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Biomedical subjects

J M Connell

Publications and source records attributed to J M Connell.

At least 91 records · Page 5Linked to original sources
PubMed1995

Left ventricular mass in hereditary human hypertension: glucocorticoid-suppressible hyperaldosteronism.

BACKGROUND: The mineralocorticoid hormone aldosterone may be an important mediator of pathological ventricular hypertrophy and heart failure. Much of the evidence for this arises from experimental work in rat models of mineralocorticoid-dependent hypertension, and a pathological role in humans is still uncertain. SUBJECTS: Eleven subjects with glucocorticoid-suppressible hyperaldosteronism, a hereditary form of hyperaldosteronism and hypertension, and 10 age- and sex-matched control subjects were studied. RESULTS: The subjects with glucocorticoid-suppressible hyperaldosteronism had a higher mean blood pressure and plasma aldosterone concentration, and lower plasma renin concentration, than the control subjects. Left ventricular mass index was not significantly different in the subjects with glucocorticoid-suppressible hyperaldosteronism than in the control subjects. When the subjects with glucocorticoid-suppressible hyperaldosteronism were subdivided into those with and those without hypertension, no difference in left ventricular mass index could be detected between the subgroups or between either subgroup and the control subjects. However, there was a significant correlation between basal plasma aldosterone and left ventricular mass index in the subjects with glucocorticoid-suppressible hyperaldosteronism (r = 0.66, P < 0.03). CONCLUSIONS: Despite marked elevations in plasma aldosterone concentrations from birth in subjects with glucocorticoid-suppressible hyperaldosteronism, left ventricular hypertrophy did not occur. The degree of hyperaldosteronism in the subjects was mild compared with other conditions and, although an effect on left ventricular mass index could be detected, the present results indicate that other factors may be necessary for the development of left ventricular hypertrophy.

Adolescent↗
PubMed1995

Enhanced pressor response to angiotensin I in normotensive men with the deletion genotype (DD) for angiotensin-converting enzyme.

The insertion (I)/deletion (D) polymorphism of the human angiotensin-converting enzyme gene has emerged as a genetic risk factor for ischemic heart disease. However, the functional consequences of this polymorphism in humans are not known. Ten normotensive men with the DD genotype and 10 with the II genotype participated in a study in which pressor responses to stepwise infusions of incremental doses of angiotensin I (Ang I) and Ang II and Ang II production during Ang I infusion were measured. Pressor responses were expressed as PD20, which reflects the angiotensin dose required to raise mean blood pressure by 20 mm Hg. The PD20 for Ang I in subjects with the DD genotype was significantly lower than that in II genotype subjects (8.8 versus 14.8 ng/kg per minute, P = .0091), whereas the PD20 for Ang II between the two groups did not differ significantly. The ratio of PD20 for Ang I and Ang II in DD subjects was significantly lower than that in II subjects (0.85 versus 0.96, P = .0452), and the venous levels of Ang II during Ang I infusion in DD subjects were significantly higher than those in II subjects (P < .01). Our study has shown increased pressor responsiveness to Ang I, probably as a consequence of the generation of increased Ang II levels, in subjects homozygous for the DD allele of the angiotensin-converting enzyme gene. This result may be relevant to the reported adverse cardiovascular risk conferred by the D allele, as it provides a mechanistic rationale for the association between this polymorphism and cardiovascular disease.

Adult↗
PubMed1995

Microsatellite polymorphism analysis allows the individual assignment of the rat 11 beta-hydroxylase gene (Cyp11b1) and the rat aldosterone synthase gene (Cyp11b2) to chromosome 7 using rat x mouse somatic cell hybrids and identifies differences between and within various rat strains.

Mouse hepatoma x rat hepatocyte hybrids that segregate rat chromosomes were used to determine the chromosomal location of the rat genes encoding 11 beta-hydroxylase and aldosterone synthase (Cyp11b1 and Cyp11b2 respectively). By means of species-specific restriction fragments and microsatellite markers both genes were mapped to rat chromosome 7. The Cyp11b1 microsatellite marker was subsequently found to vary in length between and within rat strains. Furthermore, we compared the sequences of Cyp11b1 markers in two genetically hypertensive strains of rat with their normotensive counterparts. Previous studies have indicated that 11 beta-hydroxylase activities in Milan and Lyon hypertensive strains are different from their respective genetic controls. The Cyp11b1 microsatellite regions from Lyon hypotensive and normotensive strains of rat were similar and were both shorter by 15 bases than that of the Lyon hypertensive strain. The Cyp11b1 marker in Milan hypertensive (MHS) and normotensive (MNS) strains differ from all the Lyon strains and from each other. The MHS marker is 12 bases shorter than that of MNS rats. These differences in microsatellite length may provide useful polymorphic markers in cosegregation studies of genetic hypertension in rats.

