Regulation Of Tissue Blood Flow Research Articles

Modern view on the role of pericytes in the microcirculation

Pericytes were discovered about 150 years ago and their name can be translated as enveloping cells. The location of pericytes on the outer wall of capillaries, the presence of appendages and close contact with neighboring endothelial cells of the capillaries resulted in the hypothesis of their participation in the capillary blood flow control. Over the last years, a large number of publications confirming this hypothesis have appeared. Moreover, the data accumulated to date indicate that pericytes are multifunctional cells and play a significant and sometimes key role in such processes as regulation of tissue blood flow, functioning of the blood-brain barrier, angiogenesis, vascular remodeling, and immune responses. The participation of pericytes in the pathogenesis of certain diseases has been shown and the potential for their use as targets for therapeutic effects has been demonstrated.

Реактивність системи мікроциркуляції крові у дітей молодшого шкільного віку на температурний фактор

The purpose of the study was to investigate the adaptive capacity of the blood microcirculation system in children of primary school age for a functional test with heating. The article deals with the study of the blood microcirculation system in primary school children by laser Doppler flowmetry and the study of the reserve capacity of tissue blood flow in children on a test with increasing temperature factor. Materials and methods. The research was conducted on the basis of the laboratory of physiological research of the Department of Anatomy and Physiology of People and Animals of Bohdan Khmelnytsky Melitopol State Pedagogical University. The surveyed contingent consisted of 80 practically healthy children aged 6 to 9 years old, secondary school students in Melitopol. Based on a comprehensive morphofunctional study, we obtained data on individual-typological features of blood microcirculation in primary school children and the reserve capacity of tissue blood flow using functional tests. It is established that the adaptive features of the blood microcirculation system in boys and girls of early school age are due to different levels of local and central mechanisms of microvessel regulation. Results and discussion. The results obtained during the thermal test indicate different levels of reactivity of the body to increasing the temperature factor and the neurogenic vasoconstrictor effects of the sympathetic nervous system on the vessels of the arteriolar part of the microcirculatory tract. The reaction to the thermal test directly depends on the individual-typological features of blood microcirculation. Conclusion. At a ratio of reaction to thermal influence in children with various types of microcirculation, the maximum increase in tissue perfusion was observed in children with type III of laser Doppler flowgram. This level of microvascular reactivity, as well as the relatively rapid recovery of blood flow after thermal hyperemia is explained by the fact that children with hyperemic type of microcirculation have increased microvascular tone due to neurogenic effects of the sympathetic chain of tissue blood flow regulation. Children with the hypoemic type of microcirculation, on the other hand, have a somewhat reduced sympathetic tone relative to the normoemic type, as a result of which the reserve of capillary blood flow is reduced and the time of blood flow recovery after thermal exposure is prolonged

Oxygen dependence of glucose sensing: role in glucose homeostasis and related pathology.

In glucose homeostasis, glucose concentration is sensed by its metabolism through glucokinase (GCK) and oxidative phosphorylation. Because oxidative phosphorylation is an integral part of the sensory system, glucose sensing is necessarily dependent on oxygen pressure. Much of the dependence on oxygen is suppressed by location of glucose sensing cells in tissues with well-regulated blood flow. In healthy individuals the oxygen dependence is primarily observed in response to transient global hypoxia events such as during birth or transition to high altitude. The GCK sensing system is, however, used to control release of both insulin and glucagon, the preeminant hormonal regulators of blood glucose, as well as glucose sensitive neuronal activity. Suppression of oxygen delivery to glucose-sensing cells or interference with regulation of tissue blood flow by either local or systemic causes, stresses the glucose regulatory system. This is true whether the stress is imposed locally, such as by altered oxygen delivery to the pancreas, or globally, as in pulmonary insufficiency or exposure to high altitude. It may be expected that chronic application of this stress predisposes individuals to developing diabetes. Type 2 diabetes is a broad class of diseases characterized by disturbance of glucose homeostasis, i.e., having either hyperglycemia and/or decreased sensitivity to insulin. Given the role of oxidative phosphorylation in glucose sensing, tissue oxygen deprivation may predispose individuals to developing diabetes as well as contributing to the disease itself. This is particularly true in age-related diabetes because the incidence of vascular insufficiency increases markedly with increasing age. NEW & NOTEWORTHY Glucose sensing requires glucose metabolism through glycolysis and oxidative phosphorylation. Dependence of the latter on oxygen concentration imposes an oxygen dependence on glucose sensing. We have used a validated computational model to quantify that dependence. Evidence is presented that tissue oxygenation plays an important role in predisposition of individuals to developing type 2 diabetes and in progression of the disease.

