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Biomedical subjects

J Y Jeremy

Publications and source records attributed to J Y Jeremy.

At least 55 records · Page 3Linked to original sources
PubMed1998

Endothelin-1 and endothelin receptors in porcine saphenous vein-carotid artery grafts.

The regional distribution of endothelin-1 (ET-1) and its receptor subtypes (ETA and ETB) in porcine saphenous vein into carotid artery interposition grafts was studied 1 month after surgery and compared to ungrafted saphenous vein and carotid artery. ET-1 immunoreactivity was identified by immunohistochemistry and ET receptor subtypes were studied using in vitro autoradiography. In vein grafts, there was a higher density of ETA compared to ETB receptor binding in both the tunica media and the neointima. ETA binding to the tunica media of ungrafted saphenous vein was greater than that in the carotid artery or vein grafts, but greater in the vein graft compared to the carotid artery. Immunoreactive ET-1 was located in endothelial cells and throughout the neointima of the vein graft. Dense ETA and ETB binding was also associated with adventitial microvessels in the graft, and ETB binding was also identified to neutrophils, which accumulated at the subendothelium and within the adventitia. ETA receptors may play a role in vein graft thickening at the medial and neointimal vascular smooth-muscle cell level, whereas ETB receptors may play a role in microangiogenesis. The high levels of ETA receptors in the tunica media of ungrafted saphenous vein, relative to the carotid artery and vein graft, may also render this conduit susceptible to neointimal formation. These data indicate that studies of the effect of ET receptor antagonists on the pathobiology of vein graft disease are warranted.

Animals↗
PubMed1998

Cigarette smoking and erectile dysfunction.

Erectile dysfunction (ED, formerly referred to as impotence, is a common (especially in diabetic and older men) and distressing condition. Several risk factors have been identified; among these are smoking, hyperlipidaemia, hypertension and diabetes mellitus. These risk factors are shared with atherosclerotic vascular disease (e.g. ischaemic heart disease). This observation underlies a common vascular pathology. Smoking may cause ED by several mechanisms, including adversely affecting intrapenile blood flow. It is important to be aware of the link between smoking and ED since this information may motivate some male smokers to quit. In this context, it is important to be aware of the link between smoking and ED since this information may motivate smokers to quit. In this context, it is relevant that there is evidence that quitting may restore/improve erectile function.

Aging↗
PubMed1998

Smoking and urological disease.

It is important to realise that virtually every part of the body, including the urological system, is adversely affected by smoking. Smoking is the most important known preventable cause of urinary bladder cancer and is also associated with a risk of prostatic and renal cancer. The exact mechanism by which smoking increases the incidence of urological malignancy is not known. One possibility is that chemicals in cigarette smoke inhibit the synthesis of cytoprotective eicosanoids. Deficient local protection, against the hostile environment caused by the presence of urine, could then encourage the process of carcinogenesis. Smoking is a powerful predictor of erectile dysfunction; cessation may restore normal function. Cigarette smoke also exerts adverse effects on sperm motility and count. Although there is no convincing evidence of reduced fertility in male smokers, it is advisable for men to quit smoking should they have marginal semen quality and wish to start a family. Smoking causes substantial urological pathology; these facts can be used to convince patients with urological problems to quit smoking.

Erectile Dysfunction↗
PubMed1998

Endothelin and erectile dysfunction: a target for pharmacological intervention?

Although erectile dysfunction (ED) is not life threatening, this common problem can significantly affect the quality of life and psychological and social well-being. The Massachusetts male ageing study (1,290 men aged 40 - 70 years) showed that 52% of men reported some degree of ED (17.1% mild, 25.2% moderate, 9.6% total). In the UK, an estimated 17 - 19% of men are thought to suffer from ED. This problem is more common with advancing age and since this proportion of the population is increasing, the prevalence of ED is expected to rise. Endothelin-1 (ET-1) belongs to a family of potent vasoconstrictor peptides consisting of 21 amino acids. We review the evidence showing that ET-1 plays a role via (ET(A) and ET(B) receptors) in the regulation of cavernosal smooth muscle tone. We also consider the various risk factors that are involved in the pathogenesis of ED and how these relate to the action of ET-1. In particular, the role of diabetes, hypertension, smoking and dyslipidaemia are discussed. The pharmaceutical industry has declared an interest in the development of ET antagonists for use in the treatment of various diseases including ED. We briefly comment on experimental ET-1 antagonists that may be of therapeutic benefit in ED.

Journal Article↗
PubMed1998

Differential alterations of prostacyclin, cyclic AMP and cyclic GMP formation in the corpus cavernosum of the diabetic rabbit.

