scholarly journals Sex differences in progesterone-induced relaxation in the coronary bed from normotensive rats

2020 ◽  
Vol 64 (2) ◽  
pp. 91-102
Author(s):  
Jéssyca Aparecida Soares Giesen ◽  
Wender do Nascimento Rouver ◽  
Eduardo Damasceno Costa ◽  
Virgínia Soares Lemos ◽  
Roger Lyrio dos Santos
Keyword(s):  
Vascular Reactivity ◽  
Coronary Perfusion Pressure ◽  
Female Group ◽  
No Production ◽  
Coronary Perfusion ◽  
Acute Administration ◽  
Langendorff Preparation ◽  
Isolated Hearts ◽  
Vasodilatory Response ◽  
Relaxing Response

Progesterone seems to play a role in cardiovascular physiology since its receptors are expressed on endothelial cells from both sexes of mammals. However, little is known about its role on the coronary circulation. Thus, this study aims to evaluate the effect of acute administration of progesterone on the coronary bed and the endothelial pathways involved in this action in normotensive rats of both sexes. A dose–response curve of progesterone (1–50 μmol/L) in isolated hearts using the Langendorff preparation was performed. Baseline coronary perfusion pressure (CPP) was determined, and the vasoactive effect of progesterone was evaluated before and after infusion with Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin, catalase, and Tiron. The analysis of nitric oxide (NO) and superoxide anion (O2 · −) was performed by DAF-2DA and DHE, respectively. Female group showed higher CPP. Nevertheless, progesterone promoted a similar relaxing response in both sexes. The use of L-NAME increased vasodilatory response in both sexes. When indomethacin was used, only the males showed a reduced relaxing response, and in the combined inhibition with L-NAME, indomethacin, and catalase, or with the use of Tiron, only the females presented reduced responses. NO and O2 ·− production has increased in female group, while the male group has increased only NO production. Our results suggest that progesterone is able to modulate vascular reactivity in coronary vascular bed with a vasodilatory response in both sexes. These effects seem to be, at least in part, mediated by different endothelial pathways, involving NO and EDH pathways in females and NO and prostanoids pathways in males.

P561Acute effects of dronedarone and amiodarone on functional, morphological and oxidative stress parameters in isolated rat heart with hypertension

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
S Simovic ◽  
J Jeremic ◽  
G Davidovic ◽  
I Srejovic ◽  
S Mitrovic ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Rat Heart ◽  
Structural Changes ◽  
Perfusion Pressure ◽  
Coronary Perfusion Pressure ◽  
Isolated Rat Heart ◽  
Coronary Perfusion ◽  
Acute Administration ◽  
Isolated Hearts ◽  
Isolated Rat

