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Biomedical subjects

I G Chadwick

Publications and source records attributed to I G Chadwick.

10 recordsLinked to original sources
PubMed1997

Pressor and hormonal responses to angiotensin I infusion in healthy subjects of different angiotensin-converting enzyme genotypes.

The effects of incremental infusion of angiotensin I on pressor and hormonal responses in relation to the angiotensin-converting enzyme (ACE) genotype were compared in healthy men of genotype DD (n = 8) and II (n = 8). The R(d)25 was the rate of angiotensin I infusion required to achieve a 25-mm Hg increase in diastolic pressure, and the R(s)25, that which caused a 25-mm Hg increase in systolic pressure. Changes in heart rate (HR25) were analysed at the time the R(d)25 was achieved. Serum ACE activity and plasma renin, angiotensin II, and aldosterone concentrations were measured at the start and end of the angiotensin I infusion. Serum ACE activity differed significantly between the genotypes with significantly higher mean values in DD subjects (46.3 +/- SEM 5.2 U/L) than II subjects (12.3 +/- 1.4 U/L; p < 0.001). Age, weight, and baseline blood pressure, heart rate, urinary sodium excretion, plasma renin, angiotensin II, and aldosterone concentrations did not differ between genotypes. The geometric mean infusion rates of angiotensin I required to achieve R(d)25 were 2.53 micrograms/min in II subjects and 2.67 micrograms/min in DD subjects (ratio of infusion rates, 0.95; 95% CI, 0.44-2.02; p > 0.05). The corresponding infusion rates for systolic blood pressure (R(s)25) were 4.47 micrograms/min in II subjects and 3.39 micrograms/min in DD subjects (ratio, 1.32; 95% CI, 0.49-3.55; p > 0.05). At the time of R(d)25, changes in heart rate from baseline were +1.2 beats/min for DD subjects and -9.5 beats/min for II subjects (diff II-DD = 10.7 beats/min; 95% CI, 6.7-14.8; p = 0.01). There were no differences in plasma renin, angiotensin, and aldosterone responses to angiotensin I infusion between the DD and II genotypes. We showed no difference in blood pressure or renin-angiotensin-aldosterone system responses to infusion of angiotensin I related to the deletion or insertion allele of the ACE gene polymorphism, but the study has insufficient power to exclude with certainty such differences. There was a significant difference between II and DD subjects in the chronotropic response to angiotensin I infusion.

Adult↗
PubMed1996

No relation between angiotensin-converting enzyme gene polymorphism and dermal response to bradykinin in healthy subjects.

1. The dermal wheal response to bradykinin is increased by drugs which inhibit angiotensin-converting enzyme, and thus provides a measure of angiotensin-converting enzyme activity at the tissue level. An insertion/deletion polymorphism of the angiotensin-converting enzyme gene predicts serum angiotensin-converting enzyme activity, but its relation to angiotensin-converting enzyme activity in tissue is unclear. 2. The relations between angiotensin-converting enzyme genotype and wheal responses to intradermal bradykinin were studied in 105 healthy subjects: 30 of genotype DD, 51 of genotype ID and 24 of genotype II. Dermal wheal area was measured by digitized planimetry and the angiotensin-converting enzyme genotype by polymerase chain reaction. 3. Bradykinin produced significant linear log dose-wheal area responses. The potency of bradykinin by parallel line bioassay did not differ significantly between the genotypes; the potency in the II subjects relative to DD subjects was 1.25 (95% confidence interval: 0.83-1.88). 4. Although the angiotensin-converting enzyme gene polymorphism is a consistent and powerful predictor of serum angiotensin-converting enzyme activity, it does not appear to predict tissue angiotensin-converting enzyme activity as measured by dermal responses to bradykinin.

Adult↗
PubMed1995

Relation between changes in blood pressure and serum ACE activity after a single dose of enalapril and ACE genotype in healthy subjects.

