Effects of in vivo metabolic acidosis  on midcortical bone ion composition

Chronic metabolic acidosis increases urine calcium excretion without altering intestinal calcium absorption, suggesting that bone mineral is the source of the additional urinary calcium. During metabolic acidosis there appears to be an influx of protons into bone mineral, lessening the magnitude of the decrement in pH. Although in vitro studies strongly support a marked effect of metabolic acidosis on the ion composition of bone, there are few in vivo observations. We utilized a high-resolution scanning ion microprobe with secondary ion mass spectroscopy to determine whether in vivo metabolic acidosis would alter bone mineral in a manner consistent with its purported role in buffering the increased proton concentration. Postweanling mice were provided distilled drinking water with or without 1.5% NH4Cl for 7 days; arterial blood gas was then determined. The addition of NH4Cl led to a fall in blood pH and [Formula: see text] concentration. The animals were killed on day 7, and the femurs were dissected and split longitudinally. The bulk cortical ratios Na/Ca, K/Ca, total phosphate/carbon-nitrogen bonds [(PO2 + PO3)/CN], and[Formula: see text]/CN each fell after 1 wk of metabolic acidosis. Because metabolic acidosis induces bone Ca loss, the fall in Na/Ca and K/Ca indicates a greater efflux of bone Na and K than Ca, suggesting H substitution for Na and K on the mineral. The fall in (PO2 + PO3)/CN indicates release of mineral phosphates, and the fall in[Formula: see text]/CN indicates release of mineral[Formula: see text]. Each of these mechanisms would result in buffering of the excess protons and returning the systemic pH toward normal.

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Metabolic alkalosis decreases bone calcium efflux by suppressing osteoclasts and stimulating osteoblasts

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.1.f216 ◽

1996 ◽

Vol 271 (1) ◽

pp. F216-F222 ◽

Cited By ~ 47

Author(s):

D. A. Bushinsky

Keyword(s):

Bone Mineral ◽

Metabolic Alkalosis ◽

Collagen Synthesis ◽

Cell Function ◽

Urinary Calcium ◽

Calcium Excretion ◽

Calcium Efflux ◽

Medium Ph ◽

Bone Calcium

In vivo and in vitro evidence indicates that metabolic acidosis, which may occur prior to complete excretion of end products of metabolism, increases urinary calcium excretion. The additional urinary calcium is almost certainly derived from bone mineral. Neutralization of this daily acid load, through the provision of base, decreases calcium excretion, suggesting that alkali may influence bone calcium accretion. To determine whether metabolic alkalosis alters net calcium efflux (JCa+) from bone and bone cell function, we cultured neonatal mouse calvariae for 48 h in either control medium (pH approximately equal to 7.4, [HCO3-] approximately equal to 24), medium simulating mild alkalosis (pH approximately equal to 7.5, [HCO3-] approximately equal to 31), or severe alkalosis (pH approximately equal to 7.6, [HCO3-] approximately equal to 39) and measured JCa+ and the release of osteoclastic beta-glucuronidase and osteoblastic collagen synthesis. Compared with control, metabolic alkalosis caused a progressive decrease in JCa+, which was correlated inversely with initial medium pH (pHi). Alkalosis caused a decrease in osteoclastic beta-glucuronidase release, which was correlated inversely with pHi and directly with JCa+. Alkalosis also caused an increase in osteoblastic collagen synthesis, which was correlated directly with pHi and inversely with JCa+. There was a strong inverse correlation between the effects alkalosis on osteoclastic beta-glucuronidase release and osteoblastic collagen synthesis. Thus metabolic alkalosis decreases JCa+ from bone, at least in part, by decreasing osteoclastic resorption and increasing osteoblastic formation. These results suggest that the provision of base to neutralize endogenous acid production may improve bone mineral accretion.

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Mechanism of proton-induced bone calcium release: calcium carbonate-dissolution

AJP Renal Physiology ◽

10.1152/ajprenal.1987.253.5.f998 ◽

1987 ◽

Vol 253 (5) ◽

pp. F998-F1005 ◽

Cited By ~ 21

Author(s):

D. A. Bushinsky ◽

R. J. Lechleider

Keyword(s):

