Contrasting effects of circulating nitric oxide and nitrergic transmission on exocrine pancreatic secretion in rats

Background—Nitric oxide (NO) blockade byl-nitroarginine methyl ester (l-NAME) inhibits pancreatic secretion in vivo and aggravates caerulein induced pancreatitis. Nitric oxide synthase (NOS) is present in pancreatic islets, endothelium, and nerve fibres. l-NAME blocks all known NOS isoforms.Aim—To investigate the source of NO blocked byl-NAME that inhibits amylase secretion.Methods—Amylase output was measured in rats in response to caerulein (0.1–50 μg/kg) alone or with indazole. Baseline secretion and the response to supramaximal caerulein were also examined after administration of indazole, l-NAME, haemoglobin, or aminoguanidine under continuous blood pressure measurement. In separate experiments, pancreatic secretion was measured after blockade of afferent nerve fibres by either systemic or local capsaicin. The effect of neural NOS inhibition on caerulein induced pancreatitis was also investigated.Results—l-NAME, haemoglobin, and supramaximal caerulein (10 μg/kg) increased blood pressure, whereas indazole and suboptimal caerulein (0.1 μg/kg) did not. Indazole and capsaicin decreased basal amylase output. l-NAME and haemoglobin reduced basal amylase output to a lesser extent and potentiated the inhibitory response to supramaximal caerulein. In contrast, full neural NOS inhibition by l-NAME partially reversed the expected caerulein induced suppression of amylase output. This effect was reproduced by indazole and capsaicin. Indazole did not alter responses to either optimal (0.25 μg/kg) or suboptimal (0.1 μg/kg) caerulein, nor, in contrast with l-NAME, aggravate the outcome of caerulein induced pancreatitis.Conclusions—Reduction of circulating NO availability, probably of endothelial origin, is responsible for the decrease in amylase secretion observed in the early response tol-NAME. Nitrergic neurotransmission plays an important role in the control of pancreatic secretion and may induce opposite effects to endothelial NOS activity.

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Effect of CCK antagonist L 364718 on meal-induced pancreatic secretion in rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1990.258.2.g179 ◽

1990 ◽

Vol 258 (2) ◽

pp. G179-G184 ◽

Cited By ~ 2

Author(s):

M. F. O'Rourke ◽

R. D. Reidelberger ◽

T. E. Solomon

Keyword(s):

Pancreatic Secretion ◽

Competitive Inhibition ◽

Pancreatic Enzyme ◽

Enzyme Secretion ◽

Amylase Secretion ◽

Liquid Meal ◽

Amylase Output ◽

Pancreatic Enzyme Secretion ◽

Cck Receptor Antagonist

The specific cholecystokinin (CCK)-receptor antagonist L 364718 was used to examine the role of CCK in meal-induced pancreatic secretion. Unanesthetized rats with gastric, jugular vein, bilepancreatic, and duodenal cannulas were used; bile-pancreatic juice was recirculated. Basal amylase secretion (30% of maximal) was not inhibited by L 364718 doses of 0.5 or 2 mg/kg intravenously. L 364718 (0.02 to 2 mg/kg) caused dose-related inhibition of the maximal amylase response to CCK-8 (200 pmol.kg-1.h-1), with greater than 80% inhibition at doses greater than or equal to 0.5 mg/kg. L 364718 (0.5 mg/kg) shifted the dose-response curve to CCK-8 (25-3,200 pmol.kg-1.h-1) to the right (ED50 increased 10-fold) but did not alter maximal amylase output consistent with competitive inhibition of CCK in vivo. Ingestion of liquid food significantly increased amylase output threefold above basal. L 364718 (0.5 mg/kg) completely blocked this response. These results suggest that although CCK does not regulate basal pancreatic enzyme secretion, it is the primary mediator of pancreatic enzyme secretion in response to a liquid meal.

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Abstract P388: Extra-cardiac BCAA Catabolism Lowers Blood Pressure And Protects From Heart Failure

Circulation Research ◽

10.1161/res.129.suppl_1.p388 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Danielle Murashige ◽

Cholsoon Jang ◽

Michael Neinast ◽

Michael Levin ◽

Jae Woo Jung ◽

...

