Intraportal administration of glyceryl trinitrate or nitroprusside exerts more systemic than intrahepatic effects in anaesthetised cirrhotic rats.

BACKGROUND/AIMS: Increased intrahepatic vascular tone can be pharmacologically manipulated in isolated cirrhotic livers. Intrahepatic endothelial dysfunction may lead to a decreased production of the potent endogenous vasodilator nitric oxide in cirrhotic livers. The aims of the study were to determine whether portal pressure can be lowered in vivo by injecting nitric oxide donors glyceryl trinitrate or nitroprusside directly in the portal vein and whether this is related to a decrease in intrahepatic resistance. METHODS: In anaesthetised CCl4 cirrhotic rats, intraportal doses of glyceryl trinitrate 0.5, 1 or 5 microg/kg/ min or nitroprusside 1, 5 or 10 microg/kg/min did not decrease portal pressure but only arterial pressure. Systemic and splanchnic haemodynamics were measured before and during 15 min intraportal infusion of glyceryl trinitrate 10 microg/kg/min or nitroprusside 20 microg/kg/min. RESULTS: Glyceryl trinitrate decreased portal pressure from 14.0+/-1.1 to 11.8+/-1.4 mm Hg, splanchnic perfusion pressure from 102+/-10 to 74+/-5 mm Hg and portal sinusoidal flow from 2.11+/-0.38 to 1.70+/-0.35 ml/min/g liver (all p<0.05). Nitroprusside did not decrease portal pressure significantly but led to a reduction of the splanchnic perfusion pressure (104+/-9 to 66+/-7 mm Hg) and the portal sinusoidal flow (2.39+/-0.50 to 1.77+/-0.31 ml/min/g liver; all p<0.05). Portal sinusoidal resistance was not altered by either drug. CONCLUSIONS: Intraportal infusion of nitric oxide donors decreased arterial pressure more than portal pressure. Portal sinusoidal resistance remained unaffected, but the liver parenchyma became less perfused with high doses. The systemic effects of nitric oxide donating drugs prevailed.     

Significance of hepatic arterial responsiveness for adequate tissue oxygenation upon portal vein occlusion in cirrhotic livers

We investigated sinusoidal blood flow and hepatic tissue oxygenation during portal vein occlusion in cirrhotic rat livers to examine the effect of cirrhosis on the properties of hepatic microvascular blood flow regulation. After 8 weeks of CCl4/phenobarbital sodium treatment to induce cirrhosis Sprague-Dawley rats were prepared surgically to allow assessment of portal venous and hepatic arterial inflow using miniaturized flow probes with simultaneous analysis of hepatic microcirculation and tissue oxygenation by fluorescence microscopy and polarographic oxymetry. Age-matched noncirrhotic animals served as controls. Upon portal vein occlusion in cirrhotic livers (flow reduction to < 20%), hepatic arterial blood flow increased 1.5-fold (61 +/- 8 ml/min per 100 g liver) of baseline (40 +/- 7 ml/min per 100 g liver), reflecting an appropriate hepatic arterial buffer response (HABR), similarly as seen in control livers. The net result was a reduction in total liver inflow from 90 +/- 12 to 72 +/- 11 ml/min per 100 g liver, which was associated with a significant decrease in both sinusoidal red blood cell velocity and volumetric blood flow to approx. 71% and 76% of baseline values. However, portal vein occlusion did not cause a deterioration in hepatic tissue pO2 (11 +/- 3 vs. 10 +/- 3 mmHg at baseline). Sinusoidal diameters were found unchanged, disproving a major role of the sinusoidal tone in the regulation of HABR. Microvascular response of cirrhotic livers did not generally differ from that in noncirrhotic livers upon portal inflow restriction. We conclude that HABR in cirrhotic livers operates sufficiently to meet the liver tissue oxygen demand, most probably by an increased relative contribution of arterial perfusion of hepatic sinusoids.     

