Constriction Of Inferior Vena Cava Research Articles

Pharmacological reduction of coagulation factor XI reduces macrophage accumulation and accelerates deep vein thrombosis resolution in a mouse model of venous thrombosis

BackgroundDeep vein thrombosis (DVT) and post‐thrombotic syndrome (PTS) remain highly prevalent despite modern medical therapy. Contact activation is a promising target for safe antithrombotic anticoagulation. The anti‐factor XI (FXI) monoclonal antibody 14E11 reduces circulating levels of FXI without compromising hemostasis. The human recombinant analog, AB023, is in clinical development. The role of FXI in mediation of inflammation during DVT resolution is unknown. ObjectivesInvestigate the effects of pharmacological targeting of FXI with 14E11 in an experimental model of venous thrombosis. MethodsAdult wild‐type CD1 mice were treated with subcutaneous anti‐FXI antibody (14E11, 5 mg/kg) versus saline prior to undergoing surgical constriction of the inferior vena cava (IVC). Mice were evaluated at various time points to assess thrombus weight and volume, as well as histology analysis, ferumoxytol enhanced magnetic resonance imaging (Fe‐MRI), and whole blood flow cytometry. Results14E11‐treated mice had reduced thrombus weights and volumes after IVC constriction on day 7 compared to saline‐treated mice. 14E11 treatment reduced circulating monocytes by flow cytometry and macrophage content within thrombi as evaluated by histologic staining and Fe‐MRI. Collagen deposition was increased at day 3 while CD31 and smooth muscle cell actin expression was increased at day 7 in the thrombi of 14E11‐treated mice compared to saline‐treated mice. ConclusionPharmacologic targeting of FXI enhances the early stages of experimental venous thrombus resolution in wild‐type CD1 mice, and may be of interest for future clinical evaluation of the antibody in DVT and PTS.

Ibudilast, a Phosphodiesterase Inhibitor and Toll-Like Receptor-4 Antagonist, Improves Hemorrhagic Shock and Reperfusion-Induced Left Ventricular Dysfunction by Reducing Myocardial Tumor Necrosis Factor α

ObjectivesRapid loss of blood volume causes ischemic injury to myocardial cells and impairs cardiac function. Subsequent reperfusion, although necessary to revitalize stunned tissues, can induce production of reactive oxygen species and inflammation, causing further tissue damages and weakening cardiac function. Ibudilast, a Toll-like receptor-4 (TLR4) antagonist and an inhibitor of phosphodiesterase-4, possesses antioxidative and anti-inflammatory capacities. In this study, we aim to examine the protective efficacy of ibudilast against hemorrhagic shock and reperfusion (HSR)-induced myocardial injury and cardiac dysfunction. MethodsStudies were conducted on male Sprague-Dawley rats in 3 groups: sham-operated, HSR with, and HSR without pretreatment of ibudilast. Hemorrhagic shock was induced by withdrawing blood from the femoral artery until the mean aortic pressure dropped to around 40 mm Hg; reperfusion was conducted by replenishing blood after 120 minutes of hemorrhagic shock, and the observation continued for another 240 minutes. The left ventricular (LV) contractility, diastolic suction capacity, and ventricular stiffness were evaluated using simultaneous LV pressure, and volume was recorded during a temporary inferior vena cava constriction at the end of reperfusion. Ibudilast (10 mg/kg) was administered intraperitoneally 3 days and 20 minutes prior to HSR. Serum creatine kinase myocardial band (CK-MB) was examined at the end of both HSR, and serum CK-MB, myocardial TLR4 protein expression, and malondialdehyde (MDA) and tumor necrosis factor (TNF)-α levels at the end of reperfusion. ResultsHSR induced an increase in serum CK-MB. Subsequent reperfusion further increased serum CK-MB, upregulated myocardial TLR4 protein expression, and increased tissue levels MDA and TNF-α vs the sham (P < .05). HSR reduced LV contractility, prolonged LV relaxation time, and increased LV diastolic stiffness. Ibudilast pretreatment attenuated HSR-induced TLR4 protein expression, reduced myocardial MDA and TNF-α levels, and protected against cardiac dysfunction. ConclusionsIbudilast pretreatment reduced myocardial TLR4 expression, decreased MDA and TNF-α levels, and protected against HSR-induced decrease in LV contractility, prolonged LV relaxation time, and increased diastolic stiffness.