Animals↗
PubMed1995

Dexamethasone-suppressible hyperaldosteronism: clinical, biochemical and genetic relations.

Clinical, biochemical and molecular data on five kindreds with dexamethasone-suppressible hyperaldosteronism are reviewed. The clinical phenotype varies from severe, early onset hypertension to much milder blood pressure elevation; hypokalaemia is usually mild. The genetic basis of the syndrome reflects the presence of a chimaeric gene derived from an unequal crossover between CYP11B1 and CYP11B2, resulting in ACTH-sensitive aldosterone synthase activity. In five kindreds, at least three different mutations have been identified, suggesting that allelic predisposition might lead to increased geographical prevalence of the condition in Celtic populations.

Adrenal Cortex Hormones↗
PubMed1995

Renal artery stenosis managed by Palmaz stent insertion: technical and clinical outcome.

OBJECTIVE: To assess the technical and clinical outcome of Palmaz renal artery stent insertion in patients with renal artery stenosis. DESIGN: Twenty-nine patients with radiological evidence of renal artery stenosis and hypertension (16 patients, mean +/- SD diastolic blood pressure 100.5 +/- 8.16 mmHg) and/or renal impairment (17 patients, mean +/- SD serum creatinine 376 +/- 169 mu mol/l) were referred for radiological intervention. Of these, 22 had ostial atheromatous lesions, six had atheromatous non-ostial lesions and one patient had fibromuscular dysplasia. Palmaz stent insertion was performed where either previous or concomitant percutaneous transluminal renal angioplasty (PTRA) had been unsuccessful. Technical success was defined primarily as <30% residual stenosis. A prospective radiological and clinical follow-up was performed and the results compared with the outcome following PTRA alone in a similar group of patients from our centre. RESULTS: Immediate technical success was achieved in all 29 patients. Follow-up angiography in 24 patients after a mean of 7 months showed restenosis in four patients. The hypertension was not 'cured' in any patient; a blood pressure fall was observed in seven patients (44%) and no change in the remaining nine subjects (56%). Renal function improved in four patients (24%), two of whom had angiotensin converting enzyme inhibitor-exacerbated renal impairment. This compares with an immediate technical success of 81% for PTRA alone, with cure in 50% and improvement in 32% of patients with hypertension and improvement in renal function in 64.7% of patients with renal impairment. CONCLUSIONS: Palmaz renal artery stent insertion has a higher technical success rate than PTRA, but the clinical improvement is disappointing in our patient population.

Adult↗
PubMed1994

Guanine nucleotide regulatory protein alterations in young Milan hypertensive strain rats.

Vascular smooth muscle cell membranes from prehypertensive rats of the Milan hypertensive strain (MHS) were used to examine adenylyl cyclase activity and its regulation by guanine nucleotide regulatory proteins (G-proteins). Basal adenylyl cyclase activity was similar in MHS and Milan normotensive strain (MNS) membranes. Forskolin (10(-4) M) produced a significantly greater stimulatory response in MHS membranes, but this was not observed with NaF (10(-2) M). Isoproterenol (10(-4) M) caused a significantly decreased stimulation of adenylyl cyclase activity in MHS membranes, while prostaglandin E1 (10(-5) M) produced similar responses in the two strains. Gi function and GTP responses, as observed by biphasic effects of GTP on isoproterenol-stimulated membranes, were similar in both strains. The levels of Gi2 alpha and Gq alpha/G11 alpha were similar in the two strains, while the levels of Gs alpha (44 and 42 kDa forms) and the beta-subunit were significantly reduced by approximately 20% in MHS membranes. The alpha-subunit of Gi3 was dramatically reduced by approximately 80% in MHS membranes. The affinities of beta-adrenergic receptors for the antagonist, cyanopindolol, were similar in the two strains; however, the number of beta-adrenoceptors was substantially reduced in MHS membranes. These findings may be of relevance to altered vascular reactivity and transmembrane ion distribution observed in the MHS.

Adenylyl Cyclases↗
PubMed1994

Fetal vascular atrial natriuretic peptide receptors in human placenta: alteration in intrauterine growth retardation and preeclampsia.

