Sepsis modulates aortic AT1 and P₂Y₆ receptors to produce vascular hyporeactivity in mice

Abstract

Purpose

Hyporeactivity to vasopressors leading to multiple organ failure is a serious clinical implication in sepsis. Though the regulatory role of purinoceptors in inflammation is reported, their involvement in sepsis-induced vasoplegia is still unknown. Thus we investigated the effect of sepsis on vascular AT1 and P₂Y₆ receptors.

Materials and methods

Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Vascular reactivity was assessed by organ bath study and aortic mRNA expression of AT1 and P₂Y₆ was quantified by qRT-PCR.

Results

Both angiotensin-II and UDP produced higher contractions in the absence of endothelium as well as following inhibition of nitric oxide synthase. Angiotensin-II mediated aortic contraction was antagonized by losartan (AT1 antagonist), but not by PD123319 (AT2 antagonist) whereas UDP-induced aortic contraction was significantly inhibited by MRS2578 (P₂Y₆ antagonist). In addition, MRS2578 significantly inhibited the contractile response of Ang-II. Compared to SO mice, angiotensin-II and UDP-induced maximum contraction were found to be significantly attenuated in sepsis. Accordingly, aortic mRNA expression of AT1a receptors was significantly down-regulated while that of P₂Y₆ receptors was significantly increased in sepsis. 1400 W (a selective iNOS inhibitor) significantly reversed angiotensin-II-induced vascular hyporeactivity in sepsis without affecting UDP-induced hypo-reactivity.

Conclusion

Sepsis-induced vascular hyporeactivity to angiotensin-II is mediated by enhanced expression of iNOS. Moreover, AT1R-P₂Y₆ cross talk/heterodimerization could be a novel target for regulating vascular dysfunction in sepsis.

Keywords:

• Polymicrobial sepsis
• AT1 receptor
• P₂Y₆ receptor
• iNOS

Acknowledgement

Financial assistance for this research work by the Indian Council of Agricultural Research, New Delhi under the ‘Strengthening and Development Grant to the University’ is thankfully acknowledged. The laboratory facility established by the Department of Veterinary Pharmacology and Toxicology, DUVASU, Mathura, India, under ICAR-sponsored Niche Area of Excellence Programme (Grant No. 10 (10)/2012-EPD dated 23 March 2012) is also thankfully acknowledged.

Author contributions

SC and SK designed and conceptualized the study, JT and MG performed the functional experiments, JG, SC and VS performed the molecular experiments, JG, SC and AS analyzed the data and wrote the MS.

Disclosure statement

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.