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Biomedical subjects

J A Millar

Publications and source records attributed to J A Millar.

At least 19 recordsLinked to original sources
PubMed2000

The role of Ca2+ stores in the muscarinic inhibition of the K+ current IK(SO) in neonatal rat cerebellar granule cells.

Cerebellar granule neurons (CGNs) possess a standing outward potassium current (IK(SO)) which shares many similarities with current through the two-pore domain potassium channel TASK-1 and which is inhibited following activation of muscarinic acetylcholine receptors. The action of muscarine on IK(SO) was unaffected by the M2 receptor antagonist methoctramine (100 nM) but was blocked by the M3 antagonist zamifenacin, which, at a concentration of 100 nM, shifted the muscarine concentration-response curve to the right by around 50-fold. Surprisingly, M3 receptor activation rarely produced a detectable increase in [Ca2+]i unless preceded by depolarization of the cells with 25 mM K+. Experiments with thapsigargin and ionomycin suggested that the endoplasmic reticulum Ca2+ stores in CGNs were depleted at rest. In contrast, cerebellar glial cells in the same fields of cells possessed substantial endoplasmic reticulum Ca2+ stores at rest. Pretreatment of the cells with BAPTA AM, thapsigargin or the phospholipase C (PLC) inhibitor U-73122 all blocked the muscarine-induced Ca2+ signal but had little or no effect on muscarinic inhibition of IK(SO). Raising [Ca2+]i directly with ionomycin caused a small but significant inhibition of IK(SO). It is concluded that muscarine acts on M3 muscarinic acetylcholine receptors both to inhibit IK(SO) and to mobilize Ca2+ from intracellular stores in CGNs. While the mobilization of Ca2+ occurs through activation of PLC, this does not seem to be the primary mechanism underlying muscarinic inhibition of IK(SO).

Animals↗
PubMed2000

A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons.

Cerebellar granule neurons (CGNs) are one of the most populous cells in the mammalian brain. They express an outwardly rectifying potassium current, termed a "standing-outward" K(+) current, or IK(SO), which does not inactivate. It is active at the resting potential of CGNs, and blocking IK(SO) leads to cell depolarization. IK(SO) is blocked by Ba(2+) ions and is regulated by activation of muscarinic M(3) receptors, but it is insensitive to the classical broad-spectrum potassium channel blocking drugs 4-aminopyridine and tetraethylammonium ions. The molecular nature of this important current has yet to be established, but in this study, we provide strong evidence to suggest that IK(SO) is the functional correlate of the recently identified two-pore domain potassium channel TASK-1. We show that IK(SO) has no threshold for activation by voltage and that it is blocked by small extracellular acidifications. Both of these are properties that are diagnostic of TASK-1 channels. In addition, we show that TASK-1 currents expressed in Xenopus oocytes are inhibited after activation of endogenous M(3) muscarinic receptors. Finally, we demonstrate that mRNA for TASK-1 is found in CGNs and that TASK-1 protein is expressed in CGN membranes. This description of a functional two-pore domain potassium channel in the mammalian central nervous system indicates its physiological importance in controlling cell excitability and how agents that modify its activity, such as agonists at G protein-coupled receptors and hydrogen ions, can profoundly alter both the neuron's resting potential and its excitability.

Animals↗
PubMed2000

Implications of pulse pressure as a predictor of cardiac risk in patients with hypertension.

Previously we demonstrated that pulse pressure is a strong risk factor for coronary events in male hypertensive subjects in the MRC Mild Hypertension Trial, whereas stroke is best predicted by mean blood pressure. In this study, we have assessed the implications of this finding in the treatment of mild essential hypertension. We examined the relationship between diastolic blood pressure and both coronary disease risk and stroke when these events were predicted by the above blood pressure measures using an empirical linear model and multivariate logistic regression models that contained data from the MRC trial. Under these circumstances, the predicted stroke risk increased progressively with increasing values of diastolic blood pressure, but in both empirical and formal statistical models, the predicted risk of a coronary event exhibited a J-shaped relationship with diastolic blood pressure. These results suggest that if coronary event risk in mild essential hypertension is predicted by pulse pressure then it may increase at low values of diastolic blood pressure, in contrast to stroke risk, which declines continuously as diastolic blood pressure falls within the physiological range. This raises the possibility that different sequelae of hypertension are best predicted by different measures of blood pressure and that the effect of treatment on stroke and coronary events in some circumstances may be discordant.

