Biomedical subjects

G Thorgeirsson

Publications and source records attributed to G Thorgeirsson.

At least 37 records · Page 2Linked to original sources

PubMed1996

Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study.

BACKGROUND: Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. METHODS: The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). RESULTS: The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. CONCLUSION: The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.

Adult↗

PubMed1996

Cholesterol lowering and the use of healthcare resources. Results of the Scandinavian Simvastatin Survival Study.

BACKGROUND: Advances in the treatment of cardiovascular disease have increased costs; annual cardiovascular healthcare expenditure in the United States currently exceeds $100 billion. Physicians and third-party payers need to assess the economic impact of treatments that reduce cardiovascular morbidity and mortality. METHODS AND RESULTS: The Scandinavian Simvastatin Survival Study is a randomized, double-blind, placebo-controlled trial in which simvastatin reduced the risk of death by 30% (P=.0003) over the median follow-up period of 5.4 years in patients with previous myocardial infarction or stable angina pectoris as a result of a 42% reduction in the risk of coronary deaths (P=.00001). In the present report, data prospectively collected from hospital admissions were analyzed to evaluate the impact of simvastatin on healthcare resource use and perform a cost-minimization analysis. In the placebo group (n=2223), there were 1905 hospitalizations (average duration, 7.9 days) for acute cardiovascular events or coronary revascularization procedures among 937 patients, whereas in the simvastatin group (n=2221), there were 1403 such hospitalizations (average duration, 7.1 days) among 720 patients (all differences, P<.0001). The corresponding number of hospital days was 15089 and 9951 in the two groups, respectively (34% reduction,P<.0001). In the United States, the resulting reduction in hospitalization costs over the 5.4 years of the trial would be $3872 per patient, reducing the effective cost of simvastatin by 88% to $0.28 per day. CONCLUSIONS: In addition to reducing mortality and morbidity in coronary heart disease patients, simvastatin markedly reduces use of hospital services, thus offsetting most of its cost.

Adult↗

PubMed1996

Silent ST-T changes in an epidemiologic cohort study--a marker of hypertension or coronary heart disease, or both: the Reykjavik study.

OBJECTIVES: We sought to evaluate the prognostic value and clinical characteristics associated with electrocardiographic (ECG) ST-T changes among men without other manifestations of coronary heart disease. BACKGROUND: Recent achievements in secondary prevention and treatment of coronary heart disease have highlighted the importance of early diagnosis of both symptomatic and silent forms of the disease. The prognostic and clinical importance of ST-T changes in men with no other manifestations of coronary heart disease is still unclear. Do they reflect silent coronary heart disease or hypertension, or both, and what is their independent contribution to prognosis? METHODS: The subjects were 9,139 men born in the years 1907 to 1934 and followed up for 4 to 24 years. On initial visit they were assigned to different categories of coronary heart disease on the basis of Rose chest pain questionnaire, hospital records, 12-lead ECG, history and physical examination. RESULTS: The prevalence of silent ST-T changes among men without overt coronary heart disease was strongly influenced by age, increasing from 2% at age 40 years to 30% at age 80 years. Men with such ST-T changes were older and had higher serum triglyceride levels and worse glucose tolerance than men without such changes or other evidence of coronary heart disease. Their blood pressure was higher, and they more often had an enlarged heart or left ventricular hypertrophy and more often took antihypertensive medication, digitalis or diuretic drugs. Serum cholesterol levels were not different between the two groups. After adjustment for other risk factors, these silent ST-T changes had a risk ratio of 2.0 for death from coronary heart disease and 1.6 for subsequent myocardial infarction or angina pectoris. CONCLUSIONS: Silent ST-T changes that are ischemic by the Minnesota code are probably both a marker of silent coronary heart disease and high blood pressure. They define a distinct group of patients with highly abnormal risk factor profile. Although not specific for coronary heart disease and often transient, they are associated with the development of every clinical manifestation of coronary heart disease and are independent predictors of reduced survival.

Age Factors↗

PubMed1996

Predominance of aortic calcification as an atherosclerotic manifestation in women: the Reykjavik study.

