Plasma immunoreactive endothelin-1 concentrations in infants with persistent pulmonary hypertension of the newborn

Plasma concentrations of endothelin-1 (ET-1) have been reported to be elevated in children and adults with pulmonary hypertension. We hypothesized that infants with persistent pulmonary hypertension of the newborn (PPHN) have elevated plasma concentrations of ET-1. Plasma concentrations of immunoreactive-endothelin-1 (ir-ET-1) were measured using a radioimmunoassay in 20 infants with PPHN and 20 normal term infants. Mean birthweight and gestational age of the infants were comparable in the two groups. The mean plasma ir-ET-1 concentrations were significantly elevated in neonates with PPHN compared to those of normal term infants (2.04 +/- 0.30 versus 1.04 +/- 0.29 pg/mL, p = 0.02). A linear regression analysis demonstrated a significant relationship between ir-ET-1 concentrations and alveolar-arterial oxygen gradient (r = 0.49, p = 0.02) and mean airway pressure (r = 0.49, p = 0.02). There was also a significant correlation between ir-ET-1 concentrations and duration of extracorporeal membrane oxygenation among infants with PPHN (r = 0.44, p = 0.05). We conclude that plasma ir-ET-1 concentrations are elevated in infants with PPHN. The presence of elevated ir-ET-1 concentrations and their positive correlation with disease severity suggests that ET-1 may serve as a marker of the disease severity in these infants. However, further studies are needed to elucidate the role of ET-1 in the pathophysiology of PPHN.     

Changes in cerebrospinal fluid and cerebrovascular endothelin concentrations during hypotension and hypertension in newborn piglets with induced sterile meningitis

The effects of sterile meningitis on endothelin-1 (ET-1) and big ET-1 concentrations during hypotension and hypertension were studied in the cerebrospinal fluid and plasma of newborn piglets. Cerebrospinal fluid was obtained via cisterna magna puncture, and blood was obtained from the sagittal sinus vein and left subclavian artery. The study group consisted of 14 newborn piglets injected with 0.5 mL heat-killed group B streptococcus (GBS) (10(9) colony forming unit (cfu) equivalents), into the right cerebral lateral ventricle; the control group consisted of 10 newborn piglets injected with sterile normal saline, in a similar fashion. Hypotension (mean arterial blood pressure (MABP) 20-59 mmHg; 1 mmHg = 133.3 Pa) and hypertension (MABP 110-140 mmHg) were induced 1.5-2 h apart in random sequence in each animal, by inflating balloon-tipped catheters placed at the aortic root and descending aorta, respectively. Cerebral blood flow (CBF) was measured using radiolabeled microspheres, 15 min before and after injection of GBS or saline (normotension), during the hypotension and hypertension episodes, and during recovery normotension, immediately prior to cerebrospinal fluid and blood sampling. ET-1 and big ET-1 concentrations (pg/mL) were measured using radioimmunoassay kits. The combined effect of induced sterile meningitis and induced hypotension resulted in a significant rise in the concentration of cerebrospinal fluid ET-1 (control, 5.1 +/- 0.1; GBS, 9.3 +/- 0.2 pg/mL; p < 0.01), cerebrospinal fluid big ET-1 (control, 0; GBS, 18.1 +/- 2.7 pg/mL; p < 0.01), and sagittal sinus (cerebrovascular) big ET-1 (control, 15.5 +/- 4.2; GBS, 47.5 +/- 9.6 pg/mL; p < 0.01). In contrast, the combined effect of induced sterile meningitis and induced hypertension resulted in a marked elevation in cerebrovascular ET-1 concentrations (control, 9.5 +/- 0.9; GBS, 28.5 +/- 6.1 pg/mL; p < 0.01), with no significant change in cerebrospinal fluid concentrations. In addition, cerebrovascular production of ET-1 increased dramatically during hypertension in the GBS group (control, 0; GBS, 161.7 +/- 13.2 pg.min-1.100 g-1; p < 0.001), and was maintained during the recovery period (133.7 +/- 10.8 pg.min-1.100 g-1). Cerebrovascular ET-1 concentrations correlated significantly with total CBF and MABP in both groups of animals (control, r = 0.49, p < 0.002; GBS, r = 0.64, p < 0.0001), but the response was of a much greater magnitude in the GBS group. There was an inverse relationship between cerebrovascular big ET-1 concentrations and total CBF (r = -0.53, p < 0.0001) and MABP (r = -0.71, p < 0.0001) in the GBS group. In the MABP range of 60-110 mmHg a positive relationship was observed between cerebrovascular ET-1 concentrations and cerebral vascular resistance, in the control group only (r = 0.59, p < 0.002). The combined insult of induced sterile meningitis and induced hypotension or hypertension may be associated with increased cerebrovascular ET-1 and (or) big ET-1 concentrations. Changes in these vasoactive agents may contribute to pressure passivity of CBF in the newborn with meningitis.     