Keyword(s):

Nitric Oxide ◽

Heart Failure ◽

Blood Pressure ◽

Mendelian Randomization ◽

Multiple Models ◽

Direct Effects ◽

Heavy Isotope ◽

Branched Chain Amino Acid ◽

Branched Chain

Pharmacologic activation of branched chain amino acid (BCAA) catabolism is protective in numerous models of heart failure (HF). How this protection occurs has remained unclear, although a causative block in cardiac BCAA oxidation has been proposed. We use here in vivo heavy isotope infusion studies to show that cardiac preference for BCAA oxidation increases, rather than decreases, in multiple models of HF. We use various genetic models to show that cardiac-specific activation of BCAA oxidation does not protect from HF, even though systemic activation of BCAA oxidation does. Lowering plasma and cardiac BCAAs by genetic means is also not sufficient to confer protection comparable to that conferred by pharmacologic activation of BCAA oxidation, suggesting alternative mechanisms of protection. Surprisingly, telemetry and invasive hemodynamic studies showed that pharmacological activation of BCAA catabolism lowers blood pressure, a well-established cardioprotective mechanism. The effects on blood pressure occurred independently of nitric oxide (NO), and reflected a vascular resistance to adrenergic constriction. Finally, mendelian randomization studies revealed that elevations in plasma BCAAs portend higher blood pressure in large human cohorts. Together, these data indicate that activation of BCAA oxidation lowers blood pressure and protects from heart failure independently of any direct effects on the heart itself.

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Blood Pressure Measurement

The Physics, Clinical Measurement and Equipment of Anaesthetic Practice for the FRCA ◽

10.1093/oso/9780199595150.003.0016 ◽

2011 ◽

Author(s):

Patrick Magee ◽

Mark Tooley

Keyword(s):

Blood Pressure ◽

Arterial Pressure ◽

Pressure Measurement ◽

Blood Pressure Measurement ◽

Measurement Techniques ◽

Non Invasive ◽

Mercury Column ◽

Arterial Pressure Measurement ◽

Mercury Manometer

Blood pressure measurement occurs either non-invasively or invasively, and usually refers to systemic arterial pressure measurement, but can also refer to systemic venous or pulmonary arterial pressure measurement. In 1733 the Reverend Stephen Hales was the first person to measure the blood pressure in vivo in unanaesthetised horses by direct cannulation of the carotid and femoral arteries. In doing so he observed the pulsatile nature of flow in the circulation. In 1828 Poiseuille developed the mercury manometer, and used it to measure blood pressure in a dog. The mercury manometer has, of course, become the standard technique against which other techniques are compared. The earliest numerical information on blood pressure measurement came from direct rather than indirect measurement in 1856 by Faivre, using Poiseuille’s device. However, in the last part of the nineteenth century, non-invasive measurement techniques were developed. In 1903, Codman and Cushing introduced the concept of routine intraoperative blood pressure measurement, which at the time was a revolutionary concept. Nowadays it is a fundamental part of minimal monitoring criteria. There are several techniques of non-invasive BP (NIBP) measurement, all of which function by occluding the pulse in a limb with a proximal cuff, then detecting its onset again distally, on lowering the cuff pressure. Detection methods include palpation, auscultation, plethysmography, oscillotonometry and oscillometry. Accuracy of all non-invasive techniques depends on cuff size in relation to the limb concerned, and over which artery the cuff is placed. Such techniques of NIBP measurement are necessarily intermittent. Much discussion has taken place on the accuracy of these devices, and the accuracy of diastolic pressure measurements needs improving, and there are ideas proposed for new non-invasive devices [Tooley and Magee 2009]. In the absence of a stethoscope, this technique is simple and reliable. After inflating the cuff on the upper arm to a pressure of above that of systolic, the cuff is then deflated while palpating the brachial artery and the systolic pressure is measured with a mercury column at first detection of the pulse. A study by van Bergen [1954] showed that BP can be underestimated by this method by up to 25% at 120 mmHg.

