Calcium dobesilate potentiates endothelium‐derived hyperpolarizing factor‐mediated relaxation of human penile resistance arteries

Abstract

1 We have evaluated the participation of endothelium-derived hyperpolarizing factor (EDHF) in the endothelium-dependent relaxation of isolated human penile resistance arteries (HPRA) and human corpus cavernosum (HCC) strips. In addition, the effect of the angioprotective agent, calcium dobesilate (DOBE), on the endothelium-dependent relaxation of these tissues was investigated. 2 Combined inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) nearly abolished the endothelium-dependent relaxation to acetylcholine (ACh) in HCC, while 60% relaxation of HPRA was observed under these conditions. Endothelium-dependent relaxation of HPRA resistant to NOS and COX inhibition was prevented by raising the extracellular concentration of K þ (35 mm) or by blocking Ca 2 þ -activated K þ channels, with apamin (APA; 100 nm) and charybdotoxin (CTX; 100 nm), suggesting the involvement of EDHF in these responses. 3 Endothelium-dependent relaxation to ACh was markedly enhanced by DOBE (10 mm) in HPRA but not in HCC. The potentiating effects of DOBE on ACh-induced responses in HPRA, remained after NOS and COX inhibition, were reduced by inhibition of cytochrome P450 oxygenase with miconazole (0.3 mm) and were abolished by high K þ or a combination of APA and CTX. 4 In vivo, DOBE (10 mg kg À1 i.v.) significantly potentiated the erectile responses to cavernosal nerve stimulation in male rats. 5 EDHF plays an important role in the endothelium-dependent relaxation of HPRA but not in HCC. DOBE significantly improves endothelium-dependent relaxation of HPRA mediated by EDHF and potentiates erectile responses in vivo. Thus, EDHF becomes a new therapeutic target for the treatment of erectile dysfunction (ED) and DOBE could be considered a candidate for oral therapy for ED.

Ca2+‐activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

“…Functional differences between HPRA and HCC in response to vasoactive drugs have been previously described (Hedlund and Andersson, 1985;Angulo et al, 2002). In addition, endotheliumdependent relaxation attributed to endothelium-derived hyperpolarizing factor plays a significant role in human penile arteries but not in corpus cavernosum (Angulo et al, 2003). This endothelial process involving KCa, which is functional in penile arteries but not in trabecular tissue, is a functional divergence that could be related to the present findings.…”

“…Activators of KCa also have the capacity to relax human and animal penile smooth muscles Hewawasam et al, 2004). In addition, this type of channels has a key role in endothelium-derived hyperpolarizing factor-mediated relaxation of human penile arteries (Angulo et al, 2003). Furthermore, the delivery of the gene for human BK (hSlo) into the penis has been shown to increase erectile responses in aged rats (Melman et al, 2003) and to recover erectile function in diabetic rats (Christ et al, 2004).…”

Reduced expression of SK3 and IK1 channel proteins in the cavernous tissue of diabetic rats

“…Under physiological conditions, the endothelium exerts regulatory effects on vasodilatation, as it releases numerous vasoactive substances, such as NO, bradykinin, prostaglandin I2, substance P and so on. EDHF is another vasoactive substance and it has been found in rat, horse and human penile small arteries [5][6][7][8]17]. Moreover, in systemic arteries, several EDHF candidates have been suggested, including potassium ions, products of the cytochrome P450 pathway, C-type natriuretic peptide, hydrogen peroxide and K + [7,18,19].…”

“…Besides the well-established nitric oxide (NO)/ cyclic guanosine monophosphate pathway, recent reports have shown the existence of a second, distinct endothelial pathway involving the endothelium-dependent hyperpolarization factor (EDHF). Specifically, this factor has been shown to be involved in the relaxation of the vascular smooth muscle cells in penile arteries [5][6][7][8]. Angulo [9] has reported that diabetes can impair endothelium-dependent relaxation of human penile vascular tissues mediated by EDHF, but the causes remain unclear.…”

Physiological regulation of penile arteries and veins

“…60,61 However, the involvement of endothelial NO in the agonist-induced vasodilations of the erectile tissues is variable, being more relevant in CC 17,31,60,82 than in the small penile resistance arteries, where a non-NO non-prostanoid factor is a major component of the endothelium-dependent relaxant responses. 60,61,83,84 Clinical investigations have recently demonstrated a flow-dependent vasodilatation in penile arteries by measuring the changes in the cavernous artery diameter after 5 min occlusion of penile flow. 85 These studies showed that flow-induced vasodilatation is strongly impaired in patients with organic ED and proposed this measurement as a clinical test to evaluate penile endothelial function.…”