Showing papers by "Nilesh J. Samani published in 1997"

Glycoprotein IIIa polymorphism and risk of myocardial infarction.

Abstract: Objectives: To prospectively investigate whether the Pl A 2 variant of the platelet adhesion molecule glycoprotein IIIa influences the risk of myocardial infarction. Background: The platelet glycoprotein IIb/IIIa receptor plays an important role in platelet aggregation. The IIIa polypeptide is polymorphic due to a single base change at position 1565 resulting in either proline Pl A 1 or leucine Pl A 2 at position 33 in the protein. It has recently been reported that the Pl A 2 variant may be strongly associated with the risk of acute coronary syndromes, particularly in younger subjects. Methods: Pl A genotypes of 242 prospectively collected cases of first myocardial infarction admitted to our Coronary Care Unit were compared with those of 209 community-based control subjects. Results: We found no difference in either Pl A genotype ( P = 0.65) or allele ( P = 0.64) frequencies between cases and controls. The Pl A 2 allele frequency was 18.2 and 19.4% in cases and controls, respectively. The age- and sex-stratified odds ratio for risk of myocardial infarction associated with the Pl A 2 allele was 0.89 (95% CI 0.58–1.37, P = 0.65) and remained non-significant when the analysis was confined to subjects under the age of 60 (odds ratio 0.77, 95% CI 0.38–1.56, P = 0.44). There was no interaction between Pl A 2 and other coronary risk factors. For cases, the age at myocardial infarction was not different between those carrying the Pl A 2 allele and those not (66.3 ± 10.8 vs. 65.6 ± 11.7 years, P = 0.63). Conclusions: We conclude that, in our subjects, the Pl A 2 variant of platelet glycoprotein IIIa is not an important risk factor for myocardial infarction.

A pharmacogenetic approach to blood pressure in Lyon hypertensive rats. A chromosome 2 locus influences the response to a calcium antagonist.

Abstract: In a backcross population (n = 281) derived from a cross of the Lyon hypertensive rat with Lyon normotensive rat, we investigated whether genetic factors influence the acute cardiovascular responses to pharmacological modulation of the renin-angiotensin system, the sympathetic nervous system, and the voltage-sensitive L-type calcium channels. Using microsatellite markers, a quantitative trait locus was identified and mapped on rat chromosome 2 that specifically influences the systolic (peak LOD score 4.4) and diastolic (peak LOD score 4.1) blood pressure responses to administration of a dihydropyridine calcium antagonist, PY108-068. The locus accounted for 10.3 and 10.4% of the total variances in the systolic and diastolic responses to PY108-068, respectively. In marked contrast, the locus had no effect on either basal blood pressure or on the responses to acute administration of a ganglionic blocking agent, trimetaphan, or of an angiotensin II subtype 1 receptor antagonist, losartan. These findings provide strong direct support for the paradigm that genetic factors may influence the response to antihypertensive drugs and suggest that the heterogeneity seen in the responses to different antihypertensive agents in human essential hypertension may have a significant genetic determination.

Normotensive blood pressure in mice with a disrupted renin Ren-1d gene.

Abstract: Renin is an aspartyl protease that is involved in the conversion of angiotensinogen to angitensin II and hence participates in the regulation of blood pressure. Mice are polymorphic for the number of renin genes with some strains harbouring two renin genes, Ren-1d and Ren-2. To study the role of renin Ren-1d in regulating cardiovascular homeostasis, mice with a disrupted Ren-1d gene were created. Analyses of kidney renin mRNA expression in Ren-1d−/−/Ren-2+/+ mice demonstrated that only Ren-2 transcripts were present. Mean arterial blood pressures of Ren-1d+/+/Ren-2+/+, Ren- 1d+/−/Ren-2+/+ and Ren-1d−/−/Ren-2+/+ mice showed no significant differences. These observations demonstrate that the Ren-1d gene product is not essential for normal blood pressure maintenance under normal physiological conditions

Tissue expression of components of the renin-angiotensin system in experimental post-infarction heart failure in rats: effects of heart failure and angiotensin-converting enzyme inhibitor treatment.

