High dose intravenous aspirin, not low dose intravenous or oral aspirin, inhibits thrombus formation and stabilizes blood flow in experimental coronary vascular injury

Object The authors investigated the hemodynamic effects of recombinant human erythropoietin (rhEPO) after subarachnoid hemorrhage (SAH) in rabbits. Methods The authors used male New Zealand White rabbits in this study divided into the following groups: SAH plus saline (16 rabbits), SAH plus low-dose rhEPO (16 rabbits; 1500 IU/kg on Day 0 and 500 IU/kg on Days 2 and 4), SAH plus high-dose rhEPO (10 rabbits; 1500 IU/kg on Days 0, 2, 4, and 6), and sham (6 rabbits). Computed tomography perfusion studies and CT angiography were performed for 1 hour after SAH on Day 0, and once each on Days 2, 4, 7, 9, and 16 after SAH. Assessments of neurological function and tissue histology were also performed. Results The mortality rate was significantly lower after rhEPO treatment (12%) than after saline treatment (44%) (p < 0.05). Neurological outcomes in the low-dose and high-dose rhEPO groups were better than in the saline group after SAH (p < 0.05), and the cerebral blood flow in the high-dose rhEPO group was greater than that in the saline group (p < 0.05). The mean transit time was significantly lower on Days 2 and 4 in the low-dose and high-dose rhEPO groups than in the saline group, but increased significantly on Day 7 in both groups (p < 0.05). The hematocrit increased significantly from baseline values in the high-dose and low-dose rhEPO groups on Days 4 and 7, respectively (p < 0.05). Conclusions Treatment with rhEPO after experimental SAH is associated with improved cerebral blood flow and microcirculatory flow as reflected by lower mean transit times. Improved tissue perfusion correlated with reduced mortality and improved neurological outcomes. Further investigation of the impact of increasing hematocrit on hemodynamic changes is needed.

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Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [99mTc]mebrofenin Imaging in Rats

Pharmaceutics ◽

10.3390/pharmaceutics12060486 ◽

2020 ◽

Vol 12 (6) ◽

pp. 486

Author(s):

Solène Marie ◽

Irene Hernández-Lozano ◽

Louise Breuil ◽

Wadad Saba ◽

Anthony Novell ◽

...

Keyword(s):

Blood Flow ◽

Biliary Excretion ◽

Low Dose ◽

Organic Anion ◽

Liver Blood Flow ◽

High Dose ◽

Liver Uptake ◽

Targeted Inhibition ◽

Substrate Inhibitor

The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [99mTc]mebrofenin may be employed as a probe for hepatic MRP2 activity because its biliary excretion is predominantly mediated by this transporter. As the liver uptake of [99mTc]mebrofenin depends on organic anion-transporting polypeptide (OATP) activity, a safe protocol for targeted inhibition of hepatic MRP2 is needed to study the intrinsic role of each transporter system. Diltiazem (DTZ) and cyclosporin A (CsA) were first confirmed to be potent MRP2 inhibitors in vitro. Dynamic acquisitions were performed in rats (n = 5–6 per group) to assess the kinetics of [99mTc]mebrofenin in the liver, intestine and heart-blood pool after increasing doses of inhibitors. Their impact on hepatic blood flow was assessed using Doppler ultrasound (n = 4). DTZ (s.c., 10 mg/kg) and low-dose CsA (i.v., 0.01 mg/kg) selectively decreased the transfer of [99mTc]mebrofenin from the liver to the bile (k3). Higher doses of DTZ and CsA did not further decrease k3 but dose-dependently decreased the uptake (k1) and backflux (k2) rate constants between blood and liver. High dose of DTZ (i.v., 3 mg/kg) but not CsA (i.v., 5 mg/kg) significantly decreased the blood flow in the portal vein and hepatic artery. Targeted pharmacological inhibition of hepatic MRP2 activity can be achieved in vivo without impacting OATP activity and liver blood flow. Clinical studies are warranted to validate [99mTc]mebrofenin in combination with low-dose CsA as a novel substrate/inhibitor pair to untangle the role of OATP and MRP2 activity in liver diseases.

