P4465Acute Cardio-Selective Functional Modulation via a Small-Molecule Direct Myosin-Attenuator (MYK-581) Preserves Diaphragmatic Function in vivo: Comparison versus Disopyramide

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C L Del Rio ◽  
S Roof ◽  
A R Anto ◽  
R L Anderson
Keyword(s):  
Exercise Capacity ◽  
Small Molecule ◽  
Systolic Function ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Mechanically Ventilated ◽  
Diaphragmatic Function ◽  
Sprague Dawley Rats ◽  
Ventricular Filling

Abstract Background Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disease characterized by hyper-contractility, hindered relaxation, and impaired exercise capacity. Conventional negative inotropes can alleviate enhanced inotropy in HCM, but do not improve ventricular filling and have the potential to further decrease exercise capacity due to their off/on-target systemic effects. Recently, a novel small molecule cardiac-myosin attenuator, Mavacamten, has been shown to normalize hyper-contractility in the setting of HCM. This study evaluated and compared the in vivo functional selectivity of MYK-581, a mavacamten analog, with those of disopyramide (DISO), a commonly-used negative inotrope. Methods In vivo, the acute cardiac (left ventricular pressures) and neuro-muscular (force of diaphragmatic and skeletal muscle contractions) responses to MYK-581 (up to 0.5 mg/kg IV) and DISO (up to 10 mg/kg IV) were simultaneously evaluated using anesthetized and mechanically-ventilated Sprague-Dawley rats; diaphragmatic (both intrinsic and phrenic nerve stimulated) and skeletal contractions (stimulated quadriceps) were measured via strain gauges. Results MYK-581 decreased indices of systolic function (dP/dtmax: −32±2% and vmax: −14±2%, P<0.05 vs. pre-dose) and increased LV EDV (+9±2%, P<0.05), while preserving EDP (6±1 to 6±1 mmHg), suggesting improved ventricular distensibility. Despite these marked cardiac effects, MYK-581 preserved both diaphragmatic (23.7±2.0 to 23.3±2.2 g) and skeletal in situ function (14.9±1.4 to 13.9±0.8 g). In contrast, DISO at matched levels of negative inotropy (dP/dtmax: −25±2% and vmax: −19±2%, P<0.05 vs. pre-dose) depressed diaphragmatic force (−16±3%, 23.8±1.9 to 19.8±1.2 g, P<0.05). Finally, the cardiac selectivity of MYK-581 was confirmed in kinetic experiments evaluating the Ca2+-activated ATPase activity of both cardiac and diaphragmatic myofibrils. Conclusions Direct myosin modulation with MYK-581, a mavacamten analog, is characterized in vivo by reductions in systolic function with preserved filling pressures and improved LV compliance. Moreover, this cardiovascular profile was devoid in vivo of diaphragmatic/skeletal off-target effects that could further hinder exercise capacity in patients with HCM.

Intestinal ion transport and intracellular pH during acute respiratory alkalosis and acidosis

1984 ◽  
Vol 247 (1) ◽  
pp. G24-G31 ◽  
Author(s):  
P. Kurtin ◽  
A. N. Charney
Keyword(s):  
Intracellular Ph ◽  
Respiratory Acidosis ◽  
Respiratory Alkalosis ◽  
Electrolyte Transport ◽  
Sprague Dawley ◽  
Mechanically Ventilated ◽  
Sprague Dawley Rats ◽  
Intestinal Ion Transport

Acute respiratory alkalosis and acidosis alter rat ileal and colonic but not jejunal electrolyte transport. To examine the role of altered intracellular pH, pHi, and HCO3 concentration, (HCO3)i, we measured pHi in mucosa scraped from the jejunum, ileum, and colon of anesthetized, mechanically ventilated Sprague-Dawley rats. During states of respiratory alkalosis (Pco2 24.9 +/- 0.8 mmHg, pH 7.586 +/- 0.014), respiratory acidosis (Pco2 67.8 +/- 1.2 mmHg, pH 7.228 +/- 0.007), and normocapnia (Pco2 41.1 +/- 0.7 mmHg, pH 7.401 +/- 0.006), pHi was measured by determining the distribution of 5,5-dimethyl[2-14C]oxazolidine-2,4-dione, using [3H]inulin as a marker of extracellular space. (HCO3)i was calculated using portal vein Pco2. In the ileum, the pHi of 6.901 +/- 0.029 was similar in alkalosis [(HCO3)i 5.4 +/- 0.3 mM], acidosis [(HCO3)i 12.4 +/- 0.6 mM], and normocapnia [(HCO3)i 8.6 +/- 0.8 mM). In both the jejunum and colon, pHi was increased in alkalosis [pHi 6.998 +/- 0.038, (HCO3)i 6.7 +/- 0.6 mM] and decreased in acidosis [pHi 6.789 +/- 0.024, (HCO3)i 10.4 +/- 0.6 mM] as compared with normocapnia [pHi 6.915 +/- 0.026, (HCO3)i 8.9 +/- 0.7 mM] (colon data given). Net electrolyte transport measured by in vivo perfusion revealed that ileal and colonic, but not jejunal, net Na and Cl absorption was decreased during alkalosis and increased during acidosis. These data suggest that, during respiratory acidosis and alkalosis, pHi is maintained in a qualitatively similar way in the jejunum, ileum, and colon with quantitatively greater or lesser changes in (HCO3)i.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Impaired myocardial function does not explain reduced left ventricular filling and stroke volume at rest or during exercise at high altitude

