C-Type Natriuretic Peptide Hyperpolarizes and Relaxes Human Penile Resistance Arteries

Abstract

Introduction In addition to nitric oxide (NO), it is thought that an endothelium-derived hyperpolarizing factor (EDHF) plays an important role in the relaxation of penile arteries. Recently, it has been shown that C-type natriuretic peptide (CNP) shows the characteristics of EDHF in systemic small arteries. Aim To investigate the mechanism involved in CNP-evoked vasodilatation and to address whether CNP is an EDHF in human penile resistance arteries. Methods Erectile tissue was obtained in connection with transsexual operations. Intracavernous penile resistance arteries were isolated and mounted in microvascular myographs for recording of isometric tension. Membrane potential was recorded by the use of a small glass electrode inserted in the smooth muscle layer. Main Outcome Measure In vitro evidence for hyperpolarization and vasorelaxation induced by CNP. Results Acetylcholine (ACh) and CNP hyperpolarized smooth muscle membrane potential in resting penile resistance arteries. In penile small arteries incubated with inhibitors of NO synthase and cyclooxygenase and contracted with phenylephrine, ACh and CNP evoked concentration-dependent relaxations with maximum of 56±6% and 71±6%, respectively. Addition of a combination of blockers of small- and intermediate-conductance calcium-activated K+ channels, apamin plus charybdotoxin, respectively, and a combination thought to block the smooth muscle response of EDHF-type relaxation, barium plus ouabain, markedly reduced ACh- and CNP-evoked relaxation. Iberiotoxin, a blocker of big-conductance calcium-activated K+ channels inhibited the vasorelaxant responses evoked by ACh and CNP. A selective natriuretic peptide receptor type C (NPR-C) agonist, C-atrial natriuretic factor4−23 (cANF4−23), induced relaxations with less maximum response compared to CNP. Conclusion The present findings suggest that CNP possesses the characteristics of an EDHF in human penile resistance arteries. By activation of natriuretic peptide receptor type B and NPR-C receptors, CNP causes relaxation by activation, respectively, of large-conductance calcium-activated K+ channels and Na+/K+-adenosine triphosphatase (ATPase), and barium-sensitive inward rectifier K+ channels. Modulation of the CNP pathway opens for new treatment modalities of erectile dysfunction.

Reduced expression of SK3 and IK1 channel proteins in the cavernous tissue of diabetic rats

“…Under physiological conditions, the endothelium exerts regulatory effects on vasodilatation, as it releases numerous vasoactive substances, such as NO, bradykinin, prostaglandin I2, substance P and so on. EDHF is another vasoactive substance and it has been found in rat, horse and human penile small arteries [5][6][7][8]17]. Moreover, in systemic arteries, several EDHF candidates have been suggested, including potassium ions, products of the cytochrome P450 pathway, C-type natriuretic peptide, hydrogen peroxide and K + [7,18,19].…”

“…EDHF is another vasoactive substance and it has been found in rat, horse and human penile small arteries [5][6][7][8]17]. Moreover, in systemic arteries, several EDHF candidates have been suggested, including potassium ions, products of the cytochrome P450 pathway, C-type natriuretic peptide, hydrogen peroxide and K + [7,18,19]. EDHF-mediated relaxation is dependent on the activation of endothelial SK3 and IK1, which can be blocked by the combination of apamin and charybdotoxin.…”

“…Besides the well-established nitric oxide (NO)/ cyclic guanosine monophosphate pathway, recent reports have shown the existence of a second, distinct endothelial pathway involving the endothelium-dependent hyperpolarization factor (EDHF). Specifically, this factor has been shown to be involved in the relaxation of the vascular smooth muscle cells in penile arteries [5][6][7][8]. Angulo [9] has reported that diabetes can impair endothelium-dependent relaxation of human penile vascular tissues mediated by EDHF, but the causes remain unclear.…”

ATP-Sensitive Potassium Channel Activation Induces Angiogenesis In Vitro and In Vivo

“…CAM responses to CNP were blocked by glibenclamide, revealing for the first time a critical involvement of K ATP in CNP's endothelial effects. These actions of CNP are likely mediated via activation of the NPR-C receptor (also referred as natriuretic peptide clearance receptor), whose signaling is required for CNP-dependent hyperpolarization, vasorelaxation, and endothelial growth (Villar et al, 2007;Kun et al, 2008;Khambata et al, 2011).…”

Adenosine Signaling

“…2,[16][17][18][19] Early studies in dogs showed that intracavernous injection of adenosine induced a full erection, which was independent of acetylcholine. 20 Takahashi et al 21 further investigated the hemodynamic effects of intracavernous injection of adenosine in dogs.…”