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Biomedical subjects

M E Sullivan

Publications and source records attributed to M E Sullivan.

At least 19 recordsLinked to original sources
PubMed2001

Nitric oxide synthase inhibition increases aortic stiffness measured by pulse wave velocity in rats.

OBJECTIVE: The present study was to examine whether endogenous nitric oxide (NO) plays a role in the regulation of vascular stiffness. METHODS: Pulse wave velocity (PWV) was determined as the time delay between the foot of pressure waves recorded simultaneously at the aortic arch and abdominal aorta (just above the bifurcation) in anesthetized Sprague-Dawley rats. A decrease in vascular compliance results in an increase in PWV. RESULTS: A bolus injection of a NO synthase inhibitor, L-NAME (30 mg/kg), significantly increased PWV, accompanied by an increase in blood pressure. Since changes in blood pressure are known to affect PWV, phenylephrine (PE) was administered to mimic the blood pressure changes induced by L-NAME, thus compensating for the pressure-dependent component of the PWV changes. At each given level of mean arterial pressure (MAP), PWV was significantly higher with L-NAME than with PE treatment, suggesting that acute withdrawal of endogenous NO reduces aortic compliance independent of changes in MAP. In rats chronically treated with L-NAME (0.5 g/l in drinking water) for 3 weeks, PWV was even higher than those acutely treated with L-NAME (at MAP=150 mmHg). This additional increase in vascular stiffness may be due to the remodeling of the vascular wall as a result of chronic NOS inhibition and hypertension. CONCLUSION: These data demonstrate that NO modulates vascular compliance independent of blood pressure changes and that an intact endogenous NO system is required to maintain normal vascular compliance.

Analysis of Variance↗
PubMed2001

Angiotensin II increases urokinase-type plasminogen activator expression and induces aneurysm in the abdominal aorta of apolipoprotein E-deficient mice.

Urokinase-type plasminogen activator (uPA) is increased in human abdominal aortic aneurysm (AAA). Chronic infusion of angiotensin II (Ang II) results in AAA in apolipoprotein E-deficient mice. We tested the hypothesis that Ang II infusion results in an elevation of uPA expression contributing to aneurysm formation. Ang II or vehicle was infused by osmotic pumps into apoE-KO mice. All mice treated with Ang II developed a localized expansion of the suprarenal aorta (75% increase in outer diameter), accompanied by an elevation of blood pressure (22 mmHg), compared to the vehicle-treated group. Histological examination of the dilated aortic segment revealed similarities to human AAA including focal elastin fragmentation, macrophage infiltration, and intravascular hemorrhage. Ang II treatment resulted in a 13-fold increase in the expression of uPA mRNA in the AAA segment in contrast to a twofold increase in the atherosclerotic aortic arch. Increased uPA protein was detected in the abdominal aorta as early as 10 days after Ang II infusion before significant aorta expansion. Thus, Ang II infusion results in macrophage infiltration, increased uPA activity, and aneurysm formation in the abdominal aorta of apoE-KO mice. These data are consistent with a causal role for uPA in the pathogenesis of AAA.

Angiotensin II↗
PubMed2001

The release of spinal prostaglandin E2 and the effect of nitric oxide synthetase inhibition during strychnine-induced allodynia.

