adrenomedullin and Hypertension--Portal

The hyperdynamic circulatory syndrome observed in chronic liver diseases is a great example of research that originated from clinical observations and progressed in the last 50 years from the patient to the experimental laboratory. Our knowledge has evolved from the patient to the molecule, using experimental models that serve as a source for understanding the complex pathophysiological mechanisms that govern this complex syndrome. We now know that progressive vasodilatation is central to the detrimental effects observed in multiple organs. Although nitric oxide has been shown to be the primary vasodilator molecule in these effects, other molecules also participate in the complex mechanisms of vasodilatation. This review summarizes three major areas: first, clinical observation in patients; second, experimental models used to study the hyperdynamic circulatory syndrome; and third, the vasodilator molecules that play roles in vascular abnormalities observed in portal hypertension.

Topics: Adrenomedullin; Animals; Biological Factors; Blood Pressure; Cannabinoid Receptor Modulators; Carbon Monoxide; Chronic Disease; Disease Models, Animal; Endothelium, Vascular; Humans; Hydrogen Sulfide; Hypertension, Portal; Liver; Liver Diseases; Nitric Oxide; Peptides; Splanchnic Circulation; Tumor Necrosis Factor-alpha; Vasodilation

Nitric oxide synthase (NOS) 3-deficient (NOS-3 KO) mice have an increased systemic arterial pressure but develop portal hypertension to the same extent as wildtype (WT) mice. We hypothesized that other vasodilators in the portal circulation compensate for the lack in NOS-3 activity. We used quantitative PCR as a screening method to identify mediators that possibly compensate for NOS-3 in NOS-3 KO mice.. Mean arterial pressure (MAP) and portal venous pressure (PVP) were measured in the anaesthetized animal. mRNA levels in whole liver tissue were determined by quantitative RT-PCR.. NOS-3 KO mice had a significantly higher mean arterial pressure than WT mice, but portal venous pressure did not differ. Bile duct ligation (BDL) induced a drop in MAP and a rise in PVP in both groups. Bile duct ligation induced a significant increase in mRNA levels of the cannabinoid receptor (CB)-1, adrenomedullin and NOS-2 in the liver of NOS-3 KO and WT mice. Nitric oxide synthase-1 and NOS-3 mRNA levels were elevated in BDL WT mice compared with sham-operated WT mice. Higher mRNA levels of CB-1, NOS-1 and the adrenomedullin receptor were found in sham-operated NOS-3 KO mice compared with sham-operated WT mice.. We used quantitative PCR as a screening method to identify vasodilative mediators that might be involved in the compensation for the lack of NOS-3 activity in NOS-3 KO mice. Elevated mRNA levels in sham-operated NOS-3 KO mice compared with sham-operated WT mice were demonstrated for CB-1, NOS-1 and the adrenomedullin receptor.

Topics: Adrenomedullin; Animals; Bile Ducts; Blood Pressure; Hypertension, Portal; Ligation; Liver; Mice; Mice, Knockout; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Peptides; Receptor, Cannabinoid, CB1; Receptors, Adrenomedullin; Receptors, Peptide; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vasodilator Agents