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Potent low dose platelet inhibitory effects of clopidogrel and aspirin on coronary thrombus formation in an animal model of acute unstable angina

Thrombosis and Haemostasis ◽

10.1160/th05-05-0377 ◽

2006 ◽

Vol 95 (02) ◽

pp. 354-361 ◽

Cited By ~ 4

Author(s):

Oliver Berg ◽

Axel Heimann ◽

Thomas Münzel ◽

Christian-Friedrich Vahl ◽

Oliver Kempski ◽

...

Keyword(s):

Platelet Aggregation ◽

Low Dose ◽

Thrombus Formation ◽

Drug Application ◽

Bleeding Complications ◽

High Dose ◽

Cardiac Events ◽

Coronary Syndrome ◽

Dose Combination

SummaryApplication of clopidogrel before percutaneous coronary intervention in patients with acute coronary syndrome reduces the risk of cardiac events. Clopidogrel administration before surgery increases bleeding complications after CABG. Therefore, the antithrombotic effect of the low-dose combination of clopidogrel and aspirin was investigated in an in vivo pig model of coronary artery thrombus formation with cyclic flow reductions. The platelet inhibitory effect was determined by platelet aggregation and CFR, according to the methodology described by Folts. CFR were initiated by endothelial damage and placement of a constrictor around the LAD. 30 min after CFR were established, clopidogrel (0.1 mg/kg or5 mg/kg), aspirin (1 mg/kg or 7 mg/kg) or LDC (0.1 mg/kg clopidogrel and 1 mg/kg aspirin) were administered orally. CFR-frequency was determined for further 240 min. CFR-frequency (CFR/30 min) was significantly reduced at 60 min in response to aspirin (7 mg/kg, −48%, p<0.05), and at 120 min in response to clopidogrel (5 mg/kg, −65%, p<0.05) but not at low doses of either compound. In contrast, LDC of clopidogrel (0.1 mg/kg) plus aspirin (1 mg/kg) resulted in a complete and rapid abrogation of CFR at 90 min (−70%, p<0.05). Furthermore, LDC led to reduction of platelet aggregation when CFR-frequency was already significantly decreased. In contrast, high dose groups presented a significant reduction of platelet aggregation prior to CFR-frequency decrease. Low dose combination of clopidogrel plus aspirin demonstrates a potent over additive anti-thrombotic effect in vivo with a significant reduction in thrombus formation early after drug application. The effect occurs before inhibition of platelet aggregation is detectable.

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Bronchial vasodilation by histamine in sheep: characterization of receptor subtype

Journal of Applied Physiology ◽

10.1152/jappl.1992.72.6.2090 ◽

1992 ◽

Vol 72 (6) ◽

pp. 2090-2098 ◽

Cited By ~ 7

Author(s):

G. H. Parsons ◽

A. C. Villablanca ◽

J. M. Brock ◽

R. S. Howard ◽

S. R. Colbert ◽

...

Keyword(s):

Blood Flow ◽

Low Dose ◽

Receptor Subtype ◽

High Dose ◽

H1 Receptor ◽

Receptor Antagonists ◽

H2 Receptor Antagonists ◽

Histamine Dihydrochloride ◽

H2 Receptor ◽

Arterial Blood

Histamine has been shown to mediate features of pulmonary allergic reactions including increased tracheobronchial blood flow. To determine whether the increase in blood flow was due to stimulation of H1- or H2-histamine receptors, we gave histamine base (0.1 micrograms/kg iv) or histamine dihydrochloride as an aerosol (10 breaths of 0.5% “low dose” or 5% “high dose”) before and after H1- or H2-receptor antagonists. Blood velocity in the common bronchial branch of the bronchoesophageal artery (Vbr) was continuously measured using a chronically implanted Doppler flow probe. Pretreatment with H2-receptor antagonists cimetidine, ranitidine, or metiamide did not affect the increase in Vbr induced by intravenous histamine [106 +/- 45% (SD)]. Addition of the H1-receptor antagonists diphenhydramine or chlorpheniramine, however, reduced the Vbr response to 16 +/- 22, 21 +/- 28, 23 +/- 23, and 37 +/- 32% of the unblocked responses (P less than 0.05) when intravenous histamine was given at 3, 10, 20, and 30 min, respectively, after the H1 antagonist. At 40, 50, and 60 min the H1-receptor blockade appeared to attenuate, but subsequent continuous infusion of chlorpheniramine (2 mg.kg-1.min-1) then blocked the histamine response for 60 min. Low-dose histamine aerosol did not change mean arterial or pulmonary arterial pressures, cardiac output, or arterial blood gases but increased Vbr transiently from 15.2 +/- 3.4 to 37.6 +/- 8.4 (SE) cm/s. After chlorpheniramine, the Vbr response to histamine, 16.3 +/- 2.2 to 22.6 +/- 3.6 cm/s, was significantly reduced (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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Failure of oxygen radical scavengers to modify fatigue in electrically stimulated muscle