The removal of spinal glycinergic inhibition by intrathecal strychnine produces an allodynia-like state in rodents. Our objective was to measure spinal prostaglandin E2 (PGE2) release during strychnine-allodynia and examine the effects of Nomega-nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide synthetase. Under halothane, rats were fitted with intrathecal and spinal microdialysis catheters, and microelectrodes implanted into the locus coeruleus for measurement of catechol oxidation current (CAOC) using voltammetry. Animals were then administered urethane and treated as follows: 1) baseline control 10 min, intrathecal strychnine (40 microg) 10 min, 10 min of hair deflection, and 2) 10-min control followed by intrathecal strychnine (40 microg) with hair deflection for 60 min. Spinal dialysate samples were collected for PGE2 levels determined by using immunoassay. In separate experiments, the effect of intrathecal strychnine (40 microg) followed by hair deflection was studied in rats pretreated with intrathecal l-NOARG (50 nmol). After intrathecal strychnine, hair deflection significantly increased spinal PGE2 release (619% +/- 143%), locus coeruleus CAOC (181% +/- 6%), and mean arterial pressure (123% +/- 2%) P < 0.05. Pretreatment with intrathecal l-NOARG significantly inhibited strychnine-allodynia. In this model, hair deflection evokes spinal PGE2 release, locus coeruleus activation, and an increase in mean arterial pressure. L-NOARG pretreatment attenuated the locus coeruleus CAOC, a biochemical index of strychnine-allodynia, suggesting a mediator role of nitric oxide. A mediator role of nitric oxide is also implicated, helping to explain the pathophysiology of this allodynic pain.

Animals↗
PubMed2001

A novel synthetic inhibitor of factor Xa decreases early reocclusion and improves 24-h patency after coronary fibrinolysis in dogs.

Inhibition of factor Xa (FXa) attenuates thrombus progression. This study was designed to determine whether a novel, synthetic inhibitor of FXa (ZK-807834, molecular mass 527 Da, K(i) = 0.11 nM) administered during and briefly after pharmacologic coronary fibrinolysis increases 24-h patency. Either ZK-807834 (< or = 1.6 mg/kg, n = 10; 6.5 mg/kg, n = 8; or 13 mg/kg, n = 7); a peptide inhibitor of FXa, recombinant tick anticoagulant peptide (rTAP, 13.6 mg/kg, n = 7); heparin (150 U/kg bolus and 50 U/kg/h infusion) and aspirin (5 mg/kg) (n = 7); or saline as a control (n = 13) were administered i.v. over 135 min in conscious dogs after thrombotic occlusion induced by electrical injury to a coronary artery. Fibrinolysis was induced with recombinant human tissue-type plasminogen activator (1.0 mg/kg i.v. over 1 h), and patency was monitored continuously for 24 h with an implanted Doppler probe. Reocclusion occurred in all control and heparin/aspirin-treated dogs within 1 h after fibrinolysis. High dose ZK-807834 prevented reocclusion in five of six dogs and delayed reocclusion in the other dog (186 min after recanalization, p = 0.0005 versus heparin/aspirin). Reocclusion was delayed (406 +/- 329 min), but still occurred in three of six rTAP-treated dogs (p = 0.003 versus heparin/aspirin). Patency after 24 h was 100% in ZK-807834-treated and rTAP-treated dogs compared with 67% in control and 83% in heparin/aspirin-treated dogs. PT was increased 3.7-fold, activated partial thromboplastin time 4.9-fold, and bleeding time 2.5-fold by high dose ZK-807834 compared with 1.2-fold, 11.5-fold, and 2.3-fold, respectively, for heparin/aspirin. Inhibition of FXa with ZK-807834 decreases reocclusion and improves patency of recanalized arteries without increasing bleeding compared with heparin/aspirin.

Amidines↗
PubMed2001

Fibrinogen, lipoprotein (a) and lipids in patients with erectile dysfunction. A preliminary study.

BACKGROUND: Erectile dysfunction is associated with cardiovascular risk factors (e.g. hypertension, smoking, dyslipidemia and diabetes) and is more common in patients with cardiovascular disease. We therefore assessed the prevalence of two predictors of vascular events, fibrinogen and lipoprotein-a, in patients with and without erectile dysfunction. METHODS: Men with erectile dysfunction (48 non-smokers, 48 smokers), aged 45-70 years, were compared with controls (21 non-smokers, 21 smokers) with normal erectile function and no known pathology. RESULTS: Serum total cholesterol was significantly higher in non-smokers with erectile dysfunction compared to both control non-smokers and erectile dysfunction smokers. Men with erectile dysfunction who smoked had a significantly higher plasma fibrinogen level than control smokers. Similarly, men with erectile dysfunction, who did not smoke had higher levels of plasma fibrinogen compared to both smokers and non-smokers without erectile dysfunction. No significant difference in serum lipoprotein-a values was found. CONCLUSIONS: These findings support the concept that cardiovascular risk factors are predictors of erectile dysfunction and that this may be another manifestation of vascular disease.

