Chronic vardenafil treatment improves erectile function via structural maintenance of penile corpora cavernosa in rats with acute arteriogenic erectile dysfunction

IntroductionChronic phosphodiesterase type 5 inhibitor treatment may be useful in reversing erectile dysfunction (ED). However, the mechanisms of this improvement remain unknown.AimThe aim of this article was to determine the mechanisms of the improvement by chronic vardenafil treatment for acute arteriogenic ED in rats.MethodsEight‐week‐old male Wistar‐ST rats were divided into four groups: sham‐operated rats (Control group) and rats with acute arteriogenic ED induced by ligating bilateral internal iliac arteries (Ligation group), subsequently treated with low‐dose (0.4 mg/kg/day; VL group) or high‐dose (4.0 mg/kg/day; VH group) vardenafil for 20 days from 1 week after ligature.Main Outcome MeasuresErectile function was assessed based on changes of intracavernous pressure (ICP) followed by electrostimulation of the cavernous nerves and was evaluated by the area under the curve of ICP/area under the curve of mean arterial pressure (area of ICP/MAP). Transforming growth factor (TGF)‐β₁, vascular endothelial growth factor‐A, endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS mRNA expression levels in penile corpus cavernosum were determined by real‐time PCR. Western blotting for TGF‐β₁ protein levels and Masson trichrome staining of penile tissues were performed in each at group 4 weeks after surgery.ResultsIn the VH group, area of ICP/MAP was significantly improved when compared with the Ligation group (P < 0.01). The smooth muscle (SM)/collagen ratio in the VH group was significantly higher than in the Ligation group (P < 0.05), and was comparable with that in the Control group. TGF‐β₁ mRNA and protein levels in the VH group were significantly lower when compared with the Ligation group (P < 0.05).ConclusionsChronic vardenafil administration ameliorates impairment of penile hemodynamics and maintains normal SM to collagen ratio in cavernous tissues after acute arterial injury in rats. Hotta Y, Hattori M, Kataoka T, Ohno R, Mikumo M, Maeda Y, and Kimura K. Chronic vardenafil treatment improves erectile function via structural maintenance of penile corpora cavernosa in rats with acute arteriogenic erectile dysfunction. J Sex Med 2011;8:705–711.     

Albuminuria is an independent risk factor of erectile dysfunction in men with type 2 diabetes

IntroductionErectile dysfunction (ED) is a frequent comorbidity in men with diabetes and is frequently overlooked in routine clinical evaluation. Albuminuria, a marker of endothelial dysfunction, may link to ED.AimThe study evaluated the association of albuminuria with risk factors of ED in men with type 2 diabetes.MethodsThe diagnosis of ED was based on a self‐administered questionnaire containing Sexual Health Inventory for Men. Urinary albumin excretion rate was determined by urine albumin‐to‐creatinine ratio (UACR) in spot urine.Main Outcome MeasuresThe clinical variables and diabetes‐associated complications to risk of ED were evaluated.ResultsOf 666 patients who received the questionnaire, 455 patients completed it. Among them, 82.0%, 28.1%, and 35.8% reported having ED, severe ED, and albuminuria, respectively. The UACR level was significantly higher in ED (0.20 ± 0.83) and severe ED (0.34 ± 1.18) groups compared with non‐ED group (0.07 ± 0.33). The presence of albuminuria adjusted for age and duration of diabetes was significantly associated with ED (OR = 2.76), and macroalbuminuria has stronger impact (OR = 4.49) than microalbuminuria (OR = 2.48). The other associated risk factors included hypertension, higher level of systolic blood pressure, lower level of serum hemoglobin, and estimated glomerular filtration rate. The presence of retinopathy, neuropathy, insulin therapy, using calcium channel blocker, and higher level of HbA1c further correlated with severe ED. Men with severe ED have higher prevalence of subnormal testosterone than the no ED patients. The high sensitivity C‐reactive protein level, and the presence of metabolic syndrome were not risk factors. The 211 nonrespondents to the questionnaire had similar or worse risk profiles compared with the ED patients.ConclusionAlbuminuria is an important independent risk factor of ED in men with diabetes after adjustment of age and diabetes mellitus duration. Identification and control of albuminuria and other associated risk factors might play a role in the prevention or reversal of ED. Chuang Y‐C, Chung M‐S, Wang P‐W, Lee W‐C, Chen C‐D, Chang H‐W, Yang KD, Chancellor MB, and Liu RT. Albuminuria is an independent risk factor of erectile dysfunction in men with type 2 diabetes. J Sex Med 12;9:1055–1064.     