Abstract: 1. It has been suggested that local tissue renin-angiotensin systems may be activated in heart failure and that effects on such systems may, at least partially, explain the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in this syndrome. To investigate these hypotheses, we examined expression of renin-angiotensin system components in several tissues in a rodent model of post-myocardial infarction (MI) heart failure, and analysed whether such expression is modified by ACE inhibitor treatment. 2. Four groups of rats (n = 8 - 12 per group) were studied 30 days after surgery: (A) sham-operated rats with no treatment, (B) rats with post-MI heart failure induced by ligation of the left coronary artery, (C) sham-operated rats treated with the ACE inhibitor perindopril (1.5 mg day-1 kg-1), and (D) rats as per B, but treated with perindopril. Expression of renin, angiotensinogen, ACE and angiotensin subtype 1 receptor was assessed by quantification of their respective mRNAs by Northern blotting. 3. Renal renin mRNA increased 2-fold in animals with MI (group B) compared with controls (group A) (P < 0.05) and between 50 and 100-fold after ACE inhibitor treatment (P < 0.001). No change in renin gene expression was found in any extra-renal site either following MI or after ACE inhibitor treatment. Hepatic angiotensinogen mRNA level was similar in all groups, but kidney angiotensinogen mRNA level was increased 1.6-fold (P < 0.01) in the groups receiving perindopril. ACE mRNA level in the lung was not affected by ACE inhibitor treatment but decreased by 50% following MI (groups B and D, P < 0.01). This was associated with a similar (50%, P < 0.01) fall in lung ACE activity and was correlated with the severity of heart failure. Angiotensin subtype 1 receptor mRNA level was not affected in any tissue by either MI or ACE inhibitor treatment. 4. We did not find a systematic activation of tissue renin-angiotensin systems, as assessed by steady-state mRNA levels of key components of the system in experimental post-MI heart failure, or a major effect of ACE inhibitor treatment on expression of these components. However, we observed tissue-specific changes in expression of selected components of the renin-angiotensin system in the kidney and the lung in post-MI heart failure and after ACE inhibitor treatment, which may be of relevance to the pathophysiology of the syndrome and the effects of ACE inhibition.

Analysis of phenotypic consequences of renin gene polymorphism in Lyon rats.

Abstract: OBJECTIVE To investigate phenotypic consequences of renin gene polymorphism between Lyon hypertensive (LH) and normotensive (LN) rats because previously we demonstrated cosegregation of the LH allele with increased blood pressure in a cross of LH with LN rats. DESIGN Two studies were conducted. Study 1 used a cohort of male F2 rats from a LH x LN cross. Eighty-two rats homozygous for the hypertensive (HH) renin gene allele were compared with 82 rats homozygous for the normotensive (NN) allele. Urinary steroid excretion was measured in 24 h urine samples collected from rats aged 6 weeks. The direct aortic blood pressure was recorded in 30-week-old rats and, after they had been killed, their kidney renin concentration (KRC) was measured. In study 2, renin, angiotensinogen and angiotensin converting enzyme plasma concentrations and renin messenger RNA (mRNA) levels were measured in renal and extra-renal tissues from 6- and 25-week-old LH and LN parental and HH and NN F2 male rats. METHODS Urinary steroids and plasma components of the renin-angiotensin system (RAS) were measured using specific radioimmunoassays. mRNA levels were quantified by northern blotting. RESULTS In study 1, HH F2 rats had a higher blood pressure (151.5 +/- 8.2 versus 146.0 +/- 7.4 mmHg, P < 0.001) and a lower KRC (514 +/- 203 versus 666 +/- 304 micrograms A1/h per g cortex, P < 0.01) than did NN rats aged 30 weeks. In covariate analysis the decrease in KRC in HH rats was attributable to their increased blood pressure rather than to the renin genotype. The renin genotype of rats aged 6 weeks was not associated with a change in the urinary excretion of aldosterone, desoxycorticosterone, corticosterone or 18-hydroxy desoxycorticosterone. In study 2, we found no difference either in plasma levels of RAS components or in renal or extrarenal renin mRNA levels either between parental LH and LN rats or between HH and NN F2 rats apart from a higher plasma renin concentration in LH rats aged 6 weeks. Renal, but not extra-renal, renin mRNA levels declined with age. CONCLUSIONS We found no evidence of a renin genotype-dependent phenotypic difference in the RAS that could account for the effect of the renin locus on blood pressure in Lyon rats. Our findings suggest that the effect of the locus on blood pressure might be due to an as yet unidentified gene linked to renin.

Phenotype and genotype comparison of hereditary hypertriglyceridemic (hHTG) and brown-Norway (BN) rats. Identification of quantitative trait loci (QTLs) for the insulin resistance syndrome.

Abstract: The hereditary hypertriglyceridemic (hHTG) rat manifesting hypertriglyceridemia, hyperinsulinemia, I insulin resistance,* glucose intolerance, mild hyperuri~emia,~ and hypertension4 provides a unique animal model for the human insulin resistance syndrome5 in which it may be possible to identify genetic factors predisposing to the syndrome. The classical method for identifying quantitative trait loci (QTLs) that influence traits in animal models is by cosegregation analysis. In this approach, the diseaseprone strain is crossed with a disease-resistant strain and FZ (or backcross) progeny are examined for cosegregation of genetic markers with quantitative differences in