Aged↗
PubMed2000

Suppression of acute and chronic opioid withdrawal by a selective soluble guanylyl cyclase inhibitor.

Previous studies have shown that activation of N-methyl-D-aspartate (NMDA) receptors and formation of nitric oxide (NO) contributes to the hyperactivity of locus coeruleus (LC) noradrenergic neurons and behavioural symptoms seen during opioid withdrawal. However, the role of soluble guanylyl cyclase (sGC), the 'physiological' target of NO, in this phenomenon is unclear. In this study, the effect of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a highly selective sGC inhibitor, on the naloxone-precipitated morphine withdrawal was examined using differential normal pulse voltammetry (DNPV) to measure LC activity, in vivo microdialysis to measure glutamate/aspartate release response, and behavioural assessment to evaluate withdrawal symptoms. In halothane-anaesthetized rats, acute intracerebroventricular (i.c.v.) morphine (10 microg) reduced the catecholamine oxidation current (CA.OC) (54.5+/-4.9% of baseline). Naloxone (2 mg/kg, i.v.) reversed this action of morphine and produced a rebound increase in CA.OC (136.1+/-6.0% of baseline), representing acute morphine withdrawal. Administration of ODQ (200 nmol, i.c.v.) blocked this response without affecting acute morphine action. In animals chronically treated with morphine (15 microg/microl/h, i.c.v., 5 days), naloxone significantly increased both the CA.OC signal (270.0+/-19.6% of baseline) and the release of L-glu (193+/-30.4%) and L-asp (221.5+/-28.4%) above baseline. These responses were attenuated in animals pretreated with ODQ. In unanaesthetized chronic morphine dependent rats, ODQ treatment suppressed the signs of withdrawal precipitated by naloxone (10 mg/kg). Taken together, the results of this study suggest that sGC plays an intermediary role in the genesis of LC neuronal hyperactivity and behavioural signs of morphine withdrawal.

Analgesics, Opioid↗
PubMed2000

Relaxation of rabbit lower urinary tract smooth muscle by nitric oxide and carbon monoxide: modulation by hydrogen peroxide.

Recent studies suggest that the body produces two gaseous messengers, nitric oxide (NO) and carbon monoxide (CO), both of which activate soluble guanylyl cyclase and thus modulate the activity of smooth muscle cells. In the present study, the effects of NO and CO on the smooth muscle of the lower urinary tract were compared. In addition, the modulation of tissue NO- and CO-induced relaxation by hydrogen peroxide was examined. NO, produced endogenously by electrical field stimulation (EFS) or applied exogenously as a solution, induced a concentration-dependent relaxation of rabbit cavernosal and urethral smooth muscle strips, but not of bladder tissues. The cavernosal tissue was found to be three times more sensitive to the actions of NO than the urethra. CO also induced relaxation of both tissue types, but with no apparent difference in sensitivity between the tissues. However, CO was much less potent than NO with respect to smooth muscle relaxation. The mechanism of action of the two mediators was cyclic guanosine monophosphate (cGMP)-dependent, as evidenced by enhanced formation of cGMP and inhibition of relaxation by the guanylyl cyclase inhibitor, oxadiazoloquinoxaline-1-one (ODQ.) The data suggests that NO is the dominant messenger in these tissues, but does not exclude a role for CO. In the presence of hydrogen peroxide, the relaxation responses induced by both NO and CO were significantly increased, regardless of tissue type. The mechanism for this effect is unclear, but evidence points to a requirement for the activation of guanylyl cyclase and enhanced formation of cGMP, since potentiation by the peroxide was blocked by a specific guanylyl cyclase inhibitor. We suggest that H(2)O(2) may play a positive role in the amplification or NO and CO-mediated responses.

