Hemodynamic effects of glucagon in portal hypertension

It has been suggested that glucagon contributes to the pathogenesis of portal hypertension by increasing portal blood flow. This study examined this issue by assessing the hemodynamic effects of a pharmacological dose of glucagon (1 mg, intravenously) in patients with cirrhosis and portal hypertension (n = 10) and in subjects without significant liver disease (controls = n = 5). Patients with cirrhosis had much higher glucagon levels than control subjects (875 +/- 167 vs. 186 +/- 25 pg/ml, p less than 0.01) and showed blunted hemodynamic responses after glucagon administration. This occurred despite greater circulating glucagon levels, probably because of a significant prolongation of the plasma half-life of exogenously administered glucagon (4.9 +/- 0.4 vs. 2.7 +/- 0.1 min, p less than 0.1). Control subjects had marked increases in heart rate (+ 19% +/- 4%, p less than 0.01), cardiac index (+ 16% +/- 4%, p = 0.01) and arterial pressure (+ 10% +/- 3%, p less than 0.05), but corresponding changes in patients with cirrhosis (+ 7% +/- 1%, + 6% +/- 1%, and + 6% +/- 2%, respectively) were significantly less pronounced (p = 0.05), and there was a negative correlation between basal glucagon levels and the response of heart rate to glucagon injection (r = -0.804, p less than 0.001). Resistance to the systemic effects of glucagon in cirrhosis may thus be caused by a down-regulation of vascular glucagon receptors. In addition, glucagon administration caused a significant increase in portal pressure (from 18.1 +/- 1.1 to 19.0 +/- 1.2 mm Hg, p less than 0.01), as well as in azygos blood flow (from 0.54 +/- 0.03 to 0.64 +/- 0.04 L/min, + 19% +/- 4%, p less than 0.02), reflecting increased portocollateral blood flow. These findings are consistent with the hypothesis that glucagon is one of the factors contributing to the splanchnic vasodilatation and increased portal pressure of cirrhosis.     

Hemodynamic effects of hypothyroidism induced by methimazole in normal and portal hypertensive rats

Portal hypertension is accompanied by a hyperdynamic circulatory state that shares some similarities with thyrotoxicosis. This study was conducted in order to investigate the hemodynamic effects of hypothyroidism in a rat model with portal hypertension induced by partial portal vein ligation (PVL). Four groups of 10 rats each were studied: normal control and hypothyroid rats, and PVL control and hypothyroid rats. Hypothyroidism was induced by methimazole 0.04% in drinking water. Hemodynamic measurements were performed using the radioactive microsphere technique. Induction of hypothyroidism was confirmed by elevated TSH levels. In the PVL groups, hypothyroidism ameliorated the hyperdynamic circulation. Portal venous inflow and portal pressure dropped significantly: 7.1±0.2 vs 4.8±0.3 ml/min/100 g body wt (P<0.01) and 13.4±0.9 vs 10.9±0.8 mm Hg; (P<0.01), respectively. In normal rats, hypothyroidism was manifested by a hypodynamic circulatory state. These results demonstrate that hypothyroidism induced by methimazole is followed by amelioration of the hyperdynamic circulation, normalization of portal venous inflow, and reduction of portal pressure.     