Состояние макрогемодинамики и микроциркуляции у пациентов с окклюзионно-стенотическим поражением магистральных артерий нижних конечностей при различных типах реваскуляризующих вмешательств

Objective. The aim was to study the state of macrohemodynamics, microcirculatory bed and their relationship in patients with occlusive-stenotic lesions of the aorto-iliac-femoral arterial segment before and after revascularizing operations. Materials and methods. The results of the analysis of macrogemodynamic and microcirculatory bed state in 330 patients with obliterating atherosclerosis of lower limb arteries in various types of revascularizing interventions are presented: femoral-popliteal (group I, n=140), aorto-femoral (group II, n=97) bypass surgery, angioplasty with iliac artery stenting (group III, n=93). Results. There was a decrease in microcirculation in group I - 2.39 times, p<0.001, II - 3 times, p<0.001, III - 2.31 times, p<0.001, capillary blood flow reserve - in group I 1.63 times, p<0.001, II - 2.18 times, p<0.001, III - 1.77 times, p<0.001 and an increase in arterial-venular bypass regardless of the level of damage, as well as an oppression of endothelial mechanism and an increase in neurogenic mechanisms of regulation of microcirculation in all groups. Surgeries do not normalize microhemodynamics. Correlation interrelations of macrohemodynamics, changes in clinical status and microcirculation indices both in basal blood flow and under conditions of post-occlusive hyperemia were established. Changes in clinical status after surgery and bypass surgery had a negative-oriented correlation in all study groups (r=-0.2-0.3, p<0.05-0.01), and ankle-brachial index before and after surgery and RCC - the positive-oriented relationship (r=0.2-0.4, p<0.05-0.001). Conclusion. The state of microcirculation affects the change in clinical status after surgery, in this regard, it is necessary to take into account the parameters of microcirculation disorders and the mechanisms of regulation of tissue blood flow in surgical revascularization.

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles.

Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body's tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes. © 2017 American Physiological Society. Compr Physiol 7:485-581, 2017.

Microcirculatory dysfunction and tissue oxygenation in critical illness.

Severe sepsis is defined by organ failure, often of the kidneys, heart, and brain. It has been proposed that inadequate delivery of oxygen, or insufficient extraction of oxygen in tissue, may explain organ failure. Despite adequate maintenance of systemic oxygen delivery in septic patients, their morbidity and mortality remain high.The assumption that tissue oxygenation can be preserved by maintaining its blood supply follows from physiological models that only apply to tissue with uniformly perfused capillaries. In sepsis, the microcirculation is profoundly disturbed, and the blood supply of individual organs may therefore no longer reflect their access to oxygen.We review how capillary flow patterns affect oxygen extraction efficacy in tissue, and how the regulation of tissue blood flow must be adjusted to meet the metabolic needs of the tissue as capillary flows become disturbed as observed in critical illness. Using the brain, heart, and kidney as examples, we discuss whether disturbed capillary flow patterns might explain the apparent mismatch between organ blood flow and organ function in sepsis. Finally, we discuss diagnostic means of detecting capillary flow disturbance in animal models and in critically ill patients, and address therapeutic strategies that might improve tissue oxygenation by modifying capillary flow patterns.

Angiotensin-(1–7)–Induced Renal Vasodilation in Hypertensive Humans Is Attenuated by Low Sodium Intake and Angiotensin II Co-Infusion

Current evidence suggests that angiotensin-(1-7) plays an important role in the regulation of tissue blood flow. This evidence, however, is restricted to studies in animals and human forearm. Therefore, we studied the effects of intrarenal angiotensin-(1-7) infusion on renal blood flow in hypertensive humans. To assess the influence of renin-angiotensin system activity, sodium intake was varied and co-infusion with angiotensin II was performed in a subgroup. In 57 hypertensive patients who were scheduled for renal angiography, renal blood flow was measured ((133)Xenon washout method) before and during intrarenal infusion of angiotensin-(1-7) (3 incremental doses: 0.27, 0.9, and 2.7 ng/kg per minute). Patients were randomized into low or high sodium intake. These 2 groups of patients received angiotensin-(1-7), with or without intrarenal co-infusion of angiotensin II (0.3 ng/kg per minute). Angiotensin-(1-7) infusion resulted in intrarenal vasodilation in patients adhering to a sodium-rich diet. This vasodilatory effect of angiotensin-(1-7) was clearly attenuated by low sodium intake, angiotensin II co-infusion, or both. Regression analyses showed that the prevailing renin concentration was the only independent predictor of angiotensin-(1-7)-induced renal vasodilation. In conclusion, angiotensin-(1-7) induces renal vasodilation in hypertensive humans, but the effect of angiotensin-(1-7) is clearly attenuated by low sodium intake and co-infusion of angiotensin II. This supports the hypothesis that angiotensin-(1-7) induced renal vasodilation depends on the degree of renin-angiotensin-system activation.