Metabolic Acidosis ◽

Calcium Carbonate ◽

Bone Mineral ◽

Calcium Release ◽

Calcium Efflux ◽

Carbonate Phase ◽

Bone Calcium ◽

Calcium Carbonate Dissolution

Protons are buffered and calcium is released by bone during metabolic acidosis. Incubation of neonatal mouse calvariae in acid medium causes net calcium efflux from bone and net proton influx into bone, just as metabolic acidosis does in vivo. To determine whether the calcium carbonate phase of bone mineral is solubilized with increasing proton concentrations, we cultured calvariae for 3 h in medium in which the saturation was varied by changing pH or calcium and phosphate concentrations. We determined the driving force for crystallization by calculating the Gibbs free energy of formation (DG). With alteration of the medium pH, calcium carbonate entry or loss from bone varied linearly with the initial DG for medium calcium carbonate (r = -0.745, n = 41, P less than 0.001) as it did with alteration of the medium calcium and phosphate (r = -0.665, n = 118, P less than 0.001). There was dissolution of calcium carbonate into medium that was unsaturated with respect to calcium carbonate, net flux ceased at saturation, and calcium carbonate entered bone from supersaturated medium, indicating that the medium is in equilibrium with the calcium carbonate phase of bone mineral. Neither the mineral phase brushite nor apatite was in equilibrium with the medium. These observations indicate that in vitro, acute proton-induced calcium efflux is due to dissolution of bone calcium carbonate.

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Chronic acidosis-induced alteration in bone bicarbonate and phosphate

AJP Renal Physiology ◽

10.1152/ajprenal.00128.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. F532-F539 ◽

Cited By ~ 35

Author(s):

David A. Bushinsky ◽

Susan B. Smith ◽

Konstantin L. Gavrilov ◽

Leonid F. Gavrilov ◽

Jianwei Li ◽

...

Keyword(s):

Metabolic Acidosis ◽

Ammonium Chloride ◽

Acidic Medium ◽

Urinary Calcium ◽

Neonatal Mouse ◽

Control Medium ◽

Cross Sectional ◽

Significant Fall

Chronic metabolic acidosis increases urinary calcium excretion without altering intestinal calcium absorption, suggesting that bone mineral is the source of the additional urinary calcium. In vivo and in vitro studies have shown that metabolic acidosis causes a loss of mineral calcium while buffering the additional hydrogen ions. Previously, we studied changes in femoral, midcortical ion concentrations after 7 days of in vivo metabolic acidosis induced by oral ammonium chloride. We found that, compared with mice drinking only distilled water, ammonium chloride induced a loss of bone sodium and potassium and a depletion of mineral HCO3− and phosphate. There is more phosphate than carbonate in neonatal mouse bone. In the present in vitro study, we utilized a high-resolution scanning ion microprobe with secondary ion mass spectroscopy to test the hypothesis that chronic acidosis would decrease bulk (cross-sectional) bone phosphate to a greater extent than HCO3− by localizing and comparing changes in bone HCO3− and phosphate after chronic incubation of neonatal mouse calvariae in acidic medium. Calvariae were cultured for a total of 51 h in medium acidified by a reduction in HCO3− concentration ([HCO3−]; pH ∼7.14, [HCO3−] ∼13) or in control medium (pH ∼7.45, HCO3− ∼26). Compared with incubation in control medium, incubation in acidic medium caused no change in surface total phosphate but a significant fall in cross-sectional phosphate, with respect to the carbon-carbon bond (C2) and the carbon-nitrogen bond (CN). Compared with incubation in control medium, incubation in acidic medium caused no change in surface HCO3− but a significant fall in cross-sectional HCO3− with respect to C2 and CN. The fall in cross-sectional phosphate was significantly greater than the fall in cross-sectional HCO3−. The fall in phosphate indicates release of mineral phosphates, and the fall in HCO3− indicates release of mineral HCO3−, both of which would be expected to buffer the additional protons and help restore the pH toward normal. Thus a model of chronic acidosis depletes bulk bone proton buffers, with phosphate depletion exceeding that of HCO3−.

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Metabolic, but not respiratory, acidosis increases bone PGE2 levels and calcium release

AJP Renal Physiology ◽

10.1152/ajprenal.0355.2000 ◽

2001 ◽

Vol 281 (6) ◽

pp. F1058-F1066 ◽

Cited By ~ 51

Author(s):

David A. Bushinsky ◽

Walter R. Parker ◽

Kristen M. Alexander ◽

Nancy S. Krieger

Keyword(s):