选择性内皮素受体拮抗剂对肝硬变门脉高压症大鼠血流动力学的影响

目的研究选择性内皮素受体拮抗剂(内皮素受体A拮抗剂BQ123和内皮素受体B拮抗剂BQ788)对肝硬变门脉高压大鼠血流动力学的影响.方法肝硬变门脉高压大鼠模型由皮下注射四氯化碳诱导,肝硬变大鼠分为肝硬变对照组、肝硬变用药组,分别接受经左心室匀速给予(1 mL·h-1)的生理盐水、BQ123(5和10 nmol·kg-1·min-1),BQ788(10 nmol·kg-1·min-1),BQ123+BQ788(均10 nmol·kg-1·min-1).正常大鼠接受经左心室给予的生理盐水.用药过程中观测大鼠血压和门脉压力的变化情况,用药1 h后应用放射性微球法进行血流动力学测定.结果与正常大鼠相比,肝硬变门脉高压大鼠的动脉血压下降,MAP(17.0±0.37)vs(19.6±0.35)kPa,P＜0.01,门脉压上升,PP(1.6±0.04)vs(0.9±0.03)kPa,P＜0.01,心指数显著增加,CI(307.3±18.8)vs(163.3±21.9)mL·min-1·kg-1,P＜0.01),外周血管阻力(TPR)和内脏血管阻力(PTVR)都下降,TPR(0.1±0.003)vs(0.3±0.04)kPa·mL-1·min-1,P＜0.01,PTVR(0.7±0.03)vs(2.1±0.3)kPa·mL-1·min-1,P＜0.01,门脉血流量明显增加,PTBF(49.9±4.4)vs(26.0±4.6)mL·min-1·kg-1,P＜0.01.接受BQ123 10 mol·kg-1·min-1后,肝硬变大鼠的血压和心率迅速下降,在5min～10min内死亡;接受5 nmol·kg-1·min-1的BQ123时,则表现为MAP下降(3.4±0.7)vs(0.7±0.1)kPa,P＜0.01,PP也相应下降(0.1±0.05)vs(0.02±0.01)kPa,P＜0.05,CO继续增加(148.9±13.1)vs(113.2±3.8)mL·min-1,P＜0.05,TPR有进一步下降的趋势(0.1±0.02)vs(0.1±0.003)kPa·mL-1·min-1,P＞0.05,提示高动力循环加重;10 nmol·kg-1·min-1的BQ788可以使PP下降(0.3±0.05)vs(0.02±0.01)kPa,P＜0.01,降低肝硬变大鼠的CI(221.0±15.9)vs(307.3±18.8)mL·min-1·kg-1,P＜0.01,提高TPR(0.2±0.01)vs(0.1±0.003)kPa·mL-1·min-1,P＜0.01,部分纠正了高动力循环和门脉高压.结论肝硬变门脉高压大鼠存在高动力循环状态,BQ123可使其血流动力学状态进一步恶化,BQ788则可部分纠正高动力循环降低门脉压力,这提示ET在维持机体血压和脏器灌注中起重要作用,而由ETA介导的此作用对肝硬变大鼠尤为重要.     

Effects of somatostatin analog on splanchnic hemodynamics and plasma glucagon level in portal hypertensive rats

ＥｆｅｃｔｓｏｆｓｏｍａｔｏｓｔａｔｉｎａｎａｌｏｇｏｎｓｐｌａｎｃｈｎｉｃｈｅｍｏｄｙｎａｍｉｃｓａｎｄｐｌａｓｍａｇｌｕｃａｇｏｎｌｅｖｅｌｉｎｐｏｒｔａｌｈｙｐｅｒｔｅｎｓｉｖｅｒａｔｓＷＵＺｈｉＹｏｎｇ,ＺＨＡＮＧＸｉａｏＪｉｅ,ＪＩ...     

Hemodynamic evaluation before liver transplantation: insights into the portal hypertensive syndrome

The cardiac hemodynamics of patients awaiting liver transplantation is complex. Coronary atherosclerosis, a hyperdynamic circulatory state and cirrhotic cardiomyopathy are present to a variable degree in this population. In this contribution to the Symposium on Portal Hypertension, we expand on our published experience with coronary angiography and cardiac hemodynamics at the time of evaluation of candidacy for liver transplantation in a cohort of 161 patients. Although we confirmed the relation of systemic hemodynamics with the degree of liver failure, we noted a higher prevalence of high output heart failure, defined as an increased left ventricular end-diastolic pressure in the setting of an elevated cardiac output, most notably in patients classified as Child C. Most patients with high pulmonary artery pressure also exhibited evidence of elevated left ventricle filling pressures. A low systemic vascular resistance, a marker of arterial vasodilatation, was similar in the presence of atherosclerosis, a condition where impaired vasorelaxation occurs as a result of endothelial dysfunction. The high prevalence of coronary artery disease in this series supports the observations that atherosclerosis is a major issue in the current population with cirrhosis awaiting liver transplantation. A lower sensitivity of noninvasive screening tools for the detection of coronary atherosclerosis is likely the result of the interaction of the hyperdynamic circulation with the performance of these tests.     

