Calcification of the internal pudendal artery and development of erectile dysfunction in adenine-induced chronic kidney disease: a sentinel of systemic vascular changes.

INTRODUCTION: Chronic kidney disease (CKD), erectile dysfunction (ED), and cardiovascular disease share common vascular etiologies and risk factors. AIM: Using a rat model, this is the first study to characterize the consequences of CKD in the onset and development of ED associated with differential regional vascular calcification and circulatory changes. METHODS: Stable CKD was generated at 3 weeks in male Sprague-Dawley rats given dietary adenine and progressed until 7 weeks. Mineral content and morphometry were assessed in the internal pudendal arteries (IPAs), thoracic aorta, and carotid artery. Endothelial function was determined via changes in serum von Willebrand factor (VWF) and endothelium-dependent relaxation of the thoracic aorta. RESULTS: In severe CKD rats, calcium and phosphate content in all arteries increased, and pulse wave velocity was elevated. Distal IPA segments, in particular, were the first to calcify, but penile tissue per se did not. CKD rats had endothelial dysfunction, as indicated by a decrease in acetylcholine-mediated relaxation (∼40%) and an increase in serum VWF (∼40%), as well as increased lumen diameter (20%) of the distal IPA. Erectile function, assessed using a centrally acting dopaminergic agent, was significantly impaired by 7 weeks (∼40%). CONCLUSIONS: In CKD, the distal IPA appears to be more susceptible to vascular dysfunction and calcification. Additionally, the onset of ED may be an important sentinel of impending systemic vascular disease. To confirm this concept, future experimental and clinical studies will need to examine a range of vessel types and the use of supplementary methods to assess erectile function.

Dietary vitamin K and therapeutic warfarin alter the susceptibility to vascular calcification in experimental chronic kidney disease.

The leading cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease, with vascular calcification being a key modifier of disease progression. A local regulator of vascular calcification is vitamin K. This γ-glutamyl carboxylase substrate is an essential cofactor in the activation of several extracellular matrix proteins that inhibit calcification. Warfarin, a common therapy in dialysis patients, inhibits the recycling of vitamin K and thereby decreases the inhibitory activity of these proteins. In this study, we sought to determine whether modifying vitamin K status, either by increasing dietary vitamin K intake or by antagonism with therapeutic doses of warfarin, could alter the development of vascular calcification in male Sprague-Dawley rats with adenine-induced CKD. Treatment of CKD rats with warfarin markedly increased pulse pressure and pulse wave velocity, as well as significantly increased calcium concentrations in the thoracic aorta (3-fold), abdominal aorta (8-fold), renal artery (4-fold), and carotid artery (20-fold). In contrast, treatment with high dietary vitamin K1 increased vitamin K tissue concentrations (10-300-fold) and blunted the development of vascular calcification. Thus, vitamin K has an important role in modifying mechanisms linked to the susceptibility of arteries to calcify in an experimental model of CKD.

Characterization of the vasculature supplying the genital tissues in female rats.

INTRODUCTION: The internal pudendal arteries are the key resistance vessels controlling the peripheral circulatory component of sexual responses in both male and females. Previous studies in the male rat demonstrated that this vessel has markedly heightened susceptibility to vascular damage compared with other vessels in the body. Evidence suggests that the female may also be susceptible to vascular pathologies contributing to sexual dysfunction. AIM: The aim of this study is to characterize the anatomical, morphological, and functional properties of the pudendal artery in female rats. METHODS: The pelvic arteries in young Sprague-Dawley female rats were dissected to generate a composite representation of the vascular gross anatomy. Morphometry was performed on perfusion-fixed pudendal arteries whereas others were mounted in a wire myograph to assess responses to vasoactive drugs. These measures were contrasted with a previous study examining male rats. MAIN OUTCOME MEASURES: Outcome measures used are gross anatomy, lumen diameter, wall thickness, cross-sectional area, and contractile responses in the internal pudendal artery. RESULTS: The gross anatomy of the pudendal artery in female rats appears to parallel that found in male rats, acting as the primary feeder vessel of the clitoral, labial, and vaginal tissue. Compared with the male rat, the female pudendal artery has a smaller lumen diameter (169 ± 5.7 vs. 303 ± 13.8 µm), wall thickness (14 ± 0.7 vs. 47 ± 2.2 µm), and cross-sectional area (8 ± 0.4 vs. 52 ± 3.4 × 103 µm(2) ). These structural differences also translate into a decreased contractile capacity of the pudendal arteries from female rats vs. male rats (8.1 ± 2.7 vs. 20 ± 1.4 mN). CONCLUSIONS: Although the gross anatomical features of the vasculature tree supplying the genital tissue in male and female rats appear to have similarities, the tissue-specific properties of the vessel itself have a very different structure-function balance. We hypothesize that this discordance likely reflects the very different sex-specific roles of this vessel in regulating blood flow during arousal.