Comparative study of the effects of ouabain and digoxin on blood pressure of rats

OBJECTIVE: To compare the effect of ouabain on the blood pressure of rats with that of digoxin to find the evidences of the relationship between endogenous ouabain (EO) and development of hypertension. METHODS: Sprague-Dawley rats, which were divided into 3 groups, were infused with ouabain (23 x 75 micrograms.kg-1/day, i.p.), digoxin (36 x 84 micrograms.kg-1/day, i.p.) and normal saline (NS) once a day respectively. Systolic blood pressure and body weight were recorded weekly. Five weeks later, rats of ouabain group were randomly assigned to three infusion subgroups: Oc group, continued with ouabain infusion; Od group, added digoxin (73 x 68 micrograms.kg-1/day, i.p.) and Os group, stopped administration of ouabain. Another week later, direct blood pressure was recorded in aorta. Systolic and diastolic cardiac function, plasma renin activity and aldosterone levels of all the rats were measured. RESULTS: After a latent period of one week, blood pressure of Ouabain group increased significantly [95.4 +/- 11.8 mmHg (1 mmHg = 0.133 kPa) at the beginning of the experiment vs 122.5 +/- 16.9 mmHg at the end of week 6, P < 0.05] with normal plasma renin activity and higher aldosterone (1.28 +/- 0.45 ng/ml vs 0.69 +/- 0.27 ng/ml, P < 0.05). The blood pressure decreased after either withdrawal of ouabain or addition of digoxin (116.3 +/- 14.4 mmHg vs 100 +/- 10.7 mmHg, P < 0.05; 123.9 +/- 13.9 vs 103.3 +/- 10.5 mmHg, P < 0.05, respectively). No difference of blood pressure was found between the digoxin and NS group. CONCLUSIONS: Our results suggested that EO might be one of the causes of the development of hypertension. Aldosterone might play some role in the mechanism of ouabain-induced hypertension. Digoxin can not induce hypertension. There is a great difference between the effect of ouabain and digoxin on the blood pressure. Moreover, digoxin can reverse the hypertension induced by ouabain.     

Effects of changes in intraocular pressure on human ocular haemodynamics

PURPOSE: Myogenic autoregulation is the ability of a vascular bed to maintain blood flow despite changes in perfusion pressure. Ocular perfusion pressure is defined as the difference between ocular arterial pressure and ocular venous pressure, the latter dependent on intraocular pressure (IOP). The aim of the present study was to investigate the effect of moderate increases in IOP on ocular haemodynamics. METHODS: Changes in IOP (+ 10 mmHg, +20 mmHg) were induced by a suction cup in 10 healthy subjects. Ocular fundus pulsations in the macula and the optic disc were measured by laser interferometry; blood flow velocities in the central retinal artery (CRA) and in the ophthalmic artery (OA) were measured by Doppler sonography. RESULTS: Changes in IOP caused a significant reduction in fundus pulsations, which was more pronounced in the macula (at +10 mmHg: -9 +/- 2%, p < 0.01; at +20 mmHg: -19 +/- 3%, p < 0.001) than in the optic disc (at +10 mmHg: -5 +/- 2% (ns); at +20 mmHg: -9 +/- 3%, p < 0.01). Mean flow velocity in the CRA was reduced by -5 +/- 3% at +10 mmHg (ns) and by -14 +/- 5% at +20 mmHg (p < 0.005), resistive index was increased by +4 +/- 1% at +10 mmHg (p < 0.05) and by +6 +/- 2% at +20 mmHg (p < 0.01). In contrast, a rise in IOP did not affect blood flow parameters in the OA. CONCLUSIONS: Our results from fundus pulsation measurements indicate that choroidal blood flow decreases when IOP is increased. The Doppler sonographic findings in the CRA indicate reduced blood flow velocity in this artery during raised IOP.     

Production of endothelin-1 induced by blood transfusion in premature infants

We demonstrated a relationship between blood transfusion and plasma ET-1 levels in 10 premature infants with anemia. Changes in plasma ET-1 and lipoperoxide levels, blood pressure and available oxygen before and after the blood transfusion were determined. Plasma ET-1 levels were significantly elevated after blood transfusion (before: 8.0 +/- 2.8; after: 15.7 +/- 5.4 pg/ml, p < 0.01). A positive correlation was observed between plasma ET-1 levels and lipoperoxide levels (r = 0.887, p < 0.01). There was a significant correlation between plasma ET-1 levels and transfused blood volumes (r = 0.758, p < 0.01). No positive correlation was observed between plasma ET-1 levels and available oxygen. These results suggest that blood transfusion may be a stimulator of ET-1 overproduction and that it may lead to tissue injury through an endothelin-induced oxygen radical formation system.     

