Portopulmonary hypertension (PPH) is a rare condition worldwide, although epidemiological data are unknown in Mexico. However, chronic liver diseases are very prevalent in Mexico. PPH is the 4th subtype in frequency in the group of pulmonary arterial hypertension. Its diagnosis is made within 2 scenarios: patients with suspected pulmonary hypertension and candidates for orthotopic liver transplantation (OLT). Both echocardiogram and a right cardiac catheterisation are crucial for diagnosis in both cases. PPH is a challenge for OLT, since it can significantly increase perioperative mortality. The use of specific therapy is the cornerstone of this disease, as a measure to improve the outcome of those who become candidates for OLT with moderate to severe PPH. It is important to recognise that PPH can be a contraindication to OLT. The role of lung-liver transplantation or heart-lung-liver transplantation as a measure to heal pulmonary vascular disease in patients with PPH is still uncertain.

Portal hypertension is associated with decreased vascular responsiveness to vasoconstrictors, which may contribute to the hyperdynamic circulation in cirrhosis. Animal models of cirrhosis and portal vein ligation have helped in our understanding of portal hypertension. The etiopathogenesis of non-cirrhotic portal fibrosis (NCPF), a common cause of portal hypertension, is still poorly understood. The aim of this study was to investigate the pathophysiology of NCPF in a rabbit model.

An indwelling cannula was inserted into the gastrosplenic vein of rabbits. Animals were randomly injected with saline (Group I, n = 13) or lipopolysaccharide (Group II, n = 13) from heat killed Escherichia coli at 0, 1, 2, 7, 14 and 28 days. Portal pressure was measured at 3 months and vasoresponsiveness studied in isolated aortic rings in intact and in endothelium-denuded tissues from both groups.

In all group II compared with group I animals, the splenic weight (0.89 +/- 0.16 vs 0.62 +/- 0.1 g, P < 0.05) and the portal pressure (14.99 +/- 0.56 vs 7.04 +/- 0.42 mmHg, P < 0.05) were higher at 3 months. The group II animals showed reduced responsiveness to phenylephrine showing maximal contraction of 1.25 +/- 0.08 at 10(-4) mol/L as compared to 2.85 +/- 0.33 g tension in Group I (P < 0.05). Endothelium denudation of aortic rings had no effect on reduced reactivity in Group II animals. Acetylcholine induced an increase in vasorelaxation at lower concentrations in preconstricted aortic rings in Group II compared to Group I animals, but this decreased in higher concentrations. Nifedipine produced comparable vasodilatation in preconstricted rings in both the groups of animals.

Repeated injection of lipopolysaccharide into the gastrosplenic vein leads to the development of portal hypertension. This non-cirrhotic model of portal hypertension is characterized by generalized arterial hyporeactivity to vasoconstrictors akin to other models of portal hypertension.

Increased resistance to portal blood flow is the primary factor in the pathophysiology of portal hypertension, and is mainly determined by the morphologic changes occurring in chronic liver diseases. This is aggravated by an increased hepatic vascular tone, which results from an insufficient hepatic bioavailability of nitric oxide (NO) and an increased production of circulating and local vasoconstrictors (angiotensin, endothelin, cysteinyl-leukotrienes, and thromboxane, among others). This dynamic and reversible component provides the rationale for the use of therapies aimed at decreasing portal pressure by reducing the vascular tone. Among them, systemic and liver-selective NO donors, statins, and gene therapy with adenovirus encoding NO synthases have been used to increase NO availability with promising results. Other attempts have been the blockade of the effect of vasoconstrictors, using anti alpha-adrenergic agents and renin-angiotensin system blockers. Some of these pharmacologic approaches have already been incorporated into clinical practice while others are still under investigation.

