Background— Elevated heart rate is associated with increased cardiovascular morbidity. We hypothesized that selective heart rate reduction may influence endothelial function and atherogenesis and tested the effects of the I (f) current inhibitor ivabradine in apolipoprotein E–deficient mice. Methods and Results— Male apolipoprotein E–deficient mice fed a high-cholesterol diet were treated with ivabradine (10 mg · kg −1 · d −1 ) or vehicle for 6 weeks (n=10 per group). Ivabradine reduced heart rate by 13.4% (472±9 versus 545±11 bpm; P <0.01) but did not alter blood pressure or lipid levels. Endothelium-dependent relaxation of aortic rings was significantly improved in ivabradine-fed animals ( P <0.01). Ivabradine decreased atherosclerotic plaque size in the aortic root by >40% and in the ascending aorta by >70% ( P <0.05). Heart rate reduction by ivabradine had no effect on the number of endothelial progenitor cells and did not alter aortic endothelial nitric oxide synthase, phosphorylated Akt, vascular cell adhesion molecule-1, or intercellular adhesion molecule-1 expression but decreased monocyte chemotactic protein-1 mRNA and exerted potent antioxidative effects. Ivabradine reduced vascular NADPH oxidase activity to 48±6% and decreased markers of superoxide production and lipid peroxidation in the aortic wall ( P <0.05). The in vivo effects of ivabradine were absent at a dose that did not lower heart rate, in aortic rings treated ex vivo, and in cultured vascular cells. In contrast to ivabradine, treatment with hydralazine (25 mg · kg −1 · d −1 for 6 weeks) reduced blood pressure (−15%) but increased heart rate (37%) and did not improve endothelial function, atherosclerosis, or oxidative stress. Conclusions— Selective heart rate reduction with ivabradine decreases markers of vascular oxidative stress, improves endothelial function, and reduces atherosclerotic plaque formation in apolipoprotein E–deficient mice.

Summary Aims:  Erectile dysfunction is a major problem with an increasing prevalence in cardiovascular high‐risk patients due to its association with cardiovascular risk factors. Drugs used for evidence‐based treatment of cardiovascular diseases have been reported to decrease erectile function, but possible mechanisms are poorly characterised. Methods:  MEDLINE, EMBASE and Cochrane Registry search were performed including manuscripts until January 2010. Searching terms are: ‘erectile dysfunction or impotence’ in combination with ‘ACE‐inhibitors’, ‘angiotensin’, ‘beta‐blockers’, ‘calcium antagonist’ and ‘diuretics’. Animal studies, letters, reviews, case‐reports and manuscripts other than English language and trials dealing with combination treatment are excluded. Results:  Analysis of literature revealed five epidemiological trials evaluating the effect of different cardiovascular drugs on erectile function. There were eight trials evaluating the effect of beta‐blockers, five trials evaluating the effect of ace‐inhibitors or angiotensin‐receptor‐blockers and one trial evaluating the effect of diuretics on erectile function. Results of these trials demonstrate that only thiazide diuretics and beta‐blockers except nebivolol may adversely influence erectile function. ACE‐inhibitors, angiotensin‐receptor‐blockers and calcium‐channel‐blockers are reported to have no relevant or even a positive effect on erectile function. Conclusion:  Inappropriate patients’ concerns about adverse effects of cardiovascular drugs on erectile function might limit the use of important medications in cardiovascular high‐risk patients. Knowledge about the effects of drug‐treatments on erectile function and about the major role of the endothelium in penile function might improve patients’ adherence to evidence based treatment of cardiovascular diseases.

