Different responses to angiotensin-(1-7) in young, aged and diabetic rabbit corpus cavernosum

doi:10.1016/j.phrs.2007.05.008

Pharmacological Research

Volume 56, Issue 3, September 2007, Pages 209-216

https://doi.org/10.1016/j.phrs.2007.05.008 Get rights and content

Abstract

We evaluated the ability of angiotensin-(1-7) [Ang-(1-7)] to produce relaxation of the corpus cavernosum of New Zealand White rabbits. The reactivity of corpus cavernosal strips isolated from young rabbits (8–10 months old) was assessed in organ-bath chambers. Cumulative concentration response curves for Ang-(1-7), angiotensin II (Ang II), carbachol and sodium nitroprusside (SNP) were established. Ang-(1-7) (10⁻¹² to 10⁻⁵ M) produced a concentration-dependent relaxation of the corpus cavernosal strips with a pD₂ value of 9.8 ± 0.3. Ang-(1-7)-induced maximal relaxant response was reduced by 48 ± 2%, 57 ± 3% and 76 ± 2% in the presence of A-779 (10⁻⁶ M), a selective Ang-(1-7) receptor (AT_1-7) antagonist, nitro-l-arginine methyl ester (l-NAME) (10⁻⁴M), an inhibitor of nitric oxide (NO) synthase, or iberiotoxin (5 × 10⁻⁸ M), an inhibitor of calcium-activated potassium (BK) channels, respectively. In contrast, Ang II-induced contraction was increased in the presence of A-779. Carbachol-, SNP- and Ang-(1-7)-induced relaxations were significantly reduced whereas Ang-II induced contraction was significantly increased in the cavernosum strips from older (18–24 months old) and diabetic rabbits compared to the young. Pre-incubation of the cavernosum strips obtained from young, older or diabetic rabbits with Ang-(1-7) resulted in a significant attenuation of Ang II-induced contraction. In conclusion, these results demonstrate that Ang-(1-7) can produce nitric oxide-dependent relaxation of the corpus cavernosum through activation of AT_1-7 and BK channels. Older and diabetic animals showed impaired Ang-(1-7)-mediated relaxation suggesting that aging and diabetes related erectile dysfunction (ED) may be partly due to decreased Ang-(1-7)-mediated relaxation of the corpus cavernosum. Acute pre-incubation with Ang-(1-7) was effective in attenuating Ang II-induced contraction of rabbit corpus cavernosum suggesting that the possible role of Ang-(1-7) in treatment of ED should be investigated.

Introduction

It has been suggested that endothelial dysfunction, which reflects impairment of nitric oxide (NO) bioavailability and also reduced vascular reactivity to vasodilators, plays a major role in development of erectile dysfunction (ED) [1]. The renin–angiotensin system (RAS) plays an important role in cardiovascular physiology and cell function. One of the active members of the RAS is angiotensin II (Ang II) which is a potent vasoconstrictor that also has mitogenic, hypertrohic and inflammatory effects in the vasculature. Cavernous tissue produces physiological amounts of Ang II which participates in the regulation of cavernous smooth muscle tone in the animal models as well as the human [2], [3]. Intracavernosal infusion of Ang II induces contraction of cavernous smooth muscle and terminates spontaneous erection through activation of angiotensin type-1 (AT₁₎ receptors shown to be present in the corpus cavernosum [2], [3]. Inhibition of Ang II formation with angiotensin converting enzyme (ACE) inhibitors or blockade of AT₁ receptors with losartan results in decreased vascular resistance and increased erectile function [2], [3]. These observations indicate that agents that can antagonize the actions of Ang II may have potential in improving erectile function.