Many major complications of hepatic cirrhosis relate to the development of a characteristic hyperdynamic circulatory state in these patients, irrespective of the underlying disease aetiology. Vasodilatation of the systemic and splanchnic circulations leads to a reduced total systemic vascular resistance, increased cardiac output and intense activation of neurohumoral vasoconstrictor systems including the sympathetic nervous system, renin-angiotensin system and vasopressin. Vasoconstriction of the renal and hepatic circulations contributes to the development of renal failure and portal hypertension, respectively. Current treatments that focus on amelioration of these circulatory derangements offer much promise, however, they are often limited by side effects in these patients.

Octreotide is an effective portal hypotensive drug in the control of variceal bleeding. Tetrandrine is a type of calcium channel blocker recently reported to reduce portal hypertension. The present study was undertaken to investigate the haemodynamic effects of octreotide and tetrandrine, alone and in combination, in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation. Portal hypertensive rats were allocated into one of the four groups: vehicle group (saline, 0.5 mL/day), octreotide group (100 microg/kg per 12 h), tetrandrine group (20 mg/kg per 12 h), and octreotide (100 microg/kg per 12 h) plus tetrandrine (20mg/kg per 12 h) group. Tetrandrine or saline was administered by gavage, and octreotide by subcutaneous injection. The drug was given for 8 consecutive days, starting 1 day before ligation and continuing onwards. Haemodynamic parameters were measured thereafter, using the radioactive microsphere method. The portal venous pressure and portal tributary blood flow were significantly reduced, while portal territory and renal vascular resistances were significantly enhanced, by octreotide, tetrandrine, or octreotide plus tetrandrine in portal hypertensive rats, compared with the vehicle group. Our results showed that long-term administration of octreotide, tetrandrine, or octreotide plus tetrandrine led to portal hypotensive effects in portal hypertensive rats, but octreotide alone exerted better anti-hyperdynamic effects compared with tetrandrine alone. A combination of octreotide and tetrandrine offered no major beneficial anti-hyperdynamic effects compared with octreotide alone.

Tetrandrine is a calcium channel antagonist with reported antihypertensive effect. However, the potential role of tetrandrine as a therapeutic agent in portal hypertension has yet to be explored. The present study aimed to investigate the haemodynamic effects of chronic tetrandrine treatment on portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation in Sprague-Dawley rats. Animals were allocated into one of two groups: a tetrandrine group and a vehicle group. Tetrandrine (20 mg/kg) or vehicle was administered by gavage every 12 h for 8 consecutive days, starting 1 day before ligation and continuing thereafter. After 8 days of tetrandrine treatment, systemic haemodynamics, organ blood flow and the degree of portal-systemic shunting were measured after an overnight fast. The portal venous pressure and protal tributary blood flow were significantly decreased, while portal territory as well as hepto-collateral vascular resistance significantly increased in the tetrandrine group compared with the vehicle group. The cardiac index was increased, while systemic vascular resistance was decreased, the the tetrandrine group. Mean arterial pressure, heart rate, portal-systemic shunting and bodyweight were similar between the two groups. Renal blood flow was decreased in the tetrandrine group. In conclusion, long-term treatment of tetrandrine reduced portal venous pressure and alleviated splanchnic hyperaemina in portal hypertensive rats without affecting the portal-systemic shunting.

The introduction of pharmacological therapy has been one of the major advances in the treatment of the complications of portal hypertension. Many drugs have been shown to reduce portal hypertension in patients with cirrhosis. However, the most widely used drugs and the only ones for which there is sufficient evidence, are the beta-blockers. These drugs have been, up to now, the only accepted prophylactic therapy for oesophageal variceal bleeding and are also an alternative treatment to sclerotherapy or surgery to prevent variceal rebleeding. A reduction in portal pressure gradient by beta-blockers below 12 mmHg or by more than 20% of baseline values is associated with almost a total protection from oesophageal bleeding. Such a marked response in portal pressure is only achieved in some patients receiving propranolol. New pharmacological approaches with a greater portal pressure reducing effect may improve the beneficial effect of drugs in preventing variceal bleeding. The more promising approach is the combined administration of beta-blockers and isosorbide-5-mononitrate, which has been shown to potentiate the reduction in portal pressure and to be highly effective in initial randomized clinical trials.