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Neither endogenous nor inhaled nitric oxide influences the function of circulating platelets in healthy volunteers

Clinical Science ◽

10.1042/cs0970345 ◽

1999 ◽

Vol 97 (3) ◽

pp. 345-353 ◽

Cited By ~ 9

Author(s):

Johanna ALBERT ◽

N. Håkan WALLÉN ◽

Nailin LI ◽

Claes FROSTELL ◽

Paul HJEMDAHL

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Heart Rate ◽

Healthy Volunteers ◽

Thrombin Generation ◽

Bleeding Time ◽

Flow Cytometric ◽

Fibrinogen Binding ◽

Inhaled No

Experimental models have indicated prothrombotic effects of inhibition of nitric oxide (NO) production, and anti-thrombotic effects of inhaled NO, but the influence of NO on platelet function in vivo in humans is not well established. We therefore investigated the effects of systemic inhibition of NO synthesis by NG-monomethyl-⌊-arginine (⌊-NMMA) and of NO inhalation on platelet function in vivo. On two occasions, ⌊-NMMA (13.5 mg/kg) or saline infusion was administered to 14 healthy volunteers in a double-blind cross-over study. After a 30 min infusion of ⌊-NMMA or placebo, NO inhalation (30 p.p.m) was added during the remaining 30 min of infusion, on both occasions. Measurements included filtragometry ex vivo (reflecting platelet aggregability), flow-cytometric evaluation of platelets in whole blood (fibrinogen binding and P-selectin expression), plasma β-thromboglobulin (reflecting platelet secretion), cGMP in platelets and plasma, thrombin generation markers (thrombin fragment 1+2 and thrombin–antithrombin complexes) in plasma, and bleeding time. l-NMMA increased blood pressure and decreased heart rate. NO inhalation did not influence blood pressure or heart rate, but caused a 3-fold elevation in plasma cGMP levels (P < 0.001). Neither ⌊-NMMA nor NO influenced filtragometry readings or flow-cytometric determinations of platelet fibrinogen binding and P-selectin expression. Furthermore, plasma β-thromboglobulin, platelet cGMP and thrombin generation markers were not influenced by either treatment. Bleeding time was not influenced by ⌊-NMMA compared with placebo, but was increased by ≈ 25% during NO inhalation (P < 0.01), whether NO synthesis had been inhibited or not. The prolongation of bleeding time by inhaled NO was not accompanied by any effect on the platelet variables assessed. The present results indicate that circulating platelets are not influenced by endogenous or inhaled NO, presumably due to the rapid inactivation of NO in the blood. This does not exclude possible effects of endothelial NO in the interface between the blood and the vessel wall.

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The active form of vitamin D, calcitriol, induces a complex dual upregulation of endothelin and nitric oxide in cultured endothelial cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00156.2014 ◽

2014 ◽

Vol 307 (12) ◽

pp. E1085-E1096 ◽

Cited By ~ 32

Author(s):

Patricia Martínez-Miguel ◽

Jose Manuel Valdivielso ◽

Diana Medrano-Andrés ◽

Pablo Román-García ◽

Jose Luis Cano-Peñalver ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Vitamin D ◽

