Influence of decompression sickness on vasocontraction of isolated rat vessels

Studies conducted in divers indicate that endothelium function is impaired following a dive even without decompression sickness (DCS). Our previous experiment conducted on rat isolated vessels showed no differences in endothelium-dependent vasodilation after a simulated dive even in the presence of DCS, while contractile response to phenylephrine was progressively impaired with increased decompression stress. This study aimed to further investigate the effect of DCS on vascular smooth muscle. Thirty-two male Sprague-Dawley rats were submitted to the same hyperbaric protocol and classified according to the severity of DCS: no-DCS (without clinical symptoms), mild-DCS, or severe-DCS (dead within 1 h). A control group remained at atmospheric pressure. Isometric tension was measured in rings of abdominal aorta and mesenteric arteries. Single dose contraction was assessed with KCl solution. Dose-response curves were obtained with phenylephrine and endothelin-1. Phenylephrine-induced contraction was observed in the presence of antioxidant tempol. Additionally, plasma concentrations of angiotensin II, angiotensin-converting enzyme, and thiobarbituric acid reactive substances (TBARS) were assessed. Response to phenylephrine was impaired only among mild-DCS in both vessels. Dose-response curves to endothelin-1 were impaired after mild-DCS in mesenteric and severe-DCS in aorta. KCl-induced contraction was affected after hyperbaric exposure regardless of DCS status in aorta only. These results confirm postdive vascular dysfunction is dependent on the type of vessel. It further evidenced that vascular dysfunction is triggered by DCS rather than by diving itself and suggest the influence of circulating factor/s. Diving-induced impairment of the L-type voltage-dependent Ca2+ channels and/or influence of renin-angiotensin system is proposed.

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Critique of dose response in carcinogenesis

Human & Experimental Toxicology ◽

10.1191/0960327106ht633oa ◽

2006 ◽

Vol 25 (7) ◽

pp. 413-436 ◽

Cited By ~ 19

Author(s):

W J Waddell

Keyword(s):

Dose Response ◽

Laws Of Nature ◽

Control Group ◽

Logarithmic Scale ◽

Response Curves ◽

Data Points ◽

Mere Presence ◽

Scientific Significance ◽

Dose Response Curves ◽

Almost All

A few landmarks in the development of dose response in toxicology are presented, with an explanation of why dose should only be considered on a logarithmic scale. Examples are shown, illustrating that the current practice of labeling dose-response curves for carcinogenesis as supralinear, linear or sublinear, is meaningless unless the dose-response scales are defined. Since many reports labeling such curves as supralinear, linear, or sublinear are carried out with dose on a linear scale, the scientific significance of the shape of the curve is obscured. Examples of dose-response curves for carcinogenesis from 2-acetylaminofluorene, N-nitrosodiethylamine, aflatoxins, and radium are shown. In addition, more than 500 National Toxicology Program Technical Reports (NTP-TR) on carcinogenicity were examined; from this database, three groups of studies were selected. The first group consisted of those studies in which the lowest dose produced no tumors and the study had a positive dose response. The second group consisted of those studies with three or more doses, with a positive dose response producing tumors, but in which there were no tumors in the control group. The third group of more than 50 studies was from NTP-TR-00 to NTP-TR-52 that had only two data points with a positive dose response. These studies were all evaluated on the Rozman et al. scale, since it conforms to the laws of nature and allows evaluation of all doses. It was observed that virtually all of these NTP-TR carcinogenicity studies show a linear response when dose is on this logarithmic scale; a clear threshold for carcinogenicity is typical for nearly all of these chemicals. An exponential dose-response curve was a better fit for a few, but experimental error could account for this deviation from linearity. It is pointed out that there is strong experimental evidence that the mere presence of DNA adducts does not necessarily lead to tumor production. Hormesis probably applies to carcino-genesis and proof of this will require abandoning the no threshold concept. Experiments showing that cumulative dose is a better metric than daily dose may require reevaluating almost all carcinogenicity studies.

