muscle cells and antioxidant properties of melatonin could be responsible for the melatonin effects on vascular tone. However, the data from in vitro studies are controversial making the explanation of the melatonin effect on blood pressure in vivo difficult. In vivo, melatonin also attenuates sympathetic tone by direct activation of melatonin receptors, scavenging free radicals or increasing NO availability in the central nervous system. The central and peripheral antiadrenergic action of chronic melatonin treatment might eliminate the mechanisms counter-regulating decreased blood pressure, providing thus additional cardioprotective mechanism. The extraordinary antioxidant activity and antilipidemic effects of melatonin may enhance the modulation of blood pressure by melatonin and probably play the most important role in the amelioration of target organ damage by chronic melatonin treatment. Further investigation of these mechanisms should provide novel knowledge about pathophysiological mechanisms of cardiovascular diseases, additional explanation for their circadian and seasonal variability and potentially generate new impulses for the development of therapeutic arsenal.     

Regulatory effect of AMP-activated protein kinase on pulmonary hypertension induced by chronic hypoxia in rats: in vivo and in vitro studies

Activation of AMP-activated protein kinase (AMPK) plays an important role in cardiovascular protection. It can inhibit arterial smooth muscle cell proliferation and cardiac fibroblast collagen synthesis induced by anoxia. However, the role of AMPK-dependent signalling cascades in the pulmonary vascular system is currently unknown. This study aims to determine the effects of AMPK on pulmonary hypertension and pulmonary vessel remodelling induced by hypoxia in rats using in vivo and in vitro studies. In vivo study: pulmonary hypertension, right ventricular hypertrophy and pulmonary vascular remodelling were found in hypoxic rats. Meanwhile, AMPKα₁ and phosphorylated AMPKα₁ were increased markedly in pulmonary arterioles and lung tissues. Mean pulmonary arterial pressure, index of right ventricular hypertrophy and parameters of pulmonary vascular remodelling, including vessel wall area/total area, density of nuclei in medial smooth muscle cells, and thickness of the medial smooth muscle cell layer were markedly suppressed by AICAR, an AMPK agonist. In vitro study: the expression of AMPKα₁ and phosphorylated AMPKα₁ was increased in pulmonary artery smooth muscle cells (PASMCs) under hypoxic conditions. The effects of PASMC proliferation stimulated by hypoxia were reinforced by treatment with Compound C, an AMPK inhibitor. AICAR inhibited the proliferation of PASMCs stimulated by hypoxia. These findings suggest that AMPK is involved in the formation of hypoxia-induced pulmonary hypertension and pulmonary vessel remodelling. Up-regulating AMPK can contribute to decreasing pulmonary vessel remodelling and pulmonary hypertension induced by hypoxia.     

Integrative control of the skeletal muscle microcirculation in the maintenance of arterial pressure during exercise.

Skeletal muscle blood flow and vascular conductance are influenced by numerous factors that can be divided into two general categories: central cardiovascular control mechanisms and local vascular control mechanisms. Central cardiovascular control mechanisms are thought to be designed primarily for the maintenance of arterial pressure and central cardiovascular homeostasis, whereas local vascular control mechanisms are thought to be designed primarily for the maintenance of muscle homeostasis. To support the high metabolic rates that can be generated during muscle contraction, skeletal muscle has a tremendous capacity to vasodilate and increase oxygen and nutrient delivery. During whole body dynamic exercise at maximal oxygen consumption (VO2 max), the skeletal muscle receives 85-90% of cardiac output. Yet despite receiving such a large fraction of cardiac output during high-intensity exercise, a vasodilator reserve remains with the potential to produce further elevations in skeletal muscle vascular conductance and blood flow. However, because maximal cardiac output is reached during exercise at VO2 max, further elevations in muscle vascular conductance would produce a fall in arterial pressure. Therefore, limits on muscle perfusion must be imposed during whole body exercise to prevent such drops in pressure. Effective arterial pressure control in response to a potentially hypotensive challenge during high-intensity exercise occurs primarily through reflex-mediated increases in sympathetic nerve activity, which are capable of modulating vasomotor tone of the skeletal muscle resistance vasculature. Thus skeletal muscle vascular conductance and perfusion are primarily mediated by local factors at rest and during exercise, but other centrally mediated control systems are superimposed on the dominant local control mechanisms to provide an integrated regulation of both arterial pressure and skeletal muscle vascular conductance and perfusion during whole body dynamic exercise.     

