Experimental studies in rats indicate that hypertension results in structural and functional alterations in the cavernous tissue, just like in other vessels, and point towards significant between-class and in-class differences between antihypertensive drugs.

In a comparison study between normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) for 8 months, it was found that the cavernous smooth muscle proliferation score and the vascular smooth muscle proliferation score were significantly higher in hypertensive rats [22]. Similarly, the fibrosis score of cavernous tissue was higher in hypertensive than in normotensive rats. Another study evaluated the effects of candesartan, an ARB, on the structural alterations of cavernous tissue. Treatment with candesartan for 4 months attenuated the morphologic changes in the vessels and the cavernous spaces of erectile tissue, which were induced by hypertension, exhibiting a protective role in spontaneously hypertensive rats [23].

A disparity in the effects of different antihypertensive drugs was found in four experimental studies. The first study evaluated the effects of candesartan and atenolol for 6 months using untreated SHR and normotensive WKY rats as controls [24]. It was found that atenolol did not attenuate the structural alterations on erectile tissue associated with hypertension, while candesartan exhibited beneficial effects and the erectile morphology resembled the morphology of normotensive rats. The second study had a similar design and compared the effects of nebivolol with those of amlodipine for 6 months. It was found that amlodipine failed to attenuate the structural changes induced by hypertension in SHR, while nebivolol protected from the development of morphological alterations [25]. It was also found that nebivolol treatment enhanced the expression of endothelial nitric oxide synthase in erectile tissue reaching the levels observed in normotensive rats, while the expression was significantly lower in untreated and amlodipine-treated spontaneously hypertensive rats. In the third study, candesartan was compared with hydralazine for 4 months. The beneficial effects of candesartan on erectile structural and functional alterations were reconfirmed, while hydralazine failed to exert similar protective effects [26]. In the fourth study, losartan was compared with amlodipine for 6 months. Losartan exerted significant benefits on the morphology of erectile tissue, similar to the ones observed with candesartan in previous studies. In contrast, amlodipine therapy did not attenuate hypertension-induced structural alterations in erectile function [27]. It has to be noted that blood pressure reduction was similar between the two treatment drugs in all four experimental studies.

Taken together, the findings of experimental studies indicate that high blood pressure is associated with significant morphological and functional alterations in the erectile tissue. A large heterogeneity in the effects of antihypertensive therapy is observed. Some drugs (ARBs, nebivolol) seem to protect the erectile tissue, while other drugs (atenolol, amlodipine, hydralazine) do not have these protective properties. Therefore, the benefits of antihypertensive therapy seem to occur beyond blood pressure reduction, with significant differences not only between different drug classes (ARBs vs. calcium antagonists and hydralazine) but also within drug classes (nebivolol vs. atenolol).

The above mentioned differences between antihypertensive drugs were also observed in animals with chronic renal insufficiency via subtotal nephrectomy. It was found that RAS inhibitors (losartan and benazepril) exerted protective effects on penile structure, while amlodipine and atenolol failed to exert similar benefits [28].

Another significant set of information comes from studies that combined antihypertensive drugs with PDE-5 inhibitors. In one study, a combination therapy with losartan and sildenafil was compared to each monotherapy alone. It was found that the beneficial effects of combination therapy on penile structure and function were greater than the effects of each monotherapy alone [8]. The beneficial effects of combination therapy on the functional level were confirmed in human cavernosal with the combination of sildenafil and doxazosin [29].

Data from observational studies suggest that there exist both between-class and within-class differences in the effects of antihypertensive therapy on erectile function.

A large, observational, cross-sectional study of 634 consecutive young and middle-aged (31–65 years) individuals assessed erectile function with different antihypertensive drug classes [21]. It was reported that erectile function scores were significantly lower with older antihypertensive drugs (diuretics and beta-blockers) than with newer-generation antihypertensive drugs (calcium antagonists, ACE inhibitors, ARBs). The higher erectile function score was observed in patients on ARBs. Of note, similar results were observed in females as well in another observational cross-sectional study of 417 women [30].