Change of erectile function and responsiveness to phosphodiesterase type 5 inhibitors at different stages of streptozotocin-induced diabetes in rats

IntroductionIt has been suggested that risk of erectile dysfunction (ED) increases with duration of diabetes and phosphodiesterase type 5 inhibitors (PDE5I) are not as effective in treatment of diabetes-associated ED. However, few studies have investigated time-dependent change in erectile function during the course of diabetes.AimTo investigate time-dependent change in erectile function and responsiveness to PDE5I in streptozotocin-induced diabetic rats and to understand the pathophysiology of diabetic ED.Main Outcome MeasuresAt 6, 8, 10, 12, and 14 weeks after diabetic induction, erectile function was assessed by cavernous nerve stimulation before and after administration of DA-8159, a novel PDE5I. Penile tissue was assessed for apoptosis with immunohistochemistry. Protein expression of Rho-kinase 2 (ROCK2), myosin phosphatase targeting subunit 1 (MYPT1), and endothelial nitric oxide synthase (eNOS) was evaluated by Western blot.MethodsStreptozotocin was injected into 50 8-week-old male Sprague-Dawley rats, which were then classified into five diabetic groups according to the observation period.ResultsDiabetic rats maintained normal erectile responses until 6 weeks of diabetes. Following 8 weeks, the rats showed lower erectile responses at higher frequencies of nerve stimulation, which were normalized to control by administration of DA-8159. In contrast, erectile responses were significantly decreased in 10-week diabetic rats, and administration of DA-8159 resulted in partial recovery of normal responses. At more than 12 weeks, rats demonstrated severe deterioration of erectile function, which did not fully respond to PDE5I. Corporal apoptosis was significantly increased after 10 weeks. Upregulation of ROCK2 was found at 6 weeks, and was followed by an increase of MYPT1 phosphorylation. Phosphorylation of eNOS showed marked suppression at 6 weeks and remained lower during the experimental period.ConclusionsImpairment of erectile function was followed by decreased responsiveness to PDE5I during the course of diabetes. The RhoA/ROCK pathway played an important role in diabetes-associated ED. Cho SY, Park K, Paick J-S, and Kim SW. Change of erectile function and responsiveness to PDE5 (Type 5 phosphodiesterase) inhibitors at different stages of streptozotocin-induced diabetes in rats.     

Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes

IntroductionThe farnesoid X receptor (FXR) is critically involved in the regulation of the hepato‐biliary system. Recent data suggest a role for FXR in modulating other metabolic pathways and vascular function.AimTo investigate whether long‐term administration of the selective FXR agonist INT‐747 ameliorates erectile function, we tested it in two animal models of metabolic derangements: a rabbit model of high‐fat diet (HFD)‐induced metabolic syndrome (MetS) and a rat model of streptozotocin (STZ)‐induced type 1 diabetes.MethodsHFD rabbit or STZ rats with or without chronic INT‐747 dosing (10 mg/kg/day for 12 weeks). INT‐747 addition to rabbit penile smooth muscle cells (rpSMCs).Main Outcome MeasureEffects of INT‐747 on metabolic features and erectile function in animal models and clarification of mechanism of action in isolated cells.ResultsINT‐747 dosing normalized visceral adiposity and glucose intolerance in HFD rabbits. INT‐747 increased penile FXR expression and partially restored endothelial nitric oxide synthase and dimethylarginine dimethylaminohydrolase 1 expression as well as impaired nitric oxide (NO)‐dependent relaxation (improved responsiveness to acetylcholine and electrical field stimulation). INT‐747 was also effective in regulating NO downstream events, as shown by increased sodium nitroprusside‐induced relaxation. Because phosphodiesterase type 5 and protein kinase G (PKG) were unaltered by INT‐747, we analyzed the calcium‐sensitizing RhoA/ROCK pathway. HFD increased, and INT‐747 normalized, RhoA membrane translocation/activation. RhoA/ROCK signaling inhibition by INT‐747 was confirmed in rpSMCs by confocal microscopy, MYPT1‐phosphorylation, cytoskeleton remodeling, cell migration, and smooth muscle‐related genes expression. In STZ rats, FXR penile expression was not altered but was significantly upregulated by INT‐747 dosing. In this model, INT‐747 improved penile erection induced by electrical stimulation of cavernous nerve and hypersensitivity to intracavernous injection of a ROCK‐inhibitor, Y‐27632, without improving hyperglycemia.ConclusionIn HFD rabbits, INT‐747 dosing improved glucose sensitivity and MetS‐associated erectile dysfunction, via upregulation of NO transmission and inhibition of RhoA/ROCK pathway. In STZ rats, INT‐747 restored in vivo penile erection and sensitivity to ROCK inhibition, independently of effects on glycemia. Vignozzi L, Morelli A, Filippi S, Comeglio P, Chavalmane AK, Marchetta M, Toce M, Yehiely‐Cohen R, Vannelli GB, Adorini L, and Maggi M. Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes.     