Adipokines and the cardiovascular system: mechanisms mediating health and disease

This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.     

The venous circulation: a piscine perspective.

Vascular capacitance describes the pressure-volume relationship of the circulatory system. The venous vasculature, which is the main capacitive region in the circulation, is actively controlled by various neurohumoral systems. In terrestrial animals, vascular capacitance control is crucial to prevent orthostatic blood pooling in dependent limbs, while in aquatic animals like fish, the effects of gravity are cancelled out by hydrostatic forces making orthostatic blood pooling an unlikely concern for these animals. Nevertheless, changes in venous capacitance have important implications on cardiovascular homeostasis in fish since it affects venous return and cardiac filling pressure (i.e. central venous blood pressure), which in turn may affect cardiac output. The mean circulatory filling pressure is used to estimate vascular capacitance. In unanaesthetized animals, it is measured as the central venous plateau pressure during a transient stoppage of cardiac output. So far, most studies of venous function in fish have addressed the situation in teleosts (notably the rainbow trout, Oncorhynchus mykiss), while any information on elasmobranchs, cyclostomes and air-breathing fishes is more limited. This review describes venous haemodynamic concepts and neurohumoral control systems in fish. Particular emphasis is placed on venous responses to natural cardiovascular challenges such as exercise, environmental hypoxia and temperature changes.     

Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase

The endocannabinoid anandamide exerts neurobehavioral, cardiovascular, and immune-regulatory effects through cannabinoid receptors (CB). Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the in vivo degradation of anandamide. Recent experimental studies have suggested that targeting the endocannabinergic system by FAAH inhibitors is a promising novel approach for the treatment of anxiety, inflammation, and hypertension. In this study, we compared the cardiac performance of FAAH knockout (FAAH-/-) mice and their wild-type (FAAH+/+) littermates and analyzed the hemodynamic effects of anandamide using the Millar pressure-volume conductance catheter system. Baseline cardiovascular parameters, systolic and diastolic function at different preloads, and baroreflex sensitivity were similar in FAAH-/- and FAAH+/+ mice. FAAH-/- mice displayed increased sensitivity to anandamide-induced, CB1-mediated hypotension and decreased cardiac contractility compared with FAAH(+/+) littermates. In contrast, the hypotensive potency of synthetic CB1 agonist HU-210 and the level of expression of myocardial CB1 were similar in the two strains. The myocardial levels of anandamide and oleoylethanolamide, but not 2-arachidonylglycerol, were increased in FAAH-/- mice compared with FAAH+/+ mice. These results indicate that mice lacking FAAH have a normal hemodynamic profile, and their increased responsiveness to anandamide-induced hypotension and cardiodepression is due to the decreased degradation of anandamide rather than an increase in target organ sensitivity to CB1 agonists.     

Central and peripheral circulatory effects and metabolic effects of different prostaglandins given I.V. to man

Cardiac output, heart rate, stroke volume, pressures in the brachial artery, right ventricle and pulmonary artery, forearm blood flow, and arterial concentration of FFA, lactate and glucose were measured in healthy male volunteers during i–v infusion of PGE₁, PGE₂, PGF_2α or 15-methyl PGF_2α in increasing doses. In accordance with previous findings PGE₁ and PGE₂ increased cardiac output by a vasodilating effect in the systemic and pulmonary vascular bed, probably in combination with an inotropic effect on the heart.15-methyl PGF_2α had essentially the same cardiovascular effects as PGF_2α. They induced a slight increase in cardiac output due to effects on heart rate, while systemic vascular resistance was unchanged. Forearm vascular resistance increased and pressures in the pulmonary circulation rose, indicating a vasoconstriction in these vascular beds.Glucose concentrations were not affected nor were lactate concentrations, except for a slight decrease of unclear significance in the group receiving 15-methyl PGF_2α. FFA increased slowly in the same manner as seen spontaneously in fasting individuals. These data do not indicate direct metabolic effects of the prostaglandins studied when given i–v.     