Effect of cirrhosis on sulphation by the isolated perfused rat liver

BACKGROUND/AIMS: There is evidence to suggest that not all pathways of drug metabolism are similarly affected in cirrhosis. The effect of cirrhosis on drug oxidation and glucuronidation has been extensively investigated but little is known of the effect of cirrhosis on drug sulphation. The aim of this study was to investigate the effect of cirrhosis on sulphation. METHODS: We investigated the effect of cirrhosis on p-nitrophenol sulphation and compared this with the effect of cirrhosis on p-nitrophenol glucuronidation as well as on d-propranolol oxidation simultaneously in the single-pass isolated perfused rat liver. The perfusate contained added inorganic sulphate to maximise production of p-nitrophenol sulphate. RESULTS: About 77% and 59% of p-nitrophenol was eliminated as the sulphate conjugate by the healthy (n=6) and cirrhotic (n=7) livers, respectively. Mean total p-nitrophenol clearance was decreased in cirrhosis (healthy: 18.5+/-0.2 vs. cirrhotic 15.3+/-4.0 ml/min; p<0.05). The decrease in total clearance of p-nitrophenol was due solely to the decrease in sulphate formation clearance, which was significantly decreased (healthy: 14.1+/-1.9 vs. cirrhotic: 9.27+/-3.33 ml/min; p<0.05). Mean glucuronide formation clearance (healthy: 5.11+/-0.94 vs cirrhotic: 5.79+/-0.85 ml/ min; p>0.05) was not significantly altered. Mean total propranolol clearance was decreased in cirrhosis (healthy: 19.9+/-0.1 vs. cirrhotics: 18.0+/-1.5 ml/min; p<0.05). CONCLUSIONS: We have shown that in cirrhosis there is significant impairment of drug oxidation and sulphation, whilst glucuronidation is spared. The decreased sulphation of p-nitrophenol was most likely due to a decrease in phenol sulphotransferase and/or decrease in cofactor synthesis.     

联合测定吲哚箐绿和D-山梨醇评价肝储备功能

目的 利用高效液相法(HPLC)测定正常肝脏和肝硬化肝脏的吲哚箐绿(ICG)肝固有代谢容量,并结合D-山梨醇无创测量肝功能性血流量、肝内分流率,全面评价肝储备功能。方法 制作大鼠肝硬化模型和肝脏隔离灌注模型,据HPLC法和Bergmeyer酶分光光度法分别测量ICG和D-山梨醇的药代动力学参数。结果 (1)HPLC证实ICG包括ICG原形(ICGg)和ICG降解产物(ICGdp)两种成分,保留时间分别为8.9min和24.2min,两种成分光谱相似,但体内代谢不同。(2)据ICGg计算的肝固有代谢容量(Q_(INT,I))在对照组和肝硬化组分别为(36.57±13.03)ml/min和(14.39±5.13)ml/min,肝硬化组Q_(INT,I)明显下降(t=7.08,P<0.01)。(3)肝功能性血流量(Q_(FUNC)),肝内分流率(Q_(IHS))在对照组和肝硬化组分别为:(34.06±5.12)ml/min和(17.54±7.02)ml/min,(9.9±1.4)％和(47.5±20.9)％,肝硬化组Q_(FUNC)显著下降(t=8.41,P<0.01),Q_(IHS)显著增加(t=8.35,P<0.01)。结论(1)HPLC法可避免ICGdp的干扰,优于传统的分光光度法,能用于肝固有代谢容量测定。(2)D-山梨醇肝清除率,是无创测定正常肝脏的总血流量,和肝硬化肝脏的肝功能性血流量、肝内分流率的实用可靠方法。(3)ICG与D-山梨醇联合使用,有助于全面评价肝脏功能状态。     