In cirrhosis, the activation of nitric oxide and prostacyclin contributes to vasodilation, and ATP-sensitive K+ (KATP) channel activation or L-type calcium (Ca2+) channel inhibition may also play a role in this process. At the same time in cirrhosis, certain endogenous mechanisms may be stimulated which limit the influence of vasodilator mechanisms on vascular tone, thus altering vascular responses to exogenous substances such as nitric oxide donors, exogenous prostacyclin, KATP channel openers or L-type Ca2+ channel blockers. The aim of the present study was to examine the arterial depressor to these exogenous substances in normal rats and in rats with secondary biliary cirrhosis.

Arterial depressor dose-response curves to nitroprusside (a nitric oxide donor, 5-60 micrograms.kg-1.min-1), prostacyclin (0.5-5 micrograms.kg-1) and aprikalim (a KATP channel opener, 10-200 micrograms.kg-1) were obtained in both groups. The effects of different L-type Ca2+ channel blockers, i.e. nicardipine (a dihydropyridine, 0.02-0.5 mg.kg-1), diltiazem (a benzothiazepine, 0.5-5 mg.kg-1) and verapamil (a phenylalkylamine, 0.02-0.2 mg.kg-1. min-1), were also studied.

Cirrhosis produced hyporeactivity to the arterial depressor effect of all doses of nitroprusside, the lowest dose of prostacyclin and the highest doses of aprikalim or diltiazem. Cirrhosis did not significantly change depressor responses to nicardipine or verapamil.

Rats with cirrhosis are hyporeactive to exogenous nitric oxide, prostacyclin, KATP channel opener and benzothiazepine (an L-type Ca2+ channel blocker). Therefore, cirrhosis-induced mechanisms seem to limit the decrease in vascular tone by most vasodilators. However, these mechanisms appear to be more marked in nitric oxide-mediated vasodilation than in other vasorelaxation mechanisms.

To evaluate the effects of nicardipine on hepatic blood flow in patients with recent liver transplants. Secondly, to evaluate the liver extraction of nicardipine in order to determine the influence of liver transplantation on its disposition.

Prospective self-controlled clinical study.

University hospital intensive care unit.

Eight patients in the early postoperative period of orthotopic liver transplantation.

Patients were given 5 mg of i.v. nicardipine. Systemic and splanchnic haemodynamic and metabolic parameters were measured before nicardipine administration (T0) and at 5 min (T1), 30 min (T2), and 120 min (T3) after administration. A catheter was inserted into a hepatic vein to determine the total hepatic blood flow (HBF) and the hepatic extraction coefficient of nicardipine. Nicardipine caused no significant changes in HBF, oxygen delivery, oxygen uptake, hepatic venous oxygen saturation, or the hepatic venous partial pressure of oxygen. Likewise, neither blood lactate concentrations nor arterial and hepatic venous lactate-pyruvate ratios were modified by nicardipine. The hepatic extraction coefficient of nicardipine was approximately 0.70 in the first 3 min after complete infusion, then decreased and remained stable at approximately 0.50, showing a non-linear first-pass metabolism pattern.

Nicardipine administration after liver transplantation appears to have no deleterious effects on HBF. Nicardipine can be classified as a drug of intermediate hepatic extraction coefficient, whose elimination partly depends on hepatic enzyme activity.