HPLC fractionated soluble egg antigen from Schistosoma mansoni elicits a heterogeneous human immune response

Antihypertensive effects of beni-koji were studied using 29 outpatients with mild hypertension in a placebo-controlled double-blind comparative fashion. After a 4-week vehicle (apple juice) run-in period, 13 patients were assigned to receive beni-koji aqueous extracts containing juice once daily (27 g of beni-koji eq. per day) for 8 weeks and 16 were assigned to vehicle. Two patients assigned to the vehicle group did not complete the study. In addition to casual blood pressure, 24-hr non-invasive ambulatory blood pressure (ABP) was monitored in 6 patients given the beni-koji drink and 5 patients given the vehicle. 1) In the beni-koji group, both casual systolic and diastolic pressure decreased significantly during the treatment period (from 150 +/- 10/96 +/- 6 mmHg to 140 +/- 10/89 +/- 10 mmHg, p < 0.01). The averages of the 24-hr blood pressure recorded in ABP (24-BP) also significantly decreased (from 141 +/- 17/95 +/- 13 mmHg to 132 +/- 21/86 +/- 10 mmHg, p < 0.05) when compared with those of the control period. Casual pressure normalized (less than 140/90 mmHg) in 4 patients who received beni-koji. Circadian variation of the blood pressure by ABP showed a significant decrease during the daytime. 2) In the vehicle group, casual systolic pressure did not change significantly (from 155 +/- 8 mmHg to 151 +/- 12 mmHg), but diastolic pressure decreased significantly (98 +/- 7 mmHg to 93 +/- 6 mmHg). Casual blood pressure did not normalize in any of the patients and 24-BP did not change significantly. 3) Summative evaluation of safety showed that no problems appeared in the beni-koji group. In conclusion, beni-koji appears to be an effective and safe food material for mild essential hypertension. The mechanism of the antihypertensive effect of beni-koji still remains to be investigated.     

Transformation of the methylotrophic actinomycete Amycolatopis methanolica with plasmid DNA: stimulatory effect of a pMEA300-encoded gene

The concentration of endothelin-1 (ET-1) in the brain regions, heart, and throacic aorta of 1-, 4-, 6- and 8-week-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was determined using radioimmunoassay. ET-1-like immunoreactivity in the brain regions of 1-week-old WKY and SHR rats was lower compared to older (6 and 8 weeks) rats. ET-1 levels in the central nervous system gradually increased with age in both SHR and WKY rats. However, the concentration of ET-1 in 8-week-old rats was lower in the brain regions of SHR compared to WKY rats. The concentration of ET-1 in the thoracic aorta of SHR (224 +/- 43 pg/g tissue) rats was lower than that of WKY (452 +/- 11 pg/g tissue) rats at 1 week of age. However, ET-1 levels gradually increased with age in SHR rats. By 8 weeks of age, levels of ET-1 in SHR (623 +/- 33 pg/g tissue) rats were higher compared to WKY (439 +/- 62 pg/g tissue) rats. In the heart, ET-1 levels were similar in WKY and SHR rats at 4 weeks of age, but at 8 weeks of age ET-1 levels were higher in SHR rats (364 +/- 33 pg/g tissue) compared to WKY rats (260 +/- 31 pg/g tissue). It appears that at 8 weeks of age when hypertension is fully expressed in rats, ET-1 levels are lower in the central nervous system and are higher in the thoracic aorta and heart of SHR compared to WKY rats.     

Current progress in the development of a totally implantable Gyro centrifugal artificial heart

We studied the contractile responses to endothelin-1 (ET-1) of aortic strips from female transgenic rats, TGR(mRen2)27, heterozygous for the Ren-2 mouse gene, during the phases of developing (blood pressure in rats aged 5 weeks; 156 +/- 8 mmHg), steady (blood pressure in rats aged 11 weeks: 206 +/- 27 mmHg), and reversed (blood pressure in rats aged 35 weeks: 151 +/- 17 mmHg) hypertension. These responses were compared with those of aortae from sex- and age-matched, genetically homogeneous, normotensive Sprague-Dawley (SD) rats. Aortic strips from both transgenic and SD rats were deprived of endothelium before isometrically recording developed tension to cumulatively added ET-1. Aortic strips from 5- and 11-week-old female transgenic TGR(mRen2)27 (hfTG) rats responded to ET-1 with higher Emax values and lower EC50 values than those of age-matched SD rats. Conversely, aortic strips from 35-week-old hfTG rats exhibited lower Emax and higher EC50 values than aortic strips from SD rats. Within the hfTG rats, aortic strips from 11-week-old rats showed increased Emax and decreased EC50 of ET-1 as compared with either 5- or 35-week-old hfTG rats. These data are in keeping with the hypothesis that ET-1 contributes to the hypertension of hfTG rats and suggest that an altered vascular responsiveness to the peptide may be implicated in the changes of their systolic blood pressure occurring with ageing in this animal model.     