Adult↗
PubMed1999

Inhibition of neuronal KV potassium currents by the antidepressant drug, fluoxetine.

1. The effect of the antidepressant drug, fluoxetine on neuronal delayed rectifier (KV) potassium (K) currents was investigated using perforated-patch whole-cell electrophysiological recording methods. 2. Fluoxetine was an effective inhibitor of KV currents in cerebellar granule neurons (CGNs) and also inhibited recombinant KV1.1 channels expressed in Chinese hamster ovary (CHO) cells. 3. Fluoxetine had an IC50 of 11 microM in CGNs but was slightly less potent on KV1.1 channels (IC50=55 microM). Interestingly, fluoxetine was a much more potent inhibitor of KV1.1 expressed in mammalian cells than has been found previously for the same homomeric channel expressed in Xenopus oocytes. 4. At concentrations that produced around 50% block, the shape of the KV currents in the presence of fluoxetine was simply scaled down when compared to control currents. 5. The effect of fluoxetine on KV currents in CGNs was neither voltage-dependent nor dependent on the channels being in their open state. Both of these observations suggest that fluoxetine does not act as a simple open channel blocking agent. 6. It is concluded that block of KV currents in mammalian neurons can occur at therapeutic levels of fluoxetine. This could lead to an increase in neuronal excitability and this effect may contribute to the therapeutic antidepressant action of fluoxetine.

Animals↗
PubMed1999

Pulse pressure as a risk factor for cardiovascular events in the MRC Mild Hypertension Trial.

OBJECTIVES: The aim of this study was to determine whether pulse pressure is a risk factor for coronary artery disease using data from the MRC trial of treatment of mild hypertension, and whether the effect of anti-hypertensive drug therapy on pulse pressure may be a determinant of outcome in treated patients. METHODS: Logistic regression and Cox regression analyses were used to compare systolic and diastolic blood pressure, pulse pressure and mean blood pressure as predictors of coronary events and stroke in the MRC Mild Hypertension Trial. The effects of anti-hypertensive drug treatment with bendrofluazide and propranolol on pulse pressure were assessed using 1-year follow-up data. Event rates in the placebo-treated group and responses to anti-hypertensive treatment were measured in quartiles of age-adjusted entry pulse pressure. A 'four-corners' analysis was performed, with subjects divided into the upper and lower halves of the distributions of systolic and diastolic blood pressure at entry. RESULTS: Pulse pressure was a stronger predictor of coronary events than systolic, diastolic or mean blood pressure in males by logistic regression. Pulse pressure was similar to systolic pressure as a coronary event predictor on Cox regression. Stroke was predicted most strongly by mean blood pressure. Fatal and non-fatal coronary event rates increased progressively in ascending quartiles of age-adjusted pulse pressure, but there was also a strong correlation with systolic blood pressure. The values of partial logistic regression coefficients in models containing both systolic and diastolic blood pressure also supported a role for pulse pressure in predicting coronary events and for mean blood pressure in predicting stroke. Coronary risk, but not stroke, was inversely related to diastolic blood pressure in the four-corners analysis. In a Cox model, regressions of coronary event probability on systolic blood pressure at entry were significantly and inversely related to diastolic blood pressure categorized in quartiles. Bendrofluazide but not propranolol decreased pulse pressure significantly and was associated with a reduction in cardiovascular events overall, but no definite relationship between the effect of drugs on pulse pressure and specific responses to treatment was seen. CONCLUSION: Pulse pressure is a strong risk factor for coronary events in untreated hypertensive male subjects in the MRC Mild Hypertension Trial, whereas stroke is best predicted by mean blood pressure. Bendrofluazide and propranolol have different effects on pulse pressure which may be related to their relative efficacy in the treatment of hypertension, but this possibility requires further study in more suitable populations.