Luteinizing hormone responses to gonadotropin-releasing hormone and naloxone in menstruating women with type I diabetes of different duration

Luteinizing hormone (LH) responses to gonadotropin-releasing hormone (GnRH) (100 micrograms injected intravenously (IV)) or naloxone (4 mg injected plus 8 mg infused in 2 hours IV) were evaluated in 29 women with insulin-dependent diabetes mellitus (IDDM) (duration, group I (n = 15): less than 10 years, range 3 to 9 years; group II (n = 14): greater than 10 years, range 11 to 20 years) and in 15 normal controls, on the 22nd days of normal menstrual cycles. Both GnRH- and naloxone-induced LH responses were similar in group I diabetics and normal controls, whereas they were significantly lower in group II than in group I diabetics or normal controls. Positive correlations were found between LH responses to GnRH and naloxone, whereas negative correlations were observed between maximal LH peaks in response to GnRH or naloxone and duration of diabetes. These data indicate that a hypothalamic pituitary disorder affects LH secretion with time after the onset of IDDM.     

Cyproterone acetate improves beta-cell function in postmenopausal women with diabetes mellitus type 2

Menopause is associated with two main risk factors for the development of type 2 diabetes mellitus--impaired beta-cell insulin secretion and insulin resistance. Physiologically estrogens improve carbohydrate metabolism, but this is not the case with different progestogens. The aim of the present study was to evaluate the effect of Cyproterone acetate (a progestogen with antiandrogenic activity) on insulin secretion, peripheral insulin sensitivity, lipid parameters and parameters of oxidative stress. Seven type 2 diabetic females, of mean age 55.4 +/- 4.7 years and mean BMI 30.8 +/- 9.39 kg/m2, in menopause for average 5 years, in good borderline glycaemic control (mean HbAic 7.8%), with dyslipidaemia, normal parameters of calcium and phosphate metabolism and with osteopenia (T-score < 88%) were enrolled in the study. They were treated with Estradiol valerate + Cyproterone acetate (Climen, Schering) for three months. Phases of insulin secretion--first phase (FPIS), second phase (SPIS) and AUC for FPIS and SPIS were assessed during IVGTT. Insulin sensitivity was determined with the manual method of euglycaemic hyperinsulinaemic clamp technique. The postmenopausal diabetic women in the present study were with overweight and obesity; they did not increase their body weight during HRT and even decreased it by mean 0.7%. Insulin secretion improved after Climen--FPIS increased by 16% and SPIS by 44%. Insulin sensitivity increased by 15%; triglycerides decreased by 16% and HDL-cholesterol increased by 27%. Total antioxidant capacity of the serum (TAOK) increased by 7%. The favourable effect on the pathophysiological mechanisms improved metabolic control--HbAic was reduced by mean 3% after 3 months. In conclusion, our results suggest that HRT with the progestogen Cyproterone acetate (Climen) should be preferred in postmenopausal type 2 diabetic females with predominant beta-cell insulin secretion defect.     