急性肝内窦前型门静脉高压症大鼠肝内门体分流的变化及其意义

目的探讨急性肝内窦前型门静脉高压症时肝内门体分流的变化及其意义。方法经大鼠门静脉注射乳胶微球造成急性肝内窦前型门静脉高压症。采用肝山梨醇摄取率法测定功能性肝血流量和肝内门体分流量,采用放射性微球法测定肝内较大门体分流侧支(直径>15μm)的分流率。结果对照组肝山梨醇摄取率为(97.9±0.5)％,肝总血流量为每100g体重(2.52±0.23)ml／min。微球组,肝山梨醇摄取率锐减至(12.8±4.3)％,微球加肝动脉结扎组则下降至(4.1±0.7)％,t值为3.541和3.668,P值均<0.01;肝内门体分流量对照组、微球组、微球加肝动脉结扎组分别为每100g体重(0.06±0.02)、(1.46±0.15)和(1.16±0.19)ml／min,t值分别为5.468和6.869,P值均<0.01;门静脉血流量3组差异无统计学意义。结论肝内门体分流的直径大多<15μm。其开放可使70％的门静脉血绕过肝窦而直接注入肝静脉,并有效阻止了门静脉压力的升高。     

Reversal of adrenaline-induced increase in azygos blood flow in patients with cirrhosis receiving propranolol

In patients with cirrhosis, endogenous catecholamines may influence the circulatory effects of propranolol. We intended to evaluate the interaction of adrenaline and propranolol on azygos blood flow, an estimate of blood flow in the superior portosystemic collateral circulation. We investigated 6 patients with cirrhosis, 5 with good liver function, receiving an intravenous infusion of adrenaline (50 ng/kg/min) before and after administration of propranolol. The median value for baseline azygos blood flow was increased from 700 ml/min (range 340-1 470 ml/min) to 1 050 (range 570-1 840 ml/min) with adrenaline alone (P less than 0.05), and decreased to 610 ml/min (range 260-1 190 ml/min) with propranolol alone (P less than 0.05). The infusion of adrenaline given after propranolol further reduced azygos blood flow to a median value of 530 ml/min (range 200-730 ml/min) (P less than 0.05). Thus, following beta-adrenergic blockade, there is a reversal of the effects of adrenaline on azygos blood flow, which corresponds to a potentiation of the effects of propranolol. Similar endogenous adrenaline-propranolol interactions may play a role in preventing recurrent variceal bleeding in cirrhotic patients.     

The hepatic microcirculation in the isolated perfused human liver

In cirrhosis, capillarization of sinusoids could result in impaired exchanges between the hepatocytes and the blood perfusing the liver and contribute to liver failure irrespective of the metabolic capacity of the liver. To characterize anomalies of the hepatic microcirculation, we used the multiple-indicator dilution approach in isolated perfused livers obtained from patients with cirrhosis at the time of transplantation, and from organ donors with normal or near-normal livers or hepatic steatosis. In organ donors, the sinusoidal volume and the permeability of sinusoids to albumin, sucrose, and water were found to be comparable to that of normal dog and rat livers. The sinusoidal volume and the extravascular volume (EVV) accessible to diffusible tracers were larger after hepatic artery than after portal vein injection, probably because of an unshared arterial sinusoidal bed. In cirrhotic livers, two kinds of alterations were found: the appearance of a barrier between the sinusoids and the hepatocytes (capillarization) and intrahepatic shunts. The extravascular space accessible to albumin decreased with increasing severity of cirrhosis, and the diffusion of sucrose in the space of Disse showed a barrier-limited pattern, instead of the normal flow-limited behavior. In cirrhotic livers, a correlation was found between the hepatic extraction of indocyanine green (ICG) and the extravascular space accessible to albumin (r = .84, P < .05), suggesting that the impaired access of this protein-bound dye to the hepatocyte surface contributed to its impaired elimination. Intrahepatic shunts were found between portal and hepatic vein (21% +/- 16% of portal flow), but not between hepatic artery and hepatic veins. We conclude that (1) the behavior of diffusible tracers in human livers with normal liver architecture is comparable to that reported in normal animals; (2) the permeability of sinusoids in cirrhotic livers is abnormal, (3) permeability changes are related to changes in liver function in cirrhosis. (Hepatology 1996 Jan;23(1):24-31)     

Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol.