Endothelial Cells ◽

Active Form ◽

Vasoactive Factors ◽

Slight Rise ◽

Endothelial Nitric Oxide ◽

In Cells

Despite the presence of vitamin D receptor (VDR) in endothelial cells, the effect of vitamin D on endothelial function is unknown. An unbalanced production of vasoactive endothelial factors such as nitric oxide (NO) or endothelin-1 (ET-1) results in endothelial dysfunction, which can alter the normal cardiovascular function. Present experiments were devoted to assess the effect of active vitamin D (calcitriol) on the synthesis of endothelial vasoactive factors. The results were that, in cells, calcitriol increased ET-1 and NO productions, which were measured by ELISA and fluorimetric assay, respectively. Calcitriol also increased endothelin-converting enzyme-1 (ECE-1) and endothelial-nitric oxide synthase (eNOS) activities, their mRNA (qPCR), their protein expressions (Western-blot), and their promoter activities (transfection assays). Calcitriol did not change prepro-ET-1 mRNA. The effect was specific to VDR activation because when VDR was silenced by siRNA, the observed effects disappeared. Mechanisms involved in each upregulation differed. ECE-1 upregulation depended on AP-1 activation, whereas eNOS upregulation depended directly on VDR activation. To evaluate the in vivo consequences of acute calcitriol treatment, normal Wistar rats were treated with a single ip injection of 400 ng/kg calcitriol and euthanized 24 h later. Results confirmed those observed in cells, that production and expression of both factors were increased by calcitriol. Besides, calcitriol-treated rats showed a slight rise in mean blood pressure, which decreased when pretreated with FR-901533, an ECE-1 antagonist. We conclude that calcitriol increases the synthesis of both ET-1 and NO in endothelial cells. However, the ET-1 upregulation seems to be biologically more relevant, as animals acutely treated with calcitriol show slight increases in blood pressure.

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The Interaction of Calcium Entry and Calcium Sensitization in the Control of Vascular Tone and Blood Pressure of Normotensive and Hypertensive Rats

Physiological Research ◽

10.33549/physiolres.932639 ◽

2014 ◽

pp. S19-S27 ◽

Cited By ~ 10

Author(s):

J. ZICHA ◽

M. BEHULIAK ◽

M. PINTÉROVÁ ◽

M. BENCZE ◽

J. KUNEŠ ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Rho Kinase ◽

Calcium Entry ◽

Experimental Hypertension ◽

Hypertensive Rats ◽

Calcium Sensitization ◽

Wky Rats ◽

Kinase Pathway

Increased systemic vascular resistance is responsible for blood pressure (BP) elevation in most forms of human or experimental hypertension. The enhanced contractility of structurally remodeled resistance arterioles is mediated by enhanced calcium entry (through L type voltage-dependent calcium channels – L-VDCC) and/or augmented calcium sensitization (mediated by RhoA/Rho kinase pathway). It is rather difficult to evaluate separately the role of these two pathways in BP control because BP response to the blockade of either pathway is always dependent on the concomitant activity of the complementary pathway. Moreover, vasoconstrictor systems enhance the activity of both pathways, while vasodilators attenuate them. The basal fasudil-sensitive calcium sensitization determined in rats deprived of endogenous renin-angiotensin system (RAS) and sympathetic nervous system (SNS) in which calcium entry was dose-dependently increased by L-VDCC opener BAY K8644, is smaller in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto (WKY) rats. In contrast, if endogenous RAS and SNS were present in intact rats, fasudil caused a greater BP fall in SHR than WKY rats. Our in vivo experiments indicated that the endogenous pressor systems (RAS and SNS) augment calcium sensitization mediated by RhoA/Rho kinase pathway, whereas the endogenous vasodilator systems (such as nitric oxide) attenuate this pathway. However, the modulation of calcium entry and calcium sensitization by nitric oxide is strain-dependent because NO deficiency significantly augments low calcium entry in WKY and low calcium sensitization in SHR. Further in vivo and in vitro experiments should clarify the interrelationships between endogenous vasoactive systems and the contribution of calcium entry and/or calcium sensitization to BP maintenance in various forms of experimental hypertension.

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New Therapeutic Insight into the Effect of Ma Huang Tang on Blood Pressure and Renal Dysfunction in the L-NAME-Induced Hypertension

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/9980429 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Mi Hyeon Hong ◽

Hye Yoom Kim ◽

Youn Jae Jang ◽

Se Won Na ◽

Byung Hyuk Han ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Renal Function ◽