Pre-existing type I and type II diabetes in pregnancy

Diabetes mellitus is a long term chronic condition. The prevalence of diabetes in pregnancy is 2–5% in the UK of both gestational diabetes and pre-existing diabetes. The pregnancy outcomes for pre-existing type I and type II diabetic women are worse than for non-diabetic mothers. There is a higher incidence of stillbirth, macrosomia and congenital malformations. Pre-pregnancy counselling is essential to prepare for pregnancy, to tighten glycaemic control and review medication prior to pregnancy. Multi-disciplinary care is required throughout the antenatal period, to optimise blood glucose monitoring and control. Screening for diabetic complications such as nephropathy and retinopathy is necessary at every trimester to detect progression of disease. The timing, mode and management of delivery with a plan to maintain glycaemic control during this time should be discussed by 36 weeks. After completion of 38 weeks' gestation, induction of labour may be considered. This review will discuss the management of pre-existing type I and type II diabetic women from the preconception period to the postpartum period.     

Pre-existing type I and type II diabetes in pregnancy

Women with pre-gestational diabetes are high-risk pregnancies. Hyperglycaemic is toxic to the developing fetus and is associated with a higher incidence of congenital malformation, miscarriage, macrosomia and stillbirth. Complications can be reduced with tight glycaemic control, and management should ideally start pre-conceptually. During pregnancy a woman’s insulin requirements change and those managed pre-pregnancy on diet or oral medication may need to start insulin. Pre-gestational diabetics require close maternal and fetal monitoring, including screening for the progression of maternal diabetic complications such as retinopathy and nephropathy, and fetal growth scans. Their pregnancies are complex and a multidisciplinary approach should be used. In this article we will discuss the background physiology, the effect of pregnancy on diabetes, the potential fetal and maternal complications, and how these can be minimized by intensive management from pre-conception to the post-natal period, including the contribution of recent studies and guidelines.     

Imbalanced low-grade inflammation and endothelial activation in patients with type 2 diabetes mellitus and erectile dysfunction

IntroductionErectile dysfunction (ED) is highly prevalent among type 2 diabetes mellitus patients (T2DM). Although a link among systemic inflammation, endothelial dysfunction, and ED is described in clinical situations mainly related with coronary heart disease (CHD) risk, evidences of this link in T2DM patients are rather limited.AimsTo evaluate the association between endothelial dysfunction and balance of pro‐/anti‐inflammatory mediators with ED presence and severity in T2DM.MethodsWe conducted a cross‐sectional study of 190 T2DM patients without symptomatic CHD, 150 out of them with ED and 40 without ED. Serum levels of E‐selectin, intercellular adhesion molecule‐1, tumor necrosis factor‐α (TNF‐α), and interleukin (IL)‐10 were measured using specific enzyme‐linked immunosorbent assays (ELISAs). ED presence and severity were tested by the five‐item version of the International Index of Erectile Function questionnaire.Main Outcome MeasuresDifferences in circulating levels of endothelial dysfunction (ICAM‐1, E‐selectin) and inflammatory/anti‐inflammatory (TNF‐α, IL‐10, TNF‐α : IL‐10 ratio) markers between T2DM patients with and without ED, and assessment of biomarkers ED predictive value while adjusting for other known ED risk factors.ResultsPatients with ED were older and had longer duration of diabetes than patients without ED. E‐selectin serum levels were significantly increased, while IL‐10 were lower in patients with ED; because TNF‐α levels tend to be higher, TNF‐α : IL‐10 ratio was more elevated in ED patients. No significant differences of ICAM‐1 levels were observed between study groups. Endothelial activation markers and TNF‐α, as well as diabetes duration, were negatively correlated with erectile function. On multivariate analysis including age, duration of diabetes, insulin treatment, hypertension, insulin resistance, fair‐to‐poor glycemic control, and metabolic syndrome, increments in E‐selectin levels and TNF‐α : IL‐10 ratio predicted independently ED presence, while IL‐10 increases were associated with lower risk of ED in T2DM patients.ConclusionsED in T2DM patients without symptomatic CHD is associated with systemic endothelial dysfunction and a predominant, imbalanced low‐grade inflammatory response. Araña Rosaínz MDJ, Ojeda Ojeda M, Rodriguez Acosta J, Castelo Elías‐Calles L, Orlandi González N, Torres Herrera O, García Álvarez CT, Maciquez Rodríguez E, Estevez Báez M, Álvarez Seijas E, and Fragas Valdés R. Imbalanced low‐grade inflammation and endothelial activation in patients with type 2 diabetes mellitus and erectile dysfunction. J Sex Med 2011;8:2017–2030.     