Quinidine pharmacokinetics (half-life, volume of distribution, and clearance) as well as protein binding were evaluated following a single 200 mg. oral dose of quinidine sulfate in eight control patients, in eight patients with moderate to severe cirrhosis, and in seven patients receiving 40 to 400 mg./day of propranolol. Patients with cirrhosis had a significantly longer quinidine half-life (9 +/- 1 hr; p less than .01) when compared to control patients (6 +/- 0.5h). This was not related to a reduced quinidine clearance rate but rather to an increase in quinidine volume of distribution (4.1 +/- .4 L./Kg. in cirrhotic patients vs 2.6 +/- 1 L./Kg. in control patients; p less than .01). Abnormal quinidine binding (greater than 25 per cent unbound fraction) was noted in seven of the eight cirrhotic patients. In contrast, patients receiving propranolol had a normal quinidine half-life of 6 +/- 0.5 hr. However, these patients had a significantly reduced quinidine clearance (3.3 +/- .7 ml./min./Kg. vs. 5.3 +/- .5 ml./min./Kg. in controls; p less than .05) and higher peak concentrations (1.25 +/- .20 micrograms/ml. vs. .80 +/- .5 micrograms/ml. in controls; p less than .05). Therefore in patients receiving propranolol, quinidine levels may be higher than expected shortly after dosage, and therefore a potential for transient toxicity exists in these patients. Maintenance quinidine dosage may have to be reduced in patients with moderate to severe hepatic cirrhosis, but not in patients receiving propranolol. Total quinidine concentration measurement underestimate free quinidine concentrations in most cirrhotic patients.     

In micronodular cirrhosis, hepatocytes retain a normal C-25 hydroxylation capacity toward vitamin D3: a study using the rat carbon tetrachloride-induced cirrhotic model.

To test further the competence of the cirrhotic liver to metabolize vitamin D3 at C-25, hepatocytes were isolated from controls and from CCl4-induced cirrhotic rat livers, as well as from partially hepatectomized rats. The transformation of D3 into 25-hydroxyvitamin D3 was studied in the presence of 10(7) hepatocytes at D3 concentrations of 20 nmol/L to 15.4 mumol/L. Histologically, micronodular cirrhosis was present in all CCl4-treated rats, whereas controls had normal livers; portal venous pressure (p less than 0.008) and intrahepatic collagen content (p less than 0.0001) were significantly increased in CCl4-treated rats, whereas no difference was found between the two groups in the total and ionized serum calcium, D3 metabolites, ALT, AST and alkaline phosphatase. Cytochrome P-450 was 0.27 +/- 0.02 and 0.25 +/- 0.02 nmol/10(6) hepatocytes in controls and cirrhotic rats (N.S.), and it significantly increased in both groups after phenobarbital or 3-methylcholanthrene administration (p less than 0.0001). 25-Hydroxyvitamin D3 formation was best described by power law equations and varied between 0.02 +/- 0.0004 and 29.57 +/- 2.8 in controls, and 0.024 +/- 0.0004 and 32.0 +/- 7.0 pmol.hr-1.10(6) hepatocytes-1 in cirrhotic rats. No statistically significant difference was found in the slopes of the 25-hydroxyvitamin D3 formation, but the y-axis intercept was found to be lower in cirrhotic rats under basal resting conditions (p less than 0.005). Inducers of the mixed function oxidases significantly increased 25-hydroxyvitamin D3 formation in controls as well as in cirrhotic rats (p less than 0.005). Moreover, both groups were found to respond similarly to the addition of modulators of the enzyme such as the calcium ionophore A23187 and parathyroid hormone. Partial hepatectomy was also without effect on the activation of D3. Furthermore, the cell sequestration of D3 was also found to be unperturbed in hepatocytes obtained from either cirrhotic or partially hepatectomized livers. The data indicate that in well-compensated micronodular cirrhosis, the C-25 hydroxylation of D3 is generally intrinsically normal at the cellular level and that it also remains fully responsive to in vivo and in vitro modulators of its activity.     