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y91-220 ◽

1991 ◽

Vol 69 (10) ◽

pp. 1470-1475 ◽

Cited By ~ 3

Author(s):

Ian Shrier ◽

Sabah Hussain ◽

Sheldon Magder

Keyword(s):

Blood Flow ◽

Dose Group ◽

Gastrocnemius Muscle ◽

Low Dose ◽

Muscle Tension ◽

Oxygen Radical ◽

High Dose Group ◽

High Dose ◽

Partial Recovery ◽

Radical Scavengers

We used in situ gastrocnemius muscle of anaesthetized dogs to test the hypothesis that O2 radical production during muscle contraction contributes to fatigue. Muscle tension was measured with a force transducer and blood flow was monitored with an electromagnetic flow probe. Muscle contractions were produced by stimulating the nerve for 15 min at 20 Hz, 12 trains/min, and a duty cycle of 0.25. Three groups of seven animals were given an infusion of 0.2 mL∙min−1 of either saline, low-dose oxygen radical scavengers (250 IU∙mL−1 superoxide dismutase, 640 IU∙mL−1 polyethylene glycol (PEG)-catalase, 0.25 mg∙mL−1 deferoxamine, and 0.1 mg∙mL−1 oxypurinol), or high-dose oxygen radical scavengers (3300 IU∙mL−1 uperoxide dismutase, 6600 IU∙mL−1 PEG-catalase, 2.5 mg∙mL−1 deferoxamine, and 0.1 mg∙mL−1 oxypurinol). Blood flow and vascular resistance of the gastrocnemius muscle during stimulation did not differ among groups. After 15 min of stimulation, the developed tension (represented as a percentage of initial tension developed) was 66 ± 7% in the saline treated group, 70 ± 6% in the low-dose group, and 70 ± 4% in the high-dose group. The change in tension during recovery was not significant in the control or low-dose groups. However, there was partial recovery in the high-dose group. In conclusion, in this preparation, oxygen radical scavengers did not delay the development of decreased muscle tension.Key words: muscle fatigue, oxygen free radicals, resistance, flow.

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DIPYRIDAMOLE ALONE OR WITH LOW DOSE ASPIRIN DOES NOT PREVENT ACUTE PLATELET THROMBUS FORMATION IN STENOSED DOG CORONARY ARTERIES

10.1055/s-0038-1643577 ◽

1987 ◽

Author(s):

J D Folts ◽

S R Smith

Keyword(s):