Outpatient obstetric management of women with type I diabetes

Conventional obstetric management of diabetic women has frequently incurred extensive hospitalization. Although this approach improved perinatal results for these women and their infants, it is costly and cumbersome. The 3-year experience of an outpatient diabetic obstetric clinic is compared with the results obtained at the same facility during 5 previous years when hospitalization was used more extensively. Perinatal mortality and morbidity were not different in 51 type I diabetic women managed almost entirely as outpatients when compared with 58 similarly complicated diabetic patients receiving more conventional management. Mean prenatal admissions (1 vs 2, p = less than 0.01), mean prenatal hospital days (6 vs 12, p = 0.05), and prolonged delivery admissions of greater than 7 days (31% vs 69%, p = less than 0.01) were significantly less. Outpatient obstetric management of diabetic women efficiently decreases maternal morbidity without increasing infant morbidity and mortality.     

Factors affecting fetal weight distribution in women with type I diabetes

Objective To identify factors independently affecting fetal weight in women with type I diabetes.
Design Prospectively recorded data in consecutive women with type I diabetes, between 1975–1992.
Setting Simpson Memorial Maternity Hospital, Edinburgh.
Population Three hundred and two pregnancies with type I diabetes identified before pregnancy, with antenatal care and delivery in the Simpson Memorial Maternity Hospital, a singleton pregnancy, and the same diabetic physician.
Methods Normal ranges for birthweight were established for the total hospital population. All cases and the total population had pregnancy dating by ultrasound. The relation between standardised birth-weight and explanatory variables was investigated using correlation analysis, t tests and χ² tests as appropriate, and subsequently using multiple linear regression.
Results Standardised birthweight in cases, compared with the reference population, showed a unimodal, approximately normal distribution, markedly shifted to the right (mean + 1.26 SD). The most predictive variable was glycated haemoglobin concentration at 27–33 weeks, which explained 6.3% of the birthweight variance, while smoking explained 2.7% and maternal weight 2.0%. There was a trend towards a negative relationship with glycated haemoglobin concentration at 6–12 weeks. Smoking and glycated haemoglobin concentration were strongly intercorrelated.
Conclusions Most of the variance in standardised birthweight remains unexplained, but glycated haemoglobin concentration at 27–33 weeks is the most powerful explanatory variable. Possible reasons why there is not a stronger relationship between markers of maternal glycaemia and birthweight are discussed.     

Maternal and paternal family history of diabetes in women with gestational diabetes or insulin-dependent diabetes mellitus type I

Animal studies have shown that prenatal exposure to a diabetic intrauterine milieu leads to an increased risk in the female offspring of developing gestational diabetes (GD). In the present study, the family history of non-insulin-dependent diabetes mellitus type II (NIDDM) and insulin-dependent diabetes mellitus type I (IDDM) was evaluated in 106 women with GD, as compared to 189 women with IDDM. In GD patients, the prevalence of diabetes was significantly greater in mothers than in fathers (p = 0.03). This was mainly due to a greater prevalence of NIDDM in the mothers (p = 0.05). Furthermore, a significant aggregation of NIDDM was also observed in the maternal-grandmaternal line of GD women, as compared to the paternal-grandpaternal side (p = 0.02). In patients with IDDM no significant difference concerning the prevalence of any type of diabetes between mothers and fathers was observed. In conclusion, an aggregation of NIDDM in mothers and grandmothers of women with GD is reported here. A history of NIDDM on the maternal side of pregnant women should be considered as a particular risk factor for GD and, hence, for intergenerative transmission of NIDDM, which therefore might be prevented, at least in part, by strict avoidance of GD.     

Trends in prevalence and outcomes of pregnancy in women with pre-existing type I and type II diabetes