Increased blood flow through the portal system in cirrhotic rats

Portal venous pressure is the result of the interplay between portal venous blood flow and the vascular resistance offered to that flow. Whether portal hypertension is maintained only by an increased portal venous resistance or also by an increased blood flow within the portal venous system is still open to speculation. To resolve these differences, splanchnic and systemic hemodynamics were evaluated in cirrhotic rats, induced by CCl4. Blood flow and portal-systemic shunting were measured by radioactive microsphere techniques. All cirrhotic rats had portal hypertension (portal venous pressure 13.5 +/- 1.1 vs. 9.0 +/- 0.5 mmHg, in normal control rats; p less than 0.01), but portal-systemic shunting in cirrhosis (31% +/- 13% vs. 0.2% +/- 0.02%; p less than 0.05) was variable, ranging from 1% to 97%. Portal venous inflow, the total blood flow within the portal system, was increased in cirrhotic rats (5.75 +/- 0.04 vs. 4.52 +/- 0.36 ml/min per 100 g; p less than 0.05). Total splanchnic arterial resistance was reduced in cirrhotic rats (3.3 +/- 0.2 vs. 5.8 +/- 0.5 dyn X s X cm-5 X 10(5); p less than 0.01). Portal venous resistance, however, was not abnormally elevated in cirrhotic rats (4.6 +/- 0.5 vs. 4.7 +/- 0.5 dyn X s X cm-5 X 10(4), p = NS). Splanchnic hemodynamics in cirrhotic rats demonstrate that portal hypertension is maintained, at least in part, by a hyperdynamic portal venous inflow. The hemodynamic data in cirrhotic rats provided evidence that supports the role of an increased portal blood flow in portal hypertension and gives a quantitative definition of splanchnic hemodynamics in intrahepatic portal hypertension.     

The methionine connection: homocysteine and hydrogen sulfide exert opposite effects on hepatic microcirculation in rats

Increased intrahepatic resistance in cirrhotic livers is caused by endothelial dysfunction and impaired formation of two gaseous vasodilators, nitric oxide (NO) and hydrogen sulfide (H(2)S). Homocysteine, a sulfur-containing amino acid and H(2)S precursor, is formed from hepatic methionine metabolism. In the systemic circulation, hyperhomocystenemia impairs vasodilation and NO production from endothelial cells. Increased blood levels of homocysteine are common in patients with liver cirrhosis. In this study, we demonstrate that acute liver perfusion with homocysteine impairs NO formation and intrahepatic vascular relaxation induced by acetylcholine in methoxamine-precontracted normal livers (7.3% +/- 3.0% versus 26% +/- 2.7%; P < 0.0001). In rats with mild, diet-induced hyperhomocystenemia, the vasodilating activity of acetylcholine was markedly attenuated, and incremental increases in flow induced a greater percentage of increases in perfusion pressure than in control livers. Compared with normal rats, animals rendered cirrhotic by 12 weeks' administration of carbon tetrachloride exhibited a greater percentage of increments in perfusion pressure in response to shear stress (P < 0.05), and intrahepatic resistance to incremental increases in flow was further enhanced by homocysteine (P < 0.05). In normal hyperhomocysteinemic and cirrhotic rat livers, endothelial dysfunction caused by homocysteine was reversed by perfusion of the livers with sodium sulfide. Homocysteine reduced NO release from sinusoidal endothelial cells and also caused hepatic stellate cell contraction; this suggests a dual mechanism of action, with the latter effect being counteracted by H(2)S. CONCLUSION: Impaired vasodilation and hepatic stellate cell contraction caused by homocysteine contribute to the dynamic component of portal hypertension.     

