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Hypertension (defined as self-reported hypertension, use of antihypertensive medication, and/or >140 mmHg SBP and >90 mmHg DBP [332]) is a highly prevalent condition worldwide [333, 334] and a major risk factor in CVD [335]. The 2008/2009 NZANS [334] showed that 34% of NZ men over 15 years of age had hypertension and 14% used hypertensive medication. Although a clinical cutoff value of >140/>90 mmHg is often used, the 2003 WHO and International Society of Hypertension guidelines for the diagnosis of hypertension [332] further classify hypertension into Grade 1, 2 and 3 as shown in Table 2.10. Elevated BP is well established as a risk factor for CVD; however, this effect is modified by age with raised DBP being a better predictor in young people and elevated SBP in the middle-aged and elderly [335]. The Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [336, 337] guidelines state that: SBP>140 mmHg is more important than DBP in persons >50 years; CVD risk doubles in 20/10 mmHg increments from 115/75 mmHg and there is a 90% lifetime risk of hypertension in people who are normotensive at 55 years; and those with a SBP 120-139 mmHg or a DBP 80-89 mmHg are prehypertensive and require lifestyle modification. Additionally, pulse pressure (PP) and mean arterial pressure (MAP) are important markers of peripheral and arterial vascular resistance respectively and may be superior predictors of CVD risk in middle-aged and elderly people [335].

Table 2.10. Classification of hypertension according to the 2003 World Health Organization/International Society of Hypertension (WHO/ISH) guidelines [332].

Blood pressure (BP) Grade 1 Grade 2 Grade 3

Systolic BP (mmHg) 140-159 160-179 шϭϴϬ

Diastolic BP (mmHg) 90-99 100-109 шϭϭϬ

ED is highly prevalent in the hypertensive population [119, 318, 338] and hypertension is extremely common in men with ED [161]. Although an early RCT [321] suggested this was not the case - the Treatment of Mild Hypertension Study (TOMHS) reported that ED was relatively rare (12%) in mild hypertensives (n=902, 557 men, 45–69 years) - the inclusion criteria of this study would have excluded most ED cases. However, the results did support an association between ED and both SBP and use of antihypertensive medication. A later clinical-based study [318] (n=476) of patients with hypertension reported 68% prevalence of ED and 45% had severe ED. ED is also more prevalent in hypertensive men compared to the general population [119, 338]. In the USA, the MMAS [1] showed a 15% age-adjusted prevalence of complete ED in treated hypertensives versus 9.6% in the entire sample and ED was associated with both the duration and severity of the hypertension. The NHANES [119] found an age-adjusted prevalence rate of 15% moderate-severe ED in men with untreated hypertension and 28% in men with treated hypertension. Hypertension was present in 36% of men with ED in the multinational MALES study [161] compared with 19% in men without ED (p<0.0001). Furthermore, in a survey of general medical patients (n=7689, mean age=58.9 years), Giuliano et al [338] reported ED (IIEF-5 score <22) in 67% of hypertensive patients, 71% of diabetic patients, and 77% of patients with both conditions. Also, the prevalence was affected by the history and characteristics of the hypertension and the number and type of antihypertensives used. It is uncertain whether it is hypertension per se or antihypertensive medications or a combination of the two causing the higher prevalence of ED in epidemiological studies.

It is well established that antihypertensive therapy can cause ED [339]. However, results from the FAMAS [168] cohort showed that significantly more Australian men with hypertension had that mild ED and hypertension was a significant predictor of only mild ED (OR=1.79 [1.18- 2.71]). When hypertension was further split into diagnosed hypertension, use of antihypertensives and measured hypertension, the largest contributor to the increased risk was measured BP (OR=1.67 [1.05-2.61]), suggesting that it is predominately the hypertension and not the medication behind the higher prevalence of ED in hypertensives. They also ranked the antihypertensive medications by effect size and found the following therapies contributed significantly to the effect of hypertensive medication on mild ED (OR=1.44 [1.02-2.66]): angiotensin II inhibitors, Ca2+-channel blockers, thiazides, angiotensin-converting enzyme (ACE)

inhibitors, high ceiling diuretics and beta-blockers. This contrasts with an earlier review by Baumhakel et al [340] which found evidence to support the adverse effect of thiazide diuretics and beta-blockers (except Nebivolol) but either no effect or a favourable effect of ACE inhibitors, angiotensin-receptor blockers and Ca2+-channel blockers. Further research is needed to clarify the effect of specific medications on erectile function.

Blood flow is essential for tumescence and the primary pathogenesis of ED in hypertension is suggested to be atherosclerosis with resultant altered haemodynamics reducing penile blood flow [341]. Jensen et al [342] reported 27% of men with hypertension had ED and their SBP was significantly higher than men without ED (p=0.046). Further examination of penile function (including flaccid and dynamic PDS) revealed that the vast majority of cases (89%) were vasculogenic in aetiology and due to arterial dysfunction: IHD was a significant determinant of hypertensive ED (p=0.005). Furthermore, experimental studies have shown that Nebivolol, a beta-receptor blocker, reduces oxidative stress and improves endothelial function in the aorta and CC of apolipoprotein-e knockout mice [343]. It also appears to increase sinusoidal eNOS expression, improve relaxation and protect against structural changes to CC tissue in spontaneously hypertensive rats [344]. Sustained hypertension may result in increased oxidative stress and damage to both endothelial cells and SMC resulting in a reduction in dilation and penile blood flow [345]. PDE5 inhibitors have been shown to improve

hypertensive ED and also cause a mild reduction in overall BP; however, they are contraindicated in some cases as they may have a synergistic effect with certain hypertensive medications (e.g., organic nitrates) leading to hypotension [345]. Hypertension is well established as a risk factor for ED and the development of ED in hypertensive men indicates further deterioration in vascular health.