Pathogenesis of erectile dysfunction (ED) is related to endothelial dysfunction and therefore associated with cardiovascular risk factors. Patients with a combination of risk factors, as in metabolic syndrome, are thus likely to have an increased risk of developing endothelial and ED. The angiotensin receptor antagonist irbesartan has been shown to improve endothelial function in cardiovascular high-risk patients, which suggests a beneficial effect of treatment with irbesartan on ED. The aim of the present study was to determine the influence of irbesartan on ED in patients with a metabolic syndrome. A total of 1069 consecutive hypertensive patients with a metabolic syndrome from the Documentation of hypertension and metabolic syndrome in patients with Irbesartan Treatment survey were included. Patients were treated with irbesartan or the combination of irbesartan/hydrochlorothiazide for 6 months. ED was assessed using the international index of erectile function. The Cologne Evaluation Questionnaire of Erectile Dysfunction served as a control. Erectile function increased significantly (Po0.0001) after 6 months of treatment with irbesartan, irrespective of dosage and independent of additional treatment with hydrochlorothiazide. Prevalence of ED declined to 63.7% from 78.5% at baseline, along with a significant increase in orgasmic function (Po0.001) and intercourse satisfaction (Po0.001). Treatment with irbesartan alone, as well as in combination with hydrochlorothiazide is associated with an improvement of sexual desire, frequency of sexual contacts and erectile function in hypertensive patients with the metabolic syndrome. These results suggest a beneficial role of angiotensin receptor antagonists in the treatment of metabolic syndrome, and ED.

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Angiotensin receptor blockers enhance endothelial function and are suggested to improve erectile function. The effects and underlying mechanisms of treatment with the angiotensin receptor blocker irbesartan on penile endothelial function in apolipoprotein E (ApoE) Ϫ/Ϫ mice were determined. Wild-type (C57/ B6) and ApoE Ϫ/Ϫ mice were fed with a high-fat, cholesterol-rich diet for 7 weeks and treated with irbesartan (50 mg/kg ⅐ day) or hydralazine (250 mg/l). Vital parameters were measured with the tail-cuff method. Endothelial (aortic rings) and erectile function (corpora cavernosa) were assessed by pharmacological stimulation in an organ bath chamber. Oxidative stress and angiotensin receptor expression were determined. Blood pressure was significantly decreased in irbesartan-and hydralazinetreated ApoE Ϫ/Ϫ mice (p Ͻ 0.05) compared with controls and wild-type mice. Endothelial function of the aorta and corpus cavernosum was significantly impaired in ApoE Ϫ/Ϫ mice (p Ͻ 0.05) and could be restored by treatment with irbesartan (p Ͻ 0.05). Consistently, nitric oxide production of corpora cavernosa was impaired in ApoE Ϫ/Ϫ mice (p Ͻ 0.01), with a restoration in irbesartan-but not hydralazine-treated mice. Dihydroethidium-stained sections and lipid peroxidase assay revealed a reduction of superoxide production in irbesartan (p Ͻ 0.05) compared with hydralazine-treated and control ApoE Ϫ/Ϫ mice. In summary, irbesartan improves penile endothelial function in ApoE Ϫ/Ϫ mice by reduction of vascular and cavernosal oxidative stress. This result emphasizes the beneficial effect of inhibition of the renin-angiotensin system even in terms of erectile function.Erectile dysfunction (ED) is defined as the inability to attain or maintain penile erections sufficient for satisfactory sexual performance (NIH Consensus Development Panel on Impotence, 1993). In the Western industrialized countries, prevalence of ED in the general population is approximately 20 to 30%, with an economical and significant psychological impact (Feldman et al., 1994;Braun et al., 2000). In cardiovascular high-risk patients, prevalence of ED rises up to 75%, indicating the strong association of ED with the known cardiovascular risk factors and cardiovascular diseases Böhm et al., 2007). Impairment of endothelial function by cardiovascular risk factors such as hypertension seems to be the pathophysiological link, because nitric oxide synthesis plays a crucial role in physiology of penile erection (Yavuzgil et al., 2005).Inhibition of the renin-angiotensin system is known to reduce blood pressure effectively. Moreover, recent studies suggested a beneficial effect of antihypertensive treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists on erectile function (Fogari et al., 1998(Fogari et al., , 2001Dusing, 2003). The beneficial effect of angiotensin receptor blockade with irbesartan on erectile function was also observed in patients with metabolic syndrome and hypertension. The local synthesis of angiotensin II in th...