Effect of portacaval shunt on drug disposition in patients with cirrhosis

To examine the consequences of liver blood flow variations on drug disposition in cirrhosis, we studied the effects of portacaval shunt on drug clearance in 35 cirrhotic patients. Lidocaine clearance and bioavailability, indocyanine green (ICG) clearance, aminopyrine breath test, and hepatic blood flow were measured before and 18 months after surgery. The patients were divided into two groups according to severity of disease: 14 patients (group 1) had slight liver dysfunction (ICG extraction ratio greater than 0.25) and 21 patients (group 2) had severe liver disease (ICG extraction ratio less than 0.25). After portacaval shunt the decrease in hepatic blood flow was similar for both groups (-65%). In group 1, ICG systemic clearance decreased from 9.10 +/- 0.68 to 4.40 +/- 0.34 ml/min . kg (p less than 0.05), whereas ICG intrinsic clearance remained unchanged; lidocaine systemic clearance decreased from 7.93 +/- 0.93 to 5.09 +/- 0.33 ml/min . kg (p less than 0.05), whereas lidocaine intrinsic clearance remained unchanged; bioavailability increased from 0.601 +/- 0.076 to 1, resulting in an abrupt reduction of oral clearance from 18.01 +/- 4.90 to 5.09 +/- 0.33 ml/min . kg (p less than 0.05). In group 2, ICG systemic clearance decreased slightly from 3.90 +/- 0.39 to 2.28 +/- 0.16 ml/min . kg (p less than 0.01) and ICG intrinsic clearance was not modified; lidocaine systemic and intrinsic clearance remained unchanged; and bioavailability increased from 0.779 +/- 0.229 to 1, resulting in a decrease of oral clearance from 7.68 +/- 1.65 to 4.23 +/- 0.37 ml/min X kg (p less than 0.05). The aminopyrine breath test was not affected by surgery in either group. We conclude that reduction of hepatic blood flow after portacaval shunt has only minimal effects on drug disposition in patients with severe liver disease, but results in a notable reduction in the clearance of high-extraction drugs in cirrhotics with mild liver disease.     

Propranolol reduces the response of serum bile acids to oral chenodeoxycholic acid, possibly as a reflex reaction to reduced portal blood flow in healthy and cirrhotic subjects

To evaluate if a drug that affects splanchnic and portal flow reduces intestinal bile acid absorption, we studied the effect of propranolol (40 mg oral dose) both on the response of total bile acids (SBA) to oral chenodeoxycholic acid (CDCA 250 mg) and on the estimated hepatic flow by indocyanine green kinetics in 10 healthy and 14 cirrhotic subjects. In 18 subjects who showed a reduction in resting heart rate of almost -5%, propranolol significantly reduced the SBA area under the curve after CDCA in both healthy (mumol/l/h m +/- SD from 181.7 x 144.9 to 56.5 +/- 36.4 p less than 0.02) and cirrhotic (from 1412.1 +/- 1044.8 to 1129.2 +/- 978.8 p less than 0.01) subjects. Variable but not significant modifications were observed in estimated hepatic flow. These results suggest that the propranolol-induced changes in SBA response to CDCA could be a reflex reaction to changes in splanchnic/portal flow.     

Effect of propranolol on portosystemic collateral circulation in patients with cirrhosis

Propranolol has been demonstrated to be effective in lowering portal pressure in cirrhotic patients. This effect is mediated by a reduction of splanchnic arterial inflow and a consequent decrease of portal vein and portocollateral blood flow. Although experimental studies suggest a direct effect of the drug on portocollateral circulation, little information exists about relative flow changes occurring in the portal vein and in collateral veins feeding esophageal varices. This study addressed the problem in 12 cirrhotic patients selected on the basis of feasibility of Doppler flowmetry in both the portal and left gastric veins. Caliber, flow velocity and flow volume in both vessels were measured by Doppler ultrasound before and at 60, 120 and 180 min after an oral dose of 40 mg propranolol, together with heart rate and mean arterial pressure. A significant decrease in heart rate (-17.6% +/- 1.1%, p less than 0.001) and mean arterial pressure (-10.6% +/- 0.9%, p less than 0.005) confirmed effective beta-blockade. Baseline flow velocity was significantly lower in the portal vein than in the left gastric vein (12.4 +/- 0.6 vs. 15.4 +/- 1.5 cm/sec, p less than 0.05). Maximal hemodynamic effect was reached at 120 min after administration of propranolol. The vessel caliber did not change significantly. Flow velocity fell from 12.4 +/- 0.6 to 10.4 +/- 0.7 cm/sec in the portal vein (p less than 0.05) and from 15.4 +/- 1.5 to 11.1 +/- 0.9 cm/sec in the left gastric vein (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of hypoxia on the disposition of propranolol and sodium taurocholate by the isolated perfused rat liver