Abstract Introduction Amiodarone represents the most widely used antiarrhythmic drug, even though it has been shown that it has negative inotropic and lusitropic effect in healthy hears. On the other hand, dronedarone reduces the risk of recurrent atrial fibrillation, but with increased early mortality related to the worsening of heart failure. However, the mechanisms responsible for these fatal outcomes remain unclear and require further examinations.  Purpose To investigate acute, direct effects of Dronedarone and Amiodarone on cardiac contractility, coronary flow and oxidative stress parameters in isolated rat heart with hypertension. Methods  The present study was carried out on 18 isolated hearts of spontaneously hypertensive Wistar Kyoto male rats (6 weeks old, bodyweight 200 ± 10 g). After isolation, all hearts were retrogradely perfused according to Langendorff technique with a gradually increment of coronary perfusion pressure (CPP from 40 to 120 cm H2O) and randomly divided into 3 groups: Control (n = 6), Amiodarone (n = 6, isolated hearts perfused with Amiodarone in dose of 3 umol), Dronedarone (n = 6, isolated hearts perfused with Dronedarone in dose of 1.8 umol). During ex vivo protocol continuously were registered cardiac contractility parameters and coronary flow, while from collected coronary venous effluent markers of oxidative stress were measured. All hearts were then fixated and stained with Hematoxylin/eosin. Results  Dronedarone severely depressed the function of all cardiodynamic parameters of the heart compared with Amiodarone or Control while Amiodarone intensified the function of the isolated rat heart with hypertension compared to Control (dp/dt max mmHg/s at coronary perfusion pressure 120cmH2O Dronedarone vs. Amiodarone vs. Control 579.733 ± 202.27 vs. 3063.65 ± 467.93 vs. 2682.88 ± 368.75; p < 0.001. dp/dt min mmHg/s 120cmH2O -352.13 ± 204.65 vs. 1960 ± 242.21 vs. -1858.83 ± 118.23; p < 0.001. SLVP mmHg at CPP 120cmH20 27.8 ± 3.46 vs. 98.95 ± 11.78 vs. 71.45 ± 7.56; p < 0.001. DLVP mmHg at CPP 120cmH2O 6.32 ± 0.49 vs. 4.83 ± 0.54 vs. 0.85 ± 0.35; p < 0.001). Acute administration of Dronedarone decreased the level of NO2- and increased the level of H2O2 , while Amiodarone heightens O2- levels (O2- nmol/min g wt at coronary perfusion pressure 120cmH2O Dronedarone vs. Amiodarone vs. Control  28.62 ± 2.54 vs. 77.3 ± 8.86 vs. 31.72 ± 4.56; p < 0.001. H2O2 nmol/min g wt at CPP 120cmH2O 92.56 ± 11.65 vs. 48.63 ± 10.11 vs. 42.84 ± 84; p < 0.001. NO2- nmol/min g wt at CPP 120cmH2O 38.61 ± 4.94 vs.  82.28 ± 5.76 vs.  64.71 ± 3.51; p < 0.001). Pathohistological, structural changes were observed in both, experimental groups. Conclusions  Acute administration of Dronedarone depresses cardiac function in isolated, working rat heart with hypertension, with decreasing the NO2- levels, increasing the level of H2O2 and enhanced structural changes when compared to Amiodarone.

Hyperreactivity of coronary vasculature in platelet-perfused hearts from diabetic rats

1983 ◽  
Vol 245 (4) ◽  
pp. H640-H645 ◽  
Author(s):  
D. K. Reibel ◽  
D. M. Roth ◽  
B. L. Lefer ◽  
A. M. Lefer
Keyword(s):  
Vascular Reactivity ◽  
Perfusion Pressure ◽  
Coronary Perfusion Pressure ◽  
Diabetic Rats ◽  
Coronary Perfusion ◽  
Leukotriene D4 ◽  
Isolated Hearts ◽  
Alpha Production ◽  
Vascular Responsiveness ◽  
Perfused Hearts

Coronary vascular responsiveness to platelet-produced eicosanoids was examined in isolated perfused hearts of alloxan-diabetic rats. Coronary perfusion pressure was increased in isolated hearts of control and diabetic rats on perfusion with platelets and arachidonic acid (AA). However, the increase in perfusion pressure was approximately twofold higher in hearts of diabetic rats when compared with those isolated from control rats. This was associated with increased thromboxane B2 (TxB2) and prostaglandin F2 alpha (PGF2 alpha) production that was comparable in platelet-perfused hearts of control and diabetic animals. Ibuprofen, a cyclooxygenase inhibitor, blocked the increase in perfusion pressure and TxB2 and PGF2 alpha production by greater than 90% in both control and diabetic hearts perfused with platelets and AA. Dazoxiben, a thromboxane synthetase inhibitor, blocked the increase in perfusion pressure by 50%, totally inhibited TxB2 production, but increased PGF2 alpha production by 60% in both groups of platelet-perfused hearts. Increased levels of PGF2 alpha and possibly other constrictor eicosanoids (e.g., leukotriene D4) may account for the partial constriction observed in platelet-perfused hearts with dazoxiben. Results of the present study suggest that vascular reactivity to vasoconstrictor eicosanoids is increased in hearts of diabetic animals.