We investigated the effects of nifedipine on splanchnic haemodynamics in 13 patients with cirrhosis and portal hypertension, and in 10 control subjects using hepatic venous catheterization and pulsed Doppler ultrasound. There were no significant changes in systemic or splanchnic haemodynamics in control patients. In contrast, systemic vasodilatation, evidenced by significant decreases in mean arterial pressure and systemic vascular resistance, was observed in patients 20 min after sublingual application of 10 mg nifedipine. Moreover, hepatic venous pressure gradient and portal vein blood flow significantly increased after nifedipine administration. There was a significant correlation between the percentage increases in portal vein blood flow and in hepatic venous pressure gradient. However, no correlation was found between the percentage change in cardiac output and that in portal vein blood flow. Thus the increase in portal vein blood flow appears to be related to splanchnic arterial vasodilatation by nifedipine. Consequently, nifedipine has deleterious effects on portal haemodynamics in patients with cirrhosis. As nifedipine may potentially increase the risk of variceal haemorrhage in patients with less advanced varices, this drug should be used with caution in patients with chronic liver disease.

Following the administration of 10 mg of nifedipine to 11 patients with well-compensated alcoholic cirrhosis, there was a significant fall in mean arterial blood pressure, accompanied by an increase in heart rate, presumably due to a significant decrease in systemic vascular resistance. Despite the fall in renal perfusion pressure, there was an increase in the effective renal plasma flow and a significant decrease in renal vascular resistance. The glomerular filtration rate was preserved, suggesting that the decrease in renal vascular resistance was due to a preferential decrease in afferent arteriolar tone. There were no significant changes in the filtered sodium load or the tubular reabsorption of sodium and urinary sodium, and urinary volume did not alter significantly. Although the current study indicates that nifedipine can improve the renal circulation in patients with cirrhosis, the significant effects on the systemic circulation suggest that its potential to reverse the intense renal vasoconstriction that can complicate the clinical course of advanced liver disease is unlikely to be of value in the treatment of the hepatorenal syndrome.

The present study investigated the hemodynamic effects of nicardipine, a new calcium channel blocker, and placebo in 14 patients with cirrhosis. Sixty minutes after nicardipine administration (20 mg orally; n = 8), there was a significant increase in hepatic blood flow (25 +/- 21%; p < 0.05) and azygos blood flow (33 +/- 40%; p < 0.05) but no significant change in the hepatic venous pressure gradient. As a result of the increase in hepatic blood flow and the lack of change in the hepatic venous pressure gradient, nicardipine significantly reduced hepatic sinusoidal resistance (-14 +/- 15%; p < 0.05). Enhanced liver perfusion was associated with a significant increase in the hepatic clearance of indocyanine green (from 241 +/- 81 to 265 +/- 92 ml/min, p < 0.05). A mild, well-tolerated decrease in mean arterial pressure (-10 +/- 6%, p < 0.05), without significant changes in cardiac output, systemic vascular resistance and heart rate, was also observed. Placebo administration (n = 6) did not cause significant changes in systemic or hepatic hemodynamics. The results of the present study show that nicardipine, unlike other calcium channel blockers, effectively increases hepatic blood flow and the hepatic clearance of indocyanine green in patients with cirrhosis. The acute beneficial effects of nicardipine should be confirmed in chronic studies.

In the past 10 years, it has been clearly shown that vasoactive substances reduce portal pressure in patients or animals with portal hypertension. Some of these substances act by inducing splanchnic vasoconstriction, while others reduce hepatic and porto-systemic collateral vascular resistance and, thus, induce a portal hypotensive effect. Still others induce arterial hypotension, which causes a vasoconstrictive effect in the splanchnic territory. Since these drugs act on different vascular receptors, their combination should have a more marked effect on portal hypertension. Up to now, only nonselective beta-blockers have been used in the prevention of first gastrointestinal bleeding in patients with portal hypertension and esophageal varices and in the prevention of recurrent gastrointestinal bleeding. These trials have shown that propranolol or nadolol significantly reduce either a first episode of bleeding or recurrent bleeding. This pharmacological treatment also improves the survival rate in these patients. All of these studies have helped us to understand, in part, why gastrointestinal hemorrhage occurs in certain patients. Additional studies of beta-blockers or other substances are, nevertheless, necessary to select patients who will respond to this type of treatment. Finally, it is possible that the pharmacological treatment of portal hypertension may also be used before esophageal varices occur.