2015 ◽  
Vol 119 (10) ◽  
pp. 1219-1227 ◽  
Author(s):  
Mike Stembridge ◽  
Philip N. Ainslie ◽  
Michael G. Hughes ◽  
Eric J. Stöhr ◽  
James D. Cotter ◽  
...  
Keyword(s):  
Stroke Volume ◽  
High Altitude ◽  
Systolic Function ◽  
Left Ventricular ◽  
Limiting Factor ◽  
End Diastolic Volume ◽  
Apical Rotation ◽  
Diastolic Relaxation ◽  
Ventricular Filling

Impaired myocardial systolic contraction and diastolic relaxation have been suggested as possible mechanisms contributing to the decreased stroke volume (SV) observed at high altitude (HA). To determine whether intrinsic myocardial performance is a limiting factor in the generation of SV at HA, we assessed left ventricular (LV) systolic and diastolic mechanics and volumes in 10 healthy participants (aged 32 ± 7; mean ± SD) at rest and during exercise at sea level (SL; 344 m) and after 10 days at 5,050 m. In contrast to SL, LV end-diastolic volume was ∼19% lower at rest ( P = 0.004) and did not increase during exercise despite a greater untwisting velocity. Furthermore, resting SV was lower at HA (∼17%; 60 ± 10 vs. 70 ± 8 ml) despite higher LV twist (43%), apical rotation (115%), and circumferential strain (17%). With exercise at HA, the increase in SV was limited (12 vs. 22 ml at SL), and LV apical rotation failed to augment. For the first time, we have demonstrated that EDV does not increase upon exercise at high altitude despite enhanced in vivo diastolic relaxation. The increase in LV mechanics at rest may represent a mechanism by which SV is defended in the presence of a reduced EDV. However, likely because of the higher LV mechanics at rest, no further increase was observed up to 50% peak power. Consequently, although hypoxia does not suppress systolic function per se, the capacity to increase SV through greater deformation during submaximal exercise at HA is restricted.

Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures

2006 ◽  
Vol 290 (4) ◽  
pp. H1699-H1705 ◽  
Author(s):  
K. A. Connelly ◽  
D. L. Prior ◽  
D. J. Kelly ◽  
M. P. Feneley ◽  
H. Krum ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Systolic Function ◽  
Normal Function ◽  
Left Ventricular ◽  
Doppler Imaging ◽  
Stroke Work ◽  
Sprague Dawley ◽  
Loop Analysis ◽  
Shortening Velocity

Transgenic animal models have provided a vital insight into the pathogenesis of cardiovascular disease, but functional cardiac assessment is often limited by high heart rates and small heart size. We hypothesized that in the presence of concentric left ventricular (LV) hypertrophy (LVH), load-sensitive measures of contractility may be misinterpreted as overestimating global cardiac function, because the normal function of excess sarcomeres may displace a greater volume of blood during contraction. Conductance catheter technology was used to evaluate pressure-volume (P-V) relationships as a load-insensitive method of assessing cardiac function in vivo in 18-wk-old heterozygous (mRen-2)27 transgenic rats (a model of LVH), compared with age-matched Sprague-Dawley (SD) controls. Anesthetized animals underwent echocardiography followed by P-V loop analysis. Blood pressure, body weight, and heart rate were higher in the Ren-2 rats ( P < 0.05). Load-sensitive measures of systolic function, including fractional area change, fractional shortening, ejection fraction, and positive peak rate of LV pressure development, were greater in the Ren-2 than control animals ( P < 0.05). Load-insensitive measures of systolic function, including the preload recruitable stroke work relationship and the end-systolic P-V relationship, were not different between Ren-2 and SD rats. Regional wall motion assessed by circumferential shortening velocity suggested enhanced circumferential fiber contractility in the Ren-2 rats ( P = 0.02), but tissue Doppler imaging, used to assess longitudinal function, was not different between groups. Although conventional measures suggested enhanced systolic function in the Ren-2 rat, load-insensitive measures of contractility were not different between Ren-2 and SD animals. These findings suggest that the normal range of values for load-sensitive indexes of contractility needs to be altered according to the degree of LVH. To accurately identify changes in systolic function, we suggest that a combination of echocardiography with assessment of load-insensitive measures be used routinely.

