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Biomedical subjects

J A Millar

Publications and source records attributed to J A Millar.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1994

Effect of sex-related changes in blood pressure at entry to the MRC trial on prediction of cardiovascular risk.

1. Using the MRC trial placebo group as the data source, we examined relationships between cardiovascular risk, gender, and blood pressure (BP) at screening, on entry to the trial, and after 3 months of follow up. 2. Blood pressure on entry to the trial (162/98 mmHg) was significantly higher than at the second screening (154/95 mmHg) visit and at 3 months (144/91 mmHg). The entry BP was higher, and the changes from screening to entry and from entry to 3 months were greater in females. Females had a low cardiovascular risk, but because of the greater changes of BP at entry they were over-represented at the top of the entry BP distribution, whereas males were over-represented at the bottom. The result of these effects was that the relationship between cardiovascular risk and entry BP was shifted to the right and was flatter than the corresponding curves measured at screening or after 3 months of follow up. 3. In consequence, the severity of hypertension in the trial population was overestimated from measurement of BP at entry, and the capacity of trial entry BP to predict cardiovascular risk was weakened. 4. BP on entry to the MRC Trial was affected by a pressor effect that diminished the value of BP as a cardiovascular risk factor because it differentially affected sub-populations by gender.

Blood Pressure↗
PubMed1994

Remodelling of resistance arteries by treatment with enalapril in the New Zealand genetically hypertensive rat.

1. New Zealand genetically hypertensive (GH) rats were treated with enalapril from the age of 4 to 10 weeks and the effects of treatment on the structure of mesenteric resistance arteries (MRA) was measured by use of stereological analysis of stained sections and by myograph techniques. 2. Tail-cuff blood pressure (BP) was measured weekly and intra-arterial BP recorded just before MRA were either fixed by perfusion or mounted on a myograph. 3. Stereological techniques (Cavalieri and optical dissector) were used to determine media and lumen volume, fraction of smooth muscle (SM) within the media and SM cell density. For MRA mounted on the myograph, lumen diameter, media thickness, active tension and active pressure were recorded. 4. BP was significantly (P < 0.0001) lowered by enalapril throughout the experiment. Intraarterial BP and left ventricular (LV) mass were also significantly lower in the enalapril treated GH rats (P < 0.0001). 5. Stereological measurements showed that enalapril treatment significantly (P < 0.0001) reduced media volume by 50%, doubled lumen volume (P < 0.0001), reduced the fraction of SM in the media (P < 0.04), and had no effect on the number of SM cell layers or on SM cell density. 6. Myograph measurements showed a decrease in the ratio media thickness/lumen diameter which was accompanied by a decrease in maximum active tension and pressure development. 7. In the GH rat early treatment with enalapril causes a true loss of medial tissue that is not simply due to rearrangement of existing media around an enlarged lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Stereological studies on mesenteric resistance artery structure in New Zealand genetically hypertensive and control rats.

1. Stereological methods were used to quantitate and compare the structure of mesenteric resistance arteries (MRA) in New Zealand genetically hypertensive (GH) rats aged 4, 10 and 16 weeks and their normotensive control strain (N). 2. Blood pressure (BP) (tail-cuff and intra-arterial) were recorded before the vessels were fixed by perfusion and embedded in Technovit Kulzer GmbH D-6393, Wehrheim, Germany). 3. Media and lumen volumes were measured on transverse sections (TS), by the Cavalieri method, and numbers of smooth muscle (SM) cells were estimated by the optical disector method. 4. There were no significant differences in lumen volume per unit vessel length between GH and age-matched N groups at any age. However, at 10 and 16 weeks volume in GH groups was 9-10% lower than their respective N groups. 5. Media volume per unit vessel length increased in GH rats at all ages. The media/lumen ratio also increased in GH at all ages. 6. Smooth muscle cell density (SM cell number per unit volume of media) decreased in GH rats at all ages, i.e. there was no evidence of hyperplasia. 7. Blood pressure (tail-cuff and intra-arterial) significantly increased in GH rats at 4 weeks of age and also at 10 and 16 weeks. 8. These results show that media volume is increased in GH early in life, is not due to hyperplasia, but may be due to hypertrophy of the SM cells, an increase in the amount of extracellular matrix or a combination of both.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of cilazapril on the structure of mesenteric resistance arteries of New Zealand genetically hypertensive and normotensive control rats.