Inferior Vena Cava Constriction After Liver Transplantation Is a Severe Complication Requiring Individually Adapted Treatment: Report of a Single-Center Experience

BackgroundReports on vena cava occlusion after liver transplantation (LT) are rare, but this finding represents a severe complication in the early postoperative period. In the context of the complex presentation of a patient after LT, symptoms are often misinterpreted and can be subtle.Material/MethodsIn our cohort of 138 LTs performed between 2014 and 2017 at our University’s Transplantation Department, 117 transplantations were valid for further analysis after exclusion of pediatric transplantations and transplants with primary non-function grafts. In 101 cases (73%), patients received a deceased-donor full-size organ. Living-donor LT was performed in 8 patients (6.4%) and 8 patients (6.4%) received a split graft. We report on 6 patients who had inferior vena cava (IVC) occlusion and summarize the treatment choices.ResultsIn our series, patients with positive findings (age 38–70 years) received an orthotopic full-size deceased-donor graft with end-to-end IVC anastomosis. In the subsequent period, imaging revealing IVC occlusion was done on a follow-up basis (n=2), due to dyspnea (n=1), and for progressive ascites (n=2). In 3 cases, a thrombus was found. We give detailed information on our treatment options from interventional treatment to transcardial thrombus removal and anastomosis augmentation.ConclusionsIVC constriction and subsequent thrombosis are severe complications after LT that require individually adapted treatment in specialized centers. Since patients often present with subclinical symptoms, vascular diagnosis should be performed early to detect caval anastomosis pathologies. Despite regular ultrasonography, we favor CT and cavography for subsequent quantification. We also review the literature on IVC occlusion after LT.

Selective abdominal venous congestion to investigate cardiorenal interactions in a rat model.

Abdominal congestion may play an important role in the cardiorenal syndrome and has been demonstrated to drive disease progression. An animal model for abdominal congestion, without other culprit mechanisms that are often present in patients such as low cardiac output or chronic kidney disease, might be interesting to allow a better study of the pathophysiology of the cardiorenal syndrome. The objective of this study was to develop a clinically relevant and valid rat model with abdominal venous congestion and without pre-existing heart and/or kidney dysfunction. To do so, a permanent surgical constriction (20 Gauge) of the thoracic inferior vena cava (IVC) was applied in male Sprague Dawley rats (IVCc, n = 7), which were compared to sham-operated rats (SHAM, n = 6). Twelve weeks after surgery, abdominal venous pressure (mean: 13.8 vs 4.9 mmHg, p < 0.01), plasma creatinine (p < 0.05), plasma cystatin c (p < 0.01), urinary albumin (p < 0.05), glomerular surface area (p < 0.01) and width of Bowman’s space (p < 0.05) of the IVCc group were significantly increased compared to the SHAM group for a comparable absolute body weight between groups (559 vs 530g, respectively, p = 0.73). Conventional cardiac echocardiographic and hemodynamic parameters did not differ significantly between both groups, indicating that cardiac function was not compromised by the surgery. In conclusion, we demonstrate that constriction of the thoracic IVC in adult rats is feasible and significantly increases the abdominal venous pressure to a clinically relevant level, thereby inducing abdominal venous congestion.