Although the adverse effect of hypoxia on drug metabolism is well documented in subcellular systems, its effect on drug clearance by the intact liver has not been defined. This study was undertaken in the isolated perfused rat liver to examine the effects of acute hypoxia on the hepatic elimination of two highly cleared substances--propranolol and sodium taurocholate. Hypoxia was established by equilibrating the perfusate with 100% nitrogen rather than 100% oxygen. This led to a fall in portal vein pO2 from 300 to 30 mm Hg, and a 10-fold rise in hepatic venous lactate:pyruvate ratio, indicating a profound alteration in hepatic cellular redox state. In bolus dose studies, propranolol uptake was unimpaired by hypoxia, with a monoexponential decline in perfusate concentrations from 2,000 to 30 ng per ml, (t1/2 uptake = 2.5 min). After 20 min of hypoxia, perfusate propranolol concentrations rose from 30 to 80 ng per ml, indicating release of propranolol from liver back into the perfusate. Reoxygenation of perfusate restored hepatic extraction of propranolol to normal (t1/2 uptake = 2.37 +/- 0.19 min vs. 2.55 +/- 0.60 min p greater than 0.1) such that perfusate concentrations were undetectable by 30 min. In steady-state studies, perfusate propranolol concentrations rose from 1.55 +/- 0.50 to 4.08 +/- 1.47 micrograms per ml (p less than 0.005), after 1 hr of hypoxia indicating a change in propranolol clearance from 15 ml per min to less than 6 ml per min. Reoxygenation resulted in a fall in perfusate propranolol concentrations towards control values (2.78 +/- 1.13 vs. 1.80 +/- 0.41 micrograms per ml, p greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of angiotensin inhibition and renal denervation in two-kidney, one clip hypertensive rats

Neural and angiotensin-mediated influences that alter hemodynamic and excretory behavior of the nonclipped kidney of two-kidney, one clip hypertensive rats were assessed by sequential acute surgical denervation of the nonclipped kidney and intravenous infusion of converting enzyme inhibitor (SQ 20881), 3 mg/kg X hr. Normal and two-kidney, one clip hypertensive rats (0.2-mm silver clip on the right renal artery 3-4 weeks before study) were prepared to allow study of each kidney. Mean arterial blood pressure of two-kidney, one clip hypertensive rats fell significantly from control values of 149 +/- 6 to 135 +/- 6 mm Hg after denervation of the nonclipped kidney. Despite this decrease in arterial pressure, the nonclipped kidney exhibited significant increases in glomerular filtration rate (from 1.00 +/- 0.08 to 1.24 +/- 0.08 ml/min), sodium excretion (from 88 +/- 39 to 777 +/- 207 nEq/min), fractional sodium excretion (from 0.06 +/- 0.02 to 0.54 +/- 0.14%), and urine flow rate (from 3.7 +/- 0.5 to 8.2 +/- 1.1 microliter/min). A significant decrease in glomerular filtration rate (from 1.12 +/- 0.07 to 0.85 +/- 0.08 ml/min) with no change in excretory function was observed for the clipped kidney following denervation of the nonclipped kidney. Intravenous addition of converting enzyme inhibitor significantly increased renal blood flow (from 7.0 +/- 1.3 to 10.6 +/- 1.5 ml/min) and sodium excretion (from 777 +/- 207 to 1384 +/- 425 nEq/min) for the nonclipped kidney; blood pressure decreased from 135 +/- 6 to 123 +/- 4 mm Hg, and renal vascular resistance decreased significantly (from 22 +/- 3 to 13 +/- 2 mm Hg X min/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Des-1-Asp-angiotensin II. Possible intrarenal role in homeostasis in the dog.