Effects of calcium antagonists on hepatic and systemic hemodynamics in awake portal hypertensive rats

The effects of the calcium antagonists diltiazem and nicardipine on portal pressure and splanchnic blood flow were studied in awake, unrestrained portal hypertensive rats. Portal hypertension was induced in rats by partial portal vein ligation. Hemodynamic measurements were done using the radiolabeled microsphere technique. In portal veinligated and sham-operated rats, intraarterial diltiazem and nicardipine reduced mean arterial pressure. No significant changes, however, were observed in portal pressure and cardiac index. In portal vein-ligated rats, diltiazem and nicardipine increased portal tributary blood flow. Portal tributary vascular resistance was also significantly decreased. The decrease in the hepatocollateral vascular resistance prevented an increase in portal pressure. In sham-operated rats, these changes were not observed. It is possible that the vascular responses to calcium antagonists are altered in portal vein-ligated rats. These findings demonstrate that the hemodynamic effects of calcium antagonists occur at two levels. First, the increase in portal tributary blood flow appears to be a selective effect on portal tributary vascular resistance. Secondly, the portal pressure does not increase in parallel with the increase in portal tributary blood flow because of a similar reduction in portocollateral vascular resistance.     

Hemodynamic effects of somatostatin in the rat: relationship with plasma glucagon levels

Hepatic, splanchnic, and systemic hemodynamic effects of somatostatin infusion, as well as changes in plasma glucagon concentration, were studied in normal rats, using techniques involving radioactive microspheres and radioimmunoassay. Somatostatin infusion caused a decrease in arterial blood flow to the stomach, small intestine and spleen, with the net effect of reducing hepatic portal blood flow and portal pressure. The hepatic arterial blood flow was not altered. The systemic hemodynamic effects of somatostatin were slight, although renal blood flow diminished, Plasma glucagon concentration did not vary immediately after somatostatin infusion. The mechanism of the hemodynamic action of the hormone is not yet clear, but in normal conditions it is not related to the inhibition of glucagon secretion.     

Discrepancy between portal pressure and systemic hemodynamic changes after incremental doses of propranolol in awake portal hypertensive rats

The effects of increasing doses of propranolol were studied in awake portal hypertensive rats in order to elucidate the relative effects of the beta-blocker on systemic and splanchnic circulation. Hemodynamic responses to 0.1, 0.2 and 0.4 mg per min infusions of propranolol were compared with placebo in awake rats with portal hypertension due to portal vein stenosis. Heart rate significantly and progressively decreased from 356 +/- 13 to 293 +/- 10 beats per min (mean +/- S.E.). Cardiac output significantly decreased from 54 +/- 3 to 42 +/- 3 ml per min per 100 gm body weight at the highest dose. Significant decrease in portal tributary blood flow from 27 +/- 1 to 18 +/- 1 ml per min, at 0.4 mg per min dose, was due not only to the decrease in cardiac output but also to a significant increase in portal tributary vascular resistance from 269 +/- 17 to 368 +/- 31 dyne per sec per cm5 x 10(3). However, portal pressure showed only an insignificant decrease from 14.9 +/- 1.1 to 14.1 +/- 1.4 mmHg. The reduction in portal pressure being minimal, in spite of a significant decrease in portal tributary blood flow, is explained by an increase in combined hepatic and collateral resistance from 44 +/- 2 to 66 +/- 4 dyne per sec per cm5 x 10(3), p less than 0.05, at 0.4 mg per min dose. We conclude that the systemic and splanchnic effects of propranolol show discrepancy at two levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Simvastatin effects on portal‐systemic collaterals of portal hypertensive rats