A rat model of deep venous thrombosis induced by modified stenosis inferior vena cava constriction

Objective To develop a rat model of deep venous thrombosis (DVT) and study its pathological change.Methods Seventy-two Sprague-Dawley rats were randomly divided into 4 groups ( A,B,C,D).The rats in group A were given sham operation.The inferior vein cava (IVC) of the rats in group B was ligated.A laparotomy with ligation of the IVC below the renal veins and all visible side branches was performed in group C.The IVC was constricted and blocked by vascular clamp with visible side branches ligated in group D.At 1st,3rd,and 7th day,6 rats from each group were killed,and the IVE was taken out to observe the thrombosis rate and the thrombi were observed pathologically.Results On the day 1,3 and 7,no thrombosis was observed in group A.The positive thrombus rate in group B (50.0％,50.0％ and 16.7％ on the day 1,3 and 7) was significantly lower than in group C ( 100.0％,100.0％and 83.3％ on the day 1,3 and 7) and group D (100.0％,100.0％ and 100％ on the day 1,3 and 7),but there was no significant difference between group C and group D. The thrombus weight in group B [ ( 12.8 ±3.6) mg] was significantly reduced as compared with group C [ (24.0 ±7.5) mg] and group D [ ( 25.3 ± 10.5 ) mg],but there was no significant difference between group C and group D.The change of thrombosis in different periods and the vascular recanalization were observed pathologically.Conclusion The rat model of DVT was successfully developed and it can be used for the study on the pathological change and the evaluation of treatment. Key words: Model, animal; Deep vein thrombosis; Rat

Effects of cardiac preload reduction and dobutamine on hepatosplanchnic blood flow regulation in porcine endotoxemia

Insufficient cardiac preload and impaired contractility are frequent in early sepsis. We explored the effects of acute cardiac preload reduction and dobutamine on hepatic arterial (Qha) and portal venous (Qpv) blood flows during endotoxin infusion. We hypothesized that the hepatic arterial buffer response (HABR) is absent during preload reduction and reduced by dobutamine. In anesthetized pigs, endotoxin or vehicle (n = 12, each) was randomly infused for 18 h. HABR was tested sequentially by constricting superior mesenteric artery (SMA) or inferior vena cava (IVC). Afterward, dobutamine at 2.5, 5.0, and 10.0 μg/kg per minute or another vehicle (n = 6, each) was randomly administered in endotoxemic and control animals, and SMA was constricted during each dose. Systemic (cardiac output, thermodilution) and carotid, splanchnic, and renal blood flows (ultrasound Doppler) and blood pressures were measured before and during administration of each dobutamine dose. HABR was expressed as hepatic arterial pressure/flow ratio. Compared with controls, 18 h of endotoxin infusion was associated with decreased mean arterial blood pressure [49 ± 11 mmHg vs. 58 ± 8 mmHg (mean ± SD); P = 0.034], decreased renal blood flow, metabolic acidosis, and impaired HABR during SMA constriction [0.32 (0.18-1.32) mmHg/ml vs. 0.22 (0.08-0.60) mmHg/ml; P = 0.043]. IVC constriction resulted in decreased Qpv in both groups; whereas Qha remained unchanged in controls, it decreased after 18 h of endotoxemia (P = 0.031; constriction-time-group interaction). One control and four endotoxemic animals died during the subsequent 6 h. The maximal increase of cardiac output during dobutamine infusion was 47% (22-134%) in controls vs. 53% (37-85%) in endotoxemic animals. The maximal Qpv increase was significant only in controls [24% (12-47%) of baseline (P = 0.043) vs. 17% (-7-32%) in endotoxemia (P = 0.109)]. Dobutamine influenced neither Qha nor HABR. Our data suggest that acute cardiac preload reduction is associated with preferential hepatic arterial perfusion initially but not after established endotoxemia. Dobutamine had no effect on the HABR.