Analysis of Variance↗
PubMed1996

Impaired endothelium-dependent and independent dilatation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes: role of dyslipidaemia.

1. We measured endothelium-dependent and independent dilatation of forearm resistance arteries in 29 men with diet-treated non-insulin-dependent diabetes mellitus and 18 age- and sex-matched control subjects. None of the diabetic patients had hypercholesterolaemia, overt hypertension or microproteinuria. 2. We examined endogenous and exogenous nitric oxide-mediated vasodilatation by measuring forearm blood flow with venous occlusive plethysmography after administration of acetylcholine (7.5 and 15 micrograms/min) and sodium nitroprusside (3 and 10 micrograms/min), respectively, into the brachial artery. NG-monomethyl-L-arginine was also infused to study the inhibition of basal and stimulated release of nitric oxide. 3. The vasodilatory response to acetylcholine, expressed as area under curve, was significantly decreased in the diabetic patients compared with the control subjects (P = 0.019). NG-monomethyl-L-arginine significantly reduced basal (P < 0.001) and acetylcholine-stimulated blood flow (P < 0.02) in both groups. The vasodilatory response (also expressed as area under curve) to sodium nitroprusside was significantly less (P = 0.044) in the diabetic patients than in the control subjects. 4. In the diabetic patients, impaired vasodilatory responses to acetylcholine were significantly correlated with higher serum triacylglycerols (P = 0.048) and lower high-density lipoprotein-cholesterol concentrations (P = 0.007); the association with high-density lipoprotein was independent of age, glycated haemoglobin and blood pressure. Sodium nitroprusside responses were not correlated with lipid and lipoprotein concentrations. 5. We conclude that there is impaired endothelial and smooth muscle cell function in men with diet-treated non-insulin-dependent diabetes mellitus uncomplicated by overt hypertension or microproteinuria. Endothelial dysfunction may be related to diabetic dyslipidaemia and associated metabolic disturbances.

Acetylcholine↗
PubMed1996

Measurement of blood pressure may be affected by an interaction between subject and observer based on gender.

Retrospective studies have suggested that blood pressure (BP) may be affected by a covert gender interaction between patient and observer, which is most marked for female patients and male observers. Such an effect could be one of the determinants of the "white coat' response. We have assessed this interaction in a prospective study in 56 hospital outpatients (31 males, 25 females) in whom supine and erect BP and heart rate were measured by two male and two female subjects, and by an automatic sphygmomanometer when no persons were present. Supine systolic BP (SBP) was related to age, and fell progressively over three measurements. Absolute BP was less in females but the fall on repeated measurement was significantly greater than in males. When absolute BP was analysed by patient and observer sex, no significant interaction was present. BP measured by automatic sphygmomanometry was less than the value obtained clinically. Absolute BP showed no significant interaction with observer and patient sex, but the difference between machine and age-adjusted clinical measurements for SBP was significantly greater in female patients when BP was measured by male observers. However, this effect dissipated on repeated measurement. These data suggest that a transient gender interaction can contribute to the white-coat effect, especially in female patients when BP is measured by a male observer.

Adult↗
PubMed1995

Economic comparison of drug and lifestyle treatment of cardiovascular risk factors in high-risk patients.

1. Lifestyle interventions are routinely used in the treatment of cardiovascular risk factors in individual patients but their cost-effectiveness relative to drug treatment is largely unknown. 2. Drug treatment is effective at normalizing risk factors and is known to decrease morbidity and mortality though costs may be high. Lifestyle interventions carry a significant potential to reduce expenditure on drugs, but prospective studies on cost-effectiveness of lifestyle interventions favour drug treatment. 3. According to current evidence, lifestyle intervention in high-risk patients is not more cost-effective than drug treatment.

Cardiovascular Diseases↗
PubMed1995

Adjustment of the apparent benefits of treatment on stroke risk in the MRC mild hypertension trial using data from the placebo-treated group.