Another large, cross-sectional study evaluated the effects of beta-blockers on erectile function [31]. The study included 1,007 high-risk hypertensive patients (mean age 57.9 years) treated with beta-blockers for at least 6 months. The prevalence of erectile dysfunction was very high (71 %) in this group of patients and of relatively high severity (16.1 % severe; 16.8 % moderate; 38.1 % mild). Of major clinical significance, substantial differences between the various beta-blockers were reported. Specifically, nebivolol was associated with the lowest prevalence of erectile dysfunction, metoprolol and carvedilol were associated with the highest prevalence, and bisoprolol and atenolol lie in between.

Significant information about the effects of antihypertensive therapy on erectile function comes from clinical studies, which were specifically designed to address this issue.

A double-blind, randomized, crossover study of 90 hypertensive middle-aged men without sexual dysfunction evaluated the effects of lisinopril (20 mg) and atenolol (100 mg) for 16 weeks [32]. Sexual activity remained practically unaltered with lisinopril (from 7.1 to 7.7 sexual intercourses per month) but worsened significantly with atenolol (from 7.8 to 4.2 sexual intercourses per month), and the difference between the two groups was statistically significant (p < 0.01).

In a double-blind, randomized, crossover study of 160 newly diagnosed hypertensive males of middle age (40–49 years), free of sexual dysfunction, valsartan (80 mg) was compared to carvedilol (50 mg) for 16 weeks [33]. It was found that sexual activity was significantly improved with valsartan (from 8.2 to 10.2 sexual intercourses per month), while sexual activity deteriorated significantly with carvedilol (from 8.3 to 3.7 sexual intercourses per month). Erectile dysfunction was reported more frequently with carvedilol (13.5 %) than with valsartan (0.9 %).

Another double-blind, randomized study of 110 middle-aged hypertensive men naïve to antihypertensive therapy compared the effects of valsartan (80 mg) with those of atenolol (50 mg) for 16 weeks [34]. Sexual activity improved with valsartan (from 5.8 to 7.4 sexual intercourses per month) but deteriorated with atenolol (from 6.0 to 4.2 sexual intercourses per month), and the differences between the two groups were statistically significant (p < 0.05). Testosterone levels remained unaffected with valsartan but were significantly reduced with atenolol. Of note, similar results were observed in hypertensive women as well. In a randomized study of 120 postmenopausal hypertensive women, sexual desire and sexual fantasy were significantly improved with valsartan and worsened with atenolol [35].

These studies were of high methodological standards and were designed to assess sexual function specifically and not as a secondary end point of a study designed to evaluate other topics. However, several limitations can be identified, including the relatively small patient population, the determination of sexual intercourses as an index of sexual activity instead of global erectile function, and the use of invalidated questionnaires. Despite these limitations, the importance of information derived from these studies remains substantial, since these small clinical studies are the only studies performed in untreated patients and specifically evaluating sexual function.

Several large multicenter trials reported the effects of antihypertensive therapy on erectile function during the last decades.

The Medical Research Council (MRC) trial for mild hypertension compared the effects of bendrofluazide and propranolol with those of placebo for 23.582 patient years of observation [36]. Withdrawal from the study due to impotence was twofold higher with diuretics than with beta-blockers and substantially higher than with placebo (p < 0.001 for all comparisons).

The Trial of Antihypertensive Interventions and Management (TAIM) was a multicenter, randomized, placebo-controlled study that included 697 overweight and obese patients with mild hypertension [37]. The study compared chlorthalidone and atenolol with placebo and evaluated the effects of diet. A worsening of erectile-related problems was significantly more common with chlorthalidone (28 %; 95 %CI: 15–41 %) compared with placebo (3 %; 95%CI: 0–9 %) and atenolol (11 %; 95%CI: 2–20 %). The detrimental effects of chlorthalidone on erectile function were attenuated by weight reduction.