Hemodynamics of fetal breathing movements: the inferior vena cava

Based on the hypothesis that fetal breathing movements (FBM) enhance sections of the circulation to meet the needs of gas transport, we studied the effects of FBM on the fetal inferior vena cava (IVC), which transports blood with the lowest oxygen saturation in the fetal body. One-hundred and ten women with low-risk singleton pregnancies were included in a longitudinal study during the second half of pregnancy. Inner diameter, peak systolic velocity and time-averaged maximum blood velocity were measured in the IVC below the ductus venosus outlet during rest and FBM. Volume flow and pressure gradient were estimated in 55 observations of forced inspiratory movements at 36 weeks of gestation. The results are presented as mean and 95% CI of the mean. Based on 585 observations obtained during fetal rest and FBM, we found no difference in diameter, 0.42 (95% CI, 0.41-0.43) cm vs. 0.41 (95% CI, 0.39-0.42) cm, respectively, apart from during high-amplitude inspiratory movement, when the diameter was 0.15 (95% CI, 0.13-0.17) cm. The peak systolic velocity was different during rest and FBM, 34.0 (95% CI, 32.7-35.3) cm/s vs. 81.5 (95% CI, 76.2-87.5) cm/s, respectively, and correspondingly for time-averaged maximum velocity, 19.7 (95% CI, 18.9-20.5) cm/s vs. 37.2 (95% CI, 34.9-39.9) cm/s, respectively. Forced inspiratory movements at 36 weeks significantly reduced flow in the IVC compared with rest, 63.6 (95% CI, 44.4-88.1) mL/min vs. 186.0 (95% CI, 142.8-238.1) mL/min, respectively. The pressure gradient increased 14-fold during forced inspiration, from 0.64 to 8.76 mmHg. High-amplitude fetal inspiration substantially constricts the abdominal IVC and creates a negative pressure in the chest. The IVC constriction withholds abdominal blood, thus temporarily giving way to other flows.

Lymphatic Pump Treatment Increases Thoracic Duct Lymph Flow in Conscious Dogs with Edema Due to Constriction of the Inferior Vena Cava

Osteopathic lymphatic pump treatments (LPT) are used to treat edema, but their direct effects on lymph flow have not been studied. In the current study, we examined the effects of LPT on lymph flow in the thoracic duct of instrumented conscious dogs in the presence of edema produced by constriction of the inferior vena cava (IVC). Six dogs were surgically instrumented with an ultrasonic flow transducer on the thoracic lymph duct and catheters in the descending thoracic aorta and in IVC. After postoperative recovery, lymph flow and hemodynamic variables were measured 1) pre-LPT, 2) during 4 min LPT, 3) post-LPT, in the absence and presence of edema produced by IVC constriction. This constriction increased abdominal girth from 60 +/-2.6 to 75 +/- 2.9 cm. Before IVC constriction, LPT increased lymph flow (P < 0.05) from 1.9 +/- 0.2 ml/min to a maximum of 4.7 +/-1.2 ml/min, whereas after IVC constriction, LPT increased lymph flow (P < 0.05) from 7.9 +/-2.2 to a maximum of 11.7 +/-2.2 ml/min. The incremental lymph flow mobilized by 4 min of LPT (ie, the flow that exceeded 4 min of baseline flow), was 10.6 ml after IVC constriction. This incremental flow was not significantly greater than that measured before IVC constriction. Edema caused by IVC constriction markedly increased lymph flow in the thoracic duct. LPT increased thoracic duct lymph flow before and after IVC constriction. The lymph flow mobilized by 4 min of LPT in presence of edema was not significantly greater than that mobilized prior to edema.

Lymphatic Pump Treatment Increases Thoracic Duct Lymph Flow in Conscious Dogs with Edema Due to Constriction of the Inferior Vena Cava

ObjectiveTo examine the effects of osteopathic lymphatic pump treatment (LPT) on lymph flow in the thoracic duct of instrumented conscious dogs in the presence of edema produced by constriction of the inferior vena cava (IVC).MethodsSix dogs were surgically instrumented with an ultrasonic flow transducer on the thoracic lymph duct and catheters in the descending thoracic aorta and in the IVC. After post‐operative recovery, lymph flow and hemodynamic variables were measured 1) pre‐LPT, 2) during 4 min LPT, 3) post‐LPT, in the absence and presence of edema produced by IVC constriction.ResultsIVC constriction increased abdominal girth from 60±2.6 to 75±2.9 cm. Before IVC constriction, LPT increased lymph flow (P&lt;0.05) from 1.9±0.2 ml/min to a maximum of 4.7±1.2 ml/min, whereas after IVC constriction, LPT increased lymph flow (P&lt;0.05) from 7.9±2.2 to a maximum of 11.7±2.2 ml/min. The incremental lymph flow mobilized by 4 min of LPT, i.e., the flow that exceeded 4 min of baseline flow, was 10.6 ml after IVC constriction (not different from before IVC constriction).ConclusionsEdema caused by IVC constriction markedly increased lymph flow in the thoracic duct. LPT increased thoracic duct lymph flow before and after IVC constriction. The lymph flow mobilized by 4 min of LPT in presence of edema was not significantly greater than that mobilized prior to edema. (Support: NIH grant U19 AT002023 and Osteopathic Research Center.)