1. The effects of a single oral dose of enalapril 10 mg on serum ACE activity and blood pressure in relation to the ACE genotype were studied in 27 healthy men, n = 9 each of genotype DD, ID and II, in a parallel group study design. 2. Before treatment serum ACE activity differed significantly between the genotypes, with serum ACE activity 56% higher in DD than II subjects, and the genotype explaining 40% of between-subject variance in serum ACE activity. 3. After oral enalapril 10 mg the absolute fall in serum ACE activity was significantly larger in DD than II subjects at 2, 4, and 6 h (by 9.0 (95% CI 0.7-17.2), 10.7 (3.8-17.6), and 9.7 (2.8-16.6) nmol ml-1 min-1 respectively), but not at 24 h (fall in II > DD by 1.1 (-8.9 to 6.7) nmol ml-1 min-1). 4. Serum ACE activity remained significantly related to the ACE genotype at each time-point after enalapril, with the genotype explaining 22-46% of between-subject variance in serum ACE. 5. Falls in mean arterial pressure in response to enalapril were not significantly related to the ACE genotype, with the average fall over 6 h in DD > II genotype by 0.7 mm Hg (95% CI -5.5 to 4.1). 6. Blood pressure responses to enalapril did not correlate significantly with the initial serum ACE, or the absolute or percent reductions in serum ACE activity after enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Pressor effect of hyperventilation in healthy subjects.

Hyperventilation is an important feature of panic disorder, and an association has been reported between panic disorder and hypertension. We have examined the effect of hyperventilation on the blood pressure (BP) of healthy subjects. Twenty six subjects were randomised in a balanced two-period cross-over study to compare the effects of hyperventilation with that of normal breathing on sitting BP, heart rate and the electrocardiogram. Each study phase lasted 40 min, with 15 min of baseline observation, 5 min of hyperventilation or normal breathing, and 20 min of continued observation. Hyperventilation significantly increased SBP by 8.9 mm Hg (95% CI 3.8-13.8, P < 0.01), diastolic blood pressure by 8.2 mm Hg (95% CI 1.7-14.7, P < 0.05), mean arterial pressure by 10.0 mm Hg (95% CI 3.3-16.7, P < 0.01) and heart rate by 36 beats/min (95% CI 31-44, P < 0.01). The changes in diastolic and mean arterial pressure correlated significantly with the total volume of air expired during hyperventilation (r = 0.57, p < 0.01 and r = 0.50 P < 0.01, respectively), but not with the change in expired carbon dioxide. In the electrocardiogram, T wave changes occurred in the inferior leads in 10 of 26 subjects, but there were no significant changes in other measurements. Hyperventilation significantly increased the BP of healthy subjects, and the role of hyperventilation in the link between panic disorder and hypertension deserves further study.

Adult↗
PubMed1995

Resolution of ACE inhibitor cough: changes in subjective cough and responses to inhaled capsaicin, intradermal bradykinin and substance-P.