Intracellular EDEMA does not adversely affect the ability to cryopreserve intact hearts

1993 ◽  
Vol 51 ◽  
pp. 278-279
Author(s):  
CL Hastings ◽  
RD Carlton ◽  
FG Lightfoot ◽  
AF Tryka
Keyword(s):  
Cell Injury ◽  
Median Sternotomy ◽  
Left Ventricular ◽  
Ventricular Free Wall ◽  
Hypoxic Cell ◽  
Free Wall ◽  
Sprague Dawley ◽  
Left Ventricular Free Wall ◽  
Sprague Dawley Rats

The earliest ultrastructural manifestation of hypoxic cell injury is the presence of intracellular edema. Does this intracellular edema affect the ability to cryopreserve intact myocardium? To answer this guestion, a model for anoxia induced intracellular edema (IE) was designed based on clinical intraoperative myocardial preservation protocol. The aortas of 250 gm male Sprague-Dawley rats were cannulated and a retrograde flush of Plegisol at 8°C was infused over 90 sec. The hearts were excised and placed in a 28°C bath of Lactated Ringers for 1 h. The left ventricular free wall was then sliced and the myocardium was slam frozen. Control rats (C) were anesthetized, the hearts approached by median sternotomy, and the left ventricular free wall frozen in situ immediately after slicing. The slam frozen samples were obtained utilizing the DDK PS1000, which was precooled to -185°C in liguid nitrogen. The tissue was in contact with the metal mirror for a dwell time of 20 sec, and stored in liguid nitrogen until freeze dry processing (Lightfoot, 1990).

Toxicokinetic and Genotoxicity Study of NNK in Male Sprague-Dawley Rats Following Nose-Only Inhalation Exposure, Intraperitoneal Injection, and Oral Gavage

2021 ◽  
Author(s):  
Shu-Chieh Hu ◽  
Matthew S Bryant ◽  
Estatira Sepehr ◽  
Hyun-Ki Kang ◽  
Raul Trbojevich ◽  
...  
Keyword(s):  
Human Lung ◽  
Inhalation Exposure ◽  
Systemic Exposure ◽  
Sprague Dawley ◽  
Oral Gavage ◽  
Sd Rats ◽  
New Information ◽  
Sprague Dawley Rats ◽  
Tissue Specimens

Abstract The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5x10−5, 5x10−3, 0.1, or 50 mg/kg body weight (BW) of NNK, 75% propylene glycol (vehicle control), or air (sham control) was administered to male Sprague-Dawley (SD) rats (9-10 weeks age) via nose-only inhalation (INH) exposure for 1 hour. For comparison, the same doses of NNK were administered to male SD rats via intraperitoneal (IP) injection and oral gavage (PO). Plasma, urine, and tissue specimens were collected at designated timepoints and analyzed for levels of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and tissue levels of DNA adduct O6-methylguanine by LC/MS/MS. TK data analysis was performed using a non-linear regression program. For the genotoxicity subgroup, tissues were collected at 3 hours post-dosing for comet assay analysis. Overall, the TK data indicated that NNK was rapidly absorbed and metabolized extensively to NNAL after NNK administration via the three routes. The IP route had the greatest systemic exposure to NNK. NNK metabolism to NNAL appeared to be more efficient via INH than IP or PO. NNK induced significant increases in DNA damage in multiple tissues via the three routes. The results of this study provide new information and understanding of the toxicokinetics and genotoxicity of NNK.

scholarly journals Pharmacological comparison of four biopolymeric natural gums as hemostatic agents for management of bleeding wounds: preliminary in vitro and in vivo results

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Himanshu Kushwah ◽  
Nidhi Sandal ◽  
Meenakshi Chauhan ◽  
Gaurav Mittal
Keyword(s):  
Xanthan Gum ◽  
Guar Gum ◽  
Human Lymphocytes ◽  
Sprague Dawley ◽  
Gum Tragacanth ◽  
Civilian Trauma ◽  
Sprague Dawley Rats ◽  
Cytotoxicity Studies