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Effect of Warfarin on the Metabolism of Phylloquinone (Vitamin K1): Dose—Response Relationships in Man

Clinical Science ◽

10.1042/cs0520621 ◽

1977 ◽

Vol 52 (6) ◽

pp. 621-630 ◽

Cited By ~ 4

Author(s):

M. J. Shearer ◽

A. McBurney ◽

A. M. Breckenridge ◽

P. Barkhan

Keyword(s):

Vitamin K ◽

Dose Response ◽

Oral Anticoagulants ◽

Plasma Concentrations ◽

Pharmacological Action ◽

Progressive Increase ◽

Normal Male ◽

Vitamin K1 ◽

Response Curves ◽

Dose Response Curves

1. The dose—response relationship between the oral anticoagulant, warfarin, and its effect on the metabolism of phylloquinone (vitamin K1) has been examined in normal male volunteer subjects. 2. In each study the subject received a single, oral dose of warfarin and, 2 h later, an intravenous injection of [1′,2′-3H2]phylloquinone. Changes in the metabolism of phylloquinone were assessed by the fractionation and chromatographic separation of labelled phylloquinone and its metabolites in plasma and urine samples. 3. Increasing doses of warfarin did not affect the rate of disappearance of injected phylloquinone from the plasma but caused the accumulation of increasing amounts of the metabolite, phylloquinone epoxide. 4. Increasing doses of warfarin were found to decrease the proportion of labelled conjugates excreted in the urine as glucuronides and to block progressively the excretion of the normal aglycones of phylloquinone. At the same time there was a progressive increase in the excretion of at least three abnormal aglycones of phylloquinone. 5. The doses or plasma concentrations of warfarin were related to the increase in phylloquinone epoxide in the plasma and to the decrease in the proportion of normal aglycones of phylloquinone in urine by typical log dose—response curves, which were linear over the therapeutic range. 6. The nature of the metabolites detected suggested that the dose—response curves reflected the progressive inhibition by warfarin of the enzyme, phylloquinone epoxide reductase. 7. The results are consistent with the hypothesis that the pharmacological action of oral anticoagulants is closely linked to their ability to inhibit the cyclic interconversion of vitamin K and vitamin K epoxide.

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Contraction and endothelium-dependent relaxation in mesenteric microvessels from pregnant rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.6.h1899 ◽

1995 ◽

Vol 269 (6) ◽

pp. H1899-H1904 ◽

Cited By ~ 3

Author(s):

I. F. Pascoal ◽

M. D. Lindheimer ◽

C. Nalbantian-Brandt ◽

J. G. Umans

Keyword(s):

Dose Response ◽

Effective Concentration ◽

Mesenteric Arteries ◽

Half Maximum ◽

Response Curves ◽

Pregnant Rats ◽

No Release ◽

Dose Response Curves ◽

Mesenteric Microvessels ◽

Endothelium Dependent Relaxation

We assessed KCl- and phenylephrine (PE)-induced vasoconstriction as well as acetylcholine (ACh)-induced endothelium-dependent vasodilation in small, isometrically mounted mesenteric arteries from virgin and gravid rats, studied in the absence and presence of NG-nitro-L-arginine (L-NNA). Neither maximal vasoconstriction nor PE potency differed significantly between vessels from virgin and pregnant rats, either in the absence or presence of L-NNA. L-NNA resulted in similar twofold leftward shifts in the PE dose-response curves for both groups. ACh-induced relaxation was potentiated in vessels from gravid rats (half-maximum effective concentration = 0.25 vs. 0.04 microM, virgin and gravid rats, respectively). After L-NNA, maximal relaxation was inhibited significantly more in vessels from gravid rats (62 vs. 31%). Likewise, maximal slope of ACh dose-response curves and ACh potency were decreased in this group so that values no longer differed from those in virgins. We conclude that pregnancy does not alter basal nitric oxide (NO) synthesis in these isolated microvessels, but it does enhance ACh-induced NO release, while apparently inhibiting the action of a NO-independent, endothelium-derived vasodilator.

