C.S. Thompson

Does severity of ischaemic coronary disease correlate with erectile function

An association between diminution in the quality of male sexual function and ischemic coronary disease has been suggested. Patients with ischemic heart disease who underwent coronary angiography participated in this study which aimed to document the impact of the extent of coronary disease upon sexual function in 40 patients (mean age 56.6 y). The 11-questions accepted questionnaire addressing sexual drive, erectile function, and ejaculation was used. Information regarding, age, medications, hypertension, diabetes, relevant risk factors, medical history, and the number of occluded coronary vessels was retrieved from the patients’ records. A statistically significant correlation was demonstrated between erectile function and the number of coronary vessels involved. Patients with one-vessel disease had more (P<0.04) and firmer erections (P<0.001) with fewer difficulties in achieving an erection (P<0.007) than men with two- or three-vessel disease. Age, diabetes, and hypertension also had a negative effect on the quality of the erection (P<0.05) in all patients.

Platelets, oxidant stress and erectile dysfunction: an hypothesis

Time for primary review 30 days. The successful use of sildenafil (Viagra™) to treat vasculogenic erectile dysfunction (VED) has heightened awareness of the widespread prevalence of this disorder [1–3]. Sildenafil acts through the augmentation of nitric oxide (NO) actions on vascular/corpus cavernosal smooth muscle cell relaxation [1–4] (Fig. 1). Thus, the therapeutic use of sildenafil has also highlighted the central role played by NO in mediating normal erection and in the pathogenesis of VED. Nevertheless, we still know little about the basic pathophysiology of VED. Since prevention is preferable to cure, it is imperative to improve our understanding of the pathophysiology of VED. In this brief review, we suggest that another major consequence of diminished NO formation is the increased adhesion of platelets and leukocytes, in particular neutrophils, which may counter erection through release of vasconstrictors, superoxide and other oxygen free radicals. We also suggest that erection itself may trigger events that contribute to exacerbation of the disorder in the long-term, again through the adhesion of platelets and leukocytes. Fig. 1 Key events in normal penile erection — the central role of NO. Upon sexual arousal, sympathetic drive initiates erection through both sympathetic and non-adrenergic, non-cholinergic (NANC) innervation of the corpus cavernosum and pudendal arteries. NANC fibres release NO and acetylcholine stimulates the release of NO from local endothelium by activation of NO synthase (NOS). NO promotes relaxation of arterial and cavernosal smooth muscle through activation of guanylate cyclase and suppression of activator Ca2+ which in turn results in erection. It is now well established that impairment of the above systems is central to the aetiology of vasculopathic erectile dysfunction. Sildenafil promotes erection through inhibition of type V phosphodiesterase which blocks the metabolism of cGMP to inactive GMP. Thus, cGMP accumulates thereby promoting relaxation of the relevant VSMCs. Patients with … * Corresponding author. Tel.: +44-117-928-3154; fax: +44-117-929-9737 j.y.jeremy{at}bristol.ac.uk

Experimental diabetes mellitus inhibits prostacyclin synthesis by the rat penis: pathological implications

SummaryIn view of the marked increase in blood flow into the penis during erection and the association of diabetes mellitus with impotence, we used the diabetic rat model to investigate the possibility that: (a) the penis may produce prostacyclin; and (b) prostacyclin secretion may be decreased in diabetes. Rats given a high dose of streptozotocin (120 mg/kg body weight) developed acute ketotic diabetes and were killed after 48 h. Animals given a low dose of streptozotocin (65 mg/ kg body weight) developed non-ketonuric diabetes and were killed after 7 or 62 days. Aortic rings and penile tissue discs were incubated in buffer, which was assayed for 6-oxo-pros-taglandin F1α, the stable and spontaneous breakdown product of prostacyclin. Penile tissue from control, ketotic and non-ketonuric (7 days) animals released similar quantities of prostacyclin, whereas that from long-term non-ketonuric animals (62 days) produced significantly less prostacyclin. Production of this prostanoid by the aortic rings paralleled these changes. We conclude that: (a) penile tissue releases prostacyclin in quantities comparable to those of the aorta; (b) long-term diabetes leads to diminished prostacyclin release by penile and aortic tissue: the former may contribute to the pathogenesis of diabetic impotence; and (c) since short-term ketotic diabetes does not inhibit aortic or penile prostacyclin release, duration of diabetes rather than its severity is responsible for diminished prostacyclin release.