Since 1967 the Reykjavík study has monitored coronary artery disease and its risk factors in randomly selected cohorts. From 1979 to 1984, 3246 men and 3545 women aged 45-74 years were studied. Routine biplane chest X rays were assessed by a radiologist who noted the presence or absence of aortic calcification (AC), but had no detailed knowledge of the subjects. Overall, AC was diagnosed in 283 (8%) women, but in only 54 of the men (1.7%). In the women, the prevalence of AC increased from 2.0% at age 45-49 years to 17.1% at the age of 70-74 years, while in men it was 0 and 8.3%, respectively. In women, multivariate analysis of risk factors showed AC to be positively related to systolic and negatively related to diastolic blood pressure, indicating a potential relation to pulse pressure. Furthermore, AC was independently associated with age, drug treatment for hypertension, nonfasting blood sugar, use of antidiabetic drugs, total serum cholesterol levels, and the amount of smoking. Too few men had AC for multivariate assessment of risk factors. In addition, in women AC was also related to a previous myocardial infarction (p < 0.05), mortality from coronary artery disease (p < 0.01), and the presence of intermittent claudication (p < 0.01). In men, however, AC was related only to total mortality (p < 0.05). Thus, these data show AC to be more prevalent in women, independently associated with recognized atherosclerotic risk factors, and a potential marker for coronary and peripheral artery disease.

Aged↗

PubMed1995

Unrecognized myocardial infarction: epidemiology, clinical characteristics, and the prognostic role of angina pectoris. The Reykjavik Study.

OBJECTIVE: To evaluate the incidence, prevalence, characteristics, and prognosis associated with clinically unrecognized myocardial infarction as diagnosed by electrocardiographic changes. DESIGN: Prospective, population-based cohort study with 4- to 20-year follow-up. SETTING: Icelandic Heart Association Preventive Clinic. PARTICIPANTS: 9141 men residing in the Reykjavik area who were born between 1907 and 1934. MEASUREMENTS: Patients were assigned to categories of coronary heart disease at first visit on the basis of hospital records, Rose chest pain questionnaire, standardized 12-lead electrocardiogram, and history and physical examination. Incidence and prevalence of unrecognized myocardial infarction were determined, survival was measured, and causes of death were determined from death certificates and autopsy records. RESULTS: Prevalence was strongly influenced by age. Nearly undetectable in the youngest age group, it increased to more than 5% in the group aged 75 to 79 years. Incidence was almost zero up to age 40, then increased steeply to more than 300 cases per year per 100,000 persons at age 60, and decreased with age after age 65. Ten- and 15-year survival probabilities were 51% and 45%, respectively, and were similar to those for patients with recognized myocardial infarction. One third of men with unrecognized and 58% of men with recognized myocardial infarction had a history of angina pectoris (P < 0.001). Angina pectoris had a greater effect on coronary heart disease mortality in the former group than in the latter. The risk ratio for unrecognized myocardial infarction was 4.6 without angina (95% CI, 2.4 to 8.6) and 16.9 with angina (CI, 9.4 to 30.3); the risk ratio for recognized myocardial infarction was 6.3 without angina (CI, 3.7 to 10.6) and 8.5 with angina (CI, 5.8 to 12.6). CONCLUSION: At least one third of all myocardial infarctions were unrecognized. Prognosis and risk factor profiles for patients with recognized and unrecognized myocardial infarction were similar. Although those with unrecognized myocardial infarction were less likely than those with recognized myocardial infarction to have a history of angina pectoris, angina in these cases was usually associated with ischemic electrocardiographic changes and a poor prognosis, suggesting severe coronary heart disease.

Adult↗

PubMed1995

Long-term prognosis of different forms of coronary heart disease: the Reykjavik Study.