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Vascular function in arteries of intertidal fish Girella laevifrons(Kyphosidae)

Brazilian Journal of Biology ◽

10.1590/bjb.2014.0099 ◽

2014 ◽

Vol 74 (3) ◽

pp. 739-743 ◽

Cited By ~ 3

Author(s):

FA Moraga ◽

N Urriola-Urriola

Keyword(s):

Dose Response ◽

Vascular Function ◽

Isometric Tension ◽

Mesenteric Arteries ◽

Response Curves ◽

Cholinergic Pathways ◽

Cholinergic Pathway ◽

Dose Response Curves ◽

Intertidal Fish ◽

Low Sensitivity

Preliminary studies showed that dorsal artery contraction mediated by acetylcholine (ACh) is blocked with indomethacin in intertidal fish (Girella laevifrons). Our objective was to characterise the cholinergic pathway in several artery vessels of the G. laevifrons. Afferent and efferent branchial, dorsal and mesenteric arteries were dissected of 6 juvenile specimens, isometric tension studies were done using dose response curves (DRC) for Ach (10–13 to 10–3 M), and cholinergic pathways were obtained by blocking with atropine or indomethacin. CRC to ACh showed a pattern of high and low sensitivity. Furthermore, these contractions were blocked in the presence of atropine and indomethacin in all vessels. Our results suggest that contraction observed with acetylcholine is mediated by receptors that activate a cyclooxygenase contraction pathway.

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Canine gastrocnemius disuse atrophy: resistance to paralysis by dimethyl tubocurarine

Journal of Applied Physiology ◽

10.1152/jappl.1984.57.5.1502 ◽

1984 ◽

Vol 57 (5) ◽

pp. 1502-1506 ◽

Cited By ~ 13

Author(s):

G. A. Gronert ◽

R. S. Matteo ◽

S. Perkins

Keyword(s):

Dose Response ◽

Plasma Concentrations ◽

Blood Levels ◽

Maximal Effect ◽

Disuse Atrophy ◽

Response Curves ◽

Dose Response Curves ◽

Gastrocnemius Muscles ◽

The Hill

Ten dogs developed unilateral gastrocnemius disuse atrophy after unilateral hindlimb immobilization in a cast for 25 days. Dose-response curves to dimethyl tubocurarine (MTC) were determined during anesthesia with pentobarbital sodium-N2O. Bolus and continuous infusion increments of MTC every 30 min provided steady-state blood levels at each stage of paralysis. Both gastrocnemius tendons were sectioned and attached to transducers. Both sciatic nerves were stimulated every 30 min: 2 Hz for 2 s, a 15-s pause, 50 Hz for 2 s. Dose-response curves, computer calculated by nonlinear regression using a sigmoid maximal effect model of the Hill equation, were parallel for the data relating blocking of tetanus to dose of MTC. The 50% paralyzing dose (tetanus) for control vs. casted gastrocnemius muscle was 64 vs. 813 mg/kg; corresponding plasma concentrations were 0.12 vs. 2.0 micrograms/ml. Thus in vivo simultaneous tension measurements of both gastrocnemius muscles, one casted and one uncasted, demonstrated resistance to paralysis by MTC in muscle with disuse atrophy.

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The Importance of Enzyme Inhibition Kinetics for the Effect of Thrombin Inhibitors in a Rat Model of Arterial Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657729 ◽

1997 ◽

Vol 78 (04) ◽

pp. 1286-1292 ◽

Cited By ~ 91

Author(s):

Margareta Elg ◽

David Gustafsson ◽

Johanna Deinum

Keyword(s):