Animals↗
PubMed2000

Inhibition of diabetic bladder smooth muscle cell proliferation by endothelin receptor antagonists.

Urinary bladder hypertrophy and hyperplasia are well recognised in diabetic cystopathy. The urinary bladder is known to synthesise endothelin-1 (ET-1), a potent vasoconstrictor peptide with mitogenic properties. Using diabetic New Zealand White (NZW) rabbits, we investigated the potential role of ET receptor subtypes (ETA and ET(B)) on the proliferation of bladder smooth muscle cells (SMC). Diabetes mellitus was induced in adult male NZW rabbits. After 6 months, control (n = 6) and diabetic (n = 6) bladders were removed and SMC from the dome and bladder neck were grown using standard explant methodology. At passage two, the cells were made quiescent and then further incubated in foetal calf serum (FCS), control age-matched rabbit serum (CRS) or diabetic rabbit serum (DRS) in the presence or absence of ET(A)-antagonist (BQ123) or ET(B)-antagonist (BQ788). SMC proliferation was then measured with 5-bromo-2'deoxy-uracil 24 h later and by cell counting (using a haemocytometer) at 48 h. Neither BQ123 nor BQ788 influenced detrusor or bladder neck SMC proliferation in FCS or CRS. However, in the presence of DRS, BQ123 and BQ788 significantly inhibited diabetic detrusor and bladder neck SMC proliferation at 30 and 100 nmol/l (P < 0.03 and P < 0.01, respectively). Cell counts were also significantly reduced from the diabetic detrusor and bladder neck (P < 0.01 and P < 0.03 with BQ123 and BQ788, respectively). These results suggest that ET may play a pathophysiological role in the bladder SMC hyperplasia associated with diabetes mellitus.

Animals↗
PubMed2000

The standardized vascular clinic: an alternative to the traditional ambulatory setting.

PURPOSE: To investigate the effectiveness of a standardized vascular clinic (SVC) in teaching diagnostic and management skills for common vascular problems, as compared with that of the traditional ambulatory setting. METHODS: Third-year medical students participating in the required surgical clerkship participated in this study. Students were randomly assigned to attend either a 4-hour SVC experience (group 1, n = 64) or a 4-hour traditional ambulatory experience (group 2, n = 60). Students completed a satisfaction rating scale and a preencounter and postencounter self-efficacy rating scale at the end of the experience. Student t tests were used to compare the groups in the areas of knowledge acquisition, problem solving, clinical skills and satisfaction with the encounter. Analysis of covariance was used to compare the change between pre and post self-efficacy ratings. RESULTS: Students in group 1 performed significantly higher than students in group 2 in the areas of problem solving, clinical skills, and student satisfaction. They also demonstrated a higher level of confidence in their vascular skills than students assigned to the traditional setting. CONCLUSION: The SVC may be more effective in teaching problem-solving and clinical skills. It also may promote more student satisfaction with the experience and confidence in clinical skills than the traditional ambulatory setting.

Ambulatory Care↗
PubMed2000

A double-blind randomized controlled trial and economic evaluation of transurethral resection vs contact laser vaporization for benign prostatic enlargement: a 3-year follow-up.

OBJECTIVE: To evaluate the effect of contact laser prostate surgery in the treatment of benign prostatic hyperplasia. PATIENTS AND METHODS: A prospective double-blind randomized controlled trial of transurethral resection of the prostate (TURP) and contact laser prostatectomy was conducted, with an economic evaluation of both procedures. The primary outcome measure was the change in the American Urologic Association symptom score, with secondary outcome measures being the peak urinary flow rate, treatment-related complications, re-operation rate and health service costs. RESULTS: The perioperative blood loss and transfusion requirements were statistically significantly lower for laser prostatectomy than for TURP. There was no clinically significant difference between TURP and contact laser prostatectomy in the mean change in symptom scores and flow rates. There were distinct perioperative advantages in favour of the contact laser treatment, but some disadvantages in terms of re-catheterization and re-operation rates. CONCLUSIONS: Contact laser prostatectomy is a valid treatment for benign prostatic hypertrophy. The performance of contact laser prostatectomy as day-case surgery would have cost advantages to the National Health Service.