Effects of polyvinylpolypyrrolidone, synthetic zeolite and bentonite on serum biochemical and haematological characters of broiler chickens during aflatoxicosis

Angiotensin II (Ang II) may induce arterial hypertrophy either directly or through an increase in arterial pressure. To separate these 2 mechanisms, rats were implanted with osmopumps delivering either Ang II (100 ng x kg-1 x min-1) or saline. 5-Bromo-2'-deoxyuridine (BrdU) was delivered to both groups by osmopump (2.5 microg x kg-1 x min-1). Half of the rats in each group were given minoxidil (9 mg x kg-1 . d-1) in their drinking water. After 14 days, systolic blood pressure was 117+/-2, 124+/-3, and 115+/-2 mm Hg in the control, Ang II-minoxidil, and minoxidil groups, respectively, and 181+/-6 mm Hg in the Ang II group (P<0.05). After perfusion-fixation, the thoracic aorta, carotid artery, small mesenteric artery, external spermatic artery, and kidneys were harvested, paraffin-embedded, and used for morphological measurements, immunohistochemistry for BrdU, and in situ hybridization with a 35S-labeled riboprobe for platelet-derived growth factor-A chain (PDGF-A) mRNA. The walls of the aorta and carotid arteries hypertrophied in the Ang II group only. There were no significant morphological differences in the small arteries. BrdU was negative in all arteries but positive in the renal tubules. Expression of PDGF-A was elevated 8-fold in the thoracic aorta of the Ang II group (P<0.05). These results show that (1) arterial hypertrophy from Ang II infusion occurs in response to elevated arterial pressure, (2) hypertrophy was not associated with hyperplasia or polyploidy of vascular smooth muscle cells, and (3) PDGF-A expression correlated with elevated pressure and arterial wall hypertrophy.     

Child feeding and care behaviors are associated with xerophthalmia in rural Nepalese households

OBJECTIVE: To compare the blood-pressure-lowering effects of an angiotensin converting enzyme inhibitor, perindopril, with those of an angiotensin II type 1 receptor antagonist, L-158,809, for adult spontaneously hypertensive rats. DESIGN: A cross-over design was used, to treat adult spontaneously hypertensive rats with one drug for 10 weeks, and then with the other for 5 weeks. METHODS: Adult, male spontaneously hypertensive rats (aged 15 weeks) were treated daily by gavage for 10 weeks with perindopril (P group) or L-158,809 (L group), then treatment was crossed over so that rats in the P group were treated with L-158,809 (P/L group) and rats in the L group were treated with perindopril (L/P group) for 5 weeks. Blood pressure was measured weekly. Plasma angiotensin converting enzyme activity, renal angiotensin receptor density, and arterial structure and functioning were measured after the single and crossover treatment periods. RESULTS: Treatment lowered the blood pressure from 206 +/- 2 mmHg in rats in the control group, to 126 +/- 2 in rats in the P group and 150 +/- 2 in rats in the L group. After the cross-over period, blood pressure decreased further from 150 +/- 2 to 129 +/- 3 mmHg in rats in the L/P group, whereas blood pressure of spontaneously hypertensive rats in the P/L group increased from 126 +/- 2 to 148 +/- 2 mmHg. Perindopril treatment almost abolished plasma angiotensin converting enzyme activity, whereas L-158,809 treatment had no effect. Renal angiotensin II receptor density was decreased versus baseline in rats in the P and L groups. The affinity of binding was decreased versus baseline in rats in the L group. A positive correlation to blood pressure was found for mesenteric artery wall thickness and wall: lumen ratio. Concentration for half-maximal effect for the response of mesenteric arteries from rats in the P group to norepinephrine was lower than that of the control group rats. Angiotensin II potentiated the norepinephrine-stimulated contraction of arteries from rats in the control and P groups, but not that of arteries from rats in the groups treated with L-158,809. CONCLUSION: Perindopril was more effective than was L-158,809 at lowering the blood pressure of adult spontaneously hypertensive rats, and at altering the structure and functioning of the arteries.     

Reduced pulmonary clearance of endothelin-1 contributes to the increase of circulating levels in heart failure secondary to myocardial infarction

BACKGROUND: The pulmonary vascular bed is a major site for endothelin-1 (ET-1) clearance. A reduced clearance could contribute to the increase in circulating ET-1 levels found in heart failure (HF). We therefore evaluated the effect of HF on pulmonary ET-1 clearance and on plasma ET-1 concentrations. METHODS AND RESULTS: Rats with myocardial infarction (n=24) were compared with sham-operated rats (n=22). The lungs were isolated and perfused at a constant flow rate of 10 mL/min. Pulmonary ET-1 clearance was measured by the single-bolus indicator-dilution technique with 125I-labeled ET-1. Infarct rats developed HF with mild pulmonary hypertension. ET-1 extraction was reduced by HF from 63+/-1.5% to 41+/-4.5% (mean+/-SEM, P<0.001). Mixed venous (MV) and aortic ET-1 levels doubled with HF. There was a plasma ET-1 gradient across the lungs of sham rats (MV-aortic levels, 0.21+/-0.12 pg/mL) but not in lungs of HF rats (0.01+/-0.17 pg/mL). Plasma ET-1 levels correlated closely and inversely with ET-1 extraction (P<0.001). CONCLUSIONS: HF is associated with reduced pulmonary ET-1 clearance that contributes to the increase in circulating levels.     