Clinical Trials ◽

Blood Flow ◽

Coronary Arteries ◽

Low Dose ◽

Thrombus Formation ◽

Arterial Stenosis ◽

In Vivo Model ◽

Acute Ischemia ◽

Pig Coronary Arteries

Dipyridamole (Dip) is reputed to inhibit (I) platelet aggregation (PA) and acute thrombus formation (ATF) by two mechanisms including inhibiting 1.) platelet (Pt) phosphodiesterase, 2.) adenosine (A) reuptake by red cells, which should raise plasma A. Both effects should raise Pt cyclic AMP and thus be a potent platelet inhibitor (PI). Because aspirin (AS) inhibits Pt thromboxane A2 production, a synergistic (S) PI effect for ASA and Dip given together has been postulated and used in clinical trials but this S has never been shown to I ATP in any in vivo model, which reasonably mimics human arterial stenosis. We have shown that ATF followed by embolization, occurs periodically in mechanically stenosed (MS) monkey and rabbit carotid arteries, and dog (D) and pig coronary arteries (CA), causing cyclical reductions in coronary blood flow (CRF) (measured with EMF probes) and periodic acute ischemia, and that these CRF can be abolished with a variety of PI including 3.0 mg/kg of ASA. To determine if there is a S effect between ASA and Dip, in open chest D, Dip was given, 2.0 mg/kg IV to D with a MS circumflex CA and having 14±5 CRF’s per hour, due to periodic ATF; and simultaneously flow measured in an unstenosed normal LAD CA. The frequency and size of CRF’s were not changed by Dip, although ABP decreased 21±9 mm Hg and blood flow in the unstenosed LAD increased 259±47%. A low dose of ASA, 1.0 mg/kg, which by itself diminishes but does not abolish CRF’s in this model was given IV 10 min. after Dip and CRF’s continued unchanged. When a second dose of ASA 1.0 mg/kg was given IV to reach the minimum effective dose of ASA in this model, CRF were abolished in all D. Thus Dip was not effective alone or in combination with low dose ASA to I CRF in this model which simulates the patient with stenosed CA. The majority of clinical trials that show inhibition of ATF, used ASA and Dip together without 3 separate patient groups on Dip alone, ASA alone and ASA plus Dip. The widespread use of Dip with ASA to prevent ATF in man needs to be reevaluated.

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Effects of indomethacin on brain blood flow and cerebral metabolism in hypoxic newborn piglets

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.1.h141 ◽

1993 ◽

Vol 264 (1) ◽

pp. H141-H149 ◽

Cited By ~ 3

Author(s):

M. G. Coyle ◽

W. Oh ◽

B. S. Stonestreet

Keyword(s):

Blood Flow ◽

Glucose Metabolism ◽

Dose Group ◽

Low Dose ◽

Severe Hypoxia ◽

High Dose Group ◽

High Dose ◽

Brain Blood Flow ◽

Newborn Piglets ◽

Dose Dependent

We tested the hypotheses that in newborn piglets indomethacin (Indo) pretreatment blunts the hyperemic brain blood flow (BF) and alters the cerebral metabolic responses to hypoxia and that these responses are dose dependent. We studied 23 chronically instrumented piglets exposed to graded hypoxia (O2 content: 7.1-0.4 microM O2/ml) after pretreatment with high (5 mg/kg, n = 8)-or low (0.3 mg/kg, n = 6)-dose Indo or placebo (diluent, n = 9). Total and regional brain BF increased significantly with decreasing O2 content values (P < 0.01) in all three groups. However, the rise in the brain BF curves with decreasing O2 content values was significantly (P < 0.05) lower in the high-compared with the low-dose group in all brain regions with the greatest effect in the caudal regions. Furthermore, the BF curves in the placebo-treated animals were similar to the low-dose group. The cerebral metabolic rate of O2 (CMR(O2)) and glucose metabolism were preserved in the three groups over all hypoxic ranges until severe hypoxia (O2 content < or = 1.1 microM O2/ml) was achieved in the high-dose group, when CMR(O2) decreased (P < 0.05), and glucose metabolism increased (P < 0.05). The mean arterial blood pressure in the high-dose group during severe hypoxia was 45 mmHg (P > 0.05). Although coupling of cerebral BF and CMR(O2) was preserved in the three groups, this association was significantly altered with high-dose pretreatment. We conclude that an attenuation in the hypoxia-induced brain perfusion by Indo is dose dependent. Alterations in CMR(O2) and glucose metabolism are observed with high-dose pretreatment during severe hypoxia, and the responses to hypoxia are similar with placebo and low-dose Indo pretreatment.

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Haemodynamic effects of vasopressin in man are related to posture

Clinical Science ◽

10.1042/cs0700177 ◽

1986 ◽

Vol 70 (2) ◽

pp. 177-184 ◽

Cited By ~ 6

Author(s):

H. C. R. Simpson ◽

J. E. Zubillaga ◽

J. G. Collier ◽

E. D. Bennett ◽

V. T. Y. Ang ◽

...