MECHANISMS OF PERIPHERAL TISSUE BLOOD FLOW INFLUENCED BY HIGH SALT DIET IN YOUNG HEALTHY FEMALE HUMAN SUBJECTS

Cavka, A.1; Grizelj, I.1; Jelakovic, B.2; Lombard, J. H.3; Mihaljevic, I.4; Koller, A.5; Drenjancevic, I.1 Author Information

Postprandial Vascular Effects of VIAject Compared With Insulin Lispro and Regular Human Insulin in Patients With Type 2 Diabetes

OBJECTIVERecent studies suggested an impact of prandial insulin delivery on postprandial regulation of tissue blood flow. This study compared the effect of VIAject with human regular insulin and insulin lispro on postprandial oxidative stress and endothelial function in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSFourteen patients (seven men; aged 61.5 ± 1.8 years; duration of diabetes 6.6 ± 4.6 years; A1C 7.2 ± 0.5% [mean ± SEM]) received a prandial injection of VIAject, human regular insulin, and insulin lispro. At baseline and after a standardized liquid meal test (Ensure Plus), the postprandial increases in asymmetric dimethylarginine (ADMA) and nitrotyrosine levels were investigated. In addition, the postprandial effects on microvascular blood flow, skin oxygenation, and vascular elasticity were measured.RESULTSTreatment with VIAject resulted in a significant reduction in the peak postprandial generation of ADMA compared with human insulin and insulin lispro (VIAject −27.3 ± 22.6, human insulin 97.7 ± 24.4, and insulin lispro 66.9 ± 33.9 nmol/l; P < 0.05, respectively). The postprandial increases in nitrotyrosine levels were significantly less after VIAject than after human regular insulin (VIAject −0.22 ± 0.17 vs. human insulin 0.25 ± 0.15 μg/ml; P < 0.05), whereas nitrotyrosine after insulin lispro was in between (insulin lispro 0.09 ± 0.07 μg/ml; NS). In parallel, earlier and more pronounced increases in microvascular blood flow and skin oxygenation were obtained after VIAject compared with those after human insulin or insulin lispro (P < 0.05, respectively). All insulin formulations resulted in comparable improvements in central arterial elasticity.CONCLUSIONSTreatment with VIAject reduced postprandial oxidative stress and improved endothelial function compared with human regular insulin or insulin lispro.

Increased myogenic responsiveness of skeletal muscle arterioles with juvenile growth

Previous studies from this laboratory suggest that during juvenile growth, structural changes in the arteriolar network are accompanied by changes in some of the mechanisms responsible for regulation of tissue blood flow. To test the hypothesis that arteriolar myogenic behavior is altered with growth, we studied gracilis muscle arterioles isolated from Sprague-Dawley rats at two ages: 21-28 and 42-49 days. When studied at their respective in vivo pressures, the myogenic index (instantaneous slope of the active pressure-diameter curve) of arterioles from 42-49-day-old rats was more negative than that of arterioles from 21-28-day-old rats, indicating greater myogenic responsiveness. Endothelial denudation, or prostaglandin H(2) (PGH(2))/thromboxane A(2) (TxA(2)) receptor antagonism without denudation, significantly reduced the myogenic responsiveness of arterioles from the older rats over a wide range of pressures but had no consistent effects on the myogenic responsiveness of arterioles from the younger rats. The heme oxygenase inhibitor chromium (III) mesoporphyrin IX chloride had no effect on the myogenic activity of arterioles from either age group. These findings indicate that microvascular growth in young animals is accompanied by an increase in the myogenic behavior of arterioles, possibly because PGH(2) or TxA(2) assumes a role in reinforcing myogenic activity over this period. As a result, the relative contribution of myogenic activity to blood flow regulation in skeletal muscle may increase during rapid juvenile growth.