A study of cis-diamminedichloroplatinum(II) suppositories for the treatment of rabbit uterine endometrial carcinoma

OBJECTIVE: To determine the effects of continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) on endothelin-1 (ET-1) levels in patients with end-stage renal disease (ESRD) and to assess the relationship between plasma ET-1 levels and selected patient parameters. DESIGN: Prospective, nonrandomized comparison study. SETTING: Outpatient CAPD and HD units of a university medical center. PARTICIPANTS: Twelve ESRD patients (6 on CAPD and 6 on HD) and 5 healthy normotensive subjects. INTERVENTIONS: CAPD patients had blood and peritoneal dialysate samples collected and measurements made following an overnight exchange. HD patients had blood collected and measurements made at 0 hours (basal) and again at 3 hours during a midweek HD session. Blood samples were also collected from normal subjects and served as ET-1 controls. MEASUREMENTS: ET-1 and patient parameters (creatinine, peritoneal dialysate volume, blood pressure, body weight, age, and treatment duration) were determined. Data are reported as the mean +/- one standard deviation. RESULTS: Plasma and dialysate ET-1 levels in the CAPD group were 19.5 +/- 4.2 pg/mL and 9.2 +/- 4.2 pg/mL, respectively. The control group plasma and unused dialysate contained no detectable ET-1 (< 3.0 pg/mL, the limit of detection). The peritoneal clearance of ET-1 was less than that of creatinine (2.29 +/- 0.69 mL/minute vs 4.22 +/- 0.66 mL/minute, p = 0.005). The basal (0 hour) plasma ET-1 level in the HD group (16.5 +/- 7.8 pg/mL) did not differ from that of the CAPD group, p = 0.423. Furthermore, no differences in patient parameters were detected between the CAPD and basal HD groups. Although the mean arterial pressure (MAP) decreased during HD, the plasma ET-1 level at 3 hours (13.5 +/- 5.4 pg/mL) remained unchanged from the basal level, p = 0.307. An analysis of pooled data from the CAPD and HD groups revealed no significant correlation between plasma ET-1 and MAP, body weight, creatinine, or treatment duration. There was, however, a positive correlation between plasma ET-1 and age (r = 0.643, p = 0.024).     

Balloon valvuloplasty for the treatment of pulmonary stenosis in dogs

OBJECTIVE: To measure the effect of hypertension on neointima formation after balloon injury of rat aorta and its association with the local angiotensin converting enzyme (ACE) concentration. Balloon angioplasty of the thoracic aorta using a 2 French Fogarty catheter was performed in spontaneously hypertensive rats (SHR) and normotensive Sprague-Dawley (SD) rats. RESULTS: The injured aortic wall of SHR had already significantly higher ACE concentrations than did the uninjured aortic wall of normotensive SD rats (media: 729 +/- 37 dpm/mm2 in SHR versus 496 +/- 38 dpm/mm2 in SD rats, P < 0.01; intima: 83 +/- 5 dpm/mm2 versus 68 +/- 6 dpm/mm2 in SD rats, P < 0.01). Fourteen days after injury of the aorta the hypertensive rats had significantly higher neointima: media ratios than did the normotensive rats (0.83 +/- 0.09 versus 068 +/- 0.01, P < 0.01). This was associated with a significant increase in vascular media and neointima ACE concentrations in SHR (media 965 +/- 25 dpm/mm2, neointima 614 +/- 48 dpm/mm2) compared with those in normotensive SD rats after balloon angioplasty (media 669 +/- 23 dpm/mm2, neointima 287 +/- 33 dpm/mm2, P < 0.01). ACE inhibitor treatment with 10 mg/kg body weight lisinopril daily for 14 days by gavage reduced neointima proliferation in hypertensive and normotensive rats (neointima: media ratio: 0.35 +/- 0.02 for SHR, P < 0.01, versus untreated SHR with balloon injury; 0.28 +/- 0.01 for SD, P < 0.01, versus untreated SD rats with balloon injury). This was associated with significant vascular media ACE inhibition (SHR 149 +/- 9 dpm/mm2; SD rats 118 +/- 7 dpm/mm2; P < 0.01 versus untreated controls with balloon injury) and neointima ACE inhibition (SHR 73 +/- 4 dpm/mm2, SD rats 63 +/- 7 dpm/mm2, P < 0.01, versus untreated controls with balloon injury), but also lowered the blood pressure in SHR significantly (to 148 +/- 5 mmHg, P < 0.01, versus untreated SHR with balloon injury). When this drop in blood pressure was prevented by feeding the rats a high-salt diet (SHR with ACE inhibitor plus high salt-diet group blood pressure 193 +/- 3 mmHg, P = 0.57, versus untreated SHR) hypertension per se without the local ACE increase (ACE concentration in SHR with ACE inhibitor high-salt diet rats' media 167 +/- 10 dpm/mm2 and neointima 81 +/- 9 dpm/mm2) had only a mild effect on neointima formation after balloon angioplasty (neointima: media ratio 0.4 +/- 0.01 for SHR with ACE inhibitor plus high-salt diet versus 0.35 +/- 0.02 for SHR with ACE inhibitor plus normal-salt diet P < 0.05). Treatment with 10 mg/kg body weight angiotensin II subtype 1 receptor antagonist losartan potassium daily for 14 days by gavage was associated with a reduction in neointima formation similar to that observed with the ACE inhibitor both for SHR and for SD rats (neointima: media ratio 0.32 +/- 0.04 for SHR with losartan, 0.27 +/- 0.03 for SD rats with losartan; P < 0.01, versus untreated controls with balloon injury) suggesting that ACE inhibitor prevented neointima formation, at least in part by, reducing the local production of angiotensin II. CONCLUSION: Neointima formation after balloon angioplasty in SHR is increased compared with that in normotensive SD rats. This is due mainly to there being a higher degree of activation of the renin-angiotensin system in the aorta of the SHR before and after balloon injury compared with that in normotensive SD rats measured in terms of the increased vascular ACE concentrations. Blood pressure alone had only a moderate effect on neointima formation.     