1. New Zealand genetically hypertensive (GH) rats and their normotensive controls (N) rats between the ages of 10 and 16 weeks were treated with cilazapril in the diet for 6 weeks. 2. Systolic blood pressure (SBP; tail-cuff) was measured weekly and intra-arterial blood pressure (BP) was measured at the end of the treatment period. 3. The effect of cilazapril on the structure of mesenteric resistance arteries (MRA) was evaluated by both stereological and myographic techniques. 4. Cilazapril lowered SBP significantly throughout the treatment period (16 weeks; GH with cilazapril 135 +/- 5 vs GH 216 +/- 9 mmHg, P < 0.001; N cilazapril 91 +/- 6 vs N 137 +/- 3 mmHg, P < 0.001); intra-arterial BP was also significantly lowered. 5. Bodyweight (BW) of treated GH rats was significantly lower than that of untreated GH at 16 weeks (P < 0.01; t-test); however, the weight of treated N rats was not significantly affected. Ventricular mass was reduced by cilazapril in GH and N rats (GH 259 +/- 10 vs 306 +/- 11, P < 0.001; N 171 +/- 3 vs 195 +/- 4 mg/100 g BW, P < 0.001). 6. Lumen volume of MRA was not significantly affected by cilazapril in either strain; media volume was reduced by 14% in both strains and the media/lumen ratio was significantly reduced. Vascular smooth muscle cell density significantly increased in cilazapril-treated GH rats.

Animals↗
PubMed1990

Differences in mitogenic responses to angiotensin II, calf serum and phorbol ester in vascular smooth muscle cells from two strains of genetically hypertensive rat.

Vascular smooth muscle cells cultured from spontaneously hypertensive (SHR), New Zealand genetically hypertensive (GH) rat strains and their control strains (Wistar-Kyoto (WKY) and normal Wistar (N) rats) were compared for mitogenic responses [( 3H]-thymidine incorporation) to angiotensin II (AII), fetal calf serum (FCS), and the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). SHR cells showed enhanced basal [3H]-thymidine incorporation and increased responses to all three factors. In contrast, basal and FCS-stimulated [3H]-thymidine incorporation was the same or less in GH than in N cells. However, DNA synthesis was greater in GH cells in response to AII, AII + TPA or FCS + TPA. These results suggest that vascular smooth muscle cells from both hypertensive rat strains display enhanced mitogenesis, but the enhancement occurs via different intracellular signalling pathways.

Angiotensin II↗
PubMed1990

Growth factor activity of endothelin on vascular smooth muscle.

Endothelin is a novel peptide secreted by endothelial cells, the vasoconstrictor effects of which appear dependent on the activation of phospholipase C. We examined in tissue culture its potential as a growth factor for vascular smooth muscle. In quiescent cultures of rat aortic smooth muscle cells, endothelin rapidly elevated levels of c-fos and c-myc mRNA. Peak effects on c-fos mRNA occurred between 15 and 30 min and were completely gone after 2 h. The elevation in c-fos mRNA was, in part, dependent on protein kinase C, since phorbol myristate acetate (PMA) also elevated c-fos mRNA and further increased c-fos mRNA expression by endothelin, but the effects were not additive. Furthermore, the endothelin-induced elevation in c-fos mRNA was attenuated but not abolished in protein kinase C-depleted cells. Maximum levels of c-myc mRNA occurred between 15 and 30 min after exposing the cells to endothelin and persisted for at least 6 h. The effects of simultaneous addition of endothelin and PMA on c-myc mRNA levels were essentially similar to those observed with c-fos mRNA. [3H]thymidine incorporation into DNA occurred 8 h after exposing the cells to endothelin. The mitogenic effect of endothelin was smaller than that observed with either fetal calf serum or epidermal growth factor and was dependent on both pertussis toxin-insensitive and -sensitive pathways. Sensitivity to the latter pathway did not appear dependent on attenuation of phospholipase C activity, since neither peak intracellular calcium concentrations nor c-fos mRNA levels were reduced in pertussis toxin-treated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Sensitivity to Ca2+ and the effects of a calcium channel antagonist in resistance vessels from two strains of genetically hypertensive rat.

