Different responses to angiotensin-(1-7) in young, aged and diabetic rabbit corpus cavernosum
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 (AT1-7) and releasing vasodilatory prostaglandins [6]. Ang II does not activate AT1-7 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 (Emax) 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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