Surgically induced deficiency of sex hormones modulates coronary vasodilation by estradiol in hypertension

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Wender do Nascimento Rouver ◽  
Cassiano Ricardo Souza Ferreira ◽  
Nathalie Tristão Banhos Delgado ◽  
Roger Lyrio dos Santos
Keyword(s):  
Direct Action ◽  
Sodium Deoxycholate ◽  
Coronary Perfusion Pressure ◽  
Female Group ◽  
Coronary Perfusion ◽  
Spontaneously Hypertensive ◽  
Isolated Hearts ◽  
Vascular Bed ◽  
Before And After ◽  
Hormonal Dysfunction

AbstractObjectivesThe effect of oestrogen in hormonal dysfunction is not clear, especially in the coronary vascular bed. This study aimed at estradiol action (E2) in the coronary vascular bed from sham-operated and gonadectomized female and male spontaneously hypertensive rats (SHRs).MethodsMale and female SHRs had their mean arterial pressure (MAP) and baseline coronary perfusion pressure (CPP) determined. The effects of E2 (10 μM) were evaluated in isolated hearts by in bolus infusion before and after endothelium denudation (0.25 μM sodium deoxycholate) or perfusion with 100 μM NG-nitro-l-arginine methyl ester (L-NAME), 2.8 μM indomethacin, 0.75 μM clotrimazole, L-NAME after endothelium denudation, L-NAME plus indomethacin, or 4 mM tetraethylammonium (TEA).ResultsMAP was higher in males than in females, with gonadectomy increasing in females and reducing in males. CPP was higher in female group, remaining unaltered after gonadectomy. E2-induced vasorelaxation was observed in all groups, with no differences having been found between sexes even after gonadectomy. Perfusion with TEA, L-NAME, L-NAME plus indomethacin, and L-NAME after endothelium removal attenuated the relaxing response in all groups. Clotrimazole inhibited vasorelaxation only in female groups, and indomethacin did so only in gonadectomized groups. Endothelium participation was confirmed in female groups and in the gonadectomized male group.ConclusionsOur results indicated that the vasodilator effect of E2 was mediated by an indirect mechanism – via endothelium – as well as by direct action – via vascular smooth muscle – in both groups. The characterization of these mechanisms in coronary arteries might shed light on the functional basis of hormonal dysfunction symptoms in hypertension.

Prostacyclin-induced vasodilation in rabbit heart is mediated by ATP-sensitive potassium channels

1993 ◽  
Vol 264 (1) ◽  
pp. H238-H243 ◽  
Author(s):  
W. F. Jackson ◽  
A. Konig ◽  
T. Dambacher ◽  
R. Busse
Keyword(s):  
Nitric Oxide ◽  
Potassium Channels ◽  
Potassium Channel ◽  
Muscle Relaxation ◽  
Rabbit Heart ◽  
Coronary Perfusion Pressure ◽  
Smooth Muscle Relaxation ◽  
Coronary Perfusion ◽  
Langendorff Preparation ◽  
Oxide Synthase

We tested the hypothesis that prostacyclin and its stable analogue iloprost act as agonists of ATP-sensitive potassium channels (KATP) to induce vasodilation of the coronary circulation. The selective blocker of KATP, glibenclamide, was used as a probe for vasodilation mediated by KATP in saline-perfused rabbit hearts (constant flow, Langendorff preparation). Glibenclamide (10-300 nM) significantly increased coronary perfusion pressure and inhibited vasodilation induced by iloprost (1-30 nM), prostacyclin (10 nM), adenosine (0.3 microM), and cromakalim (0.1 microM), a known agonist of KATP. This potassium channel antagonist also inhibited vasodilation of rabbit hearts in response to 10 nM bradykinin in the presence of an inhibitor of nitric oxide synthase (30 microM NG-nitro-L-arginine). Because bradykinin-induced vasodilation is mediated by prostacyclin released from endothelial cells when nitric oxide synthesis is inhibited, these data indicate that glibenclamide is also effective against endogenous prostacyclin. The inhibitory effects of glibenclamide were selective: vasodilation induced by sodium nitroprusside (1-10 microM) or acetylcholine (1 microM) were not inhibited by this potassium channel antagonist. In addition, basal and bradykinin-stimulated release of 6-ketoprostaglandin F1 alpha was not affected by this antagonist of KATP. Glibenclamide also did not inhibit the activation of adenylate cyclase, as indicated by its lack of effect on adenosine 3',5'-cyclic monophosphate accumulation induced by iloprost (10 nM-1 microM) in bovine coronary arterial segments, a tissue in which iloprost-induced vascular smooth muscle relaxation is inhibited by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of coronary perfusion and myocardial edema on pressure-volume diagram of left ventricle