Impact of hypertension, aging, and antihypertensive treatment on the morphology of the pudendal artery.

INTRODUCTION: Aging and hypertension increase the risk of erectile dysfunction (ED) and cardiovascular disease. Arterial insufficiency is likely a primary factor in hypertension-related ED. Given the dominance of internal pudendal arteries in controlling penile vascular resistance, pathological changes in this vessel would be critical for inducing ED in aged hypertensives. AIM: We assessed the age-related impact of hypertension and its treatment on erectile function and pudendal artery structure in young and old spontaneously hypertensive rats (SHRs). METHODS: Erectile responses were monitored in 15- and 77-week-old SHR and Wistar Kyoto (WKY) rats using apomorphine (80 mg/kg). At sacrifice, the vasculature was perfusion-fixed and aorta, renal, mesenteric, and internal pudendal arteries assessed morphometrically using light and electron microscopy. A separate group of 15-week SHR were treated with enalapril and hydrochlorothiazide (30 mg/kg/day, 2 weeks) followed by 2 weeks off treatment, after which the same vessels were assessed morphometrically. Arterial pressures were determined using radiotelemetry. MAIN OUTCOMES MEASURED: Erectile function, vessel morphology (lumen diameter, wall thickness, cross-sectional area, extracellular matrix [ECM]) and arterial pressure. RESULTS: Erectile responses were similar in young SHR and WKY (1.7 ± 0.80 vs. 1.4 ± 0.85) but declined significantly in aged SHR (0.3 ± 0.49). Vascular aging in SHR was associated with striking pudendal remodeling, characterized by marked neointimal proliferation and disruptions of the internal elastic lamina. This remodeling involved thickening of the medial layer (35 ± 6.0 µm vs. 81 ± 3.5 µm, P < 0.01), decreased lumen diameter (282 ± 6.3 µm vs. 250 ± 12.4 µm, P < 0.05) and increased ECM (10 ± 2.0 µm² vs. 26 ± 10.6 µm², P < 0.001). In old pudendals, there were significantly more round synthetic smooth muscle cells bordering the intima and in the neointima. Antihypertensive treatment decreased the wall:lumen ratio in young SHR pudendal arteries (-17%). CONCLUSIONS: Vascular aging in SHR with ED involved distinctive pathogenic remodeling in the internal pudendal artery. In young SHR, brief antihypertensive therapy was able to regress this abnormal morphology.

Morphological and functional evidence for the contribution of the pudendal artery in aging-induced erectile dysfunction.

INTRODUCTION: Aging increases the risk of both erectile dysfunction (ED) and cardiovascular disease. These conditions have similar etiologies and commonly coexist. One unifying concept is the role of arterial insufficiency which is a primary factor in the onset of age-related ED. AIM: Based on the novel finding that the pudendal arteries contribute 70% of the total penile vascular resistance, our objective was to morphometrically and functionally characterize this vessel in young and old normotensive rats. METHODS: Erectile function was monitored in 15- and 77-week Sprague-Dawley rats using the apomorphine bioassay (80mg/kg, s.c.). Anesthetized animals were perfusion-fixed, aortic, renal, and internal pudendal arteries were excised, embedded, sectioned, stained, and morphometrically assessed using light microscopy. Hearts were excised, separated, and weighed prior to perfusion. Contractile and relaxation responses to acetylcholine (ACh) and phenylephrine (PE) were assessed by wire myograph. MAIN OUTCOME MEASURES: Erectile function, morphological measurements, concentration response curves to ACh and PE. RESULTS: With age, there were marked decreases in erectile responses compared to younger rats (2.8±0.87 vs. 0.3±0.58). The pudendal arteries had a relatively small lumen (303±13.8µm) and a thick medial layer (47±2.2µm). In aged pudendal arteries, the lumen diameter did not change, and yet the medial layer, cross sectional area, and extracellular matrix were markedly increased. In contrast, the lumen diameter and wall thickness of the aorta and renal arteries in aged rats increased proportionally. An increase in small, round, smooth muscle cells was seen in aged pudendal arteries. Functionally, there were no differences in contractile responses to PE; however, ACh-induced relaxation decreased with age. CONCLUSIONS: In aged rats, erectile function was severely diminished when pudendal arteries had undergone marked phenotypic changes. Specifically, there was endothelial dysfunction and pathological remodeling of this vessel with age, characterized by medial thickening, impaired vasodilation and significantly reduced capacity for penile blood flow.