Another active member of the RAS is angiotensin-(1-7) [Ang-(1-7)], which has been shown to oppose the cardiovascular effects of pressor agents such as Ang II, norepinephrine and endothelin-1 [4], [5], [6], [7], [8], [9]. Ang-(1-7) is formed from Ang I and II by several endopeptidases and carboxypeptidases, including angiotensin-converting enzyme-2 (ACE2) [4], [5]. Ang-(1-7) is present in the circulation and in the kidney at concentrations that are comparable to Ang II and circulating levels of the peptide are increased with ACE inhibitors and angiotensin receptor blockers [4], [5], [6]. Our studies were the first to show that Ang-(1-7) can produce blood pressure lowering effects by acting through a unique receptor (AT_1-7) and releasing vasodilatory prostaglandins [6]. Ang II does not activate AT_1-7 receptors [7]. Ang-(1-7) was shown to be able to release NO and to have anti-thrombotic and anti-proliferative properties [4], [5], [8], [10]. Ang-(1-7) produces relaxation of several vascular beds including coronary, cerebral, renal, pulmonary, femoral and mesenteric arteries [11]. In the human, Ang-(1-7) attenuates Ang II-induced vasoconstriction in resistant vessels [12]. Our recent studies have shown that treatment with Ang-(1-7) can attenuate end-organ damage in models of diabetes, hypertension and endothelial dysfunction [13], [14]. The objective of this study was to test the hypothesis that (1) Ang-(1-7) can produce NO-mediated relaxation of the corpus cavernosum smooth muscle in New Zealand White rabbits by activating its own receptor, (2) Ang-(1-7)-induced relaxation is impaired in aged rabbits and rabbits with diabetes, and (3) Ang-(1-7) can antagonize Ang II-induced contraction of the corpus cavernosum.

Section snippets

Isolation of rabbit corpus cavernosum

Young adult (control: 8–10 months old) and older (18–24 months old) male New Zealand White rabbits were used in this study. The rabbits were anesthetized by intravenous injection of pentobarbital (50 mg kg⁻¹) via the marginal ear vein. Animals were then emarginated and the penis removed en bloc. A ventral incision was made and the cavernosal tissue exposed. The corpus cavernosum was cleaned of the adjacent tissue and cut into longitudinal strips of 2 mm × 15 mm.

Force measurements

Strips of the corpus cavernosum were

Effect of Ang-(1-7)

Ang-(1-7) (10⁻¹² to 10⁻⁵ M), carbachol (10⁻⁹ to 10⁻⁶ M) and SNP (10⁻⁹ to 10⁻⁴ M) produced concentration-dependent relaxation of the rabbit corpus cavernosum (Fig. 1). The maximal relaxation (E_max) to Ang-(1-7) was 83 ± 5% with a pD₂ value of 9.8 ± 0.3 (Table 1).

Effect of A-779 on Ang-(1-7)-induced relaxation

Ang-(1-7)-induced relaxation (10⁻¹² to 10⁻⁵ M) was significantly reduced in the corpus cavernosum pre-incubated in KH solution containing A-779 (10⁻⁶ M) (Fig. 2A). Similar results were obtained when different concentrations (10⁻⁴ and 10⁻⁵ M) of

Discussion

The results of the present study show that Ang-(1-7) can produce nitric oxide-dependent relaxation of the corpus cavernosum through activation of its own receptor and BK channels. Ang-(1-7) receptor antagonist A-779 increased Ang II-induced contraction indicating that endogenous Ang-(1-7) may be a contributing factor to the tone of the corpus cavernosum. Ang-(1-7)-, carbachol- and SNP-induced relaxation were reduced whereas Ang-II induced contraction was increased in the cavernosum strips from