Lysophospholipids and the cardiovascular system

The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) have varied effects on the cardiovascular system. S1P is necessary for normal vascular development and may play an important role in angiogenesis. These molecules may exert potentially detrimental effects. Both S1P and LPA are released from activated platelets and can in turn stimulate platelet aggregation. These thrombogenic effects would further enhance ischemia in acute coronary syndromes and myocardial infarction. LPA is a major component of the lipid core of human atherosclerotic plaques and can stimulate vascular smooth muscle proliferation. Both LPA and S1P cause cardiac myocyte hypertrophy in vitro. Beneficial effects include cardioprotection both in vitro and during ischemia/reperfusion in an ex vivo whole heart mouse model. Understanding both the acute and the chronic physiologic and pathophysiologic roles of the lysophospholipids and their cognate receptors and signaling pathways in the cardiovascular system, which are likely to be species-, tissue-, and cell-specific, may allow the development of molecules that can be targeted to stimulate or inhibit a specific function.     

Effect of age on cardiovascular responses to static muscular contraction in beagles.

Induced muscular contraction in anesthetized animals results in significant hemodynamic and regional blood flow (RBF) changes. Although reflex cardiovascular responses initiated in contracting muscle have been firmly established, little is known about the effects of age on these responses. Because other reflex responses that involve sympathetic activation appear to be attenuated with age, it was hypothesized that reflex efferent cardiovascular responses that normally occur during muscular contraction would be impaired in senescent dogs. Therefore, hemodynamic and RBF responses to induced static hindlimb contraction (HLC) were evaluated in 8- to 14- and 2- to 3-yr-old beagles during alpha-chloralose anesthesia. Most baseline hemodynamic parameters were similar in both groups, but heart rate was significantly (P < 0.05) higher in old dogs. During HLC, heart rate and blood pressure increased in the young and old dogs. However, increases in stroke volume and cardiac output were greater in old dogs, combined with a reduction in systemic vascular resistance not observed in young dogs. No age-related difference in baseline RBF (microspheres) was observed in six of eight abdominal regional circulations and in each of four skeletal muscle groups. During HLC, RBF reductions occurred in six of eight abdominal organs in young and old dogs. However, the reduction in RBF and concomitant increase in vascular resistance in all eight abdominal regions combined was almost twice as great in young vs. old dogs. In noncontracting skeletal muscle, RBF decreased and vascular resistance increased four times more in young vs. old dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative haemodynamic studies of resting and active skeletal muscle in anaesthetised rats: role of nitric oxide.

Our previous studies have indicated that nitric oxide takes part in the basal regulation of vascular tone in skeletal muscle. The purpose of this study was to investigate whether nitric oxide has a role in the active hyperaemic response of a working muscle in a resting subject. Haemodynamic effects of nitric oxide synthase (NOS) inhibition (L-NAME, 10 mg/kg/30 min i.v. infusion) were determined simultaneously in the resting m. quadriceps femoris and in the working (breathing) m. rectus abdominis in anaesthetised rats (86Rb accumulation technique). L-NAME increased blood pressure and total peripheral resistance (TPR) while it decreased cardiac output. Blood flow (BF) decreased and vascular resistance (VR) increased both in resting (BF: 8.91+/-1.97-->5.92+/-2.59 ml/min/100 g, p<0.05: VR: 106+/-29.9-->212+/-113 R, p<0.01) and working (BF: 17.0+/-4.78-->6.93+/-2.15 ml/min/100 g, p<0.001; VR: 57.0+/-18.5-->160+/-56.7 R, p<0.01) muscle following NOS inhibition, but the percentile change of BF was higher in the working muscle (59%) than in the resting one (34%, p<0.001). There was a positive correlation between the cardiac output and the blood flow of the resting muscle with or without L-NAME administration, but blood flow of the working muscle failed to have any correlation with the cardiac output in control animals. However, L-NAME administration decreased both the cardiac output and the blood flow and similarly to the resting muscle a positive correlation was found. In conclusion, the haemodynamic effects of NOS inhibition are higher in working muscle than in the resting one: the nitric oxide may have important role in vasodilatation during muscle activity.     

Impaired vascular contractility and blood pressure homeostasis in the smooth muscle alpha-actin null mouse.

