Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin

1986 ◽  
Vol 61 (1) ◽  
pp. 185-191 ◽  
Author(s):  
C. A. Hales ◽  
R. D. Brandstetter ◽  
C. F. Neely ◽  
M. B. Peterson ◽  
D. Kong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Resistance ◽  
Systemic Blood Pressure ◽  
Physiological Effect ◽  
High Dose ◽  
Systemic Blood ◽  
Eicosanoid Production ◽  
Circulating Levels

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

Abstract 066: The Undescribed Protein Caskin2 Is a Novel Regulator of eNOS Phosphorylation and Systemic Blood Pressure

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Sarah B Mueller ◽  
Susan B Gurley ◽  
Christopher D Kontos
Keyword(s):  
Blood Pressure ◽  
Molecular Mechanisms ◽  
Systemic Blood Pressure ◽  
Regulatory Subunit ◽  
Systemic Blood ◽  
Homologous Expression ◽  
Ongoing Work ◽  
Inducing Factors

Disruptions in the function of the quiescent endothelial cells (ECs) that line mature vessels can both result in and contribute to the progression of numerous cardiovascular diseases including hypertension, atherosclerosis, and disorders of vascular permeability. Despite recent attention, the signaling pathways that are active in quiescent ECs remain poorly characterized relative to those that regulate EC activation. In an effort to provide mechanistic insight into these pathways, we have characterized the previously undescribed protein Caskin2, which we hypothesize is a novel regulator of EC quiescence. Caskin2 is expressed in ECs throughout the vasculature, including the aorta, coronary arteries, and renal glomeruli. In vitro, Caskin2 promotes a quiescent EC phenotype characterized by decreased proliferation and increased resistance to apoptosis-inducing factors. Caskin2 knockout mice are viable and fertile. However, preliminary radiotelemetry measurements indicate that Caskin2 knockout (KO) mice have mildly elevated systemic blood pressure (BP). Compared to wild type (WT) littermates (n=8), Caskin2 KO mice (n=7) had increased mean arterial pressure (119+/-1 vs. 113+/-1, p=0.012), systolic BP (138+/-2 vs. 132+/-2, p=0.023), and diastolic BP (99+/-1 vs. 93+/-1, p=0.014) at baseline. To explore the molecular mechanisms of Caskin2’s effects, we used mass spectrometry to identify interacting proteins. Among the 67 proteins identified were the Ser/Thr phosphatase protein phosphatase 1 (PP1) and eNOS. Using standard in vitro biochemical techniques, we demonstrated that Caskin2 acts as a PP1 regulatory subunit. Interestingly, homologous expression of Caskin2 in vitro resulted in a marked increase in phosphorylation of eNOS on S1177, which is known to promote eNOS activity, and a decrease in phosphorylation on T495, which is associated with eNOS inhibition. Finally, PP1 has been shown to dephosphorylate eNOS T495 in vitro, suggesting a molecular mechanism for our in vivo findings. Ongoing work aims to determine if the interaction of Caskin2 and PP1 is required for the Caskin2-induced increase in activating phosphorylation of eNOS and to characterize the physiological mechanisms responsible for Caskin2’s effects on BP in more detail.

scholarly journals Oh, the places you'll go! My many colored serotonin (apologies to Dr. Seuss)

2016 ◽  
Vol 311 (5) ◽  
pp. H1225-H1233 ◽  
Author(s):  
Stephanie W. Watts
Keyword(s):  
Blood Pressure ◽  
Systemic Blood Pressure ◽  
Systemic Blood ◽  
Chronic Infusion ◽  
History Of ◽  
Normotensive Subjects ◽  
Arterial Tone ◽  
Venous Vasculature

Serotonin [5-hydroxytryptamine (5-HT)] has a truly fascinating history in the cardiovascular world. Discovered in the blood, 5-HT has long been appropriately regarded as a vasoconstrictor. A multitude of in vitro studies of isolated vessels support that addition of 5-HT causes vascular contraction. In only a few cases was 5-HT a vasodilator. Moreover, the potency and threshold of 5-HT causing contraction is increased in arteries from hypertensive vs. normotensive subjects, both animal and human. As such, we and others have hypothesized that 5-HT would contribute to hypertension by elevating arterial tone. In stark contrast to these decades of findings, we observed that a chronic infusion of 5-HT into conscious rats caused a reduction in blood pressure and nearly normalized blood pressure of experimentally hypertensive rats. Going back to the early work of Irvine Page, one of the scientists who discovered 5-HT, reveals an early recognized but never understood ability of 5-HT to reduce systemic blood pressure. Our laboratory, in collaboration with colleagues around the world, has dedicated itself to understanding the mechanisms of 5-HT-induced reduction in blood pressure. This manuscript takes you through a brief history of the discovery of 5-HT, in vitro serotonergic pharmacology of blood vessels, in vivo work with 5-HT and our studies that suggests the venous vasculature, potentially in combination with small arterioles, may be important to the actions of 5-HT in reducing blood pressure. 5-HT has certainly ended up in a place I never expected it to go.

