Abstract
Given that the role of C-type natriuretic peptide (CNP) in the regulation of vascular tone in hypertensive states is unclear, we hypothesized that impaired response of the nitric oxide system to CNP in spontaneously hypertensive rats (SHR) could affect vascular relaxation induced by the peptide in this model of hypertension, and that other endothelial systems or potassium channels opening could also be involved. We examined the effect of CNP on isolated SHR aortas, and the hindlimb vascular resistance (HVR) in response to CNP administration compared to normotensive rats. Aortas were mounted in an isometric organ bath and contracted with phenylephrine. CNP relaxed arteries in a concentration-dependent manner but was less potent in inducing relaxation in SHR. The action of CNP was diminished by removal of the endothelium, inhibition of nitric oxide synthase by Nω-nitro-L-arginine methyl ester, and inhibition of soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one in both groups. In contrast, blockade of cyclooxygenase or subtype 2 bradykinin receptor increased CNP potency only in SHR. In both Wistar and SHR, CNP relaxation was blunted by tetraethylammonium and partially inhibited by BaCl2 and iberiotoxin, indicating that it was due to opening of the Kir and BKCa channels. However, SHR seem to be more sensitive to Kir channel blockade and less sensitive to BKCa channel blockade than normotensive rats. In addition, CNP decreases HVR in Wistar and SHR, but the effect of CNP increasing blood flow was more marked in SHR. We conclude that CNP induces aorta relaxation by activation of the nitric oxide system and opening of potassium channels, but the response to the peptide is impaired in conductance vessel of hypertensive rats.
Highlights
C-type natriuretic peptide (CNP) is extensively distributed in the cardiovascular system, in vascular endothelial cells [1,2]
Physiological effects of CNP are mainly mediated through the membrane-integrated natriuretic peptide receptors subtypes B and C (NPR-B and NPR-C, respectively), which are strongly expressed in venous tissue, aortic smooth muscle and aortic endothelial cells [4,5].We previously demonstrated that acute CNP administration decreases mean arterial pressure and increases excretion of nitric oxide (NO) metabolic end products in hypertensive rats [6]
Similar results were obtained with soluble guanylyl cyclase (sGC) inhibitor in both Wistar and spontaneously hypertensive rats (SHR), suggesting that CNP-induced relaxation is partially mediated by the NO-cGMP pathway in intact endothelium rings of both groups (Fig 1B and 1C)
Summary
C-type natriuretic peptide (CNP) is extensively distributed in the cardiovascular system, in vascular endothelial cells [1,2]. Physiological effects of CNP are mainly mediated through the membrane-integrated natriuretic peptide receptors subtypes B and C (NPR-B and NPR-C, respectively), which are strongly expressed in venous tissue, aortic smooth muscle and aortic endothelial cells [4,5].We previously demonstrated that acute CNP administration decreases mean arterial pressure and increases excretion of nitric oxide (NO) metabolic end products in hypertensive rats [6]. In our previous studies we showed that the peptide increases endothelial NO synthase (eNOS) activity through NPR-C-coupled Gi protein activation in aorta of spontaneously hypertensive rats (SHR). It is well documented that endothelial production of NO causes vasorelaxation primarily by activating soluble guanylyl cyclase (sGC) in smooth muscle cells and by increasing intracellular cGMP, which in turn activates protein kinase G to induce vasorelaxation by decreasing cytosolic Ca2+ concentration [8,9]
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