Atrial BNP endocrine function during chronic unloading of the normal canine heart

The goal of the study was to define the effect of chronic unloading of the normal heart on atrial endocrine function with a focus on brain natriuretic peptide (BNP), specifically addressing the role of load and neurohumoral stimulation. Although produced primarily by atrial myocardium in the normal heart, controversy persists with regard to load-dependent vs. neurohumoral mechanisms controlling atrial BNP synthesis and storage. We used a unique canine model of chronic unloading of the heart produced by thoracic inferior vena caval constriction (TIVCC), which also resulted in activation of plasma endothelin (ET-1), ANG II, and norepinephrine (NE), known activators of BNP synthesis, compared with sham. TIVCC was produced by banding of the inferior vena cava for 10 days (n = 6), whereas in control (n = 5) the band was not constricted (sham). In a third group (n = 7), the band was released on day 11, thus acutely reloading the heart. Chronic TIVCC decreased cardiac output and right atrial pressure with a decrease in atrial mass index consistent with atrial atrophy. Atrial BNP mRNA decreased compared with sham. Immunoelectron microscopy revealed an increase in BNP in atrial granules consistent with increased storage. Acute reloading increased cardiac filling pressures and resulted in an increase in plasma BNP. We conclude that chronic unloading of the normal heart results in atrial atrophic remodeling and in suppression of atrial BNP mRNA despite intense stimulation by ET, ANG II, and NE, underscoring the primacy of load in the control of atrial endocrine function and structure.

Sequential opening of IP(3)-sensitive Ca(2+) channels and SOC during alpha-adrenergic activation of rabbit vena cava.

Alpha(1)-aderenoceptor-mediated constriction of rabbit inferior vena cava (IVC) is signaled by asynchronous wavelike Ca(2+) oscillations in the in situ smooth muscle. We have shown previously that a putative nonselective cationic channel (NSCC) is required for these oscillations. In this report, we show that the application of 2-aminoethoxyphenyl borate (2-APB) to antagonize inositol 1,4,5-trisphosphate (InsP(3))-sensitive Ca(2+) release channels (IP(3)R channels) can prevent the initiation and abolish ongoing alpha(1)-aderenoceptor-mediated tonic constriction of the venous smooth muscle by inhibiting the generation of these intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations. The observed effects of 2-APB can only be attributed to its selective inhibition on the IP(3)R channels, not to its slight inhibition of the L-type voltage-gated Ca(2+) channel and the sarco(endo)plasmic reticulum Ca(2+) ATPase. Furthermore, 2-APB had no effect on the ryanodine-sensitive Ca(2+) release channel and the store-operated channel (SOC) in the IVC. These results indicate that the putative NSCC involved in refilling the sarcoplasmic reticulum (SR) and maintaining the tonic contraction is most likely an SOC-type channel because it appears to be activated by IP(3)R-channel-mediated SR Ca(2+) release or store depletion. This is in accordance with its sensitivity to Ni(2+) and La(3+) (SOC blockers). More interestingly, RT-PCR analysis indicates that transient receptor potential (Trp1) mRNA is strongly expressed in the rabbit IVC. The Trp1 gene is known to encode a component of the store-operated NSCC. These new data suggest that the activation of both the IP(3)R channels and the SOC are required for PE-mediated [Ca(2+)](i) oscillations and constriction of the rabbit IVC.