Neural mechanism underlying basilar arterial constriction by intracisternal L-NNA in anesthetized dogs

1993 ◽  
Vol 265 (1) ◽  
pp. H103-H107 ◽  
Author(s):  
N. Toda ◽  
K. Ayajiki ◽  
T. Okamura
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Cerebral Arteries ◽  
Neural Mechanism ◽  
Systemic Blood Pressure ◽  
Systemic Blood ◽  
Anesthetized Dogs ◽  
Arterial Constriction ◽  
Synthase Inhibitor

Basilar arterial diameters were angiographically measured in anesthetized dogs in which systemic blood pressure and heart rate were also monitored. Injections of NG-nitro-L-arginine (L-NNA), a NO synthase inhibitor, into the cisterna magna produced a significant, persistent decrease in arterial diameter, the effect being reversed by intracisternal injections of L-arginine. The vasoconstrictor effect of L-NNA was diminished in dogs treated with hexamethonium. On the other hand, treatment with phentolamine in a dose sufficient to lower blood pressure to a level similar to that attained with hexamethonium did not inhibit, but rather potentiated, the effect of intracisternal L-NNA. Nicotine injected into the vertebral artery significantly dilated the basilar artery. The effect was abolished by treatment with L-NNA applied intracisternally, the inhibition being reversed by the addition of L-arginine. Systemic blood pressure and heart rate were not altered by intracisternally applied L-NNA and L-arginine. These findings support the hypothesis that basilar arterial constriction caused by intracisternal L-NNA is associated with a suppression of NO synthesis in nitroxidergic nerves innervating the cerebroarterial wall rather than an elimination of basal release of NO from the endothelium. Functional importance of nitroxidergic vasodilator innervation in cerebral arteries in vivo is thus clarified.

Cardiovascular effects and cardiopulmonary plasma gradients following intravenous infusion of neuropeptide Y in humans: negative dromotropic effect on atrioventricular node conduction

2002 ◽  
Vol 103 (6) ◽  
pp. 535-542 ◽  
Author(s):  
Bengt ULLMAN ◽  
John PERNOW ◽  
Jan M. LUNDBERG ◽  
Hans ÅSTRÖM ◽  
Lennart BERGFELDT
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Neuropeptide Y ◽  
Bolus Injection ◽  
Plasma Concentrations ◽  
Systemic Blood Pressure ◽  
Cardiac Conduction ◽  
Systemic Blood ◽  
Av Node

Neuropeptide Y (NPY) is co-released with noradrenaline from sympathetic nerves, has a strong vasoconstrictive action, and causes an attenuation of parasympathetic action in animal experiments. The plasma level of NPY is greatly elevated in patients with congestive heart failure, but the clinical relevance of this finding is unclear. Central haemodynamic effects, cardiac conduction system electrophysiology and coronary sinus blood flow were therefore studied in two sets of experiments, each carried out on seven healthy men. In the first series, NPY was given intravenously at doses of 3, 10 and 30pmolμmin-1μkg-1, and in the second it was given as a bolus injection of 90, 200 or 900pmol/kg, which resulted in plasma concentrations similar to those seen in heart failure patients. During continuous infusion of NPY, systemic blood pressure increased slightly, but myocardial perfusion, cardiac output, pulmonary arterial pressure, cardiac conduction intervals and atrioventricular (AV) node functional measures remained unchanged. In contrast, the bolus injection of NPY evoked prolongation and block (in four out of seven subjects) of AV node conduction, but did not affect haemodynamic variables, apart from a minor increase in systemic blood pressure. Impaired AV node conduction is a novel observation, which might reflect a baroreceptor-mediated vagal reflex, or–more likely–an NPY-induced direct negative dromotropic effect, caused by a reduction of the L-type calcium current as observed in vitro, or a combination of the two.