OBJECTIVE: To investigate the effect of alloxan-induced diabetes mellitus (DM, a major risk factor for erectile dysfunction and associated with impaired endothelial function) on the formation of nitric oxide (NO), prostacyclin (PGI2), cGMP and cAMP in the corpus cavernosum of rabbits. MATERIALS AND METHODS: Rabbits were rendered diabetic (hyperglycaemic, nonketotic) with alloxan; after 3 and 6 months, the penises were excised and the corpus cavernosum processed for the study of PGI2, NO, cAMP and cGMP formation, using a range of stimulators and radioimmunoassays. RESULTS: PGI2 formation in response to acetylcholine and phorbol ester, but not arachidonate, and cGMP formation in response to A23187 (NO-release dependent), was significantly diminished in diabetic rabbit corpus cavernosum compared with controls at both 3 and 6 months after the induction of DM. cAMP formation in response to forskolin and prostaglandin E1 was reduced after 6 but not 3 months, although nitroprusside-stimulated cGMP (activates guanylyl cyclase directly) was unaffected in cavernosal tissue from diabetic rabbits. CONCLUSIONS: These results show that the formation of NO and PGI2, and adenylyl cyclase activity but not guanylyl cyclase, are impaired in the corpus cavernosum of diabetic rabbits. As NO and PGI2 are produced by the endothelium, these studies consolidate the view that endothelial dysfunction is a major contributor to erectile dysfunction in diabetes mellitus.

Alloxan↗
PubMed1997

Nitric oxide synthase and adenylyl and guanylyl cyclase activity in porcine interposition vein grafts.

BACKGROUND: A high proportion of autologous saphenous vein grafts occlude as the result of intimal thickening. Blood vessels synthesize substances that may inhibit such intimal thickening. These include cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are stimulated by prostacyclin and nitric oxide, respectively. The prostacyclin-cAMP and nitric oxide-cGMP axes were therefore investigated in porcine vein grafts. METHODS: Saphenous vein-carotid artery interposition graft procedures were carried out in pigs. One month after the operation, ungrafted saphenous veins, vein grafts, and carotid arteries were excised, the formation of cAMP and cGMP was assessed by radioimmunoassay, and the nitric oxide synthase content was determined by autoradiography. RESULTS: The formation of cAMP and nitroprusside-stimulated cGMP was significantly diminished in vein grafts compared with ungrafted saphenous veins and carotid arteries. Calimycin-stimulated cGMP synthesis (nitric oxide release dependent) and the endothelial nitric oxide synthase content (autoradiography) were significantly elevated in vein grafts compared with ungrafted saphenous veins but were significantly less than those in carotid arteries. CONCLUSIONS: Adenylyl and guanylyl cyclase activity are down-regulated in vein grafts, which may contribute to the development of intimal and medial thickening. Nitric oxide release and endothelial nitric oxide synthase content are up-regulated in vein grafts, which is indicative of an adaptation to the arterial conditions of shear stress and pulsatile pressure.

Adaptation, Physiological↗
PubMed1997

The influence of surgical preparation on cyclic nucleotide synthesis in an organ culture of human saphenous vein.

OBJECTIVES: To investigate adenosine cyclic 3'5' monophosphate (cAMP) and guanosine cyclic 3'5' monophosphate (cGMP) synthesis in freshly isolated and surgically prepared human saphenous vein before and after culture. SETTING: Bristol Heart Institute, Bristol, U.K. METHODS: Freshly isolated and surgically prepared human saphenous vein was obtained from patients undergoing coronary artery bypass graft surgery. cAMP and cGMP synthesis, was assessed by radioimmunoassay in response to specific simulators in segments of saphenous veins after collection and following 14 days culture. RESULTS: Immediately after collection there was a significant reduction in the synthesis of cAMP (forskolin and prostaglandin E1-stimulated) and cGMP (sodium nitroprusside-stimulated) in surgically prepared compared to freshly isolated saphenous veins. In contrast, following 14 days in culture, cAMP and cGMP synthesis was significantly elevated in surgically prepared compared to freshly isolated saphenous veins. CONCLUSIONS: These data indicate that surgical preparation results in a marked reduction in cyclic nucleotide synthesis in saphenous vein which may be relevant to the pathophysiology of early vein graft failure. The normalisation of both cAMP and cGMP synthesis in surgically prepared veins following 14 days culture indicates that cyclic nucleotide synthesising capacity may not be a major determinant of neointima formation in this experimental model.

Acetylcholine↗
PubMed1997

Effect of copper on nitric oxide synthase and guanylyl cyclase activity in the rat isolated aorta.