Comparable potent coronary constrictor effects of endothelin-1 and big endothelin-1 in humans

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor produced from the precursor big ET-1 in endothelial cells. The coronary effects of these peptides in humans in vivo are unknown. Therefore, the effects of ET-1 and big ET-1 on coronary blood flow in relation to plasma ET-1 and big ET-1 levels were compared in healthy subjects. METHODS AND RESULTS: The peptides were infused intravenously at the rates of 0.2, 1, and 8 pmol/kg per minute. Each dose administered for 20 minutes except the highest dose of ET-1, which was administered for 10 minutes. ET-1 and big ET-1 evoked dose-related increases in mean arterial blood pressure from 93 +/- 4 to 107 +/- 4 mm Hg and from 89 +/- 2 to 122 +/- 5 mm Hg, respectively, at the highest dose. ET-1 and big ET-1 reduced coronary sinus blood flow, measured with thermodilution by a maximum of 25 +/- 4% and 28 +/- 8% and increased coronary vascular resistance by 50 +/- 9% and 107 +/- 26%, respectively. Coronary sinus, but not arterial, oxygen saturation was reduced in parallel with the coronary sinus blood flow. The effects of ET-1 and big ET-1 were similar at corresponding time points. During infusion of ET-1, a 19 +/- 5% extraction of ET-1 was observed over the coronary vascular bed (P < .05). Administration of big ET-1 elevated arterial plasma ET-1 levels by 2.4-fold, and after correction for the local extraction of ET-1, a myocardial production of ET-1 was observed. CONCLUSIONS: ET-1 and big ET-1 induce comparable increases in blood pressure and coronary constriction in humans in vivo. The results also suggest a net local removal of circulating ET-1 and big ET-1 and a local conversion of big ET-1 into ET-1 within the coronary vascular bed.     

Molecular analysis of the histone gene cluster of Psammechinus miliaris: III. Polarity and asymmetry of the histone-coding sequences

The Ca2+ antagonistic coronary vasodilator, Nifedipine, was sublingually administered by a dose of 30 mg to 19 patients with hypertension. Blood pressure of patients with with essential hypertension (n=14) decreased from 177 +/- 24 to 123 +/- 13 mmHg systolic and from 108 +/- 12 to 80 +/- 11 mmHg diastolic (mean +/- SD) (p less than 0.01). Plasma renin activity (PRA) increased significantly from 0.73 +/- 0.62 to 1.50 +/- 1.02 ng/ml/h (p less than 0.05). The same tendency was observed in malignant and renovascular hypertension. In primary aldosteronism (n = 2), blood pressure decreased but PRA did not increase. Hypotensive action and increased plasma renin activity by Ca2+ antagonist, Nifedipine, were clearly demonstrated in patients with hypertension.     

Main hypotheses on diet and cancer investigated in the EPIC Study. European Prospective Investigation into Cancer and Nutrition

This study examines the effect of long-term magnesium-deficient diet on blood pressure and vascular reactivity in aged spontaneously hypertensive rats (SHR) with established hypertension. Thirty-one-week old male SHR received control (0.15 per cent magnesium) and magnesium-deficient (0.015 per cent magnesium) diets for 30 weeks. Systolic blood pressure was measured by tail-cuff method. At the end of the study, the heart, aorta and kidney were collected to measure total magnesium and calcium concentrations; the ex vivo effects of the different magnesium diets on vascular reactivity were examined in isolated aorta and in the isolated perfused mesenteric vascular bed. After 30 weeks, magnesium deficiency had no effect on systolic blood pressure and heart rate of SHR. The tissue concentrations of total magnesium in aorta, heart and kidney were not modified by magnesium deficient diet. Total calcium concentration was significantly higher in the heart of the SHR fed the magnesium-deficient diet (p < 0.01). The aortic responsiveness to contractile agents norepinephrine, endothelin-1, CaCl2 and KCl, and to vasorelaxant agents acetylcholine and isoproterenol were not modified by magnesium deficiency. The vasoconstrictor activity to norepinephrine, CaCl2 and KCl was significantly enhanced in the isolated perfused mesenteric vascular bed of magnesium-deficient SHR (p < 0.05). In conclusion, magnesium deficient diet fails to elevate blood pressure in aged SHR maintained on deficiency for 30 weeks despite an enhanced ex vivo vasoconstrictor activity.     

