Stimulation of nitric oxide-sensitive soluble guanylate cyclase in monocrotaline-induced pulmonary hypertensive rats.

Abstract

AIMS:

In this study, we examined whether a disruption in the balance between nitric oxide (NO)-sensitive and -insensitive soluble guanylate cyclase (sGC) is observed in pulmonary hypertension (PH) and whether treatment with NO-enhancing drugs can halt disease progression.

MAIN METHODS:

Rats were injected subcutaneously with saline or 60 mg/kg monocrotaline (MCT). At 14 days after injection, the vascular reactivity of isolated extralobar pulmonary arteries was assessed by organ chamber technique. In a separate experiment, isosorbide mononitrate (0.3 or 1 g/L) or sodium nitrite (30 or 300 mg/L) was administered in drinking water for the last 14 days (from day 15 to day 28), and their therapeutic potential was evaluated.

KEY FINDINGS:

The NO-sensitive sGC stimulant BAY 41-2272 and the NO-insensitive sGC stimulant BAY 60-2770 both relaxed the pulmonary arteries, which was comparable between saline- and MCT-injected rats. Treatment with isosorbide mononitrate suppressed the MCT-induced right ventricular systolic pressure (RVSP) elevation and pulmonary arterial medial thickening but not right ventricular hypertrophy. However, the beneficial effects on RVSP and pulmonary vascular remodeling were not observed when a high dose was administered. The same results were obtained following the sodium nitrite treatment. Interestingly, NO-enhancing drugs did not increase plasma nitrite plus nitrate levels at a dose that provided the greatest therapeutic advantage.

SIGNIFICANCE:

These findings suggest that the balance between NO-sensitive and -insensitive sGC is not disrupted in the early stage of MCT-induced PH. Furthermore, supplementation with an adequate amount of NO may be a useful therapy to prevent the progression of PH.

• Authors: Masashi Tawa, Takahide Furukawa, Hiroko Tongu, Mai Sugihara, Satoko Taguwa, Misaki Yamanaka, Yoko Yano, Hiroaki Matsumori, Rie Kitada, Tatsuya Sawano, Ryosuke Tanaka, Mamoru Ohkita, Yasuo Matsumura
• Journal: Life sciences (Life Sci) Vol. 203 Pg. 203-209 (Jun 15 2018) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 29705351 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Bronchodilator Agents
• Nitric Oxide
• Monocrotaline
• Soluble Guanylyl Cyclase

Topics

• Animals
• Blood Pressure (drug effects)
• Bronchodilator Agents (pharmacology)
• Hypertension, Pulmonary (chemically induced, drug therapy, enzymology, pathology)
• Male
• Monocrotaline (toxicity)
• Nitric Oxide (pharmacology)
• Pulmonary Artery (drug effects, enzymology)
• Rats
• Rats, Sprague-Dawley
• Soluble Guanylyl Cyclase (metabolism)