Metabolic Acidosis ◽

Calcium Release ◽

Calcium Absorption ◽

Respiratory Acidosis ◽

Urinary Calcium ◽

Calcium Excretion ◽

Calcium Efflux ◽

Bicarbonate Concentration ◽

Blood Ph ◽

Urine Calcium Excretion

First published July 12, 2001; 10.1152/ajprenal.00355.2001.— A decrease in blood pH may be due to either a reduction in bicarbonate concentration ([HCO[Formula: see text]]; metabolic acidosis) or to an increase in Pco 2 (respiratory acidosis). In mammals, metabolic, but not respiratory, acidosis increases urine calcium excretion without altering intestinal calcium absorption, indicating that the additional urinary calcium is derived from bone. In cultured bone, chronic metabolic, but not respiratory, acidosis increases net calcium efflux ( J Ca), decreases osteoblastic collagen synthesis, and increases osteoclastic bone resorption. Metabolic acidosis increases bone PGE2production, which is correlated with J Ca, and inhibition of PGE2 production inhibits this acid-induced J Ca. Given the marked differences in the osseous response to metabolic and respiratory acidosis, we hypothesized that incubation of neonatal mouse calvariae in medium simulating respiratory acidosis would not increase medium PGE2 levels, as observed during metabolic acidosis. To test this hypothesis, we determined medium PGE2 levels and J Ca from calvariae incubated at pH ∼7.1 to model either metabolic (Met; [HCO[Formula: see text]] ∼11 mM) or respiratory (Resp; Pco 2 ∼83 Torr) acidosis, or at pH ∼7.5 as a control (Ntl). We found that after 24–48 and 48–51 h in culture, periods when cell-mediated J Capredominates, medium PGE2 levels and J Ca were increased with Met, but not Resp, compared with Ntl, and there was a direct correlation between medium PGE2 levels and J Ca. Thus metabolic, but not respiratory, acidosis induces the release of bone PGE2, which mediates J Ca from bone.

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Cardiovascular Effects of Micromeria graeca (L.) Benth. ex Rchb in Normotensive and Hypertensive Rats

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666191206163136 ◽

2020 ◽

Vol 20 (8) ◽

pp. 1253-1261

Author(s):

Mourad Akdad ◽

Mohamed Eddouks

Keyword(s):

Blood Pressure ◽

Cardiovascular System ◽

Arterial Blood Pressure ◽

Antihypertensive Activity ◽

Computer Assisted ◽

Hypertensive Rats ◽

Vasorelaxant Effect ◽

Arterial Blood

Aims: The present study was performed in order to analyze the antihypertensive activity of Micromeria graeca (L.) Benth. ex Rchb. Background: Micromeria graeca (L.) Benth. ex Rchb is an aromatic and medicinal plant belonging to the Lamiaceae family. This herb is used to treat various pathologies such as cardiovascular disorders. Meanwhile, its pharmacological effects on the cardiovascular system have not been studied. Objective: The present study aimed to evaluate the effect of aqueous extract of aerial parts of Micromeria graeca (AEMG) on the cardiovascular system in normotensive and hypertensive rats. Methods: In this study, the cardiovascular effect of AEMG was evaluated using in vivo and in vitro investigations. In order to assess the acute effect of AEMG on the cardiovascular system, anesthetized L-NAME-hypertensive and normotensive rats received AEMG (100 mg/kg) orally and arterial blood pressure parameters were monitored during six hours. In the sub-chronic study, rats were orally treated for one week, followed by blood pressure assessment during one week of treatment. Blood pressure was measured using a tail-cuff and a computer-assisted monitoring device. In the second experiment, isolated rat aortic ring pre-contracted with Epinephrine (EP) or KCl was used to assess the vasorelaxant effect of AEMG. Results: Oral administration of AEMG (100 mg/kg) provoked a decrease of arterial blood pressure parameters in hypertensive rats. In addition, AEMG induced a vasorelaxant effect in thoracic aortic rings pre-contracted with EP (10 μM) or KCl (80 mM). This effect was attenuated in the presence of propranolol and methylene blue. While in the presence of glibenclamide, L-NAME, nifedipine or Indomethacin, the vasorelaxant effect was not affected. Conclusion: This study showed that Micromeria graeca possesses a potent antihypertensive effect and relaxes the vascular smooth muscle through β-adrenergic and cGMP pathways.

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Vasorelaxant and Antihypertensive Effects of Mentha pulegium L. in Rats: An in vitro and in vivo Approach

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200909093908 ◽

2020 ◽

Vol 20 ◽

Author(s):

Mohammed Ajebli ◽

Mohamed Eddouks

Keyword(s):

Blood Pressure ◽

Acute Experiment ◽

Antihypertensive Activity ◽

Mentha Pulegium ◽

In Vitro Experiment ◽

Arterial Blood ◽

Dose Dependent ◽

Ca2 Channels

Aims and objective: The aim of the study was to investigate the effect of aqueous aerial part extract of Mentha pulegium L. (Pennyrile) (MPAE) on arterial pressure parameters in rats. Background: Mentha pulegium is a medicinal plant used to treat hypertension in Morocco. Material and methods: In the current study, MPAE was prepared and its antihypertensive activity was pharmacologically investigated. L-NAME-hypertensive and normotensive rats have received orally MPAE (180 and 300 mg/kg) during six hours for the acute experiment and during seven days for the sub-chronic treatment. Thereafter, systolic, diastolic, mean arterial blood pressure and heart rate were evaluated. While, in the in vitro experiment, isolated denuded and intact thoracic aortic rings were suspended in a tissue bath system and the tension changes were recorded. Results: A fall in blood pressure was observed in L-NAME-induced hypertensive treated with MPAE. The extract also produced a dose-dependent relaxation of aorta pre-contracted with NE and KCl. The study showed that the vasorelaxant ability of MPAE seems to be exerted through the blockage of extracellular Ca2+ entry. Conclusion: The results demonstrate that the extract of pennyrile exhibits antihypertensive activity. In addition, the effect may be, at least in part, due to dilation of blood vessels via blockage of Ca2+ channels.