BACKGROUND: While coronary heart disease (CHD) is a serious and often fatal disease the prognosis is variable and major effort has been invested in risk stratification. The purpose of this study was to examine the relation between long-term prognosis and risk factors in different clinical categories of CHD. METHODS: A general population sample of 9141 men, aged 34-79 at entry into the study was divided into six groups with respect to manifestations of CHD at entry: I. Symptomatic infarction. II. Silent or unrecognized infarction. III. Angina pectoris with ischaemic changes on ECG. IV. Angina without ischaemic changes. V. Angina by Rose questionnaire but not confirmed by a physician. VI. No manifestations of CHD. RESULTS: The risk factor profile varied considerably between the different categories and by life-table analysis marked differences in survival were demonstrated between the groups. The risk factors maintained their detrimental effects on prognosis in the presence of CHD. Thus, age, serum total cholesterol, impaired glucose tolerance and smoking were found by Cox's regression to be statistically significant independent risk factors of CHD mortality among men having manifestations of CHD (groups I-V). Furthermore, the composite risk score, a measure of the overall risk factor exposures had marked effect on the prognosis of the various CHD groups. When the comprehensive risk factor score for both CHD mortality and all-cause mortality was accounted for marked differences persisted in the long-term prognosis. Compared to those without CHD the infarct groups had about a 7.6- and 3.7-fold risk of dying from CHD and all causes respectively. Those with angina had from 2.5- to 3.2-fold risk of CHD mortality and 1.7- to 2.2-fold risk of all-cause mortality depending on the subgroup of angina, again compared to those without manifestations of CHD. CONCLUSION: Different categories of CHD had different risk factor profiles and the long-term prognosis resulted from a complex interplay between those factors and the diagnostic category of CHD. The risk factors maintained their detrimental effects on prognosis in the presence of CHD and after accounting for the comprehensive risk factor score marked differences persisted in the long-term prognosis, being worst for those having suffered a myocardial infarction, either symptomatic or silent.

Adult↗

PubMed1995

Glucose tolerance and blood pressure in a population-based cohort study of males and females: the Reykjavik Study.

OBJECTIVE: To investigate the relationship between fasting and postprandial glucose levels and the risk of hypertension, both cross-sectionally in different age and body mass index (BMI) groups, and prospectively. DESIGN: Long-term prospective health survey in the Reykjavik area, of a large representative population sample of males and females in various age groups, conducted since 1967. METHODS: Values from 8285 males and 9183 females were included in the cross-sectional analysis. The prospective analysis included 2639 males and 2346 females, with two consecutive observations for each individual, with a 3- to 8-year interval. RESULTS: After controlling for year of examination, age, BMI and various other risk factors, we found a strongly significant relationship between the blood glucose level, both fasting and 90 min after an oral glucose load, and risk for hypertension. The strength of the correlation between postprandial glucose value and blood pressure was similar in different age and BMI groups, except for in the males, in whom there was a stronger correlation with diastolic blood pressure with higher BMI. The 90-min glucose level was also predictive for development of hypertension 3-8 years later. The predictive power was somewhat stronger for females. Fasting glucose level was predictive for hypertension only for the females. Concurrent weight gain had a very strong independent explanatory power for development of hypertension. CONCLUSIONS: This study confirms the role of metabolic factors in hypertension. The correlation between impaired glucose tolerance and hypertension was found to be remarkably consistent throughout adult life, for both sexes and all values of BMI. Fasting glucose was predictive of hypertension in the females, and blood glucose at 90 min after the glucose-tolerance test was predictive of future development of hypertension in both sexes.

Adult↗

PubMed1994

Endothelin secretion is regulated by cyclic AMP and phosphatase 2A in endothelial cells.

Endothelin is a 21 amino acid peptide secreted by endothelial cells and is the most potent vasoconstrictor known. The present study examines regulatory mechanisms of endothelin secretion, focusing on the role of protein phosphorylation. Endothelin secretion was measured by radioimmunoassay in primary cultures of human umbilical vein endothelial cells. While treatment that raised cAMP levels reduced the basal endothelin secretion rate, agents that elevated cGMP had no effect. Downregulation or inhibition of protein kinase C resulted in decreased endothelin secretion, suggesting that protein kinase C regulates endothelin secretion in the opposite direction to cAMP dependent protein kinases. Okadaic acid, at concentrations that selectively inhibit protein phosphatases 2A, reduced the endothelin secretion and the effects of okadaic acid and db-cAMP were additive. Endothelin production was stimulated by fetal calf serum and by the protein kinase inhibitor 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine (H7), but was inhibited by the calmodulin antagonist trifluoperazine. The present findings that regulators of cAMP-dependent protein kinases, protein kinase C, calmodulin, and protein phosphatase 2A all affect endothelin secretion suggest that endothelin secretion is controlled by phosphorylation/dephosphorylation of as yet unidentified regulatory proteins within the cell.