Growth-dependent changes in endothelial factors regulating arteriolar tone

Previous studies from this laboratory suggest that during maturation, rapid microvascular growth is accompanied by changes in the mechanisms responsible for regulation of tissue blood flow. To further define these changes, we studied isolated gracilis muscle arterioles from weanling ( approximately 25 days) and juvenile ( approximately 44 days) Sprague-Dawley rats to test the hypothesis that endothelial mechanisms for the control of arteriolar tone are altered with growth. Responses to the endothelium-dependent dilator acetylcholine (ACh) were greater in weanling arterioles (WA) than in juvenile arterioles (JA), whereas there were no consistent differences between age groups in arteriolar responses to other endothelium-dependent agonists (A-23187, vascular endothelial growth factor, and simvastatin). Inhibition of nitric oxide synthase (NOS) with N(omega)-nitro-l-arginine methyl ester (l-NAME) attenuated ACh-induced dilation in JA but not in WA. In JA, combined inhibition of NOS and cyclooxygenase (with indomethacin) reduced the dilator responses to ACh and simvastatin by approximately 90% and approximately 70%, respectively, but had no effect in WA. Cytochrome P450 epoxygenase inhibition [with 2-(propargyloxyphenyl) hexanoic acid] had no effect on responses to ACh or simvastatin in either age group. Inhibition of Ca(2+)-activated or ATP-dependent potassium channels (with tetraethylammonium or glibenclamide, respectively) reduced these arteriolar responses in JA but not those in WA. These findings suggest that in fully grown microvascular networks, endothelium-dependent arteriolar dilation is mediated by the combined release of endothelial nitric oxide and vasodilator prostanoids, and in part through activation of Ca(2+)-activated and ATP-dependent potassium channels. However, during earlier microvascular growth, this dilation is mediated by other factors yet to be identified. This may have significant implications for the regulation of tissue perfusion during microvascular development.

Arthur C. Guyton, MD

The sudden loss of Dr Arthur C. Guyton in an automobile accident on April 3, 2003 and the loss of his devoted and remarkable wife, Ruth Weigle Guyton, one week later as a result of injuries from the accident stunned and saddened all who were privileged to know them. Arthur Guyton was a giant in the fields of physiology and medicine, a leader among leaders, a master teacher, and an inspiring role model for people throughout the world. Arthur Clifton Guyton was born in Oxford, Mississippi, to Dr William (Billy) S. Guyton, an eye, ear, nose, and throat specialist and dean of the University of Mississippi Medical School, and Kate Smallwood Guyton, a math and physics teacher who had been a missionary in China before their marriage. During his formative years, he enjoyed watching his father work at the Guyton Clinic, playing chess and swapping stories with William Faulkner, and building sailboats (one of which he later sold to Faulkner) and countless mechanical and electrical devices, which he continued to do throughout his life. Arthur Guyton’s brilliance shone early. He graduated top in his class at the University of Mississippi, distinguished himself at Harvard Medical School, and began his postgraduate surgical training at Massachusetts General Hospital. His medical training was interrupted twice—once to serve in the Navy during World War II and again in 1946 when he was stricken with poliomyelitis during his final year of residency training. Suffering paralysis in his right leg, left arm, and both shoulders, he spent nine months in Warm Springs, Georgia, recuperating and applying his inventive mind to building the first motorized wheelchair controlled by a “joy stick,” motorized hoists for lifting patients, special leg braces, and other devices to aid the handicapped. For those inventions he received a Presidential Citation. He returned to …

Relation between oxygen consumption and cardiac output during inhalation anesthesia under the influence of catecholamines. A study in dogs

