CPU 86017, p-chlorobenzyltetrahydroberberine chloride, attenuates monocrotaline-induced pulmonary hypertension by suppressing endothelin pathway.

Abstract

AIM:

To elucidate the involvement of the endothelin (ET) pathway in the pathogenesis of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and the therapeutic effect of CPU 86017 (p-chlorobenzyltetrahydroberberine chloride) in rats.

METHODS:

Rats were injected with a single dose (60 mg/kg, sc) of MCT and given CPU 86017 (20, 40, and 80 mg/kg-1/d-1, po) or saline for 28 d. The hemodynamics, mRNA expression, and vascular activity were evaluated.

RESULTS:

Right ventricular systolic pressure and central venous pressures were elevated markedly in the PAH model and decreased by CPU 86017. In the PAH group, the endothelin-1 (ET-1) in serum and lungs was dramatically increased by 54% (79.9 pg/mL, P<0.01) and 93% (166.2 pg/mL, P<0.01), and mRNA levels of preproET-1, eNOS, and iNOS also increased dramatically compared with control. Compared with PAH group, CPU 86017 decreased the content of ET-1 to the normal level in lung tissue, but was less effective in serum. The level of NO was significantly increased in CPU 86017 at 80 and 40 mg/kg-1/d-1 groups in tissue, whereas the difference in serum was not significant. A significant reduction in MDA production and an increase in the SOD activity in the serum and lungs was observed in all three CPU 86017 groups. CPU 86017 80 mg/kg-1/d-1 po increased the activity of cNOS by 33% (P<0.01). The up-regulation of eNOS and iNOS mRNA levels induced by MCT was significantly reversed in 3 CPU 86017 groups, and preproET-1 mRNA abundance was also reduced notably in CPU 86017 80 mg/kg-1/d-1 group vs the PAH group. The KCl-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but recovered partially after CPU 86017 intervention. The constrictions in the presence of Ca(2+) was not improved by CPU 86017. The phenylephrine-induced vasoconstrictions in the calcium-free medium decreased markedly in PAH group but not recovered after CPU 86017 intervention. The constrictions in the presence of Ca(2+) completely returned to the normal after CPU 86017 intervention.

CONCLUSION:

CPU 86017 suppressed MCT-induced PAH mainly through an indirect suppression of the ET-1 system, which was involved in the pathogenesis of the disease.

• Authors: Tian-tai Zhang, Bing Cui, De-zai Dai, Wei Su
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 26 Issue 11 Pg. 1309-16 (Nov 2005) ISSN: 1671-4083 [Print] United States
• PMID: 16225752 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-chlorobenzyltetrahydroberberine
• Calcium Channel Blockers
• Endothelin-1
• RNA, Messenger
• Berberine
• Nitric Oxide
• Monocrotaline
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III

Topics

• Animals
• Berberine (analogs & derivatives, pharmacology)
• Blood Pressure (drug effects)
• Calcium Channel Blockers (pharmacology)
• Endothelin-1 (biosynthesis, blood, genetics)
• Hypertension, Pulmonary (chemically induced, metabolism, pathology)
• Lung (metabolism)
• Male
• Monocrotaline
• Nitric Oxide (blood, metabolism)
• Nitric Oxide Synthase Type II (biosynthesis, genetics)
• Nitric Oxide Synthase Type III (biosynthesis, genetics)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Vasoconstriction (drug effects)