Inhaled hexadecyl-treprostinil provides pulmonary vasodilator activity at significantly lower plasma concentrations than infused treprostinil

We investigated the effects of vasoactive intestinal peptide (VIP) in the feline pulmonary vascular bed under conditions of controlled pulmonary blood flow when pulmonary vascular tone was at base-line levels and when vascular resistance was elevated. Under base-line conditions, VIP caused small but significant reductions in lobar arterial pressure without affecting left atrial pressure. Decreases in lobar arterial pressure in response to VIP were greater and were dose related when lobar vascular resistance was increased by intralobar infusion of U 46619, a stable prostaglandin endoperoxide analogue. Acetylcholine and isoproterenol also caused significant decreases in lobar arterial pressure under base-line conditions, and responses to these agents were enhanced when lobar vascular tone was elevated. Moreover, when doses of these agents are expressed in nanomoles, acetylcholine and isoproterenol were more potent than VIP in decreasing lobar arterial pressure. Responses to VIP were longer in duration with a slower onset than were responses to acetylcholine or isoproterenol. Pulmonary vasodilator responses to VIP were unchanged by indomethacin, atropine, or propranolol. The present data demonstrate that VIP has vasodilator activity in the pulmonary vascular bed and that responses are dependent on the existing level of vasoconstrictor tone. These studies indicate that this peptide is less potent than acetylcholine or isoproterenol in dilating the feline pulmonary vascular bed and that responses to VIP are not dependent on a muscarinic or beta-adrenergic mechanism or release of a dilator prostaglandin.

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Pulmonary vasodilation to adrenomedullin: a novel peptide in humans

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.268.6.h2211 ◽

1995 ◽

Vol 268 (6) ◽

pp. H2211-H2215 ◽

Cited By ~ 8

Author(s):

J. Heaton ◽

B. Lin ◽

J. K. Chang ◽

S. Steinberg ◽

A. Hyman ◽

...

Keyword(s):

Arterial Pressure ◽

Pulmonary Arterial Pressure ◽

Vasomotor Tone ◽

Pulmonary Vasodilation ◽

Vascular Bed ◽

Pulmonary Vasodilator ◽

Vasodilator Activity ◽

Pulmonary Arterial ◽

Cgrp Receptor Antagonist ◽

Pulmonary Vascular Bed

The present study investigates the effects of human adrenomedullin (ADM) on the pulmonary vascular bed of isolated, blood-perfused rat lung. Because pulmonary blood flow and left atrial pressure were constant, changes in pulmonary arterial pressure directly reflect changes in pulmonary vascular resistance. Under conditions of resting (low) pulmonary vasomotor tone, intra-arterial bolus injections of ADM-(1-52) and two truncated sequences of ADM-(1-52) [ADM-(1-12) and ADM-(13-52)] did not alter pulmonary arterial pressure. When pulmonary vasomotor tone was increased by U-46619, a thromboxane A2 mimic, intra-arterial bolus injections of ADM-(1-52) and ADM-(13-52) at similar doses produced similar, dose-dependent reductions in pulmonary arterial pressure. On a molar basis, ADM-(1-52) had greater pulmonary vasodilator activity than isoproterenol. In contrast, ADM-(1-12) had no activity. When pulmonary vasomotor tone was actively increased to the same level using KCl, the pulmonary vasodilator activity of ADM-(13-52) was decreased 10-fold. The present data demonstrate that ADM-(1-52) dilates the pulmonary vascular bed and suggest that the pulmonary vasodilator activity of ADM is greater on pulmonary blood vessels preconstricted through a receptor-dependent mechanism. Because meclofenamate, nitro-L-arginine methyl ester, methysergide, BW A-1433U83, U-37883A, and calcitonin gene-related peptide [CGRP-(8-37)], a CGRP-receptor antagonist, did not alter the pulmonary vasodilator response to ADM-(1-52), the present data suggest that ADM dilates the pulmonary vascular bed independently of cyclooxygenase products, endothelium-derived relaxation factor, serotoninergic receptors, adenosine1 purinoreceptors, ATP-dependent potassium channels, and CGRP receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

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Daily rhythm of NaCl intake in rats fed low-Ca2+ diet: relation to plasma and urinary minerals and hormones

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.270.3.r505 ◽

1996 ◽

Vol 270 (3) ◽

pp. R505-R517 ◽

Cited By ~ 4

Author(s):

M. G. Tordoff ◽

A. Okiyama

Keyword(s):