Slow calcium channel antagonists are widely used among transplanted patients suffering from hypertension, although some of them tend to reduce hepatic blood flow. The aim of our study was to determine the pharmacological properties of nicardipine in transplanted patients with hypertension. Ten hours after liver transplantation, six patients (three men, three women) received 5 mg of intravenous nicardipine to prevent high blood pressure during intensive care. Prior to the administration and during the study (at the completion of the infusion, 3, 5, 10, 15, 20, 30, 45, and 60 min after infusion), the systemic and splanchnic parameters were measured (Swan Ganz catheter). Blood samples were drawn simultaneously from radial artery and free hepatic veins, in order to obtain the hepatic extraction of nicardipine. The hepatic extraction ratio was around 70% for the first 3 min, then decreased and remained stable thereafter, around 45%, showing a non linear first-pass metabolism pattern. Plasma hepatic clearance of nicardipine (699-850 ml/min) was close to total plasma clearance throughout the study (978 +/- 222 ml/min, from 71 to 87%) and half of the estimated hepatic plasma flow values at the same times (1467-1770 ml/min, from 44 to 51%). No statistically significant changes were observed in cardiac output and hepatic blood flow during the study, although there was a decrease in mean arterial blood pressure from 87 +/- 6 mmHg baseline level to 76 +/- 3 mmHg, 60 min after administration. Nicardipine chlorhydrate seems to be appropriate in post operative liver transplant patients when blood pressure must be decreased. Nicardipine safely lowers peripheral resistance, and does not induce changes in hepatic blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

The pathogenesis of portal hypertension remains poorly understood. Similarly, pharmacological manipulation for the prevention and treatment of variceal haemorrhage has not fulfilled the promise of the 1980s. This article reviews current concepts in the pathophysiology of portal hypertension and considers pharmacotherapy for the treatment of variceal bleeding.

The effects of single-dose (10 mg) and short-term (10 mg tid) nifedipine treatment on apparent hepatic blood flow, as assessed by indocyanine green (ICG) clearance, were studied in ten healthy male subjects. ICG was measured by both spectrophotometric and high performance liquid chromatography (HPLC) assay methods. Blood clearance of ICG and apparent hepatic blood flow were increased by 30 and 50%, respectively, after single-dose nifedipine, whereas after 4 days' treatment these values were 12 and 30%. The spectrophotometric assay significantly overestimated ICG plasma concentrations from 7 minutes onwards. Although the spectrophotometric and HPLC assay showed marked differences in calculated half-lives and volume of distribution of ICG, the ICG clearance values were similar for the two assay methods.

Nitroglycerin is reportedly an effective treatment for portal hypertension. However, the effects of graded doses have not been examined. We administered nitroglycerin intravenously to 10 patients with alcoholic cirrhosis, beginning at 10 micrograms/min and doubling the dose every 10 min thereafter until mean arterial pressure fell 10-15 mmHg. We compared the response to that of 10 patients receiving a control infusion. The median infusion rate of nitroglycerin was 40 micrograms/min (range 10-160 micrograms/min). Nitroglycerin significantly reduced cardiac output as well as pulmonary artery, pulmonary capillary and mean arterial pressure. The overall effects of nitroglycerin on the hepatic venous pressure gradient and azygous (gastroesophageal collateral) blood flow were heterogeneous. However, the hepatic venous pressure gradient significantly increased in nitroglycerin-treated patients with high pulmonary capillary pressures (greater than or equal to 12 mmHg) compared to control patients with similar cardiac filling pressures at both median and maximum rates of infusion. Nitroglycerin is therefore not a uniformly effective treatment for portal hypertension. Cardiac filling pressure may be a determinant of the splanchnic hemodynamic response to nitroglycerin.