Neurokinin-1 receptor immunoreactivity in hypotension sensitive sympathetic preganglionic neurons

Substance P activation of neurokinin-1 (NK1) receptors on spinal sympathetic preganglionic neurons (SPN) influences blood pressure. We identified SPN likely to subserve the baroreceptor reflex and established if these neurons showed NK1 receptor-immunoreactivity. Nitroprusside (NP) infusion or inferior vena cava (IVC) constriction activated similar numbers of SPN. Of these, about 40% were NK1 receptor-immunoreactive after NP infusion, but only about 20% were NK1 receptor-immunoreactive after IVC constriction. The distribution of Fos/NK1 receptor SPN suggested that substance P may preferentially target sympathoadrenal SPN.

Systolic pressure predicts plasma vasopressin responses to hemorrhage and vena caval constriction in dogs.

We have proposed that the reflex increase in arginine vasopressin (AVP) secretion in response to hypovolemia is due to arterial baroreceptor unloading. If arterial pressure is the key to the mechanism, the slope relating plasma AVP to arterial pressure should be the same in response to hemorrhage, a model of true hypovolemia, and in response to thoracic inferior vena caval constriction (IVCC), a model of central hypovolemia. We tested this hypothesis in conscious, chronically instrumented dogs (n = 8). The mean coefficient of determination (r(2)) values obtained from the individual regressions of log AVP onto systolic pressure (SP) and mean arterial pressure (MAP) in response to hemorrhage were 0.953 +/- 0.009 and 0.845 +/- 0.047, respectively. Paired comparisons indicated a significant difference between the means (P < 0.05), hence, SP was used in subsequent analyses. The mean slopes relating the log of plasma AVP to SP in response to hemorrhage and IVCC were -0.034 +/- 0.003 and -0.032 +/- 0.002, respectively, and the means were not significantly different (P = 0.7). The slopes were not altered when the experiments were repeated during acute blockade of cardiac receptors by intrapericardial procaine. Finally, sinoaortic denervation (n = 4) markedly reduced the slope in both the hemorrhage and IVCC treatments. We conclude that baroreceptors monitoring arterial pressure provide the principal reflex control of AVP secretion in response to hypovolemia.

Mechanical unloading versus neurohumoral stimulation on myocardial structure and endocrine function In vivo.

BACKGROUND-Mechanical load and humoral stimuli such as endothelin (ET) and angiotensin II (Ang II) are potent modulators of cardiac structure and endocrine function, specifically gene expression and production and release of atrial natriuretic peptide (ANP). We define the contribution of mechanical load compared with neurohumoral stimulation in vivo with specific focus on myocardial and circulating ANP during chronic myocardial unloading produced by thoracic inferior vena caval constriction (TIVCC). METHODS AND RESULTS-TIVCC was produced by banding the IVC for 10 days in 7 dogs, whereas in the 6 control dogs, the band was not constricted. TIVCC was characterized by a decrease in cardiac output, right atrial pressure, and left ventricular (LV) end-diastolic diameter and marked activation of ET and Ang II in plasma and atrial and ventricular myocardium. Despite neurohumoral stimulation, LV mass index and myocyte diameters in unloaded hearts decreased, reflecting myocyte atrophy. The total number of myocytes in the LV remained unchanged. Atrial stores of ANP increased, but plasma ANP did not change, in association with a trend toward ANP gene expression to decrease in unloaded hearts. CONCLUSIONS-Chronic mechanical unloading of the heart results in myocardial atrophy and lack of activation of ANP synthesis despite marked neurohumoral stimulation by the growth promoters ET and Ang II.

Arterial baroreceptors control plasma vasopressin responses to graded hypotension in conscious dogs.