Ca sensitivity and sensitivity to diltiazem were studied in two strains of genetically hypertensive rat [spontaneously hypertensive rats (SHRs) and genetically hypertensive (GH) rats] and their normotensive control strains [Wistar-Kyoto (WKY) and normal Wistar (N) rats] at two ages before and after establishment of significant hypertension. Ca sensitivity was equal in both hypertensive/normotensive strain pairs from young rats but significant relative increases in Ca sensitivity were present in older rats. Sensitivity to the vasodilating action of diltiazem in vessels precontracted using K+ was also present in adult rats. These results suggest that the abnormality in Ca sensitivity seen in genetic hypertension in rats is an acquired characteristic not involved in the etiology of hypertension.

Animals↗
PubMed1990

Mitogenesis in cultured vascular smooth muscle cells from two rat models of hypertension in response to fetal calf serum and angiotensin II.

Hypertension may result from vascular hypertrophy or hyperplasia due to enhanced growth of vascular smooth muscle cells (VSMCs), which has been demonstrated in VSMCs from spontaneously hypertensive rats (SHRs) compared to Wistar-Kyoto (WKY) rats. To determine whether this enhanced mitogenesis is peculiar to SHRs or a general phenomenon in genetic models of hypertension, we have measured indices of cell growth [3H]-thymidine uptake in VSMCs from SHRs and New Zealand genetically hypertensive (GH) rats and controls [WKY and normal Wistar (N) rats] cultured in fetal calf serum (FCS) or angiotensin II (Ang II, 0.1 microM) in either 3% heat-treated FCS or serum-free medium. SHR cell numbers increased faster in response to both mitogens compared to WKY rats. However, GH and N rat responses to FCS were the same. Ang II caused a significant but similar increase in cell numbers in both GH and N rat cells (i.e., Ang II caused hyperplasia in all four strains) but [3H]thymidine uptake was significantly greater in GH rat cells. Ang II increased the total well protein content but not protein normalized on cell number, i.e., no hypertrophic effect of Ang II was seen in these actively dividing cells. We conclude that (a) growth properties of VSMCs from rats with genetic hypertension vary between strains; the differences in growth may reflect strain-specific variation in the activity of intracellular signalling systems subserving mitogenesis; and (b) Ang II causes VSMC hyperplasia.

Angiotensin II↗
PubMed1990

Blood pressure, change in blood pressure, and cardiovascular event rates in placebo-treated patients in the Medical Research Council Trial.

The relationship between cardiovascular event rate (stroke + coronary events), entry blood pressure (BP), change in BP over 6 months, and other variables was examined in the 8,654 placebo-treated patients in the Medical Research Council (MRC) trial. Entry BP was greater than screening pressures and fell significantly after randomization to placebo. The entry pressure was significantly greater but the fall after entry was less in those who had a cardiovascular event during 5.5 years of follow-up. Thus, patients with high entry pressure that remained elevated during follow-up had the highest event rates. This pattern was marked for stroke but was also found for coronary events. Other variables strongly related to event occurrence were sex, age, and smoking habit. Discriminant analysis based on these variables correctly identified 67% of those who had an event but incorrectly classified 40% of the much larger group who did not. These results suggest that failure of BP to fall after screening examinations is a cardiovascular risk factor. Thus, high-risk patients may be identified by repeated measurements of BP before treatment is started.

Age Factors↗
PubMed1990

Flow cytometric analysis of cell cycle of cultured aortic smooth muscle cells from two strains of genetically hypertensive rats.

The growth curves of aortic smooth muscle cells (SMCs) from spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats, and genetically hypertensive (GH) rats and their normotensive outbred controls (N) were compared. The proportion of cells in the various phases of the cell cycle was measured by flow cytometry. SHR cells showed significantly shorter doubling time than WKY rat cells, but doubling times for GH and N rats did not differ and were nearly the same as for SHRs. SHRs showed significantly greater proportion of S-phase (DNA-synthesizing) cells compared to WKY rat cells in the exponential growth phase. No significant difference was observed between GH and N rats in the proportion of cells in other phases of the cell cycle. GH and N rat cells stopped dividing in fetal calf serum (FCS)-free Dulbecco's Modified Eagle Medium (DMEM), whereas SHR and WKY rat cells continued to progress through the cell cycle in serum-free DMEM. The responses of FCS-deprived-arrested cells to the addition of FCS were similar in GH and N rats. SHRs showed a prolonged increase in S-phase cells in response to FCS compared to WKY rat cells, but maximum effects were similar. Enhanced cell proliferation in SHRs is not present in the other hypertensive strain of rats and is not explained by a simple hyperresponse to FCS.

Animals↗