Flow-Evoked Vasodilation is Blunted in Penile Arteries from Zucker Diabetic Fatty Rats

Schjørring, Olav Lilleholt; Kun, Attila; Flyvbjerg, Allan; Kirkeby, Hans Jørgen; Jensen, Jørgen Bjerggaard; Simonsen, Ulf

doi:10.1111/j.1743-6109.2012.02743.x

Cited by 15 publications

(21 citation statements)

References 55 publications

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“…In addition to NO, an EDH, a non‐NO non‐prostanoid component, also plays a role in the acetylcholine‐evoked relaxation in the present study. These results are in agreement with previous observations where the presence of both NO and EDH in acetylcholine‐evoked relaxation have been demonstrated in penile resistance arteries isolated from human beings , rat , horse and rabbit .…”

Section: Discussionsupporting

confidence: 94%

Involvement of Large‐Conductance Ca²⁺‐Activated K⁺ Channels in both Nitric Oxide and Endothelium‐Derived Hyperpolarization‐Type Relaxation in Human Penile Small Arteries

Király

Pataricza

Bajory

et al. 2013

Basic Clin Pharma Tox

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Large-conductance Ca 2+ -activated K + channels (BK Ca ), located on the vascular smooth muscle, play an important role in regulation of vascular tone. In penile corpus cavernosum tissue, opening of BK Ca channels leads to relaxation of corporal smooth muscle, which is essential during erection; however, there is little information on the role of BK Ca channels located in penile vascular smooth muscle. This study was designed to investigate the involvement of BK Ca channels in endothelium-dependent and endothelium-independent relaxation of human intracavernous penile arteries. In human intracavernous arteries obtained in connection with transsexual operations, change in isometric force was recorded in microvascular myographs, and endotheliumdependent [nitric oxide (NO) and endothelium-derived hyperpolarization (EDH)-type] and endothelium-independent (NO-donor) relaxations were measured in contracted arteries. In penile small arteries contracted with phenylephrine, acetylcholine evoked NO-and EDH-type relaxations, which were sensitive to iberiotoxin (IbTX), a selective blocker of BK Ca channels. Iberiotoxin also inhibited relaxations induced by a NO-donor, sodium nitroprusside. NS11021, a selective opener of BK Ca channels, evoked pronounced relaxations that were inhibited in the presence of IbTX. NS13558, a BK Ca -inactive analogue of NS11021, failed to relax human penile small arteries. Our results show that BK Ca channels are involved in both NO-and EDH-type relaxation of intracavernous penile arteries obtained from healthy men. The effect of a selective opener of BK Ca channels also suggests that direct activation of the channel may be an advantageous approach for treatment of impaired endothelium-dependent relaxation often associated with erectile dysfunction.Erection is a haemodynamic event where vasodilatation of intracavernous arteries is followed by increased arterial blood inflow to the corpora cavernosa. During this process, activation of parasympathetic pelvic nerves leads to arterial dilatation and to initiation of erection while flow stimulation of the endothelium in the penis contributes to the sustained vasodilatation during erection. Nitric oxide (NO) released from both parasympathetic nerves and endothelial cells is a key mediator in erection [1]. In addition to NO, prostanoids and a non-NO/ non-prostanoid endothelium-derived hyperpolarization (EDH) have also been suggested to play a role in endothelium-dependent relaxation in erectile tissue [2]. EDH induces vascular relaxation in human [3,4], horse [5], bovine [6] and rat [7] penile arteries. The nature of EDH is still unclear, but myoendothelial gap junctions [8], potassium ions [9], products of the cytochrome P450 pathway [10], C-type natriuretic peptide (CNP) [3,11] and hydrogen peroxide [12] have been suggested to mediate EDH and lead to smooth muscle hyperpolarization and vasodilatation. Both smooth muscle inward-rectifier K + channels, Na-K-ATPase, and large-conductance calcium-activated K + channels have been proposed to be in...

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Section: Discussionsupporting

confidence: 94%

Involvement of Large‐Conductance Ca²⁺‐Activated K⁺ Channels in both Nitric Oxide and Endothelium‐Derived Hyperpolarization‐Type Relaxation in Human Penile Small Arteries

Király

Pataricza

Bajory

et al. 2013

Basic Clin Pharma Tox

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“…Mean arterial blood pressure (MAP) and intracavernous blood pressure (ICP) was measured using catheters placed, respectively, in the carotid artery and corpus cavernosum as previously described 11 . Maximal stimulation (6 V, 1ms, 16 Hz, 60 s) was applied to check maximal erectile function at the beginning of each experiment, before incremental frequencies (2, 4, 8 and 16 Hz) were applied at 1.5, 3, and 6 V. At the end of the experiment the maximal response was repeated to ensure that the cavernous nerve was intact and erectile function maintained.…”

Section: Methodsmentioning

confidence: 99%

“…In rat penile arteries, we found that K Ca 2.3 and K Ca 3.1 channels contribute to flow-induced vasodilation and that these dilatations were impaired in type 2 diabetic Zucker diabetic fatty (ZDF) rats 11 . Moreover, in mesenteric arteries from ZDF rats an opener of K Ca 2.1–3 and K Ca 3.1 channels restored endothelium-derived hyperpolarization (EDH) type relaxations induced by acetylcholine 12 .…”