1961 ◽  
Vol 201 (1) ◽  
pp. 102-108 ◽  
Author(s):  
Cecil E. Cross ◽  
P. Andre Rieben ◽  
Peter F. Salisbury
Keyword(s):  
Diastolic Pressure ◽  
Myocardial Edema ◽  
Ventricular Volume ◽  
Coronary Perfusion Pressure ◽  
Left Ventricular ◽  
Similar Degree ◽  
Coronary Perfusion ◽  
Fluid Accumulation ◽  
Tension Development ◽  
Isolated Hearts

Pressure-volume diagrams of paced, isolated hearts were derived from isovolumic contractions and auxotonic contractions (simultaneous changes of pressure and volume). Coronary perfusion, fluid accumulation in heart muscle, and left ventricular volume and pressure were measured and controlled. Pressure-volume diagrams from isovolumic and auxotonic contractions were virtually identical in the same heart and were influenced by the same factors to a similar degree. At equal diastolic volumes the magnitude of systolic, as well as of diastolic pressures, and the occurrence of a systolic descending limb were directly related to coronary perfusion pressure. At equal diastolic volumes, other factors being constant, myocardial edema did not influence the contractile strength (i.e., maximum contractile tension development) of a ventricle, but did decrease its distensibility (i.e., increase diastolic pressure) in proportion to fluid accumulation. Myocardial water content and coronary factors (coronary arterial and venous pressures, coronary blood volume and flow) therefore constitute intrinsic mechanisms which can regulate the performance of a ventricle by changing its contractile strength, its distensibility, or both. The effects of coronary factors and of myocardial edema on the distensibility of a ventricle are sufficient in magnitude to explain hemodynamic abnormalities which characterize certain types of congestive heart failure.

scholarly journals Progesterone modulates endothelium-dependent coronary vascular reactivity in SHR

2021 ◽  
Author(s):  
Débora Tacon da Costa ◽  
Leticia Tinoco Gonçalves ◽  
Jéssyca Aparecida Soares Giesen ◽  
Roger Lyrio dos Santos
Keyword(s):  
Vascular Reactivity ◽  
Sham Group ◽  
Coronary Circulation ◽  
Perfusion Pressure ◽  
Coronary Perfusion Pressure ◽  
Ovariectomized Rats ◽  
Coronary Perfusion ◽  
Coronary Vasodilation ◽  
Progesterone Treatment ◽  
Before And After

Although progesterone has the ability to promote dilation of vascular smooth muscle, its role in coronary circulation is still poorly characterized, especially in essential hypertension and in a model of endogenous deficiency of ovarian hormones. Thus, this study evaluated the effect of progesterone treatment on endothelium-dependent coronary vascular reactivity in hypertensive (SHR) and ovariectomized rats. Adult SHR aged 8 to 10 weeks were divided into: SHAM, Ovariectomized (OVX) and Ovariectomized + treatment with 2 mg/kg/day of progesterone for 15 days (OVX-P4). Coronary vascular reactivity was investigated using modified Langendorff method. After stabilization, baseline coronary perfusion pressure (CPP) was recorded and vascular reactivity to bradykinin (BK, 0.1-1000 ng) assessed before and after infusion, either individually or in combination, with Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin or clotrimazole. Scanning electron microscopy was used for qualitative analysis of the endothelium. OVX and OVX-P4 groups had a higher baseline CPP compared to that of the SHAM group. BK was able to promote vasodilation in all groups. However, relaxation to BK was less pronounced in the OVX group when compared to SHAM, with architecture loss and areas of cell atrophy having been observed. Progesterone treatment prevented this injury. Perfusion with L-NAME induced greater damage to the SHAM group, while the use of indomethacin led to a significant reduction in the vasodilator response to BK in the OVX-P4 group. Taken together, our results show that progesterone modulates endothelium-dependent coronary vasodilation in SHR ovariectomized, preventing damage caused by ovarian hormonal deficiency through a mechanism that involves prostanoid pathway.

