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

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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. Kun A, Kiraly I, Pataricza J, Marton Z, Krassoi I, Varro A, Simonsen U, Gy. Papp J, and Pajor L. C-type natriuretic peptide hyperpolarizes and relaxes human penile resistance arteries.
Funding Information
  • Hungarian Society of Urology (OTKA NI-61902)
  • Danish Medical Research Council