Background and Aim: Portal‐systemic collateral vascular resistance and vasoconstrictor responsiveness are crucial in portal hypertension and variceal bleeding control. Statins enhance vasodilators production, but their influence on collaterals is unknown. This study aimed to survey the effect of simvastatin on collaterals. Methods: Partially portal vein‐ligated rats received oral simvastatin (20 mg/kg/day) or distilled water from ?2 to +7 day of ligation. After hemodynamic measurements on the eighth postoperative day, baseline perfusion pressure (i.e. an index of collateral vascular resistance) and arginine vasopressin (AVP, 0.1 nM–0.1 µM) responsiveness were evaluated with an in situ perfusion model for collateral vascular beds. RT‐PCR of endothelial NO synthase (eNOS), inducible NOS (iNOS), cyclooxygenase‐1 (COX‐1), COX‐2, thromboxane A₂ synthase (TXA₂‐S) and prostacyclin synthase genes was performed in parallel groups for splenorenal shunt (SRS), the most prominent intra‐abdominal collateral vessel. To determine the acute effects of simvastatin, collateral AVP response was assessed with vehicle or simvastatin. SRS RT‐PCR of eNOS, iNOS, COX‐1, COX‐2 and TXA₂‐S, and measurements of perfusate nitrite/nitrate, 6‐keto‐PGF1_α and TXB₂ levels were performed in parallel groups without AVP. Results: Acute simvastatin administration enhanced SRS eNOS expression and elevated perfusate nitrite/nitrate and 6‐keto‐PGF1_α concentrations. Chronic simvastatin treatment reduced baseline collateral vascular resistance and portal pressure and enhanced SRS eNOS, COX‐2 and TXA₂‐S mRNA expression. Neither acute nor chronic simvastatin administration influenced collateral AVP responsiveness. Conclusion: Simvastatin reduces portal‐systemic collateral vascular resistance and portal pressure in portal hypertensive rats. This may be related to the enhanced portal‐systemic collateral vascular NO and prostacyclin activities.     

Intestinal vascular sensitivity to vasopressin in portal hypertensive rats

The intestinal vascular responsiveness to arginine vasopressin was evaluated in rats with chronic portal hypertension. Male Sprague-Dawley rats were made portal hypertensive by stenosis of the portal vein. Ten to twelve days after the induction of chronic portal hypertension, the responsiveness of the small intestinal circulation to cumulative doses of vasopressin was evaluated using an isolated pump-perfused small intestinal preparation. The ED50 for maximal vasoconstriction was increased twofold in portal hypertensive rats compared with control rats. To determine if the impaired responsiveness to arginine vasopressin was related to the hyperglucagonemia of chronic portal hypertension, plasma glucagon levels were elevated in normal rats to levels previously measured in portal hypertensive rats (i.e. approximately 450 pg/mL), and the dose response studies were repeated. Glucagon significantly attenuated the responsiveness of the intestinal vasculature to vasopressin. Equipotent doses of nitroprusside also attenuated intestinal vascular responsiveness to vasopressin. The results indicate that there is a reduced vascular sensitivity to vasopressin in the intestine of portal hypertensive animals and suggest that elevations in circulating vasodilators in portal hypertensive conditions may partially explain this altered vascular responsiveness.     

Responsiveness to synthetic parathyroid hormone in the portal vein of portal hypertensive rats.