Objective  To describe recent trends in prevalence, outcomes and indicators of care for women with pre-existing type I or type II diabetes.
Design  Regional population-based survey.
Setting  All maternity units in the North of England.
Population  A total of 1258 pregnancies in women with pre-existing diabetes delivered between 1996 and 2004.
Methods  Data from the Northern Diabetic Pregnancy Survey. Outcome of pregnancy cross-validated with the Northern Congenital Abnormality Survey and the Northern Perinatal Mortality Survey.
Main outcome measures  Perinatal mortality, congenital anomaly and total adverse perinatal outcome (perinatal mortality and live births with congenital anomaly).
Results  The prevalence of pregestational diabetes increased from 3.1 per 1000 births in 1996–98 to 4.7 per 1000 in 2002–04 (test for linear trend, P < 0.0001), driven mainly by a sharp increase in type II diabetes. Perinatal mortality declined from 48 per 1000 births in 1996–98 to 23 per 1000 in 2002–04 ( P = 0.064). There was a significant reduction in total adverse perinatal outcome rate ( P = 0.0194) from 142 per 1000 in 1996–98 to 86 per 1000 in 2002–04. There were substantial improvements in indicators of care before and during pregnancy and in glycaemic control throughout pregnancy, but indicators of preconceptual care, such as use of folic acid, remained disappointing.
Conclusion  We observed improvements in pregnancy care and outcomes for women with diabetes in a region with an established audit and feedback cycle. There remains considerable scope for further improvement, particularly in periconceptual glycaemic control. The rising prevalence of type II diabetes presents a challenge to further improvement.     

Glycaemic control throughout pregnancy and risk of pre-eclampsia in women with type I diabetes

The aim of this study was to examine the influence of pre-pregnancy care and its effect on early glycaemic control and also the effect of glycaemic control in later pregnancy on risk of pre-eclampsia in women with type I diabetes. A prospective cohort study of 290 consecutive nonselected pregnancies in women with type I diabetes was performed from 1991 to 2002. We examined the relationship of monthly glycosylated haemoglobin (HbA1c) level, pre-pregnancy care, parity, diabetes duration, microvascular complications, maternal age, weight and smoking with risk of pre-eclampsia. Pre-eclampsia developed in 31/243 singleton births (12.8%). HbA1c level at 24 weeks was significantly increased in women with pre-eclampsia compared with women without pre-eclampsia (6.0 versus 5.6%, P= 0.017) and was, after nulliparity, the strongest independent predictor of increased risk (OR 1.65 for each 1% increase in HbA1c; P= 0.01). In contrast, there was no relationship between pre-pregnancy care or HbA1c level at booking and risk of pre-eclampsia.     

Functional and morphological improvement in erectile tissue of hypertensive rats by long-term combined therapy with phosphodiesterase type 5 inhibitor and losartan

IntroductionErectile dysfunction (ED) is highly associated to cardiovascular disease, especially arterial hypertension. Phosphodiesterase type 5 (PDE5) inhibitors and angiotensin II receptor blockers (ARB) are both common and efficient therapy in patients with ED and arterial hypertension, respectively.AimTo evaluate the effect of PDE5 inhibitor, sildenafil (S), and of ARB Losartan (L) in a continuous combined therapy for a long term on penile structures in a hypertensive rat model.MethodsDuring 6 months, four groups of male spontaneously hypertensive rats (SHR) and one of Wistar-Kyoto (WKY) rats, as control group, were studied: no-treatment SHR, SHR with L, SHR with S, SHR with S + L, and no-treatment WKY. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries, collagen type III (COL-III), and endothelial nitric oxide synthase (eNOS) expression in cavernous space were evaluated.Main Outcome MeasureFunctional and morphological differences between S and L in a continuous combined therapy vs. either drug as monotherapy on penile structures.ResultsAfter 6 months, SHR that received L, S, or combined therapy showed a similar reduction in blood pressure compared with untreated SHR. Nevertheless, SHR + L + S and control WKY showed significantly lower values of (i) CSM (P < 0.01), (ii) VSM (P < 0.01), and (iii) COL-III (P < 0.01) when compared with the untreated SHR and also with the SHR with monotherapy. Additionally, SHR + L + S, presented a higher eNOS expression in sinusoidal endothelium in comparison with the untreated SHR and the SHR with monotherapy (P < 0.01). In vitro studies revealed that SHR + L + S displayed a better relaxation response to acetylcholine than the untreated SHR and the SHR with monotherapy (P < 0.01).ConclusionsThese results suggest that a long-term combined therapy using L and S is a useful tool for functional and structural modification in cavernous tissue from SHR. Toblli JE, Cao G, Lombraña A, and Rivero M. Functional and morphological improvement in erectile tissue of hypertensive rats by long-term combined therapy with phosphodiesterase type 5 inhibitor and losartan.