Soluble guanylate cyclase chronic stimulation effects on cardiovascular reactivity in cafeteria diet-induced rat model of metabolic syndrome.

Abstract

Metabolic syndrome is linked to an increased risk of cardiovascular complications by a mechanism involving mainly decreased nitric oxide (NO) bioavailability and impaired NO-soluble guanylate cyclase (sGC)- cyclic guanosine monophosphate (cGMP) signalling (NO-sGC-cGMP). To further develop this scientific point, this study aimed to investigate the effects of long-term treatment with BAY 41-2272 (a sGC stimulator) on cardiovascular reactivity of spontaneously hypertensive rats (SHR) as a model of metabolic syndrome. SHR were randomly divided into 3 groups: control group, cafeteria diet (CD)-fed group and CD-fed group treated daily with BAY 41-2272 (5 mg/kg) by gastric gavage for 12 weeks. In vivo measurements of body weight, abdominal circumference, blood pressure and glucose tolerance test were performed. At the end of the feeding period, ex vivo cumulative concentration-response curves were performed on isolated perfused heart (isoproterenol (0.1 nM - 1 μM)) and thoracic aorta (phenylephrine (1 nM-10 μM), acetylcholine (1 nM-10 μM), and sodium nitroprusside (SNP) (0.1 nM-0.1 μM)). We showed that chronic CD feeding induced abdominal obesity, hypertriglyceridemia, glucose intolerance and exacerbated arterial hypertension in SHR. Compared to control group, CD-fed group showed a decrease in β-adrenoceptor-induced cardiac inotropy, in coronary perfusion pressure and in aortic contraction to phenylephrine. While relaxing effects of acetylcholine and SNP were unchanged. BAY 41-2272 long-term treatment markedly prevented arterial hypertension development and glucose intolerance, enhanced the α1-adrenoceptor-induced vasoconstriction, and restored cardiac inotropy and coronary vasodilation. These findings suggest that BAY 41-2272 may be a potential novel drug for preventing metabolic and cardiovascular complications of metabolic syndrome.

• Authors: Yosra Doghri, Laurence Dubreil, Valérie Lalanne, Ophélie Hélissen, Romain Fleurisson, Chantal Thorin, Jean-Claude Desfontis, M Yassine Mallem
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 899 Pg. 173978 (May 15 2021) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 33691164 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
• Enzyme Activators
• Pyrazoles
• Pyridines
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Soluble Guanylyl Cyclase
• Cyclic GMP

Topics

• Animals
• Aorta, Thoracic (drug effects, enzymology, physiopathology)
• Cardiovascular Diseases (enzymology, etiology, physiopathology, prevention & control)
• Coronary Circulation (drug effects)
• Cyclic GMP (metabolism)
• Disease Models, Animal
• Enzyme Activation
• Enzyme Activators (pharmacology)
• Glucose Intolerance (enzymology, etiology, physiopathology, prevention & control)
• Hypertension (enzymology, etiology, physiopathology, prevention & control)
• Hypertriglyceridemia (enzymology, etiology, physiopathology, prevention & control)
• Isolated Heart Preparation
• Male
• Metabolic Syndrome (enzymology, etiology, physiopathology, prevention & control)
• Nitric Oxide Synthase Type II (metabolism)
• Obesity, Abdominal (enzymology, etiology, physiopathology, prevention & control)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Rats, Inbred SHR
• Soluble Guanylyl Cyclase (metabolism)
• Vasoconstriction (drug effects)
• Vasodilation (drug effects)
• Ventricular Function, Left (drug effects)
• Ventricular Pressure (drug effects)