1-Methyl-3-isobutylxanthine↗

PubMed1994

A marked decline in the prevalence and incidence of intermittent claudication in Icelandic men 1968-1986: a strong relationship to smoking and serum cholesterol--the Reykjavik Study.

The epidemiology of peripheral vascular disease has been studied much less extensively than the epidemiology of coronary heart disease (CHD). The prospective Reykjavik Study gave an opportunity to monitor secular trends from 1968 to 1986 of clinical intermittent claudication (IC) amongst Icelandic males, aged 34-80 and to assess the importance of possible risk factors. Both prevalence and incidence of IC decreased sharply after 1970 in all age groups, and this decline occurred a few years earlier than the decline of CHD in Iceland. The only significant risk factors for intermittent claudication, in addition to age, were smoking which increased the risk of IC 8- to 10-fold and serum cholesterol level. Approximately one-half of the striking decline in the incidence of IC can be explained by decreased smoking and cholesterol levels amongst Icelandic men. A follow-up study verified that IC patients stood twice the risk of cardiovascular and total mortality as non-IC patients, indicating that IC is a high risk group which should receive all possible preventive measures.

Adult↗

PubMed1994

Low iron-binding capacity as a risk factor for myocardial infarction.

BACKGROUND: In a recent Finnish study, ferritin was suggested to be an independent risk factor for acute myocardial infarction. This study suggested that high levels of iron stores might thus be atherogenic and possibly explain partly the sex difference in the incidence of ischemic heart disease. METHODS AND RESULTS: A randomly selected group (n = 2036), men and women aged 25 to 74 years, were examined between June and September 1983. All classic risk factors for coronary artery disease were measured as well as basic hematologic parameters and the parameters of iron metabolism, ie, iron, total iron-binding capacity (TIBC), and ferritin. During the follow-up for 8.5 years, 81 subjects experienced acute myocardial infarction (63 men and 18 women). The differences in the iron parameters between men and women were almost exclusively seen in ferritin values (198 micrograms/L in men and 91 micrograms/L in women), whereas small differences were seen in TIBC. The Cox proportional hazards model was used to estimate the contribution of independent variables to the risk of myocardial infarction. TIBC was found to be a strong independent negative risk factor in men (RR = 0.95; 95% CI, 0.92 to 0.98), whereas ferritin (RR = 0.999; 95% CI, 0.997 to 1.001) or other iron parameters had no significant predictive power. Each increase in TIBC of 1 mumol/L was associated with a 5.1% decrease in the risk of myocardial infarction. The classic major risk factors, ie, blood pressure, smoking, total cholesterol, and high-density lipoprotein, had significant independent correlation with myocardial infarction. When Cox multivariate analysis was carried out on both sexes combined, TIBC was still an independent negative risk factor, and the logarithmic transform of ferritin had a weak negative correlation but was not statistically significant. Sex was in this group still a very strong risk factor after taking into account all classic risk factors as well as the parameters of iron metabolism. CONCLUSIONS: This study suggests that transferrin, measured as TIBC, is an independent negative risk factor for myocardial infarction. Other parameters of iron metabolism, including ferritin, were not found to contribute to the risk.

Adult↗

PubMed1993

The epidemiology of right bundle branch block and its association with cardiovascular morbidity--the Reykjavik Study.

This study is based on the Reykjavik Study, a long-term prospective cardiovascular survey, which included a representative population of 9135 men and 9627 women, 33-79 years old, who were invited to participate during the years 1967-91. Right bundle branch block (RBBB) was found in 126 men and 67 women. The prevalence increased with age, from 0% among men and women 30-39 years of age to 4.1% and 1.6% in men and women, respectively, who where 75-79 years old. The incidence increased with age. In men younger than 60 years RBBB had a significant relationship with hypertension (P < 0.05), elevated fasting blood glucose (P = 0.05), and increased heart size (P < 0.05). In men with RBBB regardless of age, an association was found with cardiomegaly (P < 0.05), ischaemic heart disease (P < 0.05), arrhythmias (P < 0.001) and bradycardia (P < 0.01). A higher mortality from heart disease (P < 0.01) was found in men with RBBB compared to the control population. This was not significant when risk factors of heart disease were taken into account by multivariate Cox analysis. There was a relationship (P < 0.05) between hypertension and RBBB in women younger than 60 years. RBBB in women younger than 60 years is often associated with hypertension and in men younger than 60 it is often associated with an underlying cardiovascular disease, hypertension, cardiomegaly and elevated blood glucose.