Dark Period ◽

Plasma Concentrations ◽

Salt Appetite ◽

Sprague Dawley ◽

Lower Plasma ◽

Plasma Osmolarity ◽

Dihydroxyvitamin D3 ◽

Sprague Dawley Rats ◽

The Difference ◽

Plasma Phosphorus

To assess daily rhythms of salt appetite, we measured spontaneous 300 mM NaCl intake of male Sprague-Dawley rats fed a diet containing 150 or 25 mmol Ca2+/kg. Both groups drank most NaCl at night, but, as the dark period progressed, intakes of controls remained constant or diminished, whereas intakes of rats fed low-Ca2+ diet increased. During the late dark period, when the difference in NaCl intake between the two dietary groups was greatest, rats fed a low-Ca2+ diet lost more corticosterone and sodium in urine, had lower plasma osmolarity, and had higher plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations than did controls. Over the 24-h cycle, rats fed the low-Ca2+ diet excreted less Ca2+ and more corticosterone in urine than did controls. They also had consistently lower plasma concentrations of Ca2+ and renin activity and consistently higher plasma phosphorus, arginine vasopressin, parathyroid hormone, thyroxine, calcitonin, and 1,25-dihydroxyvitamin D3. These findings support the hypothesis that salt appetite induced by dietary Ca2+ deficiency involves a subtle dysfunction of the ACTH-corticosterone axis, but they also raise several other possibilities.

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Thromboxane mediates acute pulmonary hypertension in sheep extracorporeal perfusion

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1982.243.3.h471 ◽

1982 ◽

Vol 243 (3) ◽

pp. H471-H479 ◽

Cited By ~ 1

Author(s):

M. B. Peterson ◽

P. C. Huttemeier ◽

W. M. Zapol ◽

E. G. Martin ◽

W. D. Watkins

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Artery ◽

Acid Metabolism ◽

Plasma Concentrations ◽

Arachidonic Acid Metabolism ◽

Pulmonary Vasoconstriction ◽

Pulmonary Vasodilator ◽

Systemic Hypoxia ◽

General Activation ◽

Acute Pulmonary Hypertension

We measured serial plasma concentrations of thromboxane B2 (TXB2), the stable metabolite of the putative pulmonary vasoconstrictor thromboxane A2 (TXA2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolite of the pulmonary vasodilator prostacyclin (PGI2) by double-antibody radioimmunoassay during partial venovenous bypass in 25 awake sheep. The onset of bypass caused mean pulmonary artery pressure (PAP) to increase from 16 +/- 1 to 28 +/- 2 mmHg at 12 +/- 2 min, due to an increase of pulmonary vascular resistance, followed by a return to control within 45 min. There was no systemic hypoxia. TXB2 increased simultaneously with the onset of pulmonary hypertension (PH) (236 +/- 36 to 700 +/- 120 pg/ml at 0 and 5 min) and peaked at 1,724 +/- 172 pg/ml 10 min after maximum PAP was achieved. Positive pulmonary artery-to-aortic differences of TXB2 were measured. 6-Keto-PGF1 alpha increased from 51 +/- 3 to 842 +/- 367 pg/ml at 35 min. PGF2 alpha was unchanged (130 +/- 45 pg/ml). PH, TXB2, and 6-keto-PGF1 alpha increases were blocked by pretreatment with indomethacin or ibuprofen. PH and TXB2 increases were prevented with an imidazole derivative. PH caused by a continuous infusion of an endoperoxide analog did not induce lung release of TXB2 or PGF2 alpha. We conclude that 1) transient pulmonary vasoconstriction is caused by thromboxane; 2) the lung is the primary site of thromboxane synthesis; and 3) bypass causes selective alterations in arachidonic acid metabolism rather than general activation of the cascade.

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Plasma concentration of norepinephrine, β-endorphin, and substance P in lame dairy cows

Journal of Veterinary Research ◽

10.2478/jvetres-2018-0029 ◽

2018 ◽

Vol 62 (2) ◽

pp. 193-197 ◽

Cited By ~ 2

Author(s):

Alfredo Rosamel Rodriguez ◽

Daniel Eduardo Herzberg ◽

Marianne Patricia Werner ◽

Heine Yacob Müller ◽

Hedie Almagro Bustamante

Keyword(s):

Plasma Concentration ◽

Substance P ◽

Dairy Cows ◽

Milk Yield ◽

Plasma Concentrations ◽

Lower Plasma ◽

Intense Pain ◽

Lactation Stage ◽

Jersey Cows ◽

Potential Use

AbstractIntroductionLameness is a painful and debilitating condition that affects dairy cows worldwide. The aim of this study was to determine the plasma concentration of norepinephrine, β-endorphin, and substance P in dairy cows with lameness and different mobility scores (MS).Material and MethodsA total of 100 Friesian and Jersey cows with lameness (parity range: 1–6; weight: 400–500 kg; milk yield: 22–28 L a day, and lactation stage less than 230 days) were selected. Animals were selected and grouped according to MS (MS 0–3; n = 25), and plasma concentration of norepinephrine, substance P, and β-endorphin was measured using ELISA.ResultsCows with MS 3 had higher plasma concentrations of norepinephrine and substance P and lower plasma concentrations of β-endorphins when compared to MS 0 cows.ConclusionVariations in plasma concentration of norepinephrine, substance P, and β-endorphin could be associated with intense pain states in dairy cows with lameness, but are insufficient to differentiate these states from the mildest pain states. Further studies are necessary in order to evaluate the potential use of these biomarkers in the detection of chronic bovine painful conditions.

