Clinical science
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Increasing evidence has implicated endothelin-1 (ET-1), a potent vasoconstrictive peptide, in the pathophysiology of cerebral vasospasm after subarachnoid haemorrhage (SAH). Endothelin-converting enzyme-1 (ECE-1), the protease involved in the final step of post-translational processing of ET-1, cleaves the inactive precursor big ET-1 at the Trp(21)-Val (22) peptide bond. In our previous study, we found that an inhibitor of ECE-1, CGS 26303, could prevent and reverse the arterial narrowing after SAH in rabbits. ⋯ The levels of free CGS 26303 in the CSF were increased in a dose-dependent manner in all three CGS 26393-treated groups. This study provides the first evidence that oral administration of an inhibitor of ECE-1, CGS 26393, is capable of preventing and reversing cerebral vasospasm following SAH. These findings also reinforce evidence demonstrating that treatment with an ECE-1 inhibitor is a potentially viable therapeutic approach for reducing cerebral vasospasm after SAH.
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This study compares the haemodynamic and hormonal responses during haemorrhage of conscious dogs pre-treated with an endothelin-A (ET-A) receptor inhibitor. The dogs were studied in two different randomized groups: the control group and a group that was given the ET-A receptor antagonist ABT-627 (as a bolus of 1 mg x kg of body weight(-1) followed by 0.01 mg x kg body weight(-1) x min(-1) intravenously). The time-course was the same for both groups: after a 1 h baseline period (pre-haemorrhage), blood (25 ml x kg of body weight(-1)) was withdrawn within 5 min. ⋯ We conclude from our results that dogs receiving the selective ET-A inhibitor ABT-627 seem to show a different hormonal response after haemorrhage compared with controls, displaying considerably higher noradrenaline concentrations. Independent of ET-A receptor inhibition, cardiac output during haemorrhage was maintained within the control range. This may indicate that the organism is defending blood flow (cardiac output) over blood pressure during haemorrhage, and that this defence strategy is not compromised by ET-A receptor inhibition.
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The purpose of the study was to assess whether increased pulmonary flow and subsequent development of pulmonary vascular remodelling could alter the expression of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) in the rat lung. Nine 42-day-old Wistar rats underwent abdominal aortocaval shunt to increase pulmonary blood flow for 12 weeks. The shunt resulted in significant medial hypertrophy of pulmonary artery without significant alterations in pulmonary or systemic blood pressure. ⋯ However, the plasma ET-1 concentration in the pulmonary artery (sham: 5+/-0.7 pg/ml; shunt: 6+/-0.8 pg/ml) or the lung ET-1 content (sham: 218+/-41 ng/g protein; shunt: 224+/-40 ng/g protein) was unchanged. There was an elevated immunohistochemical expression of eNOS, but not ET-1, in the pulmonary vascular endothelium in rats with the shunt. These results suggest that eNOS and ET-1 may be involved in remodelling prior to the development of pulmonary hypertension.
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Mean arterial pressure (MAP) is estimated at the brachial artery level by adding a fraction of pulse pressure (form factor; =0.33) to diastolic pressure. We tested the hypothesis that a fixed form factor can also be used at the aortic root level. We recorded systolic aortic pressure (SAP) and diastolic aortic pressure (DAP), and we calculated aortic pulse pressure (PP) and the time-averaged MAP in the aorta of resting adults (n=73; age 43+/-14 years). ⋯ In conclusion, the aortic form factor was strongly influenced by age, aortic pressure and wave reflection. An empirical formula (MAP=DAP+PP/3+5 mmHg) that is consistent with mechanical principles in the arterial system gave a more precise estimate of MAP in the aorta of resting humans. Only two distinct pressure-powered functions were carried out in the (SAP, DAP, MAP, PP) four-pressure set.
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Pyruvate dehydrogenase (PDH) has low activity in the circulating lymphocytes (CL) of obese adolescents and adults. In vitro, it is unresponsive to insulin at 5 micro-units/ml and is activated at 50 micro-units/ml, in contrast with activation and inhibition respectively at these concentrations in CL from controls. These changes are seen as being indicative of a molecular disorder underlying insulin resistance. ⋯ PDH responses in vitro to insulin in CL taken from the control subjects at t(-3) and t(240) and in CL taken from the obese subjects at t(-3) were as reported above, but were normal (i.e. the same as in control CL) in CL taken from the obese subjects at t(240). Baseline PDH activity was inversely correlated with body mass index and with fasting insulin, and directly correlated with S(I). These results show that a brief and sharp enhancement of blood insulin overcomes derangements in PDH that reflect systemic insulin resistance in obese adolescents.