Adult↗

PubMed1993

Prevalence of coronary heart disease in Icelandic men 1968-1986. The Reykjavik Study.

The prevalence of coronary heart disease (CHD) was determined in a general population sample of 9141 Icelandic men aged 34-79 years, and the prevalence of four different forms of CHD was estimated separately: symptomatic infarction fulfilling WHO-MONICA criteria for definite myocardial infarction; myocardial infarction detected by ECG changes only (unrecognized, silent infarction); angina pectoris detected by the Rose questionnaire and associated with ECG manifestations of myocardial ischaemia, either at rest or during exercise, but no manifestations of myocardial infarction; angina pectoris without ECG changes indicative of myocardial ischaemia. The study was conducted in five stages allowing evaluation of trends from 1968-1986. Age was a major determinant of the prevalence of all forms of CHD. Thus, the prevalence of myocardial infarction (symptomatic or silent) rose from undetectable levels in the youngest age group (30-34 years) to around 12% (7% symptomatic and 5% silent) in the oldest group (75-79 years) and the prevalence of all forms of CHD rose from 4% in the youngest age group to 23% in the age group 70-74 years. Age-standardized comparison was carried out on the prevalence of the different forms of CHD at different stages of the study in 50-64-year-old men who were represented in all stages of the study. There was a gradual increase in the prevalence of myocardial infarction from 3% (symptomatic and silent combined, CI 1.9-4.8) in 1968 to 4.9% in 1986 (CI 3.9-6.1) (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Acute emergency service in Reykjavik.

The cardiac arrest survival rate has improved since the emergency ambulance service manned by specially trained paramedical personnel and doctors was introduced in Iceland. As the response time has been reduced, specific resuscitation measures can be applied sooner.

Aged↗

PubMed1992

Role of ADP-ribosylation in endothelial signal transduction and prostacyclin production.

ADP-ribosylation of proteins by the enzymatic transfer of ADP-ribose from NAD has been implicated in a number of biological processes. We report that inhibitors of ADP-ribosylation, most notably the novel inhibitor of arginine specific cellular mono(ADP-ribosyl) transferase, meta-iodobenzylguanidine (MIBG) as well as nicotinamide, L-arginine methyl ester (LAME) and guanyltyramine, inhibit histamine-induced endothelial production of inositol phosphates, release of arachidonic acid and production of prostacyclin (PGI2). Those same responses were unaffected by MIBG when triggered by thrombin or leukotriene C4. These findings suggest that ADP-ribosylation serves a role in histamine-induced production of prostacyclin and imply differences in transduction pathways employed by the different agonists.

3-Iodobenzylguanidine↗

PubMed1992

Predictive value of apolipoproteins in a prospective survey of coronary artery disease in men.

Some studies have suggested that measurements of apolipoproteins may be valuable in the clinical assessment of susceptibility to coronary artery disease, over and above the lipoprotein lipids. Only a few of these studies have been prospective in nature and further knowledge is therefore needed to clarify the issue. The independent prognostic value of apolipoproteins (apo-B, apo-AI and apo[a]) with regard to coronary artery disease was estimated from a prospective survey among 1,332 randomly selected Icelandic men, aged 45 to 72 years, participating in a health survey from 1979 to 1981. The group was followed for 8.6 years, and during that period 104 men had fatal or nonfatal myocardial infarction. The Cox's proportional hazards model was used to estimate the significance of independent variables. The results of multivariate analysis showed that apo(a) was a significant independent risk factor (odds ratio 1.22 for 1 SD), but apo-AI was a stronger negative risk factor (odds ratio 0.70 for 1 SD). Apo-B was a highly significant risk factor in a univariate analysis, but not in a multivariate analysis when serum cholesterol was included. Previous population surveys in Iceland have confirmed the importance of cigarette smoking, cholesterol, triglycerides and blood pressure as risk factors for coronary artery disease. The present results illustrate additional importance of apo-AI and apo(a) concentrations in predicting coronary artery disease among Icelandic men, whereas apo-B did not contribute anything further to the prediction than serum total cholesterol.