Intima Media Thickness ◽

Dependent Manner ◽

Vascular Relaxation ◽

Sprague Dawley ◽

Induced Hypertension ◽

Ma Huang

In this study, we evaluated the effect of a traditional herbal formula, Ma Huang Tang (MHT), on blood pressure and vasodilation in a rat model of NG‐nitro‐L‐arginine methylester- (L-NAME-) induced hypertension. We found that MHT-induced vascular relaxation in a dose-dependent manner in rat aortas pretreated with phenylephrine. However, pretreatment of endothelium-intact aortic rings with L‐NAME, an inhibitor of nitric oxide synthesis (NOS), or 1H‐[1, 2, 4]‐oxadiazole‐[4, 3‐α]‐quinoxalin‐1‐one (ODQ), an inhibitor of soluble guanylyl cyclase, significantly abolished vascular relaxation induced by MHT. MHT also increased the production of guanosine 3′,5′-cyclic monophosphate (cGMP) in the aortic rings pretreated with L-NAME or ODQ. To examine the in vivo effects of MHT, Sprague Dawley rats were treated with 40 mg/kg/day L-NAME for 3 weeks, followed by administration of 50 or 100 mg/kg/day MHT for 2 weeks. MHT was found to significantly normalize systolic blood pressure and decreased intima-media thickness in aortic sections of rats treated with L-NAME compared to that of rats treated with L-NAME alone. MHT also restored the L-NAME-induced decrease in vasorelaxation response to acetylcholine and endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) expression. Furthermore, MHT promoted the recovery of renal function, as indicated by osmolality, blood urea nitrogen (BUN) levels, and creatinine clearance. These results suggest that MHT-induced relaxation in the thoracic aorta is associated with activation of the nitric oxide/cGMP pathway. Furthermore, it provides new therapeutic insights into the regulation of blood pressure and renal function in hypertensive patients.

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3-Hydroxyphenylacetic Acid: A Blood Pressure-Reducing Flavonoid Metabolite

Nutrients ◽

10.3390/nu14020328 ◽

2022 ◽

Vol 14 (2) ◽

pp. 328

Author(s):

Patrícia Dias ◽

Jana Pourová ◽

Marie Vopršalová ◽

Iveta Nejmanová ◽

Přemysl Mladěnka

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Ex Vivo ◽

Laboratory Animals ◽

Spontaneously Hypertensive ◽

Porcine Coronary Artery ◽

Arterial Blood ◽

Hydroxyphenylacetic Acid ◽

Dose Dependent Decrease

Regular intake of polyphenol-rich food has been associated with a wide variety of beneficial health effects, including the prevention of cardiovascular diseases. However, the parent flavonoids have mostly low bioavailability and, hence, their metabolites have been hypothesized to be bioactive. One of these metabolites, 3-hydroxyphenylacetic acid (3-HPAA), formed by the gut microbiota, was previously reported to exert vasorelaxant effects ex vivo. The aim of this study was to shed more light on this effect in vivo, and to elucidate the mechanism of action. 3-HPAA gave rise to a dose-dependent decrease in arterial blood pressure when administered i.v. both as a bolus and infusion to spontaneously hypertensive rats. In contrast, no significant changes in heart rate were observed. In ex vivo experiments, where porcine hearts from a slaughterhouse were used to decrease the need for laboratory animals, 3-HPAA relaxed precontracted porcine coronary artery segments via a mechanism partially dependent on endothelium integrity. This relaxation was significantly impaired after endothelial nitric oxide synthase inhibition. In contrast, the blockade of SKCa or IKCa channels, or muscarinic receptors, did not affect 3-HPAA relaxation. Similarly, no effects of 3-HPAA on cyclooxygenase nor L-type calcium channels were observed. Thus, 3-HPAA decreases blood pressure in vivo via vessel relaxation, and this mechanism might be based on the release of nitric oxide by the endothelial layer.