In addition to its hypotensive action, the parathyroid hormone also decreases portal pressure in portal hypertensive rats. The purpose of this study was to characterize the vascular effects of the parathyroid hormone on the portal vein of portal vein-stenosed rats. When intravenously infused at the rate of 1.62 x 10(-11) mol/kg per min, the parathyroid hormone lowered portal pressure (15.1 +/- 0.7 vs. 14.0 +/- 0.8 mmHg) without affecting systemic blood pressure. With the portal vein isolated, the parathyroid hormone shifted the dose-response curves of KCl and acetylcholine to the right. However, the vasodilator effect of the parathyroid hormone was significantly less in portal hypertensive rats (EC50 of KCl increased 129.2% and acetylcholine 199.3%), compared to sham-operated rats (EC50 of KCl increased 158.7% and acetylcholine 270.2%). Similar results were found for the vasodilator action of verapamil (10(-9)-10(-6) M). On the other hand, the vasodilator effect of forskolin was similar for both groups. These results suggest that decreased responsiveness to the parathyroid hormone may be associated with calcium utilization by vascular smooth muscles.     

Gut-brain chemokine changes in portal hypertensive rats

Background

Hepatic encephalopathy is a syndrome whose physiopathology is poorly understood; therefore, current diagnostic tests are imperfect and modern therapy is nonspecific. Particularly, it has been suggested that inflammation plays an important role in the pathogenesis of portal hypertensive encephalopathy in the rat.

Aim

We have studied an experimental model of portal hypertension based on a triple partial portal vein ligation in the rat to verify this hypothesis.

Methods

One month after portal hypertension we assayed in the splanchnic area (liver, small bowel and mesenteric lymph nodes) and in the central nervous system (hippocampus and cerebellum) fractalkine (CX3CL1) and stromal cell-derived factor alpha (SDF1-??) as well as their respective receptors (CX3CR1 and CXCR4) because of their key role in inflammatory processes.

Results

The significant increase of fractalkine in mesenteric lymph nodes (P?<?0.05) and its receptor (CX3CR1) in the small bowel (P?<?0.05) and hippocampus (P?<?0.01), associated with the increased expression of SDF1-?? in the hippocampus (P?<?0.01) and the cerebellum (P?<?0.01) suggest that prehepatic portal hypertension in the rat induces important alterations in the expression of chemokines in the gut-brain axis.

Conclusion

The present study revealed that portal hypertension is associated with splanchnic-brain inflammatory alterations mediated by chemokines.     

Comparison of the hemodynamic responses to ketanserin and prazosin in portal hypertensive rats

Ketanserin, a serotonin antagonist, is effective in lowering portal pressure in a rat model of portal hypertension. As ketanserin has alpha 1-adrenoceptor-blocking properties in addition to its serotonin-blocking effects, we sought to define further the mechanism of ketanserin's portal pressure-lowering effect. We attempted to determine whether the portal pressure-reducing effect of ketanserin was due to the unspecific effect of arterial blood pressure reduction mediated by alpha 1-adrenoceptor blockade or to serotonin receptor-blocking properties of ketanserin. The hemodynamic action of prazosin and alpha 1-adrenoceptor antagonist and ketanserin were compared in portal hypertensive rats in which the arterial pressure was equally reduced by both agents. The portal pressure was significantly lower in the ketanserin-treated group (11.3 +/- 0.4 mm Hg) when compared to the saline-treated group (13.6 +/- 0.7 mm Hg). The portal pressure was not significantly lower in the prazosin-treated group when compared to the saline-treated group (12.3 +/- 0.5 vs. 13.6 +/- 0.7 mm Hg, respectively). The same relationship held true for portal venous inflow and cardiac output. For each measurement, results in the ketanserin group were significantly lower when compared to the saline-treated group. These data in the prazosin-treated group were similar to data in the saline-treated group. The differences between the effect of ketanserin and prazosin were obtained despite similar blood pressure decreases. Ketanserin produced an 18% decrease and prazosin a 14% decrease in blood pressure when values were compared to their preinjection baselines.(ABSTRACT TRUNCATED AT 250 WORDS)     