The influence of antibodies to TNF-alpha and IL-1beta on haemodynamic responses to the cytokines, and to lipopolysaccharide, in conscious rats

Male, Long Evans rats (350-450 g) were anaesthetized and had pulsed Doppler probes and intravascular catheters implanted to allow monitoring of regional (renal, mesenteric and hindquarters) haemodynamics in the conscious state. Our main objectives were to:- assess the effects of administering human recombinant tumour necrosis factor (TNF)-alpha and human recombinant interleukin-1 (IL-1)beta, alone and together; determine the influence of pretreatment with a mixture of antibodies to TNF-alpha and IL-1beta on responses to co-administration of the cytokines; ascertain if pretreatment with a mixture of the antibodies to TNF-alpha and IL-1beta had any influence on the responses to lipopolysaccharide (LPS). TNF-alpha (10, 100 and 250 microg kg(-1), in separate groups, n=3, 9 and 8, respectively) caused tachycardia (maximum delta, +101+/-9 beats min(-1)) and modest hypotension (maximum delta, -10+/-2 mmHg), accompanied by variable changes in renal and mesenteric vascular conductance, but clear increases in hindquarters vascular conductance; only the latter were dose-related (maximum delta, +6+/-6, +27+/-9, and +61+/-12% at 10, 100 and 250 microg kg(-1), respectively). IL-1beta (1, 10, and 100 microg kg(-1) in separate groups, n = 8, 8 and 9, respectively) evoked changes similar to those of TNF-alpha (maximum delta heart rate, +69+/-15 beats min(-1); maximum delta mean blood pressure, -14+/-2 mmHg; maximum delta hindquarters vascular conductance, +49+/-17%), but with no clear dose-dependency. TNF-alpha (250 microg kg(-1)) and IL-1beta (10 microg kg(-1)) together caused tachycardia (maximum delta, +76+/-15 beats min(-1)) and hypotension (maximum A, -24+/-2 mmHg) accompanied by increases in renal, mesenteric and hindquarters vascular conductances (+52+/-6%, +23+/-8%, and +52+/-11%, respectively). Thereafter, blood pressure recovered, in association with marked reductions in mesenteric and hindquarters vascular conductances (maximum delta, -50+/-3% and -58+/-3%, respectively). Although bolus injection of LPS (3.5 mg kg(-1)) caused an initial hypotension (maximum delta, -27+/-11 mmHg) similar to that seen with co-administration of the cytokines, it did not cause mesenteric or hindquarters vasodilatation, and there was only a slow onset renal vasodilatation. The recovery in blood pressure following LPS was less than after the cytokines, and in the former condition there was no mesenteric vasoconstriction. By 24 h after co-administration of TNF-alpha and IL-1beta or after bolus injection of LPS, the secondary reduction in blood pressure was similar (-16+/-2 and -13+/-3 mmHg, respectively), but in the former group the tachycardia (+117+/-14 beats min(-1)) and increase in hindquarters vascular conductance (+99+/-21%) were greater than after bolus injection of LPS (+54+/-16 beats min ' and +439%, respectively). Pretreatment with antibodies to TNF-alpha and IL-1beta (300 mg kg(-1)) blocked the initial hypotensive and mesenteric and hindquarters vasodilator responses to co-administration of the cytokines subsequently. However, tachycardia and renal vasodilatation were still apparent. Premixing antibodies and cytokines before administration prevented most of the effects of the latter, but tachycardia was still present at 24 h. Pretreatment with antibodies to TNF-alpha and IL-1beta before infusion of LPS (150 microg kg(-1) h(-1) for 24 h) did not affect the initial fall in blood pressure, but suppressed the hindquarters vasodilatation and caused a slight improvement in the recovery of blood pressure. However, pretreatment with the antibodies had no effect on the subsequent cardiovascular sequelae of LPS infusion. the results indicate that although co-administration of TNF-alpha and IL-1beta can evoke cardiovascular responses which, in some respects, mimic those of LPS, and although antibodies to the cytokines can suppress most of the cardiovascular effects of the cytokines, the antibodies have little influence on the haemodynamic responses to LPS, possibly because, during infusion of LPS, the sites of production and local action of endogenous cytokines, are not accessible to exogenous antibodies.     