1. The potential role of copper (Cu2+) in modulating the activity of nitric oxide synthase (NOS) and guanylyl cyclase (GC) was investigated by use of diethyldithiocarbamic acid (DEDCA), a high affinity Cu2+ chelator. 2. DEDCA 100 microM inhibited sodium nitroprusside (SNP; 0.005-10 microM)-evoked relaxation of rat isolated aortic rings precontracted with 3 microM phenylephrine (PE). A lower concentration of DEDCA (10 microM) did not significantly attenuate SNP-evoked responses but did inhibit relaxation to the endothelium-dependent dilator, A23187 (0.01-10 microM). 3. The presence of 100 microM Cu2+, but not 100 microM Fe2+, alone enhanced A23187- and SNP-evoked relaxation of aortae precontracted with PE. 4. The inhibitory effect of DEDCA on SNP- and A23187-induced relaxation was reversed by equimolar concentrations of Cu2+ but not Fe2+, indicating that DEDCA does not act via removal of haem-iron from the NOS and GC complexes. 5. Superoxide dismutase (30 mu ml-1) was without effect on the inhibition of DEDCA relaxation induced by either SNP or A23187 in aortae precontracted with PE. 6. When assessed by radioimmunoassay, DEDCA inhibited SNP- and A23187-stimulated cyclic GMP formation with IC50 values of 0.5 microM and 50 microM, respectively. 7. These data demonstrate that Cu2+ plays a role in controlling NOS and GC activity in the rat aorta.

Animals↗
PubMed1997

Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro.

OBJECTIVE: To investigate further the mechanisms of action of sildenafil, a highly selective and potent inhibitor of type 5 cGMP phosphodiesterase (PDE5) that has proved effective in the treatment of erectile dysfunction, by assessing its effect on the in vitro formation of cGMP and cAMP in the corpus cavernosum of the rabbit. MATERIALS AND METHODS: Male New Zealand White rabbits (2.5 kg) were killed and their penises rapidly excised, cut into segments and pooled. Penile segments were then incubated with various concentrations of sildenafil or papaverine. The formation of cGMP was stimulated with increasing concentrations of sodium nitroprusside (SNP) and the cGMP and cAMP concentrations measured by radioimmunoassay. Responses were compared to those obtained with papaverine, which is used therapeutically as an erectogen. RESULTS: In the presence or absence of SNP, sildenafil increased cGMP concentrations in rabbit penile tissue with increasing dose; the increase was greatest (about 28-fold) when cGMP was stimulated with SNP (up to 10 mumol/L). At all stimulatory concentrations of SNP, the effective concentrations for 50% stimulation (EC50) of sildenafil were 430-520 nmol/L. Concentrations of cAMP were unaltered by sildenafil. Papaverine enhanced cGMP formation in response to SNP, but at much higher concentrations than did sildenafil (> or = 10 mumol/L). CONCLUSIONS: Sildenafil specifically increases cGMP levels in rabbit corpora cavernosa; the increase is greater in the presence of SNP indicating that, in vivo, sildenafil may enhance erection by the augmentation of nitric oxide-mediated relaxation pathways. The erectogenic effect of sildenafil is mediated by a specific enhancement of cGMP accumulation in the corpus cavernosum, consistent with the known activity of sildenafil as a potent and highly selective inhibitor of cGMP-specific PDE.

Animals↗
PubMed1997

Short-term exposure to thapsigargin inhibits neointima formation in human saphenous vein.

Vascular smooth muscle cell (VSMC) migration and proliferation are involved in the intimal thickening responsible for late vein graft failure. In addition to growth and chemotactic factors, VSMCs require expression of matrix-degrading enzymes, e.g., metalloproteinases (MMP), to relieve the antiproliferative and antimigratory constraints of the extra-cellular matrix. Thapsigargin irreversibly inhibits Ca(2+)-ATPase, eliciting an increase in intracellular Ca2- and depletion of the intracellular calcium pools that are thought to be involved in the control of VSMC migration, VSMC proliferation, and MMP activity. We therefore studied the effect of thapsigargin on VSMC migration, VSMC proliferation, and MMP expression in human saphenous vein organ cultures. Vein segments were cultured for 14 days, and VSMC proliferation and migration were determined by autoradiography. Cell death was assessed using in situ end-labeling and lactate dehydrogenase release. Using Western blotting, we examined MMP-2 and MMP-9 and tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 expression. Exposure to thapsigargin at 10 nmol/L for 60 minutes before culture significantly inhibited neointimal thickening (60%, P < .05), intimal and medial VSMC proliferation (32%, P < .05 and 37%, P < .05, respectively), and VSMC migration (36%, P < .05). Thapsigargin at 10 nmol/L did not significantly increase cell death or MMP-2, MMP-9, TIMP-1, and TIMP-2 expression. These results suggest that blockade of Ca(2+)-ATPase by thapsigargin inhibits VSMC migration and proliferation involved in neointimal formation without affecting MMP-2 and MMP-9 expression. Because short-term exposure to thapsigargin was sufficient to inhibit neointima formation, this drug may prove useful in the treatment of intimal thickening after arterial bypass graft surgery.