Section: Introductionmentioning

confidence: 95%

Down-regulation of KCa2.3 channels causes erectile dysfunction in mice

Comerma-Steffensen

Kun

Hedegaard

et al. 2017

Sci Rep

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Modulation of endothelial calcium-activated K+ channels has been proposed as an approach to restore arterial endothelial cell function in disease. We hypothesized that small-conductance calcium-activated K+ channels (KCa2.3 or SK3) contributes to erectile function. The research was performed in transgenic mice with overexpression (KCa2.3T/T(−Dox)) or down-regulation (KCa2.3T/T(+Dox)) of the KCa2.3 channels and wild-type C57BL/6-mice (WT). QPCR revealed that KCa2.3 and KCa1.1 channels were the most abundant in mouse corpus cavernosum. KCa2.3 channels were found by immunoreactivity and electron microscopy in the apical-lateral membrane of endothelial cells in the corpus cavernosum. Norepinephrine contraction was enhanced in the corpus cavernosum of KCa2.3T/T(+Dox) versus KCa2.3T/T(−Dox) mice, while acetylcholine relaxation was only reduced at 0.3 µM and relaxations in response to the nitric oxide donor sodium nitroprusside were unaltered. An opener of KCa2 channels, NS309 induced concentration-dependent relaxations of corpus cavernosum. Mean arterial pressure was lower in KCa2.3T/T(−Dox) mice compared with WT and KCa2.3T/T(+Dox) mice. In anesthetized mice, cavernous nerve stimulation augmented in frequency/voltage dependent manner erectile function being lower in KCa2.3T/T(+Dox) mice at low frequencies. Our findings suggest that down-regulation of KCa2.3 channels contributes to erectile dysfunction, and that pharmacological activation of KCa2.3 channels may have the potential to restore erectile function.

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“…Like ageing, diabetes impacts vascular function. In fact, the impairment of endothelium-dependent vasodilatation is a frequent finding in arteries from diabetic animals and patients in both in vivo and ex vivo settings Angulo et al 1998;Kim et al 2002;Rodríguez-Mañas et al 2003;Angulo et al 2003;Molnar et al 2005;Schjørring et al 2012). Furthermore, endothelial dysfunction is a predictor of CVD in diabetic patients (van Slotten et al 2014).…”

Section: Vascular Dysfunction In Diabetesmentioning

confidence: 99%

“…; Schjørring et al . ). Furthermore, endothelial dysfunction is a predictor of CVD in diabetic patients (van Slotten et al .…”

Section: Introductionmentioning

confidence: 97%

Diabetes and ageing‐induced vascular inflammation

Assar

Angulo

Rodríguez‐Mañas

2015

The Journal of Physiology

101

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Diabetes and the ageing process independently increase the risk for cardiovascular disease (CVD). Since incidence of diabetes increases as people get older, the diabetic older adults represent the largest population of diabetic subjects. This group of patients would potentially be threatened by the development of CVD related to both ageing and diabetes. The relationship between CVD, ageing and diabetes is explained by the negative impact of these conditions on vascular function. Functional and clinical evidence supports the role of vascular inflammation induced by the ageing process and by diabetes in vascular impairment and CVD. Inflammatory mechanisms in both aged and diabetic vasculature include pro‐inflammatory cytokines, vascular hyperactivation of nuclear factor‐кB, increased expression of cyclooxygenase and inducible nitric oxide synthase, imbalanced expression of pro/anti‐inflammatory microRNAs, and dysfunctional stress‐response systems (sirtuins, Nrf2). In contrast, there are scarce data regarding the interaction of these mechanisms when ageing and diabetes co‐exist and its impact on vascular function. Older diabetic animals and humans display higher vascular impairment and CVD risk than those either aged or diabetic, suggesting that chronic low‐grade inflammation in ageing creates a vascular environment favouring the mechanisms of vascular damage driven by diabetes. Further research is needed to determine the specific inflammatory mechanisms responsible for exacerbated vascular impairment in older diabetic subjects in order to design effective therapeutic interventions to minimize the impact of vascular inflammation. This would help to prevent or delay CVD and the specific clinical manifestations (cognitive decline, frailty and disability) promoted by diabetes‐induced vascular impairment in the elderly.

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Flow-Evoked Vasodilation is Blunted in Penile Arteries from Zucker Diabetic Fatty Rats

Cited by 15 publications

References 55 publications

Involvement of Large‐Conductance Ca²⁺‐Activated K⁺ Channels in both Nitric Oxide and Endothelium‐Derived Hyperpolarization‐Type Relaxation in Human Penile Small Arteries

Involvement of Large‐Conductance Ca²⁺‐Activated K⁺ Channels in both Nitric Oxide and Endothelium‐Derived Hyperpolarization‐Type Relaxation in Human Penile Small Arteries

Down-regulation of KCa2.3 channels causes erectile dysfunction in mice

Diabetes and ageing‐induced vascular inflammation

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Flow-Evoked Vasodilation is Blunted in Penile Arteries from Zucker Diabetic Fatty Rats

Cited by 15 publications

References 55 publications

Involvement of Large‐Conductance Ca2+‐Activated K+ Channels in both Nitric Oxide and Endothelium‐Derived Hyperpolarization‐Type Relaxation in Human Penile Small Arteries

Involvement of Large‐Conductance Ca2+‐Activated K+ Channels in both Nitric Oxide and Endothelium‐Derived Hyperpolarization‐Type Relaxation in Human Penile Small Arteries

Down-regulation of KCa2.3 channels causes erectile dysfunction in mice

Diabetes and ageing‐induced vascular inflammation

Contact Info

Product

Resources

About

Involvement of Large‐Conductance Ca²⁺‐Activated K⁺ Channels in both Nitric Oxide and Endothelium‐Derived Hyperpolarization‐Type Relaxation in Human Penile Small Arteries

Involvement of Large‐Conductance Ca²⁺‐Activated K⁺ Channels in both Nitric Oxide and Endothelium‐Derived Hyperpolarization‐Type Relaxation in Human Penile Small Arteries