Histamine synthesis and catabolism in various tissues in diabetic rats.

In view of the observations that (1) plasma histamine concentrations are significantly higher in diabetic patients and diabetic rats than those in controls, and (2) tissue concentrations of histamine are elevated in rats with experimental diabetes, we have investigated histamine synthesis, as reflected by histidine decarboxylase (HDC) activity, and histamine catabolism, as reflected by histaminase activity, in various tissues of the diabetic rat. Rats with streptozotocin-induced diabetes mellitus (DM) showed an increase in histamine synthesis in various tissues; this was most marked in the aorta and to a lesser, but significant, extent in the kidneys, lungs, and heart, but not in the brain, stomach, or skin. Tissue content of histamine was significantly increased in all tissues except the stomach and skin. We conclude that tissue histamine synthesis is significantly increased in diabetic animals and that this increase is most marked in the aorta. The elevation in HDC activity in these tissues probably accounts for the increase in tissue and plasma concentrations of histamine in diabetic animals, since there is no change in histamine catabolism. This increase in histamine synthesis and release may contribute to the pathogenesis of endothelial damage in diabetic microangiopathy and macroangiopathy.

Increased expression of endothelin-B receptors in the diabetic rabbit urinary bladder: Functional relevance

To determine the effect of diabetes mellitus on the density and distribution of endothelin A (ETA ) and endothelin B (ETB ) receptor subtypes in the rabbit urinary bladder, and to assess the in vitro functional properties of endothelin‐1 (ET‐1) receptors in bladder smooth muscle strips from diabetic and healthy rabbits.

Enhanced relaxation of diabetic rabbit cavernosal smooth muscle in response to nitric oxide: potential relevance to erectile dysfunction

New Zealand white rabbit cavernosal smooth muscle strips (n=6) were mounted in organ baths. Relaxations to nitric oxide (10−7–10−4 mol/l) were measured and the same procedure was repeated on strips from rabbits 6 months after alloxan-induced diabetes (n=6). Transverse cavernosal sections were obtained from the same penises. Low and high resolution autoradiographs were prepared using [3H]-L-NG-nitroarginine (an index of nitric oxide binding sites) and analysed densitometrically. Histochemical analysis was performed on adjacent sections using NADPH diaphorase (an index of nitric oxide synthase activity).Nitric oxide relaxed control rabbit cavernosal smooth muscle strips in a concentration-dependent manner. Diabetic rabbit cavernosal smooth muscle strips were significantly (P<0.03) more sensitive to nitric oxide (mean IC50=3.9 × 10−6 mol/l). Nitric oxide synthase binding sites were localised to the cavernosal endothelium and smooth muscle. Nitric oxide synthase activity was increased in 6 month diabetic cavernosal smooth muscle. These findings suggest impairments in the L-arginine-nitric oxide pathway may play a role in the pathophysiology of diabetic erectile dysfunction.

Effect of starvation and sampling time on plasma alkaline phosphatase activity and calcium homeostasis in the rat

The effect of starvation and sampling time on plasma alkaline phosphatase activity, total plasma calcium concentration and whole blood ionized calcium concentration was determined in the rat. Starvation caused a significant fall in total and ionized calcium concentrations as well as in alkaline phosphatase activity. These changes were accompanied by a fall in whole blood pH and an increase in the anion gap and a decrease in urinary excretion of calcium. These indices were restored to normal following refeeding. There was no change in serum 25-OH vitamin D concentrations following starvation for 3 days. Alkaline phosphatase activity showed a pattern compatible with the presence of a circadian rhythm when sampling took place between 0800 and 1800 h. Total and ionized calcium concentrations did not show such a rhythm when animals were fed the present diet.