Method for measuring brain tissue pressure

1975 ◽  
Vol 43 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Robert M. Clark ◽  
Norman F. Capra ◽  
James H. Halsey
Keyword(s):  
Blood Pressure ◽  
Brain Tissue ◽  
Systemic Blood Pressure ◽  
Systemic Blood ◽  
Tissue Pressure ◽  
Content Type ◽  
Pressure Changes ◽  
Local Brain

✓ The authors report a method for measuring total local brain tissue pressure (BTP) using a miniature catheter transducer stereotaxically introduced into the white matter of the cat's cerebrum. Quantitative rapid phasic pressure changes were satisfactorily demonstrated. Due to some drift of baseline of the transducers and inability to perform in vivo calibration, reliable long-term quantitative pressure measurements sometimes could not be studied. The BTP from each cerebral hemisphere and the cisternal pressure (CP) were monitored during alterations of pCO2 and systemic blood pressure, and distilled H2O injection prior to and after right middle cerebral artery (MCA) ligation. The catheter transducers functioned well on chronic implantation for up to 6 weeks. Compared to the chronically implanted catheters, acutely implanted catheters responded identically except for drift. The response of intracranial pressure and CP to MCA occlusion, alterations in pCO2, and systemic blood pressure were similar. No BTP gradients appeared in response to MCA ligation, hypercapnia, hypertension, or progressive swelling of the resulting infarction.

NaCl modulates captopril effects on glomerular prostaglandin synthesis and glomerular filtration

1990 ◽  
Vol 258 (2) ◽  
pp. F382-F387
Author(s):  
M. Rathaus ◽  
E. Podjarny ◽  
A. Pomeranz ◽  
J. Bernheim
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Specific Effect ◽  
Systemic Blood Pressure ◽  
Prostaglandin Synthesis ◽  
Volume Loading ◽  
Systemic Blood

Captopril stimulates glomerular prostaglandin (PG) synthesis and increases glomerular filtration rate (GFR) in Na-repleted rats, whereas, in Na-depleted rats, it fails to stimulate PG synthesis and decreases GFR. In the present work the influence of chronic and acute NaCl loading on PG synthesis and renal function was studied in Na-depleted rats receiving captopril (LNC rats). Glomerular PGE2 and 6-keto-PGF1 alpha were not increased in LNC rats and were significantly lower than in Na-depleted rats (LN). Na repletion, while continuing captopril, increased PG synthesis above control levels. Addition of captopril in vitro to the incubation medium stimulated PGE2 synthesis in glomeruli of control rats, whereas it depressed it in LN rats. Acute loading with NaCl in LNC rats increased inulin and PAH clearances to values significantly greater than in control rats and similar to those of normal rats receiving captopril. Comparable volume loading with isotonic mannitol or 3% albumin increased inulin and PAH clearances only to control values. The specific effect of NaCl in acute loading was prevented by cyclooxygenase inhibition and was not mediated by increased systemic blood pressure. The results provide evidence that the effects of captopril on glomerular PG synthesis and renal function depend on the state of Na balance.

The Influence of Lysine-8-vasopressin, Oxytocin, and Adrenaline on Vascular Smooth Muscle in the Human Finger

1973 ◽  
Vol 51 (4) ◽  
pp. 284-290 ◽  
Author(s):  
Peter Gaskell
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Resistance ◽  
Young Women ◽  
Systemic Blood Pressure ◽  
Apparent Effect ◽  
Opening Pressure ◽  
Systemic Blood ◽  
Critical Opening ◽  
Human Finger

Lysine-8-vasopressin, oxytocin, or adrenaline was administered by intravenous infusion to young women, and their effect on the critical opening pressure (COP) of digital vessels, vascular resistance in the finger, and systemic blood pressure was measured. All doses of lysine-8-vasopressin between 0.001 and 0.08 U/min increased the COP of digital vessels but only the largest dose raised blood pressure slightly. A dose of 0.04 U/min had little if any effect on overall vascular resistance in the finger. Nevertheless the smallest dose given (0.001 U/min), which is within the physiological range of secretion rate by the pituitary gland, increased the COP of digital vessels substantially. Oxytocin at doses of 5–160 mU/min had no apparent effect on COP or vascular resistance of digital vessels or on blood pressure. Adrenaline at 4 μg/min increased the COP of digital vessels substantially. The latter observation is consistent with the absence of β receptors in vessels of the skin of the fingers.

scholarly journals TRPV1 expressed throughout the arterial circulation enables inflammatory vasoconstriction