Dose Response ◽

Plasma Concentrations ◽

Thrombin Inhibitors ◽

Hill Coefficient ◽

Antithrombotic Effect ◽

Response Curves ◽

Dose Response Curves ◽

Association Time

SummaryThe relation between the antithrombotic effect in vivo, and the inhibition constant (K i) and the association rate constant (k on) in vitro was investigated for eight different thrombin inhibitors. The carotid arteries of anaesthetized rats were exposed to FeCl3 for 1 h, and the thrombus size was determined from the amount of incorporated 125I- fibrinogen. The thrombin inhibitors were given intravenously, and complete concentration- and/or dose-response curves were constructed. Despite a 50,000-fold difference between the k i-values comparable plasma concentrations of hirudin and melagatran were needed (0.14 and 0.12 μmol 1-1, respectively) to obtain a 50% antithrombotic effect (IC50) in vivo. In contrast, there was a comparable in vitro (k i-value) and in vivo (IC50) potency ratio for melagatran and inogatran, respectively. These results can be explained by the concentration of thrombin in the thrombus and improved inhibition by the low-molecular-weight compounds. For all eight thrombin inhibitors tested, there was an inverse relationship between k on-values in vitro and the slope of the dose response curves in vivo. Inhibitors with k on-values of <1 X 107 M-1 s-1 gave steep dose response curves with a Hill coefficient >1. The association time for inhibition of thrombin for slow-binding inhibitors will be too long to give effective antithrombotic effects at low plasma concentrations, but at increasing concentrations the association time will decrease, resulting in a steeper dose-response curve and thereby a more narrow therapeutic interval.

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Dose-response Curves in the Fibrin Plate Assay Fibrinolytic Activity of Proteases

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647705 ◽

1974 ◽

Vol 32 (02/03) ◽

pp. 356-365 ◽

Cited By ~ 12

Author(s):

F Haverkate ◽

D. W Traas

Keyword(s):

Dose Response ◽

Fibrinolytic Activity ◽

Enzyme Concentration ◽

Response Curves ◽

Agar Gel ◽

Porcine Tissue ◽

Plate Assay ◽

Fibrin Plate ◽

Different Types ◽

Dose Response Curves

SummaryIn the fibrin plate assay different types of relationships between the dose of applied proteolytic enzyme and the response have been previously reported. This study was undertaken to determine whether a generally valid relationship might exist.Trypsin, chymotrypsin, papain, the plasminogen activator urokinase and all of the microbial proteases investigated, including brinase gave a linear relationship between the logarithm of the enzyme concentration and the diameter of the circular lysed zone. A similar linearity of dose-response curves has frequently been found by investigators who used enzyme plate assays with substrates different from fibrin incorporated in an agar gel. Consequently, it seems that this linearity of dose-response curves is generally valid for the fibrin plate assay as well as for other enzyme plate bioassays.Both human plasmin and porcine tissue activator of plasminogen showed deviations from linearity of semi-logarithmic dose-response curves in the fibrin plate assay.

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BIOASSAY OF THYROID HORMONE USING HYPOTHYROID TADPOLES

Acta Endocrinologica ◽

10.1530/acta.0.0410143 ◽

1962 ◽

Vol 41 (1) ◽

pp. 143-153 ◽

Cited By ~ 2

Author(s):

U. Henriques

Keyword(s):

Thyroid Hormone ◽

Dose Response ◽

Developmental Rate ◽

Response Curves ◽

Sodium Salts ◽

Dose Response Curves

ABSTRACT A bioassay of thyroid hormone has been developed using Xenopus larvae made hypothyroid by the administration of thiourea. Only tadpoles of uniform developmental rate were used. Thiourea was given just before the metamorphotic climax in concentrations that produced neoteni in an early metamorphotic stage. During maintained thiourea neotoni, 1-thyroxine and 1-triiodothyronine were added as sodium salts to the water for three days and at the end of one week the stage of metamorphosis produced was determined. In this way identical dose-response curves were obtained for the two compounds. No qualitative differences between their effects were noted except that triiodothyronine seemed more toxic than thyroxine in equivalent doses. Triiodothyronine was found to be 7–12 times as active as thyroxine.

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