OBJECTIVE: Our purpose was to quantify fetoplacental vascular atrial natriuretic peptide receptor subtypes in human pregnancies complicated by intrauterine growth retardation or preeclampsia and to relate these parameters to the fetoplacental vascular impedance as assessed by Doppler velocimetry. STUDY DESIGN: Guanylate cyclase-coupled and uncoupled receptors were quantified by radioligand-binding methods in membrane fractions prepared from primary and secondary stem villous vessels. Data for 16 abnormal pregnancies delivered preterm were compared with that for six gestationally matched preterm controls. RESULTS: The number of guanylate cyclase-coupled receptors was significantly (p < 0.001) greater in pregnancies complicated by intrauterine growth retardation or preeclampsia irrespective of normal or abnormal umbilical artery Doppler blood flow velocity pattern. The number of guanylate cyclase-uncoupled receptors was unaltered. CONCLUSIONS: Because fetal plasma atrial natriuretic peptide concentration is normal or elevated in intrauterine growth retardation and preeclampsia, these data suggest that atrial natriuretic peptide-mediated fetoplacental vasodilation is augmented in these disorders even in the presence of increased vascular resistance within the fetoplacental unit.

Atrial Natriuretic Factor↗
PubMed1994

Effect of the acyl-CoA:cholesterol acyltransferase inhibitor DuP 128 on cholesterol absorption and serum cholesterol in humans.

Intestinal cholesterol esterification by the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) is a presumed prerequisite for cholesterol absorption. We evaluated the effect of a potent, poorly absorbed ACAT inhibitor (DuP 128: N'-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pe ntyl]- N-heptylurea) on cholesterol absorption in a randomized trial. Thirty subjects received DuP 128 for 7 weeks, 10 each at 900 mg per day, 1800 mg per day, and 3600 mg per day; six subjects received placebo; and nine subjects received 1 gm neomycin twice a day. Cholesterol absorption determinations used a continuous dual isotope 14C-cholesterol and 3H-beta sitosterol method. DuP 128 (pooled doses) induced at 14.4% +/- 11.4% reduction in cholesterol absorption (p < 0.05 versus placebo): 17.6% +/- 8.4% at 900 mg, 9.1% +/- 11.4% at 1800 mg, and 17.1% +/- 12.9% at 3600 mg. Neomycin induced a 26.4% +/- 10.7% reduction (p < 0.01). After 6 weeks, neomycin reduced serum total and low-density lipoprotein cholesterol by 22.4% +/- 9.2% and 24.0% +/- 11.6%, respectively (p < 0.01 versus placebo). DuP 128 induced reductions of 3.9% +/- 11% (difference not significant) and 4.95% +/- 14.3% (p = 0.05). ACAT inhibitors limit cholesterol absorption in humans; however, the magnitude of the effect, as exemplified by DuP 128, is small.

Adult↗
PubMed1994

Rapid diagnosis of glucocorticoid suppressible hyperaldosteronism in infants and adolescents.

Glucocorticoid suppressible hyperaldosteronism (GSH) is an uncommon form of dominantly inherited hypertension. Presentation with hypertension and complications such as stroke in early life are well recognised. The use of a simple genetic test carried out on blood or placenta facilitates the detection of infants and children with GSH before the development of hypertension, allowing prompt treatment of hypertension if it occurs, and an opportunity to study the effects of growth and environmental influences on the progression of the condition.

Adolescent↗
PubMed1994

Activity of the renin-angiotensin system in acute severe asthma and the effect of angiotensin II on lung function.

BACKGROUND: The activity of the renin-angiotensin system in asthma has not been studied previously and the effect of angiotensin II (AII) on bronchomotor tone in vivo is unknown. METHODS: Plasma levels of renin and AII levels were measured in 20 patients with acute severe asthma, nine with mild asthma, 10 with severe chronic asthma, and 16 normal volunteers. The effect of AII, given as an intravenous infusion, on bronchomotor tone was also investigated in eight mild asthmatic patients. RESULTS: In acute severe asthma plasma levels of renin [median (interquartile range)] were elevated on days 1, 2, and 5 after admission [48.7 (24-79), 44.2 (15-75), and 45.5 (21-70) microU/ml, respectively]. Plasma AII levels were significantly elevated at day 5 [56 (12-109) pg/ml]. In the second study a bronchoconstrictor response to intravenous AII was seen with a mean (SE) maximal fall in FEV1 of 0.34 (0.13) litres or 12.4 (3.3)% from baseline following the high dose infusion of AII (8 ng/kg/min) with a corresponding plasma AII concentration of 121.3 pg/ml. CONCLUSIONS: The renin-angiotensin system is activated in acute asthma and AII causes bronchoconstriction in vivo in man. These observations suggest that in some patients AII may contribute to bronchoconstriction during acute severe asthma.