We studied the role of cardiac and arterial baroreceptors in the reflex control of arginine vasopressin (AVP) and renin secretion during graded hypotension in conscious dogs. The dogs were prepared with Silastic cuffs on the thoracic inferior vena cava and catheters in the pericardial space. Each experiment consisted of a control period followed by four periods of inferior vena caval constriction, during which mean arterial pressure (MAP) was reduced in increments of approximately 10 mmHg. The hormonal responses were measured in five dogs under four treatment conditions: 1) intact, 2) acute cardiac denervation (CD) by intrapericardial infusion of procaine, 3) after sinoaortic denervation (SAD), and 4) during combined SAD+CD. The individual slopes relating MAP to plasma AVP and plasma renin activity (PRA) were used to compare the treatment effects using a 2 x 2 factorial analysis. There was a significant (P < 0.01) effect of SAD on the slope relating plasma AVP to MAP but no effect of CD and no SAD x CD interaction. In contrast, the slope relating PRA and MAP was increased (P < 0.05) by SAD but was not affected by CD. These results support the hypothesis that stimulation of AVP secretion in response to graded hypotension is primarily driven by unloading arterial baroreceptors in the dog.

Effect of portal hypertension caused by chronic high venous pressure on small-intestinal sugar absorption

The effect of portal hypertension and chronic high venous pressure on the absorption of the small intestine was examined by constricting the suprahepatic and subdiaphragmatic inferior vena cava in rats. A group of rats with the constricted suprahepatic and subdiaphragmatic inferior vena cava comprised group 1 ( n = 9) and another group of rats with only laparotomy comprised group 2 ( n = 9). Two months after the operation, sugar absorption and other parameters were measured. The blood pressures of the infrahepatic inferior vena cava and the portal vein 8 wk after the operation in group 1 were significantly higher than those in group 2. The results of d-xylose absorption tests showed that the amount of excreted d-xylose in urine in group 1 was significantly lower than that of group 2, but the d-xylose everted sac test showed no significant differences between the two groups. The glucose everted sac test showed that the amount of glucose absorption in group 1 was significantly lower than that in group 2. These findings suggest that chronic high venous pressure caused by constriction of suprahepatic inferior vena cava may lead to sugar malabsorption. We conclude that portal hypertension with high venous pressure below the diaphragm can lead to sugar malabsorption in the intestine.

Inhibition by calcium antagonism of circulating and renal endothelin in experimental congestive heart failure.

Endothelin (ET) is a potent vasoconstrictor and sodium-regulating peptide whose tissue and plasma concentrations are increased in congestive heart failure (CHF). ET may mediate its vasoconstrictor and sodium-regulatory actions secondary to an increase in intracellular calcium. Calcium influx may augment ET synthesis. Although felodipine, a dihydropyridine calcium-channel antagonist, is effective in reducing vascular resistance in generalized vasoconstriction, its actions in CHF on circulating and local tissue ET remain undefined. The current studies were designed to determine the modulating actions of felodipine (oral, 40 mg/day for 7 days; n = 6) in an experimental canine model of CHF produced by chronic thoracic inferior vena caval constriction (TIVCC) compared with normal (n = 7) and TIVCC-alone (n = 7) dogs. We hypothesized that felodipine would decrease circulating and renal ET. Plasma ET was significantly increased in TIVCC compared with normal dogs (26 +/- 0. 5 vs. 12 +/- 0.7 pg/ml, P < 0.05) and was markedly decreased by felodipine compared with TIVCC alone (14 +/- 3 vs. 26 +/- 0.5 pg/ml, P < 0.05). Renal ET immunohistochemical staining demonstrated the presence of ET in normal kidney, which was markedly increased in renal cortex and medulla in TIVCC dogs. Renal cortical and medullary ET staining densities were markedly decreased with felodipine compared with those with TIVCC alone. In the TIVCC + felodipine group, cardiovascular hemodynamics also was markedly improved compared with the TIVCC-alone group [systemic vascular resistance: 27 +/- 2 vs. 44 +/- 3 resistance units (RU), P < 0.05; pulmonary vascular resistance: 3.3 +/- 0.1 vs. 5.7 +/- 0.4 RU, P < 0.05; cardiac output: 2.9 +/- 0.2 vs. 1.7 +/- 0.1 l/min, P < 0.05]. This study demonstrates important modulating inhibitory actions of felodipine on renal and plasma ET in an experimental model of CHF.

Cardiovascular afferent signals and drinking in response to hypotension in dogs.