Drugs reported to reduce portal pressure through different mechanisms were combined in the hope of either additive portal hypotensive effects in "responders," or inducing a portal hypotensive effect in "nonresponders" to the initial drug. Seven patients with alcoholic cirrhosis received verapamil, 10 mg i.v., and, 60 min later, ketanserin, 5 mg i.v. Verapamil decreased heart rate and increased free hepatic venous pressure but had no effect on hepatic venous pressure gradient or azygos blood flow. When combined with verapamil, ketanserin significantly diminished wedged hepatic venous pressure and hepatic venous pressure gradient. Ten other patients with alcoholic cirrhosis received propranolol, 15 mg i.v., and 45 min later, ketanserin, 5 mg i.v. In all patients, heart rate, cardiac index and azygos blood flow significantly decreased after propranolol. After propranolol alone, however, wedged hepatic venous pressure decreased in only five patients, responders. In five other patients, defined as nonresponders, propranolol did not decrease this pressure. The addition of ketanserin to propranolol induced further significant reduction in wedged hepatic venous pressure, hepatic venous pressure gradient and azygos blood flow. Among the five nonresponders, three had a reduced wedged hepatic venous pressure after ketanserin was combined. We conclude that verapamil does not reduce portal pressure or collateral blood flow in patients with alcoholic cirrhosis. The splanchnic hemodynamic effects of propranolol and ketanserin appear to be independent and additive, without significant systemic alteration.

To delineate the circulatory effects of glucagon in cirrhosis, we infused two moderately supraphysiological doses of this hormone into 19 patients with cirrhosis and determined hemodynamic responses. Patients were divided into a group with good liver function (Pugh Class A, n = 8) and poorer function (Pugh Class B and C, n = 11). All patients received glucagon at 10 ng per kg per min for 20 min, then 20 ng per kg per min for a further 20 min. These doses raised serum glucagon levels to a similar degree in both groups of patients. Serum glucose levels also rose in both groups but to a lesser degree in Class BC patients. Serum noradrenaline and adrenaline remained unchanged in both groups. Heart rate, mean arterial pressure, cardiac index, systemic vascular resistance, hepatic venous pressure gradient and hepatic blood flow were measured basally and during the second glucagon infusion. None of these measurements significantly changed in either group of patients. Azygos and renal venous blood flow were measured basally and during the first and second infusions. Azygos flow increased significantly only in Group A patients: basal, 0.32 +/- 0.03 liter per min; first infusion, 0.40 +/- 0.06 liter per min; second infusion, 0.49 +/- 0.07 liter per min. Corresponding values in Group BC patients were: 0.54 +/- 0.08, 0.54 +/- 0.08 and 0.52 +/- 0.08 liter per min. Renal blood flow did not change significantly. One patient with a portacaval shunt increased superior mesenteric venous flow from 0.78 liter per min to 0.95 liter per min with glucagon.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics and effects on blood pressure and heart rate of nisoldipine were studied in 8 patients with cirrhosis and in 8 age-matched healthy controls. On separate occasions each subject received nisoldipine by i.v. infusion (0.37 mg in 40 min) and as a tablet (5 mg for patients and 20 mg for control subjects). After i.v. nisoldipine, the elimination half-life was 9.7 h in control subjects and 16.6 h in the cirrhotics. The volume of distribution was 4.1 l/kg and 6.4 l/kg and the total systemic clearance was 847 ml/min and 494 ml/min, respectively. On oral nisoldipine, systemic availability was fourfold higher in patients with cirrhosis: 14.7% versus 3.7%. After i.v. administration of nisoldipine there was a brief decrease in systolic and diastolic blood pressure in both groups, whereas the heart rate increased. After 4 h a second effect peak appeared in the control subjects. After oral nisoldipine similar effect-time profiles were found, but effects lasted longer than after i.v. administration. Comparison of the maximal total plasma concentration of nisoldipine and the maximal effect in the two groups revealed that sensitivity to nisoldipine was not different in patients with cirrhosis. A reduction in the dose of nisoldipine is recommended when cirrhotics require oral nisoldipine in therapeutic practice.