Phosphodiesterase-5 inhibition synergizes rho-kinase antagonism and enhances erectile response in male hypertensive rats

Wilkes, Nathan; White, Steven R.; Stein, Paul C.; Bernie, Jonathan E.; Rajasekaran, Mahadevan

doi:10.1038/sj.ijir.3901149

Cited by 45 publications

(50 citation statements)

References 35 publications

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“…Recent investigations in a number of experimental models of ED-disease states have revealed elevations in Rho-kinase expression/activity in association with impairments in erectile function [12][13][14][15]. The interaction of NO/cGMP signaling with RhoA/Rho-kinase has only recently been studied in the vasculature, focusing on disease states or applying in vitro techniques where changes in experimental conditions occur rather rapidly.…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesized that besides serving as an erection mediator eNOS exerts a regulatory role in the balance of biological expressions and activities of the foremost molecular effectors of penile erection. The concept that the regulatory actions of eNOS and RhoA/Rho-kinase are coordinated basally at the penile level differs from recent descriptions of their interactions in the penis involved in immediate erectogenic events [5] or occurring in relation to conditional erectile dysfunction (ED)-disease states [12][13][14][15]. The endeavor herein precisely was to gain further understanding into the operation of steady state erection regulatory biology of the penis.…”

Section: Introductionmentioning

confidence: 99%

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Endothelial Nitric Oxide Synthase Keeps Erection Regulatory Function Balance in the Penis

et al. 2007

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Objectives: We sought to evaluate the regulatory influence of endothelial nitric oxide (NO) on the basal functional states of the NO and RhoA/Rho-kinase signaling pathways in the penis employing endothelial NO synthase (eNOS) mutant mice and eNOS gene transfer technology.Methods: Four groups of mice were utilized: 1) wild type (WT), 2) eNOS gene deleted (eNOS −/−), 3) eNOS and neuronal NOS gene deleted (dNOS −/−), and 4) eNOS −/− mutant mice transfected intracavernosally with eNOS. Cyclic guanosine monophosphate (cGMP) concentration, protein kinase G (PKG) activity, activated RhoA, and Rho-kinase activity were determined in penes of WT and both mutant mouse groups. Constitutive NOS and PKG activities, RhoA, Rho-kinase-α and-β isoforms, and phosphorylated myosin light chain phosphatase target subunit (p-MYPT-1) expressions as well as Rho-kinase activity were determined in penes of eNOS−/− mice after eNOS gene transfer. Results:When compared with results in the WT penis, eNOS−/− and dNOS−/− mutant mouse penes had significant reductions in NOS activity, cGMP concentration, PKG activity, Rho-kinase activity and p-MYPT-1 expression (p<0.05) with no significant changes in activated RhoA or in RhoA and Rho-kinase-α and-β protein expressions. After eNOS gene transfer to penes of eNOS−/ − mice, Rho-kinase-β and p-MYPT-1 expressions and total Rho-kinase activity were significantly increased from baseline levels (p<0.05). Conclusions:These data suggest that endothelial NO serves a role in the penis as a regulator of the basal signaling functions of the NO and RhoA/Rho-kinase erection mediatory pathways. These data offer new insight into the homeostasis of erection regulatory biology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endothelial Nitric Oxide Synthase Keeps Erection Regulatory Function Balance in the Penis

et al. 2007

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“…The SHR is known to have a systemic overexpression of RhoA in male genital tissue [Wilkes et al, 2004]. The impact of Rho-kinase inhibition on SHR bladder function has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Rho‐kinase inhibition suppresses bladder hyperactivity in spontaneously hypertensive rats

Rajasekaran

Wilkes

Kuntz

et al. 2005

Neurourology and Urodynamics

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“…9 Wilkes' data indicate that hypertension is associated with impairment in the SHR neurogenic erectile response. 10 A dysfunctional alpha-adrenergic contraction of the corporal smooth muscle, an increased cyclooxygenase-dependent constrictor tone, and/or a defect in endothelium-dependent reactivity are associated with the altered erectile mechanisms in SHR.…”

Section: Introductionmentioning

confidence: 99%

Ultrastructural comparison of penile cavernous tissue between hypertensive and normotensive rats

et al. 2005

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Our aim was to compare the ultrastructure of penile cavernous tissue in the spontaneous hypertensive rat (SHR) and normotensive rat, and study the relation of blood pressure with erectile function. After injection of apomorphine (APO), penile erectile frequency in 16-week-old SHR (group A) and Wistar-Kyoto rat (WKY) (group B) was observed and noted. The ultrastructure of the penile cavernous tissue was studied by scanning electron microscope and transmission electron microscope. The mean blood pressures were significantly higher in group A than in group B (P ¼ 0; 171.20710.94 and 117.60712.38, n ¼ 5, for group A and group B, respectively). After treatment of the two groups with APO, the erectile frequency in group A was significantly less than in group B (P ¼ 0.007; 0.4070.55 and 2.4071.14, n ¼ 5, for group A and group B, respectively). Significant ultrastructural pathological changes were observed in the tunica albuginea and penile cavernous tissue of SHR. The elastic fibers were decreased and the collagen fibers of the sinusoid were increased in group A. The tunica albuginea thickness (mean7s.d.) was 100.2077.22 lm and 126.0077.65 lm in group A and group B, respectively. The tunica albuginea of group A was significantly thinner than that in B (P ¼ 0.001). Some endothelial cells and smooth muscle cells exhibited damaged mitochondria, and endoplasmic reticulums and Schwann cells were degenerated in group A. Although the function of penile erection might be affected by a secondary effect related to endothelial dysfunction of hypertension, these ultrastructural pathological changes of the penile cavernous tissue might also be one of the important mechanisms of erectile dysfunction caused by hypertension.

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Phosphodiesterase-5 inhibition synergizes rho-kinase antagonism and enhances erectile response in male hypertensive rats

Cited by 45 publications

References 35 publications

Endothelial Nitric Oxide Synthase Keeps Erection Regulatory Function Balance in the Penis

Endothelial Nitric Oxide Synthase Keeps Erection Regulatory Function Balance in the Penis

Rho‐kinase inhibition suppresses bladder hyperactivity in spontaneously hypertensive rats

Ultrastructural comparison of penile cavernous tissue between hypertensive and normotensive rats

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