Direct cardiac effects of vasopressin: role of V1- and V2-vasopressinergic receptors

1988 ◽  
Vol 255 (2) ◽  
pp. H261-H265 ◽  
Author(s):  
B. R. Walker ◽  
M. E. Childs ◽  
E. M. Adams
Keyword(s):  
Left Ventricular Pressure ◽  
Coronary Perfusion Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Coronary Perfusion ◽  
Cardiac Effects ◽  
Coronary Vasoconstriction ◽  
Langendorff Preparation ◽  
Wide Range ◽  
Male Wistar Rats

Experiments were performed to determine the possible direct effects of arginine vasopressin (AVP) on cardiac function in the nonworking Langendorff preparation. Hearts were isolated from male Wistar rats, and the coronary arteries were retrograde perfused at a constant rate through the aorta with a Krebs-Henseleit solution, which was continuously bubbled with 95% O2–5% CO2. The hearts were paced at 280 beats/min and measurements made of peak ventricular pressure (PVP), first derivative of left ventricular pressure (dP/dtmax), and coronary perfusion pressure (CPP). By maintaining constant coronary flow, the direct cardiac effects of AVP could be determined independent of changes in myocardial O2 delivery elicited by potential coronary vasoconstriction. Myocardial function was assessed at AVP concentrations of 0, 10, 25, 50, 100, 200, 400, and 500 pg/ml. Progressive coronary vasoconstriction was observed with increasing AVP concentration. In contrast, PVP and dP/dtmax increased at 50 and 100 pg/ml of AVP but fell at 400 and 500 pg/ml. The maximal PVP and dP/dtmax responses were at 50 pg/ml (+16 +/- 3 and +44 +/- 4%, respectively), whereas at 500 pg/ml both PVP and dP/dtmax were reduced below control (-30 +/- 4 and -34 +/- 5%, respectively). Pretreatment with the specific V1-vasopressinergic antagonist d(CH2)5Tyr(Me)AVP (40 ng/ml) totally blocked both the coronary vasoconstrictor and contractility responses to AVP. Furthermore, infusion of a specific V2-agonist was without effect even at high doses. These data suggest that although AVP causes dose-related coronary vasoconstriction over a wide range of AVP concentrations, the hormone may exert a positive inotropic effect at doses mimicking circulating levels encountered in a number of pathophysiological situations.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of peptide leukotrienes on cardiac dynamics in rat, cat, and guinea pig hearts

1985 ◽  
Vol 249 (3) ◽  
pp. H477-H484 ◽  
Author(s):  
D. M. Roth ◽  
D. J. Lefer ◽  
C. E. Hock ◽  
A. M. Lefer
Keyword(s):  
Guinea Pig ◽  
Coronary Perfusion Pressure ◽  
Contractile Force ◽  
Coronary Perfusion ◽  
Papillary Muscles ◽  
Inotropic Effects ◽  
Isolated Hearts ◽  
Cardiac Contractile ◽  
Myocardial Contractile Force ◽  
Leukotriene Antagonist

The purpose of the present investigation was to examine potential inotropic effects of leukotrienes C4 (LTC4) and D4 (LTD4) in relation to their potent coronary constricting effects. The experiments were carried out in isolated Langendorff perfused hearts and isolated electrically driven isometrically contracting papillary muscle preparations. Tissues from cat, rat, and guinea pig were used in the study. Both LTC4 and LTD4 at 50 ng/ml had no effect on papillary muscles isolated from the rat, guinea pig, or cat. These papillary muscles responded to known negative inotropic agents including pentobarbital sodium and methanol. In isolated hearts perfused under constant flow, both LTC4 and LTD4 at 50 ng/ml increased coronary perfusion pressure and decreased contractile force of the heart in all three species. In hearts perfused under constant pressure perfusion, both LTC4 and LTD4 decreased coronary flow with concomitant decreases in contractile force. The leukotriene antagonist, FPL 55712, blocked both the coronary constrictor and the cardiodepressant effects of both leukotrienes. Pentobarbital (100 micrograms/ml) significantly decreased cardiac contractile force without inducing coronary vasoconstriction. These findings demonstrate that LTC4 and LTD4 do not possess direct negative inotropic activity in cardiac muscles of these three species. However, LTC4 and LTD4 are potent coronary constrictors that can secondarily decrease myocardial contractile force via their coronary constrictor action.