The smooth muscle (SM) alpha-actin gene activated during the early stages of embryonic cardiovascular development is switched off in late stage heart tissue and replaced by cardiac and skeletal alpha-actins. SM alpha-actin also appears during vascular development, but becomes the single most abundant protein in adult vascular smooth muscle cells. Tissue-specific expression of SM alpha-actin is thought to be required for the principal force-generating capacity of the vascular smooth muscle cell. We wanted to determine whether SM alpha-actin gene expression actually relates to an actin isoform's function. Analysis of SM alpha-actin null mice indicated that SM alpha-actin is not required for the formation of the cardiovascular system. Also, SM alpha-actin null mice appeared to have no difficulty feeding or reproducing. Survival in the absence of SM alpha-actin may result from other actin isoforms partially substituting for this isoform. In fact, skeletal alpha-actin gene, an actin isoform not usually expressed in vascular smooth muscle, was activated in the aortas of these SM alpha-actin null mice. However, even with a modest increase in skeletal alpha-actin activity, highly compromised vascular contractility, tone, and blood flow were detected in SM alpha-actin-defective mice. This study supports the concept that SM alpha-actin has a central role in regulating vascular contractility and blood pressure homeostasis, but is not required for the formation of the cardiovascular system.     

Cardiovascular responses to water drinking: does osmolality play a role?

Water drinking activates the autonomic nervous system and induces acute hemodynamic changes. The actual stimulus for these effects is undetermined but might be related to either gastric distension or to osmotic factors. In the present study, we tested whether the cardiovascular responses to water drinking are related to water's relative hypoosmolality. Therefore, we compared the cardiovascular effects of a water drink (7.5 ml/kg body wt) with an identical volume of a physiological (0.9%) saline solution in nine healthy subjects (6 male, 3 female, aged 26 +/- 2 years), while continuously monitoring beat-to-beat blood pressure (finger plethysmography), cardiac intervals (electrocardiography), and cardiac output (thoracic impedance). Total peripheral resistance was calculated as mean blood pressure/cardiac output. Cardiac interval variability (high-frequency power) was assessed by spectral analysis as an index of cardiac vagal tone. Baroreceptor sensitivity was evaluated using the sequence technique. Drinking water, but not saline, decreased heart rate (P = 0.01) and increased total peripheral resistance (P < 0.01), high-frequency cardiac interval variability (P = 0.03), and baroreceptor sensitivity (P = 0.01). Neither water nor saline substantially increased blood pressure. These responses suggest that water drinking simultaneously increases sympathetic vasoconstrictor activity and cardiac vagal tone. That these effects were absent after drinking physiological saline indicate that the cardiovascular responses to water drinking are influenced by its hypoosmotic properties.     

Clinical aspects of dopamine agonists and antagonists.

Dopamine and its specific receptors are widely distributed in man. Body regions where dopaminergic activity is of special pharmacologic interest include the basal ganglions, hypothalamus, chemoreceptor trigger zone, other less well defined areas in the central nervous system, and the renal and cardiovascular systems. The search for dopaminergic agents to modify these systems in disease states has depended heavily on in vitro and in vivo bioassays. These assays involving receptor binding, enzyme activation, smooth muscle and neuronal excitation, and modification of animal behavior have provided physicians with important therapeutic tools. Indeed, the introduction of levodopa for the treatment of Parkinson's disease and of the phenothiazines and related drugs for schizophrenia and psychosis has been a hallmark of neuropharmacologic research. However, the maximal benefits that these drugs may afford have not yet been realized due to an inadequate understanding of disease processes and a relative lack of specificity of drug action.     