The metabolic regulation of tissue blood flow manifests itself in a linear relation between blood flow and oxygen consumption (VO2). It is unknown, however, if this fundamental physiological principle operates also during inhalation anaesthesia and catecholamine therapy, both known to be associated with changes of cardiac output (Q) and VO2 in opposite directions. On different days, 17 trained, healthy dogs (26-33 kg) with chronically implanted flow probes around the pulmonary artery were either anaesthetized with halothane, enflurane, isoflurane, sevoflurane, and desflurane at increasing minimum alveolar concentrations (1-3 MAC) or treated with one of the endogenous catecholamines epinephrine and norepinephrine or the synthetic ones dobutamine and dopexamine (a total of 186 experiments). Cardiac Output (ultrasound transit-time flowmeter) and VO2 (indirect calorimetry) were measured continuously and the relations between both variables (Q/VO2 relations) analyzed. In awake dogs under basal metabolic conditions, VO2 was 4.6 +/- 0.1 ml x kg-1 x min-1 and Q 105 +/- 3 ml x kg-1 x min-1 (mean +/- SEM). During inhalation anaesthesia, VO2 and Q decreased in parallel, yielding a uniform Q/VO2 relation, which was nearly linear. Above 2 MAC, O2 extraction increased by 50%, indicating compromised oxygen delivery (DO2). Imposed increases in Q and thus DO2 during anaesthesia to rates comparable to that in the awake state did not restore VO2 to baseline. Catecholamines increased both VO2 and Q in a dose-dependent manner, albeit to a different extent. The resulting Q/VO2 relations were linear up to the maximum effects, but their slopes increased about threefold in the order norepinephrine (34), epinephrine (54), dobutamine (86), and dopexamine (105). Despite these differences, VO2 and Q correlated linearly over the whole range studied, which covered a doubling of VO2 and an up to fourfold increase in Q. The metabolic regulation of blood flow apparently also operates during inhalation anaesthesia, regardless of the anaesthetic. Catecholamines (except norepinephrine) preferentially stimulated Q rather than VO2 (excess perfusion), so that agents like dopexamine might be preferred in the treatment of low cardiac output states because of its low metabolic costs. Our observations imply that cardiac output alone provides little information on the function of the circulation during inhalation anaesthesia and catecholamine therapy unless related to metabolic demands, i.e. to VO2.

3453 Mucosal hemodynamics in the watershed area of the normal colon and in hemodialysis and oxygendependent patients.

Patients on chronic hemodialysis (HD) are prone to develop ischemic colitis. The effect of the state of tissue oxygenation upon the regulation of tissue blood flow has not been well described in human studies. Aim:We used the endoscopic reflectance spectrophotometry technique which provides an index of hemoglobin concentration (IHb) and index of oxygen saturation (ISO2) to evaluate the above issues. Methods: Controls (n=11), oxygendependent (n=7) and HD (n=9) patients underwent sigmoidoscopy and IHb and ISO2 readings were obtained at the watershed area (20 cm from the anal verge) of the sigmoid colon. In the O2-dependent patients, measurements were made off and on O2 supplementation while peripheral O2 saturation was monitored by pulse oxymetry. Results: The results are summarized in the Table below. In O2-dependent patients pulse oxymetry readings were significantly lower off O2 than on O2 (85.2 ± 0.3% vs. 94.1 ± 0.2%; p

Effects of recombinant eNOS gene expression on reactivity of small cerebral arteries.

Resistance arteries are an important target for vascular gene therapy because they play a key role in the regulation of tissue blood flow. The present study was designed to determine the effects of recombinant endothelial (e) nitric oxide synthase (NOS) gene expression on vasomotor reactivity of small brain stem arteries (internal diameter, 253 +/- 2.5 microm). Arterial rings were exposed ex vivo to an adenoviral vector (10(9) and 10(10) plaque-forming units/ml) encoding eNOS gene or beta-galactosidase gene. Twenty-four hours after transduction, vascular function was examined by isometric force studies. Transgene expression was evident mainly in adventitia. In arteries with endothelium transduced with eNOS gene but not with control beta-galactosidase gene, relaxations to bradykinin and substance P were significantly augmented. Removal of endothelium abolished relaxations to bradykinin and substance P in control and beta-galactosidase arteries. However, in endothelium-denuded arteries transduced with recombinant eNOS, bradykinin and substance P caused relaxations that were abolished in the presence of the NOS inhibitor N(G)-nitro-L-arginine methyl ester. In control arteries, endothelium removal augmented relaxations to the nitric oxide donors sodium nitroprusside and diethylamine NONOate. This augmentation was absent in eNOS gene-transduced arteries without endothelium. Our results suggest that, in small brain stem arteries, expression of recombinant eNOS increases biosynthesis of nitric oxide. Adventitia of small arteries is a good target for expression of recombinant eNOS. Genetically engineered adventitial cells may serve as a substitute source of nitric oxide in cerebral arteries with dysfunctional endothelium.

Neuronal control of mesenteric circulation

The mesenteric circulation plays an important role in maintenance of systemic blood pressure and regulation of tissue blood flow. The tone of the mesenteric artery and resistance blood vessels are mainly regulated by sympathetic adrenergic nerves through the release of neurotransmitter noradrenaline and also controlled by nonadrenergic noncholinergic (NANC) nerves and possibly by parasympathetic cholinergic nerves. Noradrenaline and adrenergic cotransmitters including neuropeptide Y and adenosine triphosphate act as a vasoconstrictor neurotransmitter for sympathetic nerves. While, dopamine, calcitonin gene-related peptide and acetylcholine act as a vasodilator neurotransmitter for adrenergic, NANC and cholinergic nerves, respectively. In the mesenteric circulation, these nerves containing various neurotransmitters and cotransmitters interact and modulate each other via feedback autoregulatory mechanisms and neuromodulation of various vasoactive substance to regulate vascular resistance.