Aged↗
PubMed2000

Five-year data from the Oxford Laser Prostatectomy Trial.

OBJECTIVE: To evaluate the natural history of a group of patients who underwent contact laser prostatectomy or transurethral resection of the prostate (TURP). PATIENTS AND METHODS: Patients were followed up at 5 years after enrolling in a prospective double-blind randomized controlled trial of TURP vs contact laser prostatectomy. RESULTS: Of the initial trial patients, 11.5% had died (seven in the laser and 10 in the TURP arm) and eight (5.4%) were too incapacitated by coexistent medical disease to respond to the questionnaires. Thirty-eight patients were not available for follow-up, despite numerous invitations. Thirteen of the laser patients (18%) and 11 of the TURP patients (14.5%) had undergone re-operation. Two patients from each arm had received alpha-blockers for worsening symptoms. CONCLUSIONS: Five years after prostatic surgery, a significant number of patients were dead or disabled by coexistent medical disease. The re-operation rate after TURP and contact laser prostatectomy were similar.

Double-Blind Method↗
PubMed2000

Effects of ZK-807834, a novel inhibitor of factor Xa, on arterial and venous thrombosis in rabbits.

Inhibition of factor Xa (FXa) may interrupt thrombus progression. This study compared the antithrombotic activity of a novel FXa inhibitor, ZK-807834 [MW, 527 D; Ki (human FXa), 0.11 nM], with recombinant tick anticoagulant peptide [rTAP; MW, 6,685 D; Ki, (human FXa) = 0.28 nM], and DX-9065a [MW 445 D, Ki (human FXa), 40 nM] in rabbits with arterial thrombosis induced by electrical vascular injury. ZK-807834 also was compared with low molecular weight heparin (LMWH; MW, 5,500 D) during venous thrombosis induced by placing a copper wire and threads in the vena cava. Inhibitors were administered as an i.v. bolus and 2-h infusion. Total dosages of ZK-807834, > or =0.7 micromol/kg (n = 18); rTAP, > or =1 micromol/kg (n = 18); or DX-9065a, > or =11 micromol/kg (n = 18) decreased the incidence of arterial thrombotic occlusion compared with control animals (p < 0.05). However, five of six animals given the lowest effective dosage of rTAP and four of six animals given DX-9065a bled from a surgical incision >5 min, but only two of six animals given ZK-807834 bled >5 min. Venous clot weights were reduced compared with controls for dosages of ZK-807834 > or =0.007 micromol/kg (n = 36) or LMWH > or =0.2 micromol/kg (n = 18). Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were unchanged from baseline at the minimally effective dose of ZK-807834, whereas aPTT was increased twofold at the effective dose of LMWH. Thus ZK-807834 may be useful to attenuate thrombosis at lower dosages and with less perturbation of systemic hemostasis compared with available agents.

Amidines↗
PubMed2000

Increased aortic stiffness assessed by pulse wave velocity in apolipoprotein E-deficient mice.