Endocannabinoid system in food intake and metabolic regulation

PURPOSE OF REVIEW: As the incidence of obesity and the metabolic syndrome has increased, research has focused on the importance of the endocannabinoid system in the brain and peripheral tissues. Rimonabant, an inverse agonist of the CB1 receptor is being used therapeutically. This review presents recent advances in endocannabinoid physiology. RECENT FINDINGS: The endocannabinoid system interacts with other anorexigenic and orexigenic pathways to regulate food intake in the hypothalamus, and the hedonistic value of food in the mesolimbic system. Endocannabinoid system overactivity contributes to hepatic steatosis, increased adipose tissue inflammation, dysregulated insulin signalling in the pancreas and disturbed oxidative pathways in skeletal muscle. The breakdown pathways for anandamide and 2-arachidonoylglycerol, the endocannabinoid receptor ligands, are reviewed, and the recent discoveries of endocannabinoid receptor polymorphisms and their relationship to obesity and metabolic disease noted. The favourable effect of rimonabant on fat mass glycaemic control, lipid metabolism and overall cardiovascular risk must be tempered by adverse effects on mood. SUMMARY: The ubiquitous role of the endocannabinoid system in food intake and energy metabolism is now established. Drugs that manipulate different aspects of this system may benefit subjects with the metabolic and cachectic syndromes.     

Frank-Starling mechanism,fluid responsiveness,and length-dependent activation: Unravelling the multiscale behaviors with an in silico analysis

The Frank-Starling mechanism is a fundamental regulatory property which underlies the cardiac output adaptation to venous filling. Length-dependent activation is generally assumed to be the cellular origin of this mechanism. At the heart scale, it is commonly admitted that an increase in preload (ventricular filling) leads to an increased cellular force and an increased volume of ejected blood. This explanation also forms the basis for vascular filling therapy. It is actually difficult to unravel the exact nature of the relationship between length-dependent activation and the Frank-Starling mechanism, as three different scales (cellular, ventricular and cardiovascular) are involved. Mathematical models are powerful tools to overcome these limitations. In this study, we use a multiscale model of the cardiovascular system to untangle the three concepts (length-dependent activation, Frank-Starling, and vascular filling). We first show that length-dependent activation is required to observe both the Frank-Starling mechanism and a positive response to high vascular fillings. Our results reveal a dynamical length dependent activation-driven response to changes in preload, which involves interactions between the cellular, ventricular and cardiovascular levels and thus highlights fundamentally multiscale behaviors. We show however that the cellular force increase is not enough to explain the cardiac response to rapid changes in preload. We also show that the absence of fluid responsiveness is not related to a saturating Frank-Starling effect. As it is challenging to study those multiscale phenomena experimentally, this computational approach contributes to a more comprehensive knowledge of the sophisticated length-dependent properties of cardiac muscle.     

Astrocytes and the Renin Angiotensin System: Relevance in Disease Pathogenesis

The presence of a brain renin angiotensin system (RAS) is well documented. An overactive brain RAS contributes to the development and progression of cardiovascular and renal disorders among other conditions. In hypertension, an augmented brain RAS leads to an increase in sympathetic nervous system activity. In addition, impaired baroreceptor reflex function, increased vasopressin activity and neuroinflammation are important contributors as well. The relevance of angiotensins in central and peripheral systems, such as neurons and vascular smooth muscle cells, in cardiovascular disease pathogenesis is fairly understood. However, the role of astrocytes is less well studied. Astrocytes are a major contributor to neuroinflammation by increased synthesis and secretion of inflammatory mediators, dysregulated astrogliosis and impaired astrocyte proliferation. Astrocytes may also contribute to impaired neuromodulation. The precise molecular mechanisms by which astrocytes mediate these effects are still not fully understood. Here, we summarize the role of astrocytes in RAS -mediated pathogenesis of hypertension and other cardiovascular diseases.     

Cardiac output distribution and intrarenal haemodynamics: role of thromboxanes.

The effects of imidazole, an inhibitor of thromboxane synthesis, were studied on the distribution of cardiac output and on the intrarenal haemodynamics in anaesthetized, furthermore on the salt and water excretion in conscious rats. Imidazole treatment (10 mg/100 g b.m., intraperitoneally, twice a day for two days) failed to influence the arterial blood pressure, the cardiac output and its distribution in organs investigated (heart, muscle, lung [bronchial fraction], skin, liver, spleen, small intestine, adrenal gland and kidneys). The medullary blood flow increased, while cortical blood flow remained unchanged, but the intrarenal percentile blood flow shifted towards the medulla. Imidazole elevated the water turnover in the animals, but no change in sodium and potassium excretion occurred. It is supposed that thromboxanes may affect the renal medullary vascular tone without altering the vascular smooth muscle activity in other organs.