Abstract Background Uncontrolled bleeding is one of the primary reasons for preventable death in both civilian trauma and military battle field. This study evaluates in vitro and in vivo hemostatic potential of four biopolymeric natural gums, namely, gum tragacanth, guar gum, xanthan gum, and gum acacia. In vitro evaluation of whole blood clotting time and erythrocyte agglutination assay were carried out. In vitro cytotoxicity studies with respect to each gum were done in human lymphocytes to ascertain percent cell viability. In vivo hemostatic potential of each gum (as sponge dressing and powder form) was evaluated in Sprague Dawley rats using tail bleeding assay and compared with commercially available hemostatic sponge. Other important parameters like (a) time taken for complete hemostasis, (b) amount of blood absorbed, (c) adherence strength of developed hemostatic dressing(s), (d) incidence of re-bleeding, and (e) survival of animals were also studied. Results Of the four test gums studied, xanthan gum (@3mg/ml of blood) and gum tragacanth (@35mg/ml of blood) were able to clot blood in least time (58.75±6.408 s and 59.00±2.082 s, respectively) and exhibited very good hemostatic potential in vitro. Except for xanthan gum, all other test gums did not exhibit any significant cytotoxicity at different time points till 24 h. In rat tail bleeding experiments, gum tragacanth sponge dressing and powder achieved hemostasis in least time (156.2±12.86 s and 76±12.55 s, respectively) and much earlier than commercially available product (333.3±38.84 s; p˂0.01). Conclusion Results indicate potential of gum tragacanth to be developed into a suitable hemostatic product.

Bioavailability in Vivo of Benzo[a]Pyrene Adsorbed to Diesel Particulate

1991 ◽  
Vol 7 (3) ◽  
pp. 125-139 ◽  
Author(s):  
David R. Bevan ◽  
David M. Ruggio
Keyword(s):  
Health Risks ◽  
Quantitative Description ◽  
Intratracheal Instillation ◽  
Direct Analysis ◽  
Sprague Dawley ◽  
Reasonable Estimate ◽  
Diesel Particulate ◽  
Sprague Dawley Rats

To evaluate health risks associated with exposure to particulates in the environment, it is necessary to quantify the bioavailability of carcinogens associated with the particulates. Direct analysis of bioavailability in vivo is most readily accomplished by adsorbing a radiolabeled form of the carcinogen to the particulate. A sam ple of native diesel particulate collected from an Oldsmobile die sel engine that contained 1.03 μ g benzo[ a] pyrene ( BaP)/ g particulate was supplemented with exogenous [ 3 H]- BaP to pro duce a particulate containing 2.62 μ g BaP/g. To insure that elu tion of BaP from native and [3 H] -BaP-supplemented particulate was similar, in vitro analyses were performed. When using phos pholipid vesicles composed of dimyristoylphosphatidylcholine (DMPC), 1.52% of total BaP was eluted from native particulate into the vesicles in 18 hrs; from [ 3 H] -BaP supplemented particu late, 1.68% was eluted. Using toluene as eluent, 2.55% was eluted from native particulate, and 8.25% from supplemented particulate, in 6 hrs. Supplemented particulate was then instilled intratracheally into male Sprague-Dawley rats and distribution of radioactivity was analyzed at selected times over 3 days. About 50% of radioactivity remained in lungs at 3 days following instil lation, with 30% being excreted into feces and the remainder dis tributed throughout the organs of the rats. To estimate the amount of radioactivity that entered feces through swallowing of a portion of the instilled dose, [3 H] -BaP-supplemented particu late was instilled intratracheally into rats that had a cannula sur gically implanted in the bile duct. Rate of elimination of radio activity into bile was monitored; 10.6% of radioactivity was re covered in 6 hr, an amount slightly lower than the 12.8% ex creted in 6 hrs into feces of animals with intact bile ducts. Our studies provide a quantitative description of the distribution of BaP and its metabolites following intratracheal instillation of diesel particulate. Because rates of elution of BaP in vitro are similar for native diesel particulate and particulate with supple mental [ 3H] -BaP, our results provide a reasonable estimate of the bioavailability in vivo of BaP associated with diesel particu late.

scholarly journals The in vivo Pig-a gene mutation assay is applied to study the genotoxicity of procarbazine hydrochloride in Sprague-Dawley rats

2016 ◽  
Vol 3 (4) ◽  
pp. 167-175 ◽  
Author(s):  
Jiang Pu ◽  
Yuanyuan Deng ◽  
Xiaoyan Tan ◽  
Gaofeng Chen ◽  
Cong Zhu ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Mutation Assay ◽  
Gene Mutation Assay
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