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Proceedings: A two-energy densitometry method for measuring bone mineral concentrations and bone densities in-vitro and in-vivo

American Journal of Roentgenology ◽

10.2214/ajr.126.6.1268 ◽

1976 ◽

Vol 126 (6) ◽

pp. 1268-1269 ◽

Cited By ~ 2

Author(s):

J Rassow

Keyword(s):

Bone Mineral ◽

Mineral Concentrations

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Prehospital Diagnosis of Shortness of Breath Caused by Profound Metformin-Associated Metabolic Acidosis

Healthcare ◽

10.3390/healthcare9010074 ◽

2021 ◽

Vol 9 (1) ◽

pp. 74

Author(s):

Pietro Elias Fubini ◽

Laurent Suppan

Keyword(s):

Metabolic Acidosis ◽

Hospital Setting ◽

Blood Gases ◽

Shortness Of Breath ◽

Potential Harm ◽

Arterial Blood Gas ◽

Arterial Blood ◽

Common Causes ◽

Prehospital Diagnosis ◽

Gas Measurement

Shortness of breath is a common complaint among patients in emergency medicine. While most common causes are usually promptly identified, less frequent aetiologies might be challenging to diagnose, especially in the pre-hospital setting. We report a case of prehospital dyspnoea initially ascribed to pulmonary oedema which turned out to be the result of profound metformin-associated metabolic acidosis. This diagnosis was already made during the prehospital phase by virtue of arterial blood gas measurement. Pre-hospital measurement of arterial blood gases is therefore feasible and can improve diagnostic accuracy in the field, thus avoiding unnecessary delay and potential harm to the patient before initiating the appropriate therapeutic actions.

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Dilutional Acidosis following Hetastarch or Albumin in Healthy Volunteers

Anesthesiology ◽

10.1097/00000542-200011000-00008 ◽

2000 ◽

Vol 93 (5) ◽

pp. 1184-1187 ◽

Cited By ~ 61

Author(s):

Jonathan H. Waters ◽

Clifford A. Bernstein

Keyword(s):

Healthy Volunteers ◽

Repeated Measures ◽

Base Excess ◽

Rank Test ◽

Albumin Concentration ◽

Acid Base Balance ◽

Arterial Blood Gas ◽

Arterial Blood ◽

The Impact

Background The intent of this study was to evaluate the impact of the commonly used colloids-hetastarch and albumin-on in vivo acid-base balance. From this evaluation, a better understanding of the mechanism of dilutional acidosis was expected. Methods In a prospective, randomized fashion, 11 healthy volunteers were administered 15 ml/kg hetastarch solution, 6%, or 15 ml/kg albumin, 5%, intravenously over 30 min. Four weeks later, the study subjects were administered the other colloid. Arterial blood gas and electrolyte parameters were measured at baseline and at 30, 60, 90, 120, 210, and 300 min after colloid administration. Pre- and postlaboratory values were compared within groups using a paired t test and a Wilcoxon signed rank test and between groups using repeated-measures analysis of variance and a Wilcoxon rank sum test. Results Thirty min after infusion, subjects who were administered hetastarch showed statistically significant changes (P < 0.05) in base excess (from 2.5 +/- 0.9 mEq/l to 0.7 +/- 1.1 mEq/l), HCO3- concentration (from 27 +/- 1.0 mEq/l to 25 +/- 1.3 mEq/l), Cl- concentration (from 108 +/- 2 mEq/l to 112 +/- 2 mEq/l), albumin concentration (from 4.4 +/- 0.2 g/dl to 3.5 +/- 0.5 g/dl), and arterial carbon dioxide tension (Paco2; from 40.8 +/- 2.3 mmHg to 39. 2 +/- 3.2 mmHg), whereas only the albumin concentration (from 4.4 +/- 0.2 g/dl to 4.8 +/- 0.6 g/dl) changed significantly in the albumin-treated group. Conclusions Decreases in base excess were observed for 210 min after hetastarch administration but not after albumin. The mechanism for this difference is discussed.

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