Atherosclerosis develops and progresses spontaneously in apolipoprotein E-knockout (apoE-KO) mice. A direct consequence of atherosclerosis is an increase in vascular stiffness. Pulse wave velocity (PWV) has been used to assess the stiffness of large vessels and was found to be increased in patients with atherosclerosis. In the present study, aortic stiffness was assessed by PWV in 4- and 13-mo-old apoE-KO mice and age-matched controls (C57BL/6J). In 13-mo-old apoE-KO mice with extensive atherosclerotic lesions in the aorta (61 +/- 4%), PWV increased significantly (3.8 +/- 0.2 m/s) compared with controls (2.9 +/- 0.2 m/s). Endothelial nitric oxide (EDNO)-mediated vasorelaxation in response to ACh was markedly diminished in the aortic rings isolated from 13-mo-old apoE-KO mice compared with age-matched controls. In contrast, in 4-mo-old apoE-KO mice with only moderate atherosclerotic lesions in the aorta (23 +/- 5%), there were no significant changes in PWV and EDNO-mediated relaxation compared with controls. Blood pressure was not different among the four groups of mice. There were no significant differences in endothelium-independent vascular responses to sodium nitroprusside among different groups investigated. Histological evaluation revealed focal fragmentation of the elastic laminae in the aortic walls of 13-mo-old apoE-KO mice. These results demonstrate for the first time that aortic stiffness determined by PWV increases in 13-mo-old apoE-KO mice. Endothelial dysfunction and elastic destruction in vascular wall caused by atherosclerosis may have contributed.

Acetylcholine↗
PubMed2000

Hemodynamic changes in apolipoprotein E-knockout mice.

Apolipoprotein E-knockout (ApoE-KO) mice develop advanced atherosclerotic lesions by 1 yr of age and have been well characterized pathologically and morphologically, but little is known regarding their cardiovascular physiology and hemodynamics. We used noninvasive Doppler ultrasound to measure aortic and mitral blood velocity and aortic pulse-wave velocity in 13-mo-old ApoE-KO and wild-type (WT) mice anesthetized with isoflurane. In other mice from the same colony, we measured systolic blood pressure, body weight, heart weight, cholesterol, and hematocrit. Heart rate and blood pressure were comparable (P = not significant) between ApoE-KO and WT mice, but significant decreases (P < 0.001) were found in body weight (-22%) and hematocrit (-11%), and significant increases were found in heart weight (+23%), aortic velocity (+60%), mitral velocity (+81%) (all P < 0.001), and pulse-wave velocity (+13%, P < 0.05). We also found inflections in the aortic arch velocity signal consistent with enhanced peripheral wave reflection. Thus ApoE-KO mice have phenotypic alterations in indexes of peripheral vascular resistance and compliance and significantly elevated cardiac outflow velocities and heart weight-to-body weight ratios.

Animals↗
PubMed2000

Normal and pathological erectile function: the potential clinical role of endothelin-1 antagonists.

Erectile dysfunction (ED) is a common problem, particularly in older men. The production of penile erection involves an interplay between autonomic nerves and locally released vasoactive mediators. Endothelin-1 (ET-1) is a peptide released from endothelium in the corpus cavernosum, which causes smooth muscle contraction. Recent studies have investigated the physiological significance of ET-1 in the control of erectile function and it may play a role in detumescence. There is also much evidence to link ET-1 to risk factors for ED. ET-1 antagonists may prove beneficial in the treatment of ED and also in prevention of long term deterioration of erectile function. These antagonists may also find a role when used in combination with agents, which are established for the treatment of ED.

Animals↗
PubMed1999

Nitric oxide and penile erection: is erectile dysfunction another manifestation of vascular disease?

There is convincing evidence that the prevalence of erectile dysfunction is increased among men with ischaemic heart disease. This association may be attributed to the fact that both erectile dysfunction and ischaemic heart disease share similar risk factors (e.g. hypertension, dyslipidaemia, diabetes and smoking). Nitric oxide (NO) activity is adversely affected, in penile and vascular tissue, by these risk factors. It is therefore not surprising that a defect in NO activity is thought to play a role in the pathogenesis of both erectile dysfunction and ischaemic heart disease. We consider this evidence and propose that defective NO activity provides a unifying explanation for the association between these two conditions. Further research in this area may improve our understanding of the pathogenesis of cardiovascular diseases as a whole.

Cardiovascular Diseases↗