Acute Disease↗
PubMed1994

Pressor and subpressor doses of angiotensin II increase insulin sensitivity in NIDDM. Dissociation of metabolic and blood pressure effects.

There is evidence that the renin-angiotensin system may be involved in the metabolic as well as the cardiovascular features of diabetes and that pressor doses of angiotensin II (ANG II) increase insulin sensitivity in parallel with blood pressure (BP) in healthy subjects, but the effects of ANG II on insulin sensitivity have not been previously reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). In a randomized, double-blind, placebo-controlled, crossover study, 11 patients with NIDDM attended 3 study days to evaluate the effects of a 3-h infusion of subpressor and pressor doses of ANG II on whole body insulin sensitivity using the euglycemic hyperinsulinemic clamp. BP and heart rate were recorded, and blood samples were collected for serum insulin, C-peptide, potassium, catecholamines, plasma renin activity, and plasma ANG II concentrations. Plasma levels of ANG II (means +/- SD) were 9 +/- 4, 29 +/- 9, and 168 +/- 47 pmol/ml after placebo, low dose infusion, and high dose infusion, respectively. The higher dose of ANG II was associated with significant increases in BP (e.g., 18 mmHg systolic BP at 150 min) and plasma aldosterone. Whole body insulin sensitivity was 23.8 +/- 12.7 mumol glucose.kg-1.min-1 after placebo and 30.6 +/- 12.7 and 27.2 +/- 13.3 following low and high dose ANG II infusions, respectively (P < 0.05, analysis of variance). In summary, acute infusion of ANG II, with or without an increase in BP, increases insulin sensitivity in normotensive patients with NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Insulin resistance and essential hypertension: mechanisms and clinical implications.

The epidemiologic links among essential hypertension, obesity, and noninsulin-dependent diabetes mellitus (NIDDM) are well recognized, and it has been proposed that these links may reflect an underlying common pathophysiologic link of resistance to the action of insulin (insulin resistance). In essential hypertension, data suggest the insulin resistance pertains predominantly to nonoxidative glucose disposal, especially in skeletal muscle and adipose tissue, which contrasts with a more generalized deficit in obesity and NIDDM. A number of animal studies of genetic hypertension have confirmed the presence of insulin resistance, whereas acquired models of animal hypertension have not. The clinical significance of insulin resistance on long-term morbidity in hypertension remains unclear; there is limited evidence that insulin resistance may be an independent risk factor for subsequent vascular events, but it is more likely that it clusters with other better defined risk factors for the vascular complications of hypertension. The potential clinical sequelae of insulin resistance and hyperinsulinemia and the effect of antihypertensive medication on insulin resistance in general are addressed.

Animals↗
PubMed1993

The role of glucocorticoid activity in the inheritance of hypertension: studies in the rat.

Young (3-week-old) spontaneously hypertensive rats (SHR) had significantly higher basal plasma corticosterone levels than WKY rats and maximum responses to ACTH were also higher. In isolated adrenocortical cells from these rats, corticosterone production was also more responsive to ACTH in SHR. There was no significant difference in aldosterone production. Mononuclear leucocytes from older (10-week-old) SHR had a higher affinity for dexamethasone but a smaller number of binding sites per cell. The SHR therefore has higher circulating glucocorticoid levels and the target cells have a higher apparent affinity for this agonist. However, the target cells also have a smaller binding capacity. The precise resultant effect of these changes on glucocorticoid activity will require additional studies on specific glucocorticoid-dependent variables.

Adrenocorticotropic Hormone↗
PubMed1993

Renal and hormonal effects of chronic inhibition of neutral endopeptidase (EC 3.4.24.11) in normal man.

