Phosphodiesterase-5 inhibition synergizes rho-kinase antagonism and enhances erectile response in male hypertensive rats.
To evaluate the association between hypertension, male erectile function, Rho-kinase, and cyclic GMP pathways, we monitored neurogenic erectile response in spontaneously hypertensive (SHR) vs normotensive rats. We also evaluated SHR erectile function before and after intracavernosal injection of either the specific Rho-kinase inhibitor Y-27632 or a combination of Y-27632 and the PDE5 inhibitor zaprinast to prevent cGMP degradation. SHR had lower resting baseline corpus cavernosum pressure and a higher threshold for development of tumescence than normotensive rats. In SHR, Y-27632 administration reversed hypertension-related changes in male erectile function; Rho-kinase antagonism and PDE5 inhibition in combination had a synergistic effect in improving the neurogenic erectile response. Our data indicate that hypertension is associated with impairment in the SHR neurogenic erectile response that may involve a derangement in hemodynamic mechanisms in penile erectile tissue. Rho-kinase inhibition alone or combined with PDE5 inhibition may be of value in treating hypertension-related ED.
Wilkes
N
N
Division of Urology, University of California-San Diego Medical Center, 200 W. Arbor Drive (8897), San Diego, CA 92103-8897, USA.
White
S
S
Stein
P
P
Bernie
J
J
Rajasekaran
M
M
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004357:Drug Synergism; D004558:Electric Stimulation; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D010410:Penile Erection / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011688:Purinones / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015854:Up-Regulation; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism
D000577:Amides; D000959:Antihypertensive Agents; D047908:Intracellular Signaling Peptides and Proteins; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011725:Pyridines; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D020742:rhoA GTP-Binding Protein; C011145:zaprinast; D006152:Cyclic GMP