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Erectile dysfunction (ED) is a common diabetic complication. Recent evidence has illuminated the role of hydrogen sulfide (H₂S) as a dynamic mediator of the erection process. H₂S is a potent endogenous relaxant gas. It has been shown to relax human and animal penile tissue in vitro and induce erection in animals in vivo. The reported penile expression of H₂S-synthesizing enzymes also supports the potential role of the endogenous L-cysteine/H₂S pathway in penile homeostasis. Several pathological changes take place in the diabetic penile tissue, including inflammation, oxidative stress, neuropathy and fibrosis of the corpus cavernosum (CC), the major erectile structure of the penis. The present study is experimental and has been performed in the diabetic rat model. The study will investigate the role of H₂S as a potential protective mediator against diabetes-induced structural and functional alterations in the CC by examining if it: (1) reduces corporal contraction and/or enhances corporal relaxation following pharmacological stimulation, (2) attenuates fibromuscular changes in diabetic CC, and (3) whether there is a link with H₂S plasma/urine level and CC tissue generation, as well as studying the expression of some proteins in the transforming growth factor (TGF)-β1-associated pathway. The major findings of the study reveal that- compared to the nondiabetic controls - the diabetic animals CC showed: (1) augmented contraction and attenuated relaxation in response to phenylephrine and carbachol, respectively, (2) marked fibromuscular degeneration with a significantly lower smooth muscle/collagen ratio and upregulation of TGF-β-1/Smad/CTGF fibrosis signaling pathway, (3) reduced H₂S plasma and urinary levels and cavernosal tissue generation. Chronic GYY4137 treatment prevented most of these pathological changes in diabetic CC, thus may be considered a potential new strategy for the prevention and/or treatment of diabetes-induced ED.
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Citation Excerpt :
Positive effect of RAS modulation by AT1 blockage in aging condition has been previously reported by Park et al.48 In particular, it has been shown that chronic administration of losartan to 18-month-old rats can restore their impaired erectile function. At the same time, the effect of acute Ang-(1-7) stimulation has been studied in cavernosal strips taken from aged animals.49 In this study, Ang-(1-7) has demonstrated reduced ability to induce ex vivo relaxation of cavernosal strips of aged animals in comparison to those taken from young ones.49
The renin-angiotensin system (RAS) plays an important role in erectile function. The RAS contains 2 major axes: one deleterious, composed of ACE-Ang II-AT1 receptor, and another protective, composed of ACE2-Ang-(1-7)-Mas receptor. While aging is a well-known cause for development of male sexual disorders, little is known about local regulation of the RAS in age-related erectile dysfunction (ED).
The present study aimed to assess regulation of the RAS in aging-associated ED rat model and evaluate possible options for disease management through pharmacological modulation of the RAS.
Penile tissues were harvested from 3-, 12-, and 24-month-old Wistar rats. Local expression of major RAS components and ED markers was measured by RT-PCR. Protein expression of RAS components was assessed by western blot. Collagen deposition was measured by Sirius Red and immunohistochemical staining. Evaluation of collagen content was also performed in penile sections of Mas-knockout mice by Sirius Red and Masson’s trichrome stainings. Finally, the effect of Ang-(1-7) pretreatment on TGF-β–induced myofibroblast activation was studied in primary cavernosal and immortalized fibroblasts.
Experimental results highlighted the essential role of the RAS in modulation of cavernosal fibrosis.
The present study demonstrates local expression of angiotensinogen mRNA alongside with major RAS components, which suggests local autonomous functioning of the RAS within penile tissue. Gene expression analysis revealed strong positive correlation between ACE-Ang II-AT1 axis with markers for inflammation and fibrosis. While corpus cavernosum from 24-month-old rats was characterized by increased collagen deposition, protein expression of ACE, AT1, and Mas was shown to be upregulated in the penile tissue of this group. At the same time, penile sections from Mas-knockout mice (FVB/N background) were also shown to have increased collagen deposition. Finally, it was demonstrated that Ang-(1-7) treatment of primary cavernosal and immortalized fibroblasts was able to alleviate TGF-β–induced fibroblast-to-myofibroblast transition.
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Intracavernous administration of fesoterodine restored in vivo erectile response at 5.0- and 7.5-V levels, except for 2.5 V in diabetic rats. Basal intracavernosal pressure (5.4 ± 0.9 mm Hg) in diabetic rats was markedly increased after injection of fesoterodine (33.9 ± 7.9 mm Hg, P <.001). In bath studies, fesoterodine resulted in a relaxation of CC in a concentration-dependent manner, which was reduced in diabetic rats. Nifedipine (l-type Ca²⁺ channel blocker) inhibited maximum fesoterodine-induced relaxation by 58%. The nonselective K⁺ channel blocker tetraethylammonium and glibenclamide incubation did not change the relaxant response to fesoterodine. The relaxant responses to acetylcholine (10 µM), electrical field stimulation (10 Hz), and sodium nitroprusside (0.01 µM) in diabetic rats were increased after incubation with fesoterodine (10 µM).
Fesoterodine improved erectile function and relaxation of isolated strips of rat CC. The underlying mechanism of fesoterodine is likely due to the blocking of l-type calcium channels independent of the nitric oxide-cyclic guanosine monophosphate pathway. Further investigations are warranted to fully elucidate the restorative effects of fesoterodine on overactive bladder-induced diabetic erectile dysfunction.
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The co-treatment of the vessels with HOE140 and LNAME elicited a slightly greater degree of inhibition of the Ang-(1–7) response than the B2 antagonist alone (Fig. 3, Table 2). Since we previously demonstrated that the ATP-sensitive K+ channel contributes to the vasorelaxant effects of Ang-(1–7) in the corpus cavernosum [39], we determined whether K+ channels inhibitors influence the Ang-(1–7) response. The renal vessels were pretreated with either iberiotoxin to block the calcium-dependent K+ (BK) channel or glibenclamide to block the ATP-sensitive K+ channel.
Angiotensin-(1–7) [Ang-(1–7)] exhibits blood pressure lowering actions, inhibits cell growth, and reduces tissue inflammation and fibrosis which may functionally antagonize an activated Ang II-AT₁ receptor axis. Since the vascular actions of Ang-(1–7) and the associated receptor/signaling pathways vary in different vascular beds, the current study established the vasorelaxant properties of the heptapeptide in the renal artery of male Wistar male rats. Ang-(1–7) produced an endothelium-dependent vasodilator relaxation of isolated renal artery segments pre-contracted by a sub-maximal concentration of phenylephrine (PE) (3 × 10⁻⁷ M). Ang-(1–7) induced vasodilation of the rat renal artery with an ED₅₀ of 3 ± 1 nM and a maximal response of 42 ± 5% (N = 10). The two antagonists (10⁻⁵ M each) for the AT₇/Mas receptor (MasR) [D-Pro⁷]-Ang-(1–7) and [D-Ala⁷]-Ang-(1–7) significantly reduced the maximal response to 12 ± 1% and 18 ± 3%, respectively. Surprisingly, the AT₂R receptor antagonist PD123319, the AT₁R antagonist losartan and B₂R antagonist HOE140 (10⁻⁶ M each) also significantly reduced Ang-(1–7)-induced relaxation to 12 ± 2%, 22 ± 3% and 14 ± 7%, respectively. Removal of the endothelium or addition of the soluble guanylate cyclase (sGC) inhibitor ODQ (10⁻⁵ M) essentially abolished the vasorelaxant response to Ang-(1–7) (10 ± 4% and 10 ± 2%, P < 0.05). Finally, the NOS inhibitor LNAME (10⁻⁴ M) reduced the response to 13 ± 2% (p < 0.05), but the cyclooxygenase inhibitor indomethacin failed to block the Ang-(1–7) response. We conclude that Ang-(1–7) exhibits potent vasorelaxant actions in the isolated renal artery that are dependent on an intact endothelium and the apparent stimulation of a NO-sGC pathway. Moreover, Ang-(1–7)-dependent vasorelaxation was sensitive to antagonists against the AT₇/Mas, AT₁, AT₂ and B₂ receptor subtypes.