Clinical trials show that drug treatment significantly decreases stroke risk in hypertension. The benefit as measured in clinical trials may be affected by changes of blood pressure at entry and by departure from randomised treatment, but the magnitude of such effects is disputed. We have assessed benefit from reduction of stroke using data from the MRC Trial of mild to moderate hypertension, taking these factors into account, and have studied the likely effect of recent guidelines. The original analysis suggested that 850 patients needed treatment for 1 year to prevent one stroke. Under the more conservative of two assumptions made about the effect of treatment, this falls to 695 patients when allowance is made for reduction of stroke in placebo group patients withdrawn and actively treated, to 680 patients when allowance is made for the fall in blood pressure after entry, and to 556 patients with allowance for both. When benefit is assessed in patients whose entry diastolic blood pressure was > or = 100 mm Hg, 557 patients require treatment annually per stroke saved and this is decreased to 360 patients when allowance is made for withdrawal and active treatment of placebo group patients. These results suggest that benefit from reduction of stroke was underestimated in the MRC trial and that this is likely to be present in most trials. Changes to diagnostic criteria for hypertension in new management guidelines are likely to have significant effects on the number of patients treated per stroke prevented.

Blood Pressure↗
PubMed1995

Blood pressure, 'white-coat' pressor responses and cardiovascular risk in placebo-group patients of the MRC Mild Hypertension trial.

OBJECTIVE AND PATIENTS: To study the relationship between blood pressure and cardiovascular risk in 8654 patients randomly assigned to receive placebo in the Medical Research Council Mild Hypertension trial; 339 patients had a cardiovascular event during 5 years of follow-up. RESULTS: Tracking of blood pressure and regression of blood pressure to and from the mean were demonstrated. Cardiovascular risk was related independently and positively to blood pressure, smoking and cholesterol, and inversely to low-normal plasma sodium. The relationship with blood pressure was stronger when measurements were made at entry to the trial by nurses and weaker when measurements were made by doctors. DISCUSSION: One reason for this finding was that blood pressure increased at entry and, because the rise was greater in females, in whom the risk was lower than in males, a low-risk group predominated in the upper part of the blood pressure distribution. Another reason was that the rise itself conferred little or no cardiovascular risk. This rise might be a 'white-coat' response, because the increase in blood pressure in individuals correlated with the subsequent decrease after entry. CONCLUSION: If the rise is a 'white-coat' effect and if, as the present study suggests, it is common and relatively free from risk, then changes are needed in the design of placebo-controlled trials and in the management of hypertension.

Aged↗
PubMed1995

Heart mass and blood pressure have separate genetic determinants in the New Zealand genetically hypertensive (GH) rat.

OBJECTIVE: To determine associations between cardiovascular parameters and genotype in 205 F2 rats of both sexes and lineages from reciprocal crosses made between rats of the New Zealand genetically hypertensive (GH) and Brown Norway (BN) rat strains. METHODS: Systolic tail blood pressure, mean arterial blood pressure, pulse rate, heart mass, body mass and relative heart mass were determined for each rat in the age range 17-19 weeks, and DNA polymorphisms were examined for the guanylyl cyclase A (GCA), angiotensin converting enzyme (ACE) and renin (REN) genes. RESULTS: The phenotypic data indicated the presence of genes on the X and Y chromosomes that affected blood pressure. The GH GCA allele, in males only, and the GH ACE allele, in females only, both cosegregated with increased blood pressure. The ACE effect was confined to rats of one lineage only, namely those with GH grandfathers. A cosegregation of the GH REN allele with decreased blood pressure was also detected in females with BN grandfathers. In contrast, the GH REN allele cosegregated with a smaller heart in males only, whereas the GH ACE allele cosegregated with a larger heart both in males and in females. In males this was the consequence of a decrease in body mass with no change in absolute heart mass, whereas in females there were changes in both of these parameters. CONCLUSIONS: The results show that cardiac hypertrophy and blood pressure have independent genetic determinants in the GH rat, and indicate the importance of sex in determining the phenotypic expression of genes underlying cardiovascular pathology.

Animals↗