A nosocomial epidemic of Salmonella mbandaka which produces various broad spectrum beta-lactamases: preliminary results

1. Since plasma renin activity is increased in cyclosporin A (CsA)-induced hypertension in the rat, the role of the vascular renin-angiotensin system (RAS) in CsA-induced hypertension was investigated in rat mesenteric resistance vessels. 2. Female Wistar rats received CsA (10 mg/kg per day, s.c.) or vehicle for 30 days. CsA treatment increased tail-cuff systolic blood pressure (CsA treated 135 +/- 3 mmHg vs control 125 +/- 1 mmHg, P < 0.0001). 3. Mesenteric resistance arteries (200-300 microns) were isolated and mounted in a microvessel myograph. Concentration-response curves to tetradecapeptide renin substrate (10(-11)-10(-6) mol/L), angiotensin I (10(-11)-10(-6) mol/L) and angiotensin II (10(-12)-10(-6) mol/L) showed no differences between CsA-treated and control groups. 4. Mesenteric vascular angiotensin-converting enzyme (ACE) characteristics were determined by radioligand binding. There were no differences in the content or affinity of ACE between CsA-treated and control rats. 5. These results suggest that the mesenteric vascular RAS does not play a major role in CsA-induced hypertension in the rat.     

Differing effects of anesthetics on splanchnic arterial blood flow during hemorrhagic shock

The effect of anesthesia on splanchnic blood flow was examined during hemorrhagic shock and resuscitation. Sprague-Dawley rats were anesthetized with the inhalation anesthetic, methoxyflurane, or pentobarbital (65 mg/kg). Transonic Doppler flow probes were placed around the superior mesenteric artery (SMA) and the abdominal aorta, and the animals were subjected to acute hemorrhage (or sham) to 30 mmHg for 90 min followed by 30 min of resuscitation with shed blood (n = 6/group). At 90, 105, and 120 min, sham animals in both anesthetic groups showed comparable blood pressures with a 50% decrease in SMA and aortic blood flow. Acute hemorrhage decreased SMA blood flow by 94.5 +/- 0.01 and 86.0 +/- 2.8%, respectively, in the pentobarbital and methoxyflurane groups, with similar changes occurring in aortic blood flow. During resuscitation, arterial pressure remained significantly depressed and SMA blood flow decreased by 65% in the pentobarbital group, whereas blood pressure returned to control levels and SMA blood flow increased to 56% of control values (P < 0.001) in the methoxyflurane group. The findings indicate that the choice of anesthetic agent may significantly impact splanchnic blood flow and needs to be taken into account when designing experiments examining effects of hemorrhagic shock.     

Autonomic contribution to the blood pressure and heart rate variability changes in early experimental hyperthyroidism

A great deal of uncertainty persists regarding the exact nature of the interaction between autonomic nervous activity and thyroid hormones in the control of heart rate (HR) and blood pressure (BP). Thyrotoxicosis was produced by a daily intraperitoneal (i.p.) injection of L-thyroxine (0.5 mg/kg body wt in 1 ml of 5 mM NaOH for 5 days). Control rats received i.p. daily injections of the thyroxine solvant. Autonomic blockers were administered intravenously: atropine (0.5 mg/kg), atenolol (1 mg/kg), atenolol + atropine or prazosin (1 mg/kg). Eight animals were studied in each group. Thyroxine treatment was sufficient to induce a significant degree of tachycardia (423 +/- 6 vs 353 +/- 4 bpm; p < 0.001, unpaired Student's tests), systolic BP elevation (142 +/- 3 vs 127 +/- 2 mmHg; p < 0.001), pulse pressure increase (51 +/- 2 vs 41 +/- 2 mmHg, p < 0.01), cardiac hypertrophy (1.165 +/- 0.017 vs 1.006 +/- 0.012 g, p < 0.001), weight loss (-21 +/- 2 g; p < 0.001) and hyperthermia (37.8 +/- 0.1 vs 37.0 +/- 0.1 degrees C, p < 0.001). The intrinsic HR observed after double blockade (atenolol + atropine) was markedly increased after treatment with thyroxine (497 +/- 16 vs 373 +/- 10 bpm, p < 0.05). Vagal tone (difference between HR obtained after atenolol and intrinsic HR) was positively linearly related to intrinsic HR (r = 0.84; p < 0.01). Atenolol neither modified HR nor BP variability in rats with hyperthyrodism. The thyrotoxicosis was associated with a reduction of the 0.4 Hz component of BP variability (analyses on 102.4 sec segments, modulus 1.10 +/- 0.07 vs 1.41 +/- 0.06 mmHg; p < 0.01). Prazosin was without effect on this 0.4 Hz component in these animals. These data show a functional diminution of the vascular and cardiac sympathetic tone in experimental hyperthyroidism. Increased intrinsic HR resulting from the direct effect of thyroid hormone on the sinoatrial node is the main determinant of a tachycardia leading to a subsequent rise in cardiac output. The resulting BP elevation could reflexly induce a vagal activation and a sympathetic (vascular and cardiac) inhibition.