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REGULATION OF INSULIN SECRETION IN THE OVINE FOETUS IN UTERO. EFFECTS OF SODIUM VALERATE ON SECRETION AND OF ADRENOCORTICOTROPHIN-INDUCED PREMATURE PARTURITION ON THE INSULIN SECRETORY RESPONSE TO GLUCOSE

Journal of Endocrinology ◽

10.1677/joe.0.0560013 ◽

1973 ◽

Vol 56 (1) ◽

pp. 13-25 ◽

Cited By ~ 4

Author(s):

J. M. BASSETT ◽

G. D. THORBURN ◽

DIANNE H. NICOL

Keyword(s):

Insulin Secretion ◽

Plasma Insulin ◽

Short Chain Fatty Acid ◽

Plasma Concentrations ◽

Insulin Level ◽

In Utero ◽

Secretory Response ◽

Lower Plasma ◽

Insulin Secretory Response ◽

Corticosteroid Secretion

SUMMARY Intravenous infusions of glucose into lambs in utero (130–150 days) and after birth, confirmed the marked post-natal increase in the magnitude of the response of plasma insulin to glucose. These studies also suggest that insulin secretion in foetal lambs is stimulated by glucose at lower plasma concentrations than in lambs after birth. The short-chain fatty acid, valeric acid, given as the sodium salt, caused a very rapid increase in the plasma insulin level of foetal lambs, when given either by intravenous injection or infusion. When birth was induced after only 135 days of gestation by i.v. infusion of a synthetic adrenocorticotrophin preparation (Synacthen) into foetal lambs there was also a prematurely induced maturation of the insulin secretory response to glucose. In these prematurely born lambs the insulin secretory response to i.v. glucose infusion was similar to that of normal lambs after birth and differed greatly from that of normal foetuses of similar age. The results indicate that maturation of the insulin secretory mechanism in the lamb is associated with parturition and suggest that these changes may be consequences of the increasing corticosteroid secretion in the foetus during the last few days of gestation.

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Nebivolol has a beneficial effect in monocrotaline-induced pulmonary hypertension

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2015-0431 ◽

2016 ◽

Vol 94 (7) ◽

pp. 758-768 ◽

Cited By ~ 4

Author(s):

Edward A. Pankey ◽

Justin A. Edward ◽

Kevin W. Swan ◽

Camille R.T. Bourgeois ◽

Matthew J. Bartow ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Beneficial Effect ◽

Adrenergic Receptor ◽

Pulmonary Arteries ◽

Blocking Agent ◽

Current Treatment ◽

Systemic Arterial Pressure ◽

No Production ◽

Pulmonary Vasodilator ◽

Vasodilator Activity

Pulmonary hypertension is a rare disorder that, without treatment, is progressive and fatal within 3–4 years. Current treatment involves a diverse group of drugs that target the pulmonary vascular bed. In addition, strategies that increase nitric oxide (NO) formation have a beneficial effect in rodents and patients. Nebivolol, a selective β1 adrenergic receptor-blocking agent reported to increase NO production and stimulate β3 receptors, has vasodilator properties suggesting that it may be beneficial in the treatment of pulmonary hypertension. The present study was undertaken to determine whether nebivolol has a beneficial effect in monocrotaline-induced (60 mg/kg) pulmonary hypertension in the rat. These results show that nebivolol treatment (10 mg/kg, once or twice daily) attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension. This study demonstrates the presence of β3 adrenergic receptor immunoreactivity in pulmonary arteries and airways and that nebivolol has pulmonary vasodilator activity. Studies with β3 receptor agonists (mirabegron, BRL 37344) and antagonists suggest that β3 receptor-mediated decreases in systemic arterial pressure occur independent of NO release. Our results suggest that nebivolol, a selective vasodilating β1 receptor antagonist that stimulates β3 adrenergic receptors and induces vasodilation by increasing NO production, may be beneficial in treating pulmonary hypertensive disorders.