1. Acute pharmacological inhibition of the enzyme neutral endopeptidase (EC 3.4.24.11), which cleaves the cardiac hormone atrial natriuretic peptide, raises endogenous levels of the hormone. Short-term administration of inhibitors causes natriuresis and diuresis in normal and hypertensive subjects; we report here the effects of an orally active neutral endopeptidase inhibitor (candoxatril, 200 mg) given twice daily for 10 days to normal salt-replete male subjects (n = 12) in a placebo-controlled cross-over study. 2. Candoxatril administration caused a transient natriuresis on day 1 of treatment, but this was not sustained, and cumulative sodium excretion at the end of the study was not altered by active therapy [1720 +/- 40 versus 1734 +/- 57 (placebo) mmol; means +/- SEM]; exchangeable body sodium content was similarly unchanged. However, urinary cyclic GMP excretion was elevated throughout the active treatment phase when compared with placebo. 3. Although a change in plasma levels of atrial natriuretic peptide could not be demonstrated, platelet atrial natriuretic peptide binding sites were reduced by active treatment [23 +/- 3 versus 39 +/- 4 (placebo) fmol/10(9); P < 0.001]. 4. Basal blood pressure and heart rate were not affected by candoxatril treatment. After 10 days of therapy subjects were given incremental infusions of angiotensin II (2, 4 and 8 ng min-1 kg-1) followed by phenylephrine. Although active therapy had not altered basal plasma concentrations of active renin and angiotensin II, levels of angiotensin II during infusion of the octapeptide were higher during the active phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Effects of angiotensin II on insulin sensitivity: a placebo-controlled study.

1. There is evidence that hyperinsulinaemia increases the aldosterone response to angiotensin II, and that angiotensin-converting enzyme inhibitor drugs enhance peripheral glucose utilization, but the direct effects of angiotensin II on insulin sensitivity have not been reported previously. 2. In a randomized, double-blind, placebo-controlled, cross-over study, 12 healthy male subjects attended on 3 study days for the evaluation of the effects of a subpressor (1 ng min-1kg-1) and pressor (5 ng min-1kg-1) infusion of angiotensin II on whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. Frequent measurements of blood pressure and heart rate were recorded and blood samples were collected for determination of serum insulin, C-peptide and K+ concentration, plasma renin activity and plasma angiotensin II concentration. 3. Plasma angiotensin II concentrations (means +/- SD) were 11 +/- 5 pg/ml after placebo, and 27 +/- 9 and 125 +/- 28 pg/ml after low and high dose angiotensin II, respectively. The higher dose of angiotensin II was associated with significant increases in blood pressure (e.g. 13 mmHg systolic blood pressure at 150 min) and serum aldosterone concentration. Whole-body insulin sensitivity was 10.5 +/- 2 mg of glucose min-1kg-1 after placebo, and 10.5 +/- 2.2 and 10.9 +/- 3.4 mg of glucose min-1kg-1 after low and high dose angiotensin II (not significant). 4. Angiotensin II had no effect on hyperinsulinaemia-induced reductions in serum potassium and triacylglycerol concentrations. 5. Thus, acute infusion of angiotensin II for 3 h, with or without an increase in blood pressure, has no effect on whole-body insulin sensitivity.

Adult↗
PubMed1993

G-proteins in experimental hypertension: a study of spontaneously hypertensive rat myocardial and renal cortical plasma membranes.

OBJECTIVE: Spontaneously hypertensive rat (SHR) myocardium is known to exhibit reduced beta-adrenergic agonist-stimulated adenylyl cyclase activity. As G-proteins play a pivotal role in transducing information from the receptor to adenylyl cyclase, a study was undertaken to assess whether changes in G-protein expression and functioning could explain this. DESIGN: Studies were performed in plasma membrane homogenates from vascular tissue (myocardium) from 11-week-old SHR (weighing 255 g) and control rats from both Wistar-Kyoto (WKY) and Wistar strains. Similar studies were performed in non-vascular tissue (renal cortical plasma membranes) to assess whether any observed changes are part of a more widely distributed membrane defect. METHODS: G-protein function was inferred from studies of adenylyl cyclase activity and levels of G-protein subunits (Gs alpha, Gi alpha 1, Gi alpha 2, Gi alpha 3, Go alpha and beta) were assessed by immunoblotting. RESULTS: Differences in adenylyl cyclase activity were seen in SHR compared with WKY rat myocardium: in WKY rats adenylyl cyclase activity was greater than in SHR under forskolin-stimulated conditions and in the presence of fluoride and several ligands which couple to the catalytic unit of adenylyl cyclase via Gs, including the receptor-linked species prostaglandin E1, glucagon and isoproterenol. However, with the exception of forskolin-stimulated activity, which in SHR was greater than in Wistar rats, SHR myocardial adenylyl cyclase activities were similar to those in Wistar rat membranes. Immunoblotting studies showed similar levels of G-protein subunits in all three strains. Studies of renal cortical plasma membranes failed to identify any differences in adenylyl cyclase activity or in G-protein subunit levels. CONCLUSIONS: SHR, WKY rats and Wistar rats exhibit differences in myocardial adenylyl cyclase activity which are not seen in renal cortical plasma membranes. These are not related to hypertension or to differences in G-protein levels, and probably reflect strain differences in Gs function.

Adenylyl Cyclases↗