2020 ◽  
Author(s):  
Thieu X. Phan ◽  
Hoai T. Ton ◽  
Hajnalka Gulyás ◽  
Róbert Pórszász ◽  
Attila Tóth ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Skeletal Muscle ◽  
Smooth Muscle ◽  
Ex Vivo ◽  
Systemic Blood Pressure ◽  
Sensory Nerves ◽  
Systemic Blood ◽  
Signaling Mechanism ◽  
Arterial Circulation

AbstractThe capsaicin receptor, TRPV1, is a key ion channel involved in inflammatory pain signaling. Although mainly studied in sensory nerves, there are reports of TRPV1 expression in isolated segments of the vasculature, but whether the channel localizes to vascular endothelium or smooth muscle is controversial and the distribution and functional roles of TRPV1 in arteries remain unknown. We mapped functional TRPV1 expression throughout the mouse arterial circulation. Analysis of reporter mouse lines TRPV1PLAP-nlacZ and TRPV1-Cre:tdTomato combined with Ca2+ imaging revealed specific localization of TRPV1 to smooth muscle of terminal arterioles in the heart, fat and skeletal muscle. Capsaicin evoked inward currents and raised intracellular Ca2+ levels in arterial smooth muscle cells, constricted arterioles ex vivo and in vivo and increased systemic blood pressure in mice and rats. Further, capsaicin markedly and dose-dependently reduced coronary flow. Pharmacologic and/or genetic disruption of TRPV1 abolished all these effects of capsaicin as well as vasoconstriction triggered by lysophosphatidic acid, a bioactive lipid generated by platelets and atherogenic plaques. Notably, ablation of sensory nerves did not affect the responses to capsaicin revealing a vascular smooth muscle-restricted signaling mechanism. Moreover, unlike in sensory nerves, TRPV1 function in arteries was resistant to activity-induced desensitization. Thus, TRPV1 activation in vascular myocytes of resistance arterioles enables a persistent depolarizing current, leading to constriction of coronary, skeletal muscle, and adipose arterioles and a sustained increase in systemic blood pressure.

Ventricular Outflow Dynamics in the Lizard, Varanus Niloticus: Responses to Hypoxia, Hypercarbia and Diving

1974 ◽  
Vol 60 (3) ◽  
pp. 871-880 ◽  
Author(s):  
R. W. MILLARD ◽  
K. JOHANSEN
Keyword(s):  
Blood Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pressure Rise ◽  
Systemic Blood Pressure ◽  
Aortic Pressure ◽  
Systemic Resistance ◽  
Systemic Blood ◽  
Normal Breathing ◽  
The Right

1. Blood flow and blood pressure have been measured in the right aorta and left pulmonary artery of the semi-aquatic lizard, Varanus niloticus, during normal breathing, during hypercarbic and hypoxic breathing and during voluntary diving. 2. Mean pulmonary blood pressure during normal breathing was 19.5±2.0 cmH2O while right aortic pressure was 118.0±3.0 cmH2O. The high systemic blood pressure and high ratio of systemic to pulmonary vascular resistance (4.0-6.0) stand out among reptiles and approach values in homeotherm vertebrates. 3. Pulmonary pressure rise preceded right aortic pressure rise by 120 msec at a heart rate of 25/min. Pulmonary ejection lasted 50% of the cardiac cycle compared to 25% for aortic ejection during normal breathing. 4. CO2 breathing increased right aortic vascular resistance by 120% while pulmonary resistance increased moderately by 30%. Carotid vascular resistance decreased during CO2 breathing. The pulmonary blood pressure increase was however much higher than the systemic, but at no time did systemic and pulmonary blood pressures overlap. 5. Hypoxic breathing increased pulmonary blood pressure to 36.0±4.0 cmH2O while right aortic pressure fell to 100.0±10.0 cmH2O. Ejection time remained unchanged in the right aorta while pulmonary flow became continuous. Overall pulmonary vascular resistance increased markedly while systemic resistance changed little. 6. Voluntary diving increased pulmonary blood pressure while the systemic blood pressure fell markedly. 7. The results obtained are discussed in the light of ventricular outflow distribution in reptiles. Directional shunting of blood inside the heart of V. niloticus during cardiac systole must be reduced or absent. Intracardiac shunting during cardiac filling or by systolic residual volumes is small, placing varanid lacertilians haemodynamically closer to homoetherm vertebrates than other reptiles studied.

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