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Vascular hyporesponsiveness in simulated microgravity: role of nitric oxide-dependent mechanisms

Journal of Applied Physiology ◽

10.1152/jappl.2000.88.2.507 ◽

2000 ◽

Vol 88 (2) ◽

pp. 507-517 ◽

Cited By ~ 43

Author(s):

D. Sara Sangha ◽

N. D. Vaziri ◽

Y. Ding ◽

R. E. Purdy

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Carotid Artery ◽

Femoral Artery ◽

Simulated Microgravity ◽

Fold Increase ◽

Mechanical Removal ◽

Inducible Nos

Simulated microgravity depresses the ability of arteries to constrict to norepinephrine (NE). In the present study the role of nitric oxide-dependent mechanisms on the vascular hyporesponsiveness to NE was investigated in peripheral arteries of the rat after 20 days of hindlimb unweighting (HU). Blood vessels from control rats and rats subjected to HU (HU rats) were cut into 3-mm rings and mounted in tissue baths for the measurement of isometric contraction. Mechanical removal of the endothelium from carotid artery rings, but not from aorta or femoral artery rings, of HU rats restored the contractile response to NE toward control. A 10-fold increase in sensitivity to ACh was observed in phenylephrine-precontracted carotid artery rings from HU rats. In the presence of the nitric oxide synthase (NOS) substratel-arginine, the inducible NOS inhibitor aminoguanidine (AG) restored the contractile responses to NE to control levels in the femoral, but not carotid, artery rings from HU rats. In vivo blood pressure measurements revealed that the peak blood pressure increase to NE was significantly greater in the control than in the HU rats, but that to AG was less than one-half in control compared with HU rats. These results indicate that the endothelial vasodilator mechanisms may be upregulated in the carotid artery, whereas the inducible NOS expression/activity may be increased in the femoral artery from HU rats. These HU-mediated changes could produce a sustained elevation of vascular nitric oxide levels that, in turn, could contribute to the vascular hyporesponsiveness to NE.

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Abstract 167: A Cell-Autonomous Role for Endothelial GTP Cyclohydrolase 1 and Tetrahydrobiopterin in Blood Pressure Regulation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.167 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Surawee Chuaiphichai ◽

Eileen McNeill ◽

Gillian Douglas ◽

Mark J Crabtree ◽

Jennifer K Bendall ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Endothelial Cell ◽

De Novo ◽

Soluble Guanylate Cyclase ◽

Ex Vivo ◽

Mesenteric Arteries ◽

Gtp Cyclohydrolase ◽

Enos Uncoupling

Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase (eNOS) function and nitric oxide (NO) generation. Augmentation of BH4 levels can prevent eNOS uncoupling and improve endothelial dysfunction in vascular disease states. However, the physiological requirement for de-novo endothelial cell BH4 biosynthesis in eNOS function remains unclear. We generated a novel mouse model with endothelial cell-specific deletion of GCH1, encoding GTP cyclohydrolase 1, an essential enzyme for BH4 biosynthesis, to test the cell-autonomous requirement for endothelial BH4 biosynthesis in vivo. Mice with a floxed GCH1 allele ( GCH1 fl/fl ) were crossed with Tie2cre mice to delete GCH1 in endothelial cells. GCH1 fl/fl Tie2cre mice demonstrated virtually absent NO bioactivity and significantly greater O 2 • - production. GCH1 fl/fl Tie2cre aortas and mesenteric arteries had enhanced vasoconstriction to phenylephrine and impaired endothelium-dependent vasodilatations to acetylcholine and SLIGRL. Endothelium-dependent vasodilatations in GCH1 fl/fl Tie2cre aortas were in part mediated by NOS-derived hydrogen peroxide (H 2 O 2 ), which mediated vasodilatation through soluble guanylate cyclase. Ex vivo supplementation of aortic rings with the BH4 analogue sepiapterin restored normal endothelial function and abolished eNOS-derived H 2 O 2 production in GCH1 fl/fl Tie2cre aortas. GCH1 fl/fl Tie2cre mice had higher systemic blood pressure than wild-type littermates, which was normalised by NOS inhibitor, L-NAME. Taken together, these studies reveal an endothelial cell-autonomous requirement for GCH1 and BH4 in regulation of vascular tone and blood pressure, and identify endothelial cell BH4 as a pivotal regulator of NO vs. H 2 O 2 as alternative eNOS-derived endothelial derived relaxing factors.

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