Arterial hypotension stimulates increases in plasma arginine vasopressin (AVP), plasma renin activity (PRA), and water intake in conscious dogs. We have previously reported that increasing left atrial but not right atrial pressure completely blocks the increase in plasma AVP and PRA induced by hypotension. The goal of the present study was to examine the effect of increasing right or left atrial pressure on water intake induced by arterial hypotension. Dogs were prepared with occluding cuffs on the thoracic inferior vena cava, the pulmonary artery, and the ascending aorta. We reduced mean arterial pressure (MAP) 25% below control by either inferior vena cava constriction (IVCC), pulmonary artery constriction (PAC), or ascending aorta constriction (AAC) and measured water intake over a 2-h period. Cumulative water intake during IVCC (n = 6) and PAC (n = 6) was 7.8 +/- 2.0 and 6.7 +/- 2.6 ml/kg, respectively. There was no difference between either the latency or the volume consumed between the two treatments. In contrast, none of the dogs drank during hypotension induced by AAC (n = 5). Because the degree of arterial baroreceptor unloading was the same in each treatment by design, we conclude that stimulation of left atrial receptors inhibits drinking in response to arterial hypotension but that stimulation of right atrial receptors has no effect on the response in dogs.

Minimum sizes for remnant and transplanted livers in rats

Our new technique of hepatectomy in rats, avoiding inferior vena cava constriction, revealed that 5%–10% of the total liver is the minimum required volume for remnant liver, a smaller amount than previously reported. The characteristic histological findings of remnant liver in perioperative death are marked hepatocytosis and hepatocyte apoptosis, and extensive hepatocyte necrosis with sinusoid congestion, all of which are thought to be caused by hyperendotoxemia and mitochondrial energy crisis. Partial liver transplantation in rats with our new technique of hepatectomy in the donor operation showed that a graft of 20% liver was the minimum required volume for successful transplantation, also a smaller amount than previously reported. There was no difference in the rate of increase in wet weight after surgery between 20% remnant liver and 20% transplanted liver. Differences between 10% minimum volume remnant liver and 20% minimum transplanted liver appeared to be caused by ischemia-reperfusion and cold preservation injury to the transplanted liver.

Atrial and pulmonary endothelin mRNA is increased in a canine model of chronic low cardiac output.

Chronic thoracic inferior vena caval constriction (TIVCC) is a model of low-cardiac output congestive heart failure (CHF), in which pulmonary and atrial as well as circulating endothelin (ET) are increased. ET is a potent vasoconstrictor and mitogenic peptide whose circulating concentrations are increased in severe human and experimental CHF. To date, an increase in ET production at key sites in CHF remains controversial. Therefore, the current study was designed to determine cardiac and pulmonary ET-1 mRNA in an experimental model of CHF produced by TIVCC in which avid sodium retention, intense vasoconstriction, and elevation of circulating ET-1 occur as in human CHF. Experiments were conducted in normal dogs and dogs with 7 days of TIVCC. Cardiac and pulmonary ET-1 mRNA were measured by quantified densitometry of Northern blots. Plasma and tissue (cardiac and pulmonary) ET-1 immunoreactivity were determined by radioimmunoassay. Cardiac and pulmonary tissue localization of ET-1 were determined by immunohistochemical staining. Plasma ET-1 was significantly increased in TIVCC compared with normal dogs. ET-1 mRNA was detectable in normal canine atria, ventricle, and lung. ET-1 mRNA was significantly increased in TIVCC compared with normal dogs in both atrial and pulmonary tissues without alternations in ventricular ET mRNA. Atrial and pulmonary tissue concentrations of ET-1 also were markedly elevated in TIVCC compared with normal dogs. Immunohistochemical staining of atrial and pulmonary tissues for ET-1 demonstrated that the increased ET immunoreactivity was localized to atrial myocytes and pulmonary epithelial cells. These studies support a role for the heart and lung in the increased production of ET-1 in CHF. The current studies also suggest that ET-1 may have important autocrine and paracrine actions in cardiopulmonary regulation in experimental CHF.