The relative effects of des-a-Asp-angiotensin 3I and angiotensin II on renal function, including renin secretion, were investigated in normal and sodium-depleted dogs. Intrarenal arterial infusion of the heptapeptide fragment into normal dogs at a rate which was calculated to increase blood levels by only 7 ng/100 ml decreased renal blood flow from 254 +/- 9 ml/min to 220 +/- 12 and 219 +/- 12 ml/min (P less than 0.01 for both values) after 10 and 30 minutes of infusion, respectively; renin secretion decreased from 502 +/- 214 ng/min to 253 +/- 109 and 180 +/- 53 ng/min (P less than 0.05 for both values). Infusion of angiotensin II at the same rate decreased renal blood flow from 251 +/- 26 ml/min to 224 +/- 22 and 220 +/- 16 ml/min (P less than 0.01 and 0.025, respectively) and decreased renin secretion from 374 +/- 25 ng/min to 166 +/- 76 and 131 +/- 37 ng/min (P less than 0.025 for both values). Neither peptide significantly changed mean arterial blood pressure, creatinine clearance, or excreted sodium in these dogs. Infusion of des-1-Asp-angiotensin II into sodium-depleted dogs decreased renin secretion from 1094 +/- 211 ng/min to 768 +/- 132 and 499 +/- 31 ng/min (P less than 0.025 for both values) after 10 and 30 minutes of infusion. Angiotensin II infusion decreased renin secretion from 1102 +/- 134 to 495 +/- 235 and 502 +/- 129 ng/min in these dogs (P less than 0.05 and 0.025, respectively). Neither peptide significantly altered renal blood flow, arterial blood pressure, creatinine clearance, or excreted sodium in the sodium-depleted dogs. The data demonstrated that these two peptides have similar effects on the renin secretory mechanism and the vascular receptor at the level of the renal arterioles.     

Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis

Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of dopamine in conscious rats with secondary biliary cirrhosis

Dopamine may be used in cirrhotic patients with renal or circulatory failure, but this drug can also increase the degree of portal hypertension. Hence, the systemic and splanchnic hemodynamic effects of dopamine have been studied in portal hypertensive rats with secondary biliary cirrhosis. The dose-response curves showed that dopamine significantly increased portal pressure at the same dose (80 micrograms min-1 kg-1 body wt.) in normal and biliary cirrhotic rats. Arterial pressure only increased with higher doses of dopamine in rats with biliary cirrhosis (160 micrograms min-1 kg-1 body wt.) while in normal animals it increased (80 micrograms min-1 kg-1 body wt.). Dopamine (160 micrograms min-1 kg-1 body wt.) significantly increased mean arterial pressure in normal and biliary cirrhotic rats. It significantly increased cardiac output in biliary cirrhotic rats from 134 +/- 6 to 153 +/- 7 ml/min but not in normals. Accordingly, systemic vascular resistance increased significantly in normal rats but not in cirrhotics. Portal pressure increased significantly in normal rats from 8.0 +/- 0.3 to 12.1 +/- 0.6 mmHg and in rats with biliary cirrhosis from 15.9 +/- 1.0 to 19.0 +/- 1.3 mmHg. Portal tributary blood flow increased significantly in normal and biliary cirrhotic rats (14.1 +/- 1 to 20.9 +/- 2.3 ml/min and 18.0 +/- 0.9 to 25.5 +/- 1.8 ml/min, respectively). This study shows that an elevated dose of dopamine increases the hyperkinetic syndrome in rats with secondary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic verapamil administration lowers portal pressure and improves hepatic function in rats with liver cirrhosis

The effects of verapamil on portal pressure, microsomal liver function and extravascular albumin space were investigated in rats rendered cirrhotic by chronic exposure to phenobarbital and carbon tetrachloride. Verapamil significantly decreased splenic pulp pressure by 28% (P less than 0.05). In cirrhotic animals it improved liver function, measured by the aminopyrine and caffeine breath tests, by 36% (P less than 0.025) and 53% (P less than 0.05), respectively. The extravascular albumin space, an important determinant of drug clearance, was measured by a multiple indicator dilution technique. It was significantly larger in verapamil treated than in untreated cirrhotics (4.41 +/- 1.06 vs 2.73 +/- 0.79 ml/g; P less than 0.01). We conclude that verapamil has significant potential as a portal antihypertensive agent and its value in treating cirrhosis in man should be explored by controlled studies.