Fasting and diabetes mellitus elicit opposite effects on agonist-stimulated prostacyclin synthesis by the rat aorta

The effects of prolonged fasting and experimental nonketonuric diabetes on rat aortic prostacyclin (PGl2) synthesis were compared. Whereas fasting (for 48 hours or longer) resulted in a marked increase in trauma-, adrenaline-, and U46619-stimulated aortic PGI2 synthesis, prolonged experimental (streptozotocin-induced) nonketonuric diabetes caused a marked decrease in aortic PGI2 synthesis stimulated by the above agonists. Arachidonic acid (AA)-stimulated aortic PGI2 synthesis in fasted and diabetic rats, however, was not different from that in controls. The reduction in adrenaline- and U46619-stimulated, but not AA-induced, PGI2 synthesis in the diabetic rat suggests that the diminished production of PGI2 in diabetes may be due to diminished phospholipase A2 (or of the phospholipase C-diglyceride lipase system) activity, diminished AA stores, or both. The opposite effects of prolonged fasting and diabetes on aortic PGI2 synthesis suggest that caution should be exercised when comparing the metabolic consequences of starvation with those of diabetes.

Differential regional changes of prostacyclin and thromboxane A2 synthesis in the intestinal tract of the fasted and semistarved rat

The synthesis of prostacyclin (PGI2) and thromboxane A2 (TXA2) by the mucosal and muscular portions of the duodenum, jejunum, ileum and ascending colon, as well as that by mesenteric vessels, was investigated in starved and semistarved rats. The jejunal mucosa and muscularis showed a marked increase in PGI2 synthesis after fasting for 48 h and 72 h or semistarvation for 9 days when compared with controls. Jejunal TXA2 synthesis did not alter. In contrast, PGI2 and TXA2 synthesis in ileal mucosa and muscularis was significantly reduced after fasting for 48 h, 72 h and semistarvation for 9 days. PGI2 and TXA2 synthesis by duodenal and colonic muscularis was unaffected by fasting or semistarvation. PGI2 synthesis in mesenteric vessels was significantly increased by fasting and semistarvation. No changes in PGI2 or TXA2 were detected at 24 h in fasted rats in any of the tissues studied when compared with controls. These selective changes in PGI2/TXA2 secretion may be important mediators of adaptive changes in the small intestine in response to starvation.

Effect of the antiinflammatory prodrug, nabumetone and its principal active metabolite on rat gastric mucosal, aortic and platelet eicosanoid synthesis, in vitro and ex vivo

Nabumetone is a novel non-steroidal antiinflammatory drug which although a weak cyclooxygenase inhibitor is converted by the liver to metabolites that are more potent inhibitors of cyclooxygenase. Nabumetone may thus avoid the occurrence of prostanoid-mediated gastropathy while maintaining its efficacy as an antiinflammatory agent. We compared the effect of nabumetone and 6-methoxy-2-naphthylacetic acid (6-MNA; the principal active metabolite of nabumetone) with that of naproxen and indomethacin on the synthesis of rat gastric prostaglandins I2 and E2, in vitro and ex vivo. Ex vivo platelet TXA2 and aortic PGI2 synthesis was also investigated in order to assess peripheral activity of nabumetone metabolites. In vitro, nabumetone was completely without effect on gastric mucosal prostanoid synthesis, whereas indomethacin, naproxen and 6-MNA (in this order of potency) inhibited prostanoid synthesis. Ex vivo, low dose naproxen and indomethacin (less than 5mg.kg-1) markedly inhibited gastric mucosal prostanoid synthesis at 30 min and 2 h post gavage, whereas nabumetone was without significant effect. Nabumetone administration also resulted in the inhibition of platelet TXA2 synthesis, whereas aortic PGI2 synthesis was unaltered. These data indicate that the administration of nabumetone may avoid NSAID gastropathy by leaving gastric mucosal prostanoid synthesis intact and also that the active metabolite(s) of nabumetone are effective inhibitors of cyclooxygenase in an NSAID-target tissue (platelet). The lack of effect of nabumetone administration on vascular PGI2 synthesis may confer an additional advantage over other NSAIDs, since the inhibition of peripheral PGI2 has been implicated in hypertensive and nephrotoxic side effects of NSAIDs.