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Different responses to angiotensin-(1-7) in young, aged and diabetic rabbit corpus cavernosum

Abstract

Introduction

Section snippets

Isolation of rabbit corpus cavernosum

Force measurements

Effect of Ang-(1-7)

Effect of A-779 on Ang-(1-7)-induced relaxation

Discussion

J Urol

J Androl

Peptides

J Urol

Kidney Int

J Urol

Endothelial dysfunction in diabetic erectile dysfunction

Int J Impot Res

Angiotensin-converting enzyme 2 and angiotensin-(1-7): an evolving story in cardiovascular regulation

Hypertension

Angiotensin-(1-7) and the renin–angiotensin system

Curr Opin Nephrol Hypertens

G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor

Circulation

ACE2 of the heart: From angiotensin I to angiotensin (1-7)

Cardiovasc Res

Antihypertensive actions of angiotensin-(1-7) in spontaneously hypertensive rats

Am J Physiol Heart Circ Physiol

Molecular mechanisms of inhibition of vascular growth by angiotensin-(1-7)

Hypertension

Cardiovascular actions of angiotensin-(1-7)

Braz J Med Biol Res

Angiotensin-(1-7) attenuates vasoconstriction evoked by angiotensin II but not by noradrenaline in man

Hypertension

Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats-treated with l-NAME

Am J Physiol Heart Circ Physiol

Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction

Am J Physiol Heart Circ Physiol

Downregulation of cGMP-dependent protein kinase-1 activity in the corpus cavernosum smooth muscle of diabetic rabbits

Am J Physiol Regul Integr Comp Physiol

Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas

Proc Natl Acad Sci USA

The angiotensin II receptor blockers: opportunities across the spectrum of cardiovascular disease

Rev Cardiovasc Med

Short-term angiotensin(1-7) receptor mas stimulation improves endothelial function in normotensive rats

Hypertension

Erectile dysfunction in mice lacking the large-conductance calcium-activated potassium (BK) channel

J Physiol