Chronic treatment with C-type natriuretic peptide impacts differently in the aorta of normotensive and hypertensive rats

Abstract

The aim of this study was to determine whether exogenous administration of C-type natriuretic peptide (CNP) induces functional and morphological vascular changes in spontaneously hypertensive rats (SHR) compared with normotensive rats. Male 12week-old normotensive Wistar and SHR were administered with saline (NaCl 0.9%) or CNP (0.75 μg/h/100 g) for 14 days (subcutaneous micro-osmotic pumps). Systolic blood pressure (SBP) was measured in awake animals and renal parameters were evaluated. After decapitation, the aorta was removed, and vascular morphology, profibrotic markers, and vascular reactivity were measured. In addition, nitric oxide (NO) system and oxidative stress were evaluated. After 14-days of treatment, CNP effectively reduced SBP in SHR without changes in renal function. CNP attenuated vascular remodeling in hypertensive rats, diminishing both profibrotic and proinflammatory cytokines. Also, CNP activated the vascular NO system and exerted an antioxidant effect in aortic tissue of both groups, diminishing superoxide production and thiobarbituric acid-reactive substances, and increasing glutathione content. These results show that chronic treatment with CNP attenuates the vascular damage development in a model of essential hypertension, inducing changes in fibrotic, inflammatory, oxidative, and NO pathways that could contribute to beneficial longterm effects on vascular morphology, extracellular matrix composition, and function. The knowledge of these effects of CNP could lead to improved therapeutic strategies to not only control BP but also reduce vascular damage, primarily responsible for the risk of cardiovascular events.

C-Type Natriuretic Peptide in Essential Hypertension

“…Corresponding to individuals with essential hypertension, SHRs display increased expression of proinflammatory cytokines in both the heart and the vasculature. 3 , 4 Chronic treatment with CNP in SHRs has been shown to decrease left ventricular expression of interleukin-1β, interleukin-6, and TNF-α3, supporting previous findings in aortas of SHRs. 4 In an earlier study, Moyes et al 6 compared wild-type mice with endothelial cell–specific CNP-knockout mice, in which increased levels of leukocyte rolling on vascular beds together with neutrophils and macrophage accumulation in extravascular tissues following TNF-α administration were observed.…”

“…Also, the results suggest that long-term administration of CNP has potential in long-term treatment of hypertension, whereas short-term CNP administration may be less relevant. A possible explanation is that the acute vasodilatory response, especially in larger vessels, greatly relies on the nitric oxide system, which seems impaired in spontaneously hypertensive rats (SHRs), 3 , 4 and interaction between CNP and the nitric oxide system remains controversial. Furthermore, CNP administration in mice does not affect renal function, 2 whereas ANP or BNP can induce worsening of renal failure because of excessive vasodilation and hypotension.…”

Blood pressure in adults with short stature skeletal dysplasias

“…Of all the short stature skeletal dysplasias, however, achondroplasia and hypochondroplasia offer the most plausible biologic explanation for high hypertension prevalence based on our current understanding of elevated CNP levels in these patients (Olney et al, 2015) and the observation in average stature individuals that more vascular disease risk factors are highly correlated with elevated CNP levels in blood (Prickett et al, 2013). Though CNP has been shown to cause vasodilation in hypertensive mouse models (Caniffi et al, 2019), it is likely that the elevated CNP present in patients with achondroplasia cannot be effectively bound by its paired receptor, NPR-B. The intracellular signaling, which is activated by mutated FGFR3 in patients with achondroplasia, not only inhibits chondrocyte proliferation, but also inhibits the function of NPR-B.…”

Endogenous Vasoactive Peptides and Vascular Aging-Related Diseases

“…Moyes et al [ 96 ] found that administration of small-molecule NPR-C agonists promoted vasorelaxation of isolated resistance arteries and reduced blood pressure in WT animals. Treatment with CNP effectively attenuated vascular remodeling and reduced systolic blood pressure in hypertensive rats and decreased both proinflammatory and profibrotic cytokines [ 101 ]. In addition, CNP activated the vascular NO system and exerted an antioxidant effect in the aortic tissue of both hypertensive rats and normotensive rats [ 101 ].…”

“…Treatment with CNP effectively attenuated vascular remodeling and reduced systolic blood pressure in hypertensive rats and decreased both proinflammatory and profibrotic cytokines [ 101 ]. In addition, CNP activated the vascular NO system and exerted an antioxidant effect in the aortic tissue of both hypertensive rats and normotensive rats [ 101 ]. Impaired local endogenous CNP may be associated with increased vascular calcium deposition in rat aortas with vascular calcification [ 102 ].…”