EARLY ENDOTOXIC SHOCK RESULTS IN ENHANCED VASODILATOR RESPONSES TO NITROGLYCERIN BUT UNALTERED RESPONSES TO NEUROPEPTIDES CALCITONIN GENE-RELATED PEPTIDE AND SUBSTANCE P

To determine the role that vasoactive neuropeptides, calcitonin gene-related peptide, and substance P play in tissue-blood flow regulation during early septic shock, we examined the responsiveness of arteries removed from pigs 3 h after administration of Escherichia coli lipopolysaccharide or saline vehicle. The carotid, cranial mesenteric, and left anterior descending coronary arteries were excised, and rings were cut from each vessel. Constrictor responses were obtained to cumulative doses of norepinephrine or potassium chloride. Rings were reconstricted and challenged with acetylcholine, substance P, calcitonin gene-related peptide, and nitroglycerin. Lipopolysaccharide significantly increased the cranial mesenteric artery's response to high concentrations of norepinephrine and the response to nitroglycerin in all vessels. This enhancement of responses to nitroglycerin suggests augmented smooth-muscle responsiveness to an exogenous source of nitric oxide, possibly associated with early depression of basal endothelial function. Depression of agonist-induced nitric oxide release may mask such enhancement with endothelial-dependent dilators and may enhance the response to adrenergic constrictors in some vascular beds.

The contribution of cytochrome P450-dependent arachidonate metabolites to integrated renal function

Arachidonic acid can be metabolized to diverse products which differ widely in their biological activities. These metabolites affect basic biological mechanisms such as vascular reactivity and transport function in critical nephron segments. Metabolism of arachidonic acid is discretely localized to specific cells and differs within segments of the nephron; for example, cells of the medullary ascending limb of Henle's loop have a considerable capacity to generate cytochrome P450-dependent arachidonate metabolites but have neglible cyclooxygenase activity. Arachidonic acid metabolites participate in fluid and electrolyte homeostasis, and in the regulation of tissue blood flow, and act as modulators of vasoactive hormones, and, thereby, make important contributions to integrated renal function.

ET-3 sensitive reduction of tissue blood flow in rat liver

Changes in gastric mucosal and hepatic tissue blood flow were simultaneously determined using a laser-Doppler blood flow meter in rats given i.v. injection of endothelin-1 (ET-1) and endothelin-3 (ET-3), both at 2 nmol/kg. Gastric mucosal blood flow decreased significantly after administration of ET-1 compared to after administration of ET-3. Decreases in blood flow due to ET-1 were reversed by pre-treatment with 10 mg/kg of BQ-123 (sodium salt), an ETA receptor antagonist, to levels comparable to those induced by ET- 3, but BQ-123 had no effects on decreases in blood flow due to ET-3. On the other hand, decreases in hepatic tissue blood flow by ET-3 were significant compared to those by ET-1. Decreases in hepatic tissue blood flow due to ET-1 were slightly inhibited by pre-treatment with 10 mg/kg of BQ-123, but it had no effect at all on decreases due to ET-3. These findings indicate that decreases in gastric mucosal blood flow are mainly caused by ET-1 via ETA receptors inhibited by BQ-123, while decreases in hepatic tissue blood flow are caused mainly by ET-3 via non-ETA receptors not inhibited by BQ-123. The fact that ET-3 decreases blood flow more significantly than ET-1 suggests the involvement of ET-3 selective receptors (ETc). The findings obtained in the present study indicate that complex mechanisms are involved in the regulation of tissue blood flow by ET, with different receptor subtypes and ET family peptides being involved according to the type of tissue.

Arachidonate metabolites and kinins in blood pressure regulation.

Arachidonic acid (AA) can be metabolized to an array of products affecting biological mechanisms such as those governing vascular reactivity and transport function. Metabolism of AA by cyclooxygenase in the nephron is discretely localized and is overshadowed in some nephron segments by a considerable capacity to generate P-450 AA metabolites. The synthesis of renal P-450 AA products is increased in hypertension. AA metabolites participate in fluid and electrolyte homeostasis and regulation of tissue blood flow and act as modulators of pressor systems. In addition, eicosanoids either augment or mediate the vasodilator-diuretic actions of the kallikrein-kinin system.