Keyword(s):

Blood Flow ◽

Cardiac Output ◽

Mean Arterial Pressure ◽

Systemic Vascular Resistance ◽

Vascular Resistance ◽

Low Dose ◽

Forearm Blood Flow ◽

Haemodynamic Effects ◽

High Dose ◽

Dose Infusion

1. Ten healthy volunteers received intravenous infusions of arginine vasopressin (AVP) at 0.1 m-unit min−1 kg−1 and 5% d-glucose on separate days. AVP caused a small fall in forearm blood flow and small rises in mean arterial pressure and systemic vascular resistance. Cardiac output was unaffected. 2. When subjects were tilted to 50° the fall in forearm blood flow was much greater, mean fall being 44.8% with AVP compared with 18.2% with d-glucose. Cardiac output also fell significantly more with AVP, and diastolic pressure, mean arterial pressure and systemic vascular resistance rose significantly more on tilting during AVP infusion than with d-glucose. 3. Six of the same volunteers were given sequential infusions of ‘low dose’ (0.0125 m-unit min−1 kg−1) and ‘high dose’ (0.3 m-unit min−1 kg−1) AVP on a third occasion. Tilting still produced a mean fall in forearm blood flow of 41.2% during low dose infusion, despite a mean plasma AVP level of only 1.9 pg/ml, which is well within the physiological range. When the AVP concentration was increased 24-fold to the high dose, forearm blood flow fell only a further 8.8%. The low dose infusion was also associated with a marked fall in cardiac output on tilting and a rise in systemic vascular resistance. 4. We conclude that AVP has profound haemodynamic effects in man at physiological concentrations. Although these effects are modest in the supine position, they become marked on tilting, suggesting a possible role for AVP in the postural control of blood pressure.

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Cerebral blood flow responsivity to CO2 in anesthetized chronically diabetic dogs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.4.h1069 ◽

1993 ◽

Vol 264 (4) ◽

pp. H1069-H1075 ◽

Cited By ~ 1

Author(s):

F. E. Sieber ◽

P. R. Brown ◽

Y. Wu ◽

R. C. Koehler ◽

R. J. Traystman

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Blood Glucose ◽

Low Dose ◽

Insulin Treatment ◽

High Dose ◽

Acute Hyperglycemia ◽

Glucose Levels ◽

Cerebrovascular Resistance ◽

Diabetic Dogs

The effect of diabetes mellitus on the cerebrovascular response to CO2 is unclear. We examined the effects of diabetes on cerebral blood flow (CBF) and cerebral oxygen uptake (CMRO2) during CO2 alterations. Four groups of dogs were studied: nondiabetic, normoglycemic controls; non-diabetic acute hyperglycemia; diabetic (pancreatectomy) with high-dose insulin treatment to maintain blood glucose between 4.0 and 6.0 mM; and diabetic with low-dose insulin treatment to maintain blood glucose at 13.2 +/- 0.4 mM. Six weeks after either sham surgery or pancreatectomy, dogs were anesthetized with fentanyl (50 micrograms/kg) plus pentobarbital (10 mg/kg), and microsphere determinations of CBF were made during normo-, hypo-, and hypercapnia. On the day of the study, arterial glucose levels in the control, acute hyperglycemia, and high- and low-dose insulin diabetic groups were 4.0 +/- 0.3, 14.9 +/- 2.5, 3.3 +/- 0.8, and 13.3 +/- 0.7 mM, respectively, at control. The corresponding baseline CMRO2 levels were 2.8 +/- 0.2, 3.0 +/- 0.2, 4.1 +/- 0.4, and 4.0 +/- 0.3 ml O2.100 g-1 x min,1, and the values in both diabetic groups were higher than control. Normocapnic CBF in the acute hyperglycemia, high-dose insulin, and low-dose insulin groups was elevated from control (54 +/- 3, 50 +/- 3, 51 +/- 3 vs. 36 +/- 1 ml x 100 g-1 x min-1) and cerebrovascular resistance was lower (2.24 +/- 0.15, 2.51 +/- 0.14, 2.38 +/- 0.21 vs. 3.35 +/- 0.18 mmHg.ml-1 x 100 g.min). CBF responses to both hypercapnia and hypocapnia were similar among groups. Thus both acute hyperglycemia and diabetes decrease cerebrovascular resistance and increase CBF.(ABSTRACT TRUNCATED AT 250 WORDS)

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