Vascular Tone Regulation Induced by C-Type Natriuretic Peptide: Differences in Endothelium-Dependent and -Independent Mechanisms Involved in Normotensive and Spontaneously Hypertensive Rats

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.

C-Type Natriuretic Peptide: A Multifaceted Paracrine Regulator in the Heart and Vasculature

“…In human arteries, both GIRK and large conductance calcium-activated K + channels (BK Ca channels) have been implicated in CNP-evoked vasodilation [79]. Alternatively, studies in rats have shown that NPR-C can also couple to eNOS, resulting in the production of nitric oxide, although, this mechanism has only been reported in larger diameter vessels [81,82].…”

G-Protein-gated Inwardly-Rectifying K⁺ Channels and Large-conductance Calcium-Activated K⁺ Channels Are Involved in C-Type Natriuretic Peptide-Mediated Vasodilation in Human Arteries

“…18,20) Iberiotoxin, a specific BKCa channel blocker, partly inhibited the vasorelaxant responses evoked by CNP in human penile resistance arteries 18) and rat aorta. 20) Furthermore, in patch-clamp studies in porcine coronary arterial smooth muscle cells, CNP enhanced the amplitude of the BKCa channel current, directly demonstrating that the opening of BKCa channels of vascular smooth muscle contributed to CNP-mediated relaxations. 21) These studies accord with ours findings in human gastroepiploic arteries.…”

A Highly-sensitized Response of B-type Natriuretic Peptide to Cardiac Ischaemia Quantified by Intracoronary Pressure Measurements

“…ANP restores the attenuated cardioprotective effects in diabetic hearts, possibly due to the increase in endothelial nitric oxide synthesis (eNOS) expression and subsequent increase in NO activity 27 . Moreover, CNP induces vascular relaxation by endothelium-dependent and endothelium-independent mechanisms 28,29 . Although more precise human studies are required, the interaction left circumflex coronary artery; RCA, right coronary artery; LMT, left main trunk; VD, vessel disease; LVEF, left ventricular ejection fraction; LVEDP, left ventricular end-diastolic pressure; CI, cardiac index; SBP, systolic blood pressure; DBP, diastolic blood pressure.…”