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Clin Sci Lond [journal]
- Endothelin stimulates an endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, in experimental heart failure. [Journal Article, Research Support, Non-U.S. Gov't]
- Clin Sci (Lond) 2002 Aug.:241S-244S.
Congestive heart failure (CHF) is characterized by increased peripheral vascular resistance. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor, is present at increased concentrations in the plasma and contributes to the regulation of vascular tone in CHF. An endothelium-derived relaxing factor, nitric oxide (NO), also regulates vascular tone, but endothelium-dependent NO-mediated vasodilation is blunted in CHF. An endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), which inhibits NO production and endothelium-dependent relaxation, is present at increased levels in the plasma and plays a role in impaired endothelial function in CHF. However, at present, the relationship between ET-1 and impaired vascular relaxation in CHF is not well known. We hypothesized that ET-1 inhibits NO-mediated vasodilation via increased ADMA production in CHF, and that an endothelin receptor antagonist can prevent this increase in plasma ADMA levels. In the present study, we first examined whether circulating ADMA levels were increased in a dog model of CHF induced by 3 weeks of rapid ventricular pacing (n=5; 270 beats/min) compared with normal dogs (n=5). After 3 weeks of pacing, cardiac output had decreased significantly (1.56+/-0.16 compared with 2.93+/-0.25 litres/min; P<0.01) and systemic vascular resistance had increased (4653+/-374 compared with 3227+/-396 dyn.s.cm(-5); P<0.01) in dogs with CHF compared with normal dogs. Plasma levels of both ET-1 (4.95+/-0.83 compared with 2.12+/-0.39 pg/ml; P<0.05) and ADMA (3.27+/-0.49 compared with 1.91+/-0.25 nmol/ml; P<0.05) were significantly increased in CHF dogs. A significant positive correlation was observed between plasma ET-1 and ADMA levels (r=0.72, P<0.05). Secondly, we chronically administered an ET(A) receptor antagonist, TA-0201 (0.3 mg/kg; n=5), to paced CHF dogs. Drug administration started on day 8 of pacing and continued throughout the experiment. TA-0201 significantly increased cardiac output (2.58+/-0.24 litres/min; P<0.01) and suppressed the increases in plasma ADMA levels and systemic vascular resistance (2.36+/-0.30 nmol/ml and 2423+/-188 dyn.s.cm(-5) respectively; P<0.05 for each) compared with CHF dogs without TA-0201 treatment. In conclusion, ET-1 contributes to the regulation of vascular tone due, in part, to increased levels of an endogenous NO synthase inhibitor in CHF, and an ET(A) receptor antagonist can prevent the inhibition of NO production and the increased peripheral vascular resistance observed in CHF.
- Heart rate variability in 1-day-old infants born at 4330 m altitude. [Comparative Study, Journal Article, Research Support, Non-U.S. Gov't]
- Clin Sci (Lond) 1999 Feb; 96(2):147-53.
In fetuses and newborn infants heart rate variability changes in conditions of acute and chronic hypoxia; we therefore asked whether heart rate variability of infants born at high altitude differed from that of low-altitude infants. Short-term recordings (4-5 min) of inter-beat intervals were obtained in 19 infants in Lima (50 m altitude) and in 15 infants in Cerro de Pasco (4330 m, barometric pressure approximately 450 mmHg, inspired oxygen pressure approximately 94 mmHg) during quiet rest in warm conditions (ambient temperature, Ta, approximately 35 degrees C). In 12 infants from each group recordings were also obtained during cooling (Ta approximately 26 degrees C). Heart rate variability was evaluated from 512 consecutive inter-beat intervals, with analysis based on time-domain and frequency-domain methods. At warm Ta, heart rate variability did not differ between the two groups. During cooling, heart rate increased only in the low-altitude group. As in the warm, during cooling most parameters of heart rate variability did not differ between the two groups. The only exception was the inter-beat interval power of the high-frequency range of the spectrum (0.15-0.4 Hz), which, at least in adults, is believed to be a reflection of vagal activity, and was greater in the high-altitude group. It is concluded that gestation at high altitude, despite its blunting effects on fetal growth, does not have a major impact on heart rate variability of the newborn. Nevertheless, the possibility that differences in response to cooling may reflect some limitation in heart rate control needs to be examined further.