门高压鼠血浆前列环素与门脉压力的关系

目的 探讨门脉压力升高和门体分流在前列环素（ＰＧＩ２）或高中的作用。方法 ３６只雄性ＳＤ大随机分为四组：肝前型（ＰＨＰＨ，ｎ＝８）和肝内型门高压（ＩＨＰＨ，ｎ＝９），端侧门腔分流（ＰＣＳ，ｎ＝８）以及手术对照组（ＳＯ，ｎ＝１１），模型制备后２周；（１）测游离门脉压（ＦＰＰ）；（２）应用核素微球技术研究全身及内脏血流血压学；（３）从股动脉采集血样用放射免疫法测血浆６－酮－前列腺素Ｆ１α（６－ｋｅｔｏ     

Plasma insulin and glucagon levels in protein-malnourished rats

The plasma concentrations of insulin and glucagon were measured in an experimental rat model for protein malnutrition. Plasma insulin levels were markedly reduced, while plasma glucagon levels were comparable to adequately fed age controls.     

Hemodynamic effects of adenosine in conscious hypertensive and normotensive rats

Mean arterial pressure and heart rate were measured during intra-aortic arch (i.a.a.), intravenous, and suprarenal artery (s.r.a.) infusions of adenosine in conscious, unrestrained normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in the absence and presence of ganglionic blockade. In both groups, i.a.a. and i.v. infusions of adenosine induced comparatively larger dose-dependent reductions in mean arterial pressure than did s.r.a. infusions. In WKY, i.a.a. and i.v. infusions of adenosine were equipotent in reducing mean arterial pressure. In contrast, i.a.a. infusion of adenosine was approximately twice as potent as i.v. infusion in SHR. Also, SHR were approximately 6.5 and 2.6 times more sensitive to i.a.a. and i.v. infusions of adenosine, respectively, than were WKY. Further, i.a.a. and s.r.a. infusions of adenosine caused tachycardia in WKY, while i.v. infusions did not alter heart rate. In SHR, neither i.a.a. nor s.r.a. infusion of adenosine altered heart rate, but i.v. infusion induced a profound bradycardia. In ganglionic-blocked WKY that received a norepinephrine infusion to restore blood pressure and heart rate to pre-ganglionic blockade levels, depressor responses to i.a.a. infusion of adenosine were unchanged while the increase in heart rate was abolished. In SHR, ganglionic blockade markedly decreased the depressor response to i.a.a. and i.v. infusions of adenosine and abolished the bradycardic response to i.v. infusion. These results suggest that adenosine is an effective hypotensive agent in both WKY and SHR; however, marked between-strain differences exist in the cardiovascular response to adenosine. These differences most likely are due to changes in adenosine-pulmonary interactions and increases in the importance of adenosine-autonomic interactions in SHR.     

Hemodynamic and metabolic effects of hypomagnesemia in spontaneously hypertensive rats

The hemodynamic and metabolic effects of dietary induced hypomagnesemia were studied in two groups of 2-month-old male spontaneously hypertensive rats (SHR). All rats were given distilled water to drink ad libitum and were followed for 2 months. However, control rats (n = 12) were given a regular rat diet to eat, whereas the experimental (hypomagnesemic; HM) rats (n = 12) were given a magnesium-free diet. Metabolic and hemodynamic studies were done at the end of the 2-month observation period in the awake state. HM rats had higher mean arterial pressure, total peripheral resistance, renal vascular resistance, heart rate, UNaV, UKV and serum Na, and lower hematocrit, renal blood flow, serum K and serum Mg than the controls. No differences were observed among the two groups of rats with respect to weight, fluid intake, urine volume, serum calcium, blood urea nitrogen, cardiac index and glomerular filtration rate. In addition, HM rats had widespread myocardial and renal tissue calcification in contrast to controls, which did not show any tissue calcification. We conclude: (1) dietary-induced hypomagnesemia aggravated the hypertension of SHR; (2) it caused widespread tissue calcification; (3) the adverse effects of hypomagnesemia on arterial pressure were possibly produced through calcium-mediated systemic vasoconstriction and increase in peripheral vascular resistance.