1. In eight hypertensive patients with ACE inhibitor-induced cough the resolution of the cough was examined in a prospective observational study over 4 weeks duration. Resolution of cough was measured by visual analogue scales and questionnaire at baseline and days 3, 7, 14 and 28. In addition changes in cough sensitivity to inhaled capsaicin, and skin responses to bradykinin and substance-P were measured at the same time points. 2. All patients recorded significant subjective improvement in cough questionnaire scores for severity and night time waking, and by visual analogue scales for severity and frequency of cough (all P < 0.0005 for trend from day 0-28). Significant changes in subjective measures were recorded by 3 to 7 days for most measures, but further reductions were observed up to day 28 (all P < 0.01 day 28 vs day 0). 3. The sensitivity to inhaled capsaicin fell over the 28 days of study after stopping enalapril. The potency of capsaicin relative to day 0 was reduced to 0.25 (95% CI 0.07-0.87) by day 14, and to 0.20 (95% CI 0.06-0.67) by 28 days. 4. After stopping enalapril there was a highly significant reduction in wheal area produced by intradermal bradykinin, with the majority of the effect seen by day 3 (P < 0.0005). The wheal area to intradermal substance-P also declined with time after stopping enalapril, but significant changes were not observed until 14 days (P < 0.01). 5. Multiple regression analysis of the rates of decline for the subjective and objective measures of cough showed significant associations between the response to inhaled capsaicin and the VAS scores for severity of cough (P = 0.005) and frequency of cough (P = 0.011). Capsaicin response was not related significantly to the severity of cough measured by self-administered questionnaire. 6. There was a significant association between bradykinin response and VAS scores for frequency of cough (P < 0.04) and severity of cough (P < 0.05), but not with cough by questionnaire or the capsaicin response. The response to substance-P did not relate significantly to any of the measures of cough. 7. Cough caused by enalapril improved markedly by 14 days but took up to 28 days to resolve. It was associated with increased sensitivity to inhaled capsaicin which decreased over 28 days, and which paralleled changes in subjective cough scores.

Adult↗
PubMed1994

Non-pharmacological therapy of hypertension.

Weight reduction, moderate sodium restriction and alcohol reduction all lower blood pressure significantly in the short-term, and appear feasible in the long-term. Dynamic exercise may have a useful role in selected patients. Cessation of cigarette smoking has no important effect on blood pressure itself but is likely to improve the prognosis. No other non-pharmacological intervention warrants a place in routine management on present evidence. Regimens involving combined reduction in weight, salt and alcohol have proved less effective than drug therapy in terms of blood pressure reduction. Hypertensive patients may be shifted from just above some arbitrary intervention level to just below it by non-pharmacological treatment, and the perceived benefits of non-pharmacological management may be offset by an increased risk of vascular complications related to suboptimal blood pressure control. Moreover even simple measures such as moderate sodium restriction may affect some aspects of quality of life adversely. Non-pharmacological measures should generally be regarded as useful adjuncts to antihypertensive drug therapy rather than alternatives to it.

Alcohol Drinking↗
PubMed1994

Inhibition of CYP2D6 activity by treatment with propranolol and the role of 4-hydroxy propranolol.

1. The 4-hydroxylation of propranolol by rat and human liver microsomes is associated with formation of a chemically reactive species which binds irreversibly to cytochrome P4502D6 (CYP2D6) destroying its catalytic function. Therefore, the effect of propranolol treatment (80 mg twice daily) on debrisoquine phenotype was examined, to see if it resulted in phenocopying in vivo. The role of 4-hydroxypropranolol (4OHP) in the inhibition of CYP2D6 activity was also studied using microsomes from yeast expressing CYP2D6 and from human livers; metoprolol was used as the CYP2D6 substrate. 2. Although a significant effect on apparent oxidation phenotype was demonstrated, the absolute change in the urinary debrisoquine/4-hydroxydebrisoquine ratio (D/4HD) was small, such that no extensive metaboliser who received propranolol treatment was reclassified as a poor metaboliser. The in vitro studies indicated that 4OHP is a potent inhibitor of metoprolol metabolism (Ki approximately 1 microM). This inhibitory effect was enhanced when 4OHP was pre-incubated in the presence of a NADPH generating system and human liver microsomes. The effect was decreased significantly when reduced glutathione was added to the pre-incubation mixture. Metabolism of 4OHP occurred when incubated with human liver microsomes in the presence of a NADPH generating system and irrespective of CYP2D6 phenotype; yeast expressing CYP2D6 did not metabolise 4OHP. 3. We conclude that, although treatment with propranolol 80 mg twice daily significantly decreases the catalytic function of CYP2D6, the inhibition is insufficient to result in phenocopying. The reactive intermediate produced by further metabolism of 4OHP is probably scavenged effectively in vivo by glutathione and other nucleophiles.

Adult↗