Apoptosis↗
PubMed1997

Short-term exposure to low concentrations of thapsigargin inhibits replication of cultured human vascular smooth muscle cells.

BACKGROUND: Central to the pathophysiology of stenosis following balloon angioplasty and arterial bypass surgery is proliferation of vascular smooth muscle cells (VSMCs). To investigate the role of calcium (Ca2+) in VSMC proliferation, the effect of thapsigargin, Ca2+ ionophore A23187, ionomycin, cyclopiazonic acid and di-tert-butylhydroquinone (all of which raise intracellular Ca2+ levels) on the proliferation of cultured human VSMCs was observed. METHODS: Cultured VSMCs from human saphenous vein were treated with calcium-modulating drugs and proliferation was assessed by determining [3H]thymidine and 5-bromo-2'-deoxyuridine incorporation and cell number. RESULTS: Over a 48-h exposure, thapsigargin inhibited VSMC replication (median 50 per cent maximal inhibitory concentration 2 nmol/l) whereas the other drugs were much less effective. Short-term exposure (5, 10, 30 and 60 min) to thapsigargin elicited a significant dose-dependent inhibition of VSMC replication whereas, again, the other drugs were without significant effect. CONCLUSION: Thapsigargin-sensitive intracellular Ca2+ pools play a key role in controlling VSMC proliferation and specialized means of administering thapsigargin may constitute a possible approach to preventing stenosis.

Adult↗
PubMed1996

Reduced prostacyclin and increased leukotriene B4 synthesis in porcine venous-arterial grafts.

BACKGROUND: Migration and proliferation of vascular smooth muscle cells in the intima and superimposed atheroma are the main changes underlying late failure of saphenous vein bypass grafts. There is evidence that these events are partly modulated by complex interactions between inhibitors of vascular smooth muscle cell proliferation, such as prostacyclin (PGI2), and mitogens, such as leukotriene B4 (LTB4). Because the relative balance between these eicosanoids may play a role in vein graft failure, the synthesis of PGI2 and LTB4 was measured in porcine saphenous vein-carotid artery grafts 4 weeks after implantation and compared with ungrafted vein and common carotid artery from the same animal. METHODS: Vessels were cut into 2-mm squares and preincubated in Dulbecco's minimum essential medium for 4 hours at 37 degrees C. Tissues were then further incubated with Dulbecco's minimum essential medium containing a range of concentrations of noradrenaline, arachidonate, and calcium ionophore A23187. Release of PGI2 and LTB4 into the supernatant was then assessed by radioimmunoassay. RESULTS: In response to all stimulators, PGI2 release was markedly diminished in vein grafts compared with ungrafted saphenous veins and carotid arteries. The patterns of responses were similar in each vessel type. In contrast, LTB4 release was significantly enhanced in vein grafts compared to ungrafted saphenous veins and carotid arteries. CONCLUSIONS: These data indicate that there is a down-regulation of cyclooxygenase or PGI2 synthase in porcine vein grafts, which may constitute a further phenotypic change that would augment the hyperplastic process. Local increases in LTB4 synthesis in the vein graft, which indicates an induction of lipoxygenase and LTB4 synthase enzymes (and possibly reflects release from leukocytes which have infiltrated the graft), may contribute to increased intimal proliferation by direct promitogenic effects on smooth muscle cells.

Animals↗
PubMed1996

Hydrolysis of cyclic guanosine monophosphate and cyclic adenosine monophosphate by the penis and aorta of the diabetic rat.

OBJECTIVE: To investigate the hydrolysis of adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) by specific phosphodies-terases (PDEs) in the penis and aorta of diabetic rats. MATERIALS AND METHODS: Non-ketonuric diabetes mellitus was induced in 10 Sprague-Dawley rats with streptozotocin. After 2 months, the rats were killed and their penises and aortae excised. The tissues were incubated with [3H]-cAMP and [3H]-cGMP and the degree of hydrolysis was assessed by separating [3H]-cAMP and [3H]-cGMP from [3H]-AMP and [3H]-GMP, respectively, in the incubation supernatants using thin layer chromatography (polyethyleneimine cellulose developed in 50 mmol/L KCl). RESULTS: The hydrolysis of cAMP and cGMP was significantly reduced in penile and aortic tissue from diabetic rats compared to that of seven age-matched controls. CONCLUSIONS: Such a reduction of PDE activity would result in increased intracellular cyclic nucleotide levels (and thus corporeal smooth muscle relaxation and erection). Consequently, the altered activity of PDE enzyme systems is not related aetiologically to the pathogenesis of diabetic erectile dysfunction. Furthermore, these data consolidate the concept that enhanced cyclic nucleotide synthesis and decreased degradation constitute an adaptive response to counteract the deleterious effects of diabetes mellitus on erectogenic mechanisms. The pathophysiology and therapeutic implications of these findings warrant further investigation.

Animals↗