Free radicals upregulate complement expression in rabbit isolated heart

2000 ◽  
Vol 279 (1) ◽  
pp. H195-H201 ◽  
Author(s):  
Elaine J. Tanhehco ◽  
Koji Yasojima ◽  
Patrick L. McGeer ◽  
Ruth A. Washington ◽  
Benedict R. Lucchesi
Keyword(s):  
Free Radicals ◽  
Complement Activation ◽  
Diastolic Pressure ◽  
Tissue Injury ◽  
Isolated Heart ◽  
Membrane Attack Complex ◽  
Coronary Perfusion Pressure ◽  
Left Ventricular ◽  
Coronary Perfusion ◽  
Isolated Hearts

Both free radicals and complement activation can injure tissue. Our study determined whether free radicals alter complement production by the myocardium. Isolated hearts from New Zealand White rabbits were perfused on a Langendorff apparatus and exposed to xanthine (X; 100 μM) plus xanthine oxidase (XO; 8 mU/ml) (X/XO). The free radical-generating system significantly ( P < 0.05) increased C1q and also increased C1r, C3, C8, and C9 transcription compared with controls. Immunohistological examination revealed augmented membrane attack complex deposition on X/XO-treated tissue. X/XO-treated hearts also exhibited significant ( P < 0.05) increases in coronary perfusion pressure and left ventricular end-diastolic pressure and a decrease in left-ventricular developed pressure. N-(2-mercaptopropionyl)-glycine (3 mM), in conjunction with the superoxide dismutase mimetic SC-52608 (100 μM), significantly ( P < 0.05) reduced the upregulation of C1q, C1r, C3, C8, and C9 mRNA expression elicited by X/XO. The antioxidants also ameliorated the deterioration in function caused by X/XO. Local complement activation may represent a mechanism by which free radicals mediate tissue injury.

scholarly journals Beat-to-beat modulation of heart rate is coupled to coronary perfusion pressure in the isolated heart

1999 ◽  
Vol 86 (2) ◽  
pp. 694-700 ◽  
Author(s):  
David P. Slovut ◽  
John C. Wenstrom ◽  
Richard B. Moeckel ◽  
Christopher T. Salerno ◽  
Soon J. Park ◽  
...  
Keyword(s):  
Heart Rate ◽  
Perfusion Pressure ◽  
Isolated Heart ◽  
Sinus Node ◽  
Coronary Perfusion Pressure ◽  
High Dose ◽  
Coronary Perfusion ◽  
Perfused Heart ◽  
Langendorff Preparation ◽  
Heart Preparation

A goal of clinicians caring for heart transplant recipients has been to use heart rate variability as a noninvasive means of diagnosing graft rejection. The determinants of beat-to-beat variability in the surgically denervated heart have yet to be elucidated. We used an isolated, blood buffer-perfused porcine heart preparation to quantitatively assess the relationship between coronary perfusion and sinus node automaticity. Hearts ( n = 9) were suspended in a Langendorff preparation, and heart rate (HR) fluctuations were quantified while perfusion pressure was modulated between 70/50, 80/60, 90/70, and 100/80 mmHg at 0.067 Hz. In 32 of 32 recordings, the cross spectrum of perfusion pressure vs. HR showed the largest peak centered at 0.067 Hz. In eight of nine experiments during nonpulsatile perfusion, HR accelerated as perfusion pressure was increased from 40 to 110 mmHg (mean increase 24.2 ± 3.0 beats/min). HR increased 0.34 beats/min per mmHg increase in perfusion pressure (least squares linear regression y = −25.8 mmHg + 0.34 x; r = 0.88, P < 0.0001). Administration of low- and high-dose nitroglycerin (Ntg) resulted in a modest increase in flow but produced a significant decrease in HR and blunted the response of HR to changes in perfusion pressure (HR increase 0.26 beats ⋅ min−1 ⋅ mmHg−1, r = 0.87, P < 0.0001 after low-dose Ntg; 0.25 beats ⋅ min−1 ⋅ mmHg−1, r = 0.78, P < 0.0001 after high-dose Ntg). These experiments suggest that sinus node discharge in the isolated perfused heart is mechanically coupled to perfusion pressure on a beat-to-beat basis.

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