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Dietary Intake and Plasma Levels of Choline and Betaine in Children with Autism Spectrum Disorders

Autism Research and Treatment ◽

10.1155/2013/578429 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 12

Author(s):

Joanna C. Hamlin ◽

Margaret Pauly ◽

Stepan Melnyk ◽

Oleksandra Pavliv ◽

William Starrett ◽

...

Keyword(s):

Dietary Intake ◽

Plasma Levels ◽

Plasma Concentrations ◽

Children With Autism ◽

Autism Spectrum ◽

Research Network ◽

Control Group ◽

Lower Plasma ◽

One Carbon Metabolism ◽

Positive Correlations

Abnormalities in folate-dependent one-carbon metabolism have been reported in many children with autism. Because inadequate choline and betaine can negatively affect folate metabolism and in turn downstream methylation and antioxidant capacity, we sought to determine whether dietary intake of choline and betaine in children with autism was adequate to meet nutritional needs based on national recommendations. Three-day food records were analyzed for 288 children with autism (ASDs) who participated in the national Autism Intervention Research Network for Physical Health (AIR-P) Study on Diet and Nutrition in children with autism. Plasma concentrations of choline and betaine were measured in a subgroup of 35 children with ASDs and 32 age-matched control children. The results indicated that 60–93% of children with ASDs were consuming less than the recommended Adequate Intake (AI) for choline. Strong positive correlations were found between dietary intake and plasma concentrations of choline and betaine in autistic children as well as lower plasma concentrations compared to the control group. We conclude that choline and betaine intake is inadequate in a significant subgroup of children with ASDs and is reflected in lower plasma levels. Inadequate intake of choline and betaine may contribute to the metabolic abnormalities observed in many children with autism and warrants attention in nutritional counseling.

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Pulmonary vasodilator responses to adrenomedullin are reduced by NOS inhibitors in rats but not in cats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1996.270.5.l782 ◽

1996 ◽

Vol 270 (5) ◽

pp. L782-L789 ◽

Cited By ~ 12

Author(s):

B. D. Nossaman ◽

C. J. Feng ◽

A. D. Kaye ◽

B. DeWitt ◽

D. H. Coy ◽

...

Keyword(s):

Nitric Oxide ◽

Amino Acid ◽

Vascular Resistance ◽

Rat Lung ◽

Related Peptide ◽

Vascular Bed ◽

Pulmonary Vasodilator ◽

Vasodilator Activity ◽

Carboxy Terminal ◽

Pulmonary Vascular Bed

Responses to and the mechanism of action of adrenomedullin (ADM), the carboxy-terminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmonary vascular bed of the rat. Under conditions of elevated tone and controlled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM15-52), and CGRP caused dose-related decreases in pulmonary arterial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. After administration of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine benzyl ester or N omega-nitro-L-arginine methyl ester (L-NAME), pulmonary vasodilator responses to ADM, to ADM15-52, to CGRP, to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglycerin were not changed. However, in the pulmonary vascular bed of the cat, L-NAME had no significant effect on vasodilator responses to ADM in doses that attenuated vasodilator responses to acetylcholine and bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM15-52 was approximately three-fold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resistance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary vascular vascular resistance in the cat than in the rat, and vasodilator responses to ADM were independent of the intervention used to raise tone in the rat. The present data demonstrate that ADM and ADM15-52 have significant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM15-52, and CGRP are dependent on the release of nitric oxide in the rat. The present results indicate that pulmonary vasodilator responses to ADM are not dependent on the release of nitric oxide in the cat and suggest that responses to the peptide are mediated by different mechanisms in the pulmonary vascular bed of the rat and cat.

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Plasma Biomarkers of Alzheimer’s Disease in African Americans

Journal of Alzheimer s Disease ◽

10.3233/jad-200828 ◽

2021 ◽

Vol 79 (1) ◽

pp. 323-334

Author(s):

Kaancan Deniz ◽

Charlotte C.G. Ho ◽

Kimberly G. Malphrus ◽

Joseph S. Reddy ◽

Thuy Nguyen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

African Americans ◽

Plasma Proteins ◽

Plasma Concentrations ◽

Disease Status ◽

Lower Plasma ◽

Plasma Biomarkers ◽

Pairwise Correlations ◽

Inflammatory Proteins

Background/Objective: The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer’s disease (AD) pathology and neuroinflammation are associated with disease status in African Americans. Methods: We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer’s Disease Studies (FCA3DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aβ42, tau, IL6, IL10, TNFα) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations. Results: Plasma tau levels were higher in AD when adjusted for biological and technical covariates. APOE ɛ4 was associated with lower plasma Aβ42 and tau levels. Older age was associated with higher plasma Aβ42, tau, and TNFα. Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aβ42. Conclusion: We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aβ42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population.

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