Adrenomedullin (ADM) is a potent vasodilator peptide. ADM and nitric oxide (NO) are produced in vascular endothelial cells. Increased ADM level has been linked to hyperdynamic circulation and arterial vasodilatation in cirrhotic portal hypertension (CPH). The role of ADM in non-cirrhotic portal hypertension (NCPH) is unknown. plasma ADM levels were studied in patients with NCPH, compensated and decompensated cirrhosis in order to determine its contribution to portal hypertension (PH) in these groups.. There were 4 groups of subjects. Group 1 consisted of 27 patients (F/M: 12/15) with NCPH due to portal and/or splenic vein thrombosis (mean age: 41+/-12 years), group 2 consisted of 14 patients (F/M: 6/8) with compensated (Child-Pugh A) cirrhosis (mean age: 46+/-4), group 3 consisted of 16 patients (F/M: 6/10) with decompensated (Child-Pugh C) cirrhosis (mean age: 47+/-12). Fourteen healthy subjects (F/M: 6/8) (mean age: 44+/-8) were used as controls in Group 4. ADM level was measured by ELISA. NO was determined as nitrite/nitrate level by chemoluminescence.. ADM level in Group 1 (236+/-61.4 pg/mL) was significantly higher than that in group 2 (108.4+/-28.3 pg/mL) and group 4 (84.1+/-31.5 pg/mL) (both P<0.0001) but was lower than that in Group 3 (324+/-93.7 pg/mL) (P=0.002). NO level in group 1 (27+/-1.4 micromol/L) was significantly higher than that in group 2 (19.8+/-2.8 micromol/L) and group 4 (16.9+/-1.6 micromol/L) but was lower than that in Group 3 (39+/-3.6 micromol/L) (for all three P<0.0001). A strong correlation was observed between ADM and NO levels (r=0.827, P<0.0001).. Adrenomedullin and NO levels were high in both non-cirrhotic and cirrhotic portal hypertension and were closely correlated, Adrenomedullin and NO levels increased proportionally with the severity of cirrhosis, and were significantly higher than those in patients with NCPH. Portal hypertension plays an important role in the increase of ADM and NO. Parenchymal damage in cirrhosis may contribute to the increase in these parameters.

Topics: Adrenomedullin; Adult; Female; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Peptides; Vasodilation

To determine the expression and localization of adrenomedullin (AM) and its receptor (AM-R) in portal hypertensive (PHT) gastric mucosa after intragastric ethanol administration.. The repair of gastric mucosal injury requires reestablishment of the microvascular network. The authors previously demonstrated impaired angiogenesis of PHT gastric mucosa after ethanol-induced injury. Because AM, a potent vasodilatory peptide, is also a novel growth and angiogenic factor, the authors hypothesized that AM is involved in the impaired repair of PHT gastric mucosa and its microvasculature after damage.. Either PHT or sham-operated rats received intragastrically 100% ethanol, and the stomachs were excised at 1, 6, and 24 hours later. Expression and localization of AM and AM-R mRNA were examined by competitive reverse transcription-polymerase chain reaction and in situ hybridization. AM protein expression was examined by Western blot analysis.. One hour after ethanol administration, AM mRNA expression in PHT gastric mucosa was significantly decreased by 81%, especially in the superficial mucosa, compared with the gastric mucosa in sham-operated rats. The significant decrease lasted for 24 hours. AM protein expression was significantly decreased by 43% compared with the sham-operated gastric mucosa. Although AM-R mRNA expression in both groups was significantly increased 1 hour after ethanol administration and lasted for 24 hours compared with baseline, there were no differences between the two groups.. The expression of AM in PHT gastric mucosa after ethanol-induced injury is significantly decreased compared with controls. This finding could explain one mechanism for the impaired angiogenesis after injury of PHT gastric mucosa.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Ethanol; Gastric Mucosa; Hypertension, Portal; Peptides; Rats; Rats, Sprague-Dawley; RNA, Messenger

We examined the expression and localization of adrenomedullin (AM) mRNA, AM receptor (AM-R) mRNA and AM protein in normal and portal hypertensive (PHT) rat gastric mucosa. Methods included competitive reverse transcription-polymerase chain reaction (RT/PCR), in situ hybridization and Western blot analysis. Both AM mRNA and AM-R mRNA were strongly expressed not only in normal rat gastric mucosa but also PHT rat gastric mucosa. While total AM and AM-R mRNA abundance was similar in both normal and PHT stomachs, in the superficial mucosa-where major defense mechanisms are located-their expression was significantly reduced in PHT rats by 33% (AM mRNA) and 25% (AM-R mRNA) (both p .0.05). AM protein was also expressed similarly in both normal and PHT gastric mucosa. We conclude that AM and its receptor play a role in regulation of gastric mucosal microcirculation and thus gastric mucosal defense.

Topics: Adrenomedullin; Animals; Blotting, Western; Gastric Mucosa; Hypertension, Portal; In Situ Hybridization; Peptides; Rats; Rats, Sprague-Dawley; RNA, Messenger