- Anti-aggregatory effects of physiological concentrations of adenosine in human whole blood as assessed by filtragometry. [In Vitro, Journal Article, Research Support, Non-U.S. Gov't]
- Clin Sci (Lond) 1991 Nov; 81(5):691-4.
1. The anti-aggregatory effect of adenosine (0.3-10 mumol/l), alone or in combination with the adenosine-uptake inhibitor dipyridamole (2 mumol/l), was studied in vitro in whole blood from 11 healthy subjects by filtragometry. 2. ADP (0.05-0.1 mumol/l) was used to reduce the filter occlusion time (tA, a measure of platelet aggregate formation in blood) from approximately 600 s to 71-101 s in the absence of other agents. 3. Adenosine was infused into the tubing system of the filtragometer, yielding a contact time of approximately 25 s with the blood before the filter. Adenosine did not influence the aggregatory response to ADP significantly at 0.3 mumol/l in plasma, whereas tA was prolonged by 19 +/- 6% (P less than 0.02) at 1 mumol/l adenosine and by 259 +/- 78% (P less than 0.02) at 3 mumol/l adenosine. 4. When the rapid elimination of adenosine from plasma was prevented by 2 mumol/l dipyridamole, adenosine caused marked prolongation of ADP-induced tA, with significant effects at 0.3 mumol/l (+143 +/- 72%, P less than 0.05). Dipyridamole per se did not affect tA values. 5. The present results suggest that adenosine has a transient anti-aggregatory effect in whole blood at about 0.3 mumol/l, as this is the highest possible calculated concentration of adenosine at the filter of the apparatus when 1 mumol/l adenosine is infused in the absence of dipyridamole or when 0.3 mumol/l adenosine is infused in its presence. 6. It is concluded that adenosine has anti-aggregatory effects at submicromolar (physiological) concentrations in human whole blood.(
ABSTRACTTRUNCATED AT 250 WORDS)
- Selective dietary potassium depletion and acid-base equilibrium in the rat. [Journal Article, Research Support, Non-U.S. Gov't]
- Clin Sci (Lond) 1985 Mar; 68(3):301-9.
K+ depletion of two kinds was induced in two groups of rats by selective dietary restriction for up to 5 weeks. Complete metabolic studies for H+, K+, Na+ and Cl- were carried out daily during weeks 1, 3 and 5. In control rats of group A (receiving K+ with sodium chloride), plasma pH (7.47) and HCO3- (25 mmol/l), as well TA (titratable acid)--HCO3- and NH+4 urinary excretion rates, were stable, while balances were nil for K+ and slightly positive for Cl-. In K+-deprived rats of group A receiving sodium chloride, a progressive metabolic alkalosis developed (plasma pH reached 7.57 and HCO3- 35.8 mmol/l by 5 weeks), and TA--HCO3- and NH+4 urinary excretion rates were not different from controls. Plasma K+ fell progressively from 4.20 to 2.20 mmol/l, with negative K+ balance. Balances for Na+ and H2O were highly positive and plasma renin activity and aldosterone decreased by week 5. Hypochloraemia developed with positive Cl- balance. In control rats of group B (receiving K+ with neutral sodium phosphate), a slight metabolic alkalosis developed, and TA--HCO3- excretion rate was increased compared with control rats of group A.(
ABSTRACTTRUNCATED AT 250 WORDS)
- Trends in trabecular and cortical bone in the radius compared with whole body calcium balance in osteoporosis. [Journal Article]
- Clin Sci (Lond) 1984 Jan; 66(1):109-12.
Mean linear attenuation coefficients for trabecular bone (T) in the distal radius and total absorption coefficients (TA) in the radial mid-shafts of 22 patients with crush fracture osteoporosis were measured serially for a year by using computed tomography. After approximately 6 months, each patient was admitted to a metabolic ward for an 18-day calcium balance study. The rate of change (trend) in trabecular bone (T) in the distal radius was a better predictor of calcium balance than the trend in mid-shaft cortical bone (TA). The scatter in the regressions of the trends of T and TA on calcium balance could be accounted for by known methodological uncertainties.