Aged↗

PubMed1991

Different mechanisms of homologous and heterologous desensitization of thrombin-induced endothelial prostacyclin production.

Several workers have described desensitization of endothelial prostacyclin production but conflicting evidence has been published regarding the mechanism of desensitization, whether it is homologous (agonist specific) or heterologous, and whether inactivation of cyclooxygenase is involved. The purpose of the present study was to determine the relation between the intensity of a first thrombin stimulus and the subsequent response to a repeat thrombin, histamine, ionophore A23187 or aluminium fluoride (AlF4) stimulation and to determine possible targets of desensitization. Following thrombin stimulation of confluent cultured human umbilical vein endothelial cells (HUVEC) only homologous desensitization of inositol phosphate production was observed. Both homologous and heterologous desensitization of arachidonic acid release and prostacyclin production occurred, the latter towards both histamine and the ionophore A23187. For any given dose of the first stimulant there was a much greater effect on the homologous response than on the heterologous response. These differences suggest different mechanisms. The homologous desensitization probably involves the receptor whereas the present results suggest that the target of heterologous desensitization is distal to calcium mobilization in the signal transduction pathway. The possibilities include decreased activity of phospholipase A2 or a decreased pool of accessible arachidonic acid.

Aluminum↗

PubMed1991

Natural history of chronic left ventricular aneurysm; a population based cohort study.

In order to evaluate the morbidity and mortality of chronic left ventricular aneurysm a population based cohort study was carried out. All cardiac catheterizations performed in Iceland during the years 1983-1985 were examined (n = 1261). Sixty seven patients with left ventricular aneurysm defined as: (1) normal diastolic contour with segmental dyskinesis (n = 6), (2) abnormal diastolic contour with (a) akinetic (n = 36) or (b) dyskinetic (n = 25) segments in systole, were included. Sixty seven patients with normal diastolic contour and akinetic segments in systole served as controls. The groups had similar mean age, sex ratio, number of diseased vessels and left ventricular end diastolic pressure. Mean ejection fraction was significantly lower in the aneurysm group (46 vs 56%, p = 0.00005). Collaterals were detected significantly more often in controls (88 vs 72%, p = 0.03). At follow up in 1989, 19 in the aneurysm group had died as compared to 12 in the control group. Life table analysis revealed significant differences between survival curves. The relative risk ratio was 2.18 with 95% confidence interval of 1.00-4.74 (p less than 0.05). However, when the amount of myocardial damage was taken into account the differences in survival were no longer statistically significant (relative risk ratio 1.77 with 95% confidence interval of 0.79-3.99). We conclude that the reduced survival probability of patients with chronic left ventricular aneurysm in comparison to controls with akinetic scars is accounted for by the more extensive myocardial damage and not by the presence of aneurysm per se.

Adult↗

PubMed1989

Endothelial inositol phosphate generation and prostacyclin production in response to G-protein activation by AlF4-.

In order to elucidate the role of guanine-nucleotide-binding proteins (G-proteins) in endothelial prostacyclin (PGI2) production, human umbilical vein endothelial cells, prelabelled with either [3H]inositol or [3H]arachidonic acid, were stimulated with the non-specific G-protein activator aluminium fluoride (AlF4-). AlF4- caused a dose- and time-dependent generation of inositol phosphates, release of arachidonic acid and production of PGI2. The curves for the three events were similar. When the cells were stimulated in low extracellular calcium (60 nM), they released [3H]arachidonic acid and produced PGI2, but depleting the intracellular Ca2+ stores by pretreatment with the Ca2+ ionophore A23187 totally inhibited both events, although the cells still responded when extracellular Ca2+ was added. The Ca2+ ionophore did not inhibit the generation of inositol phosphates in cells maintained at low extracellular Ca2+. Pertussis toxin pretreatment (14 h) altered neither inositol phosphate nor PGI2 production in response to AlF4-. To investigate the functional role of the diacylglycerol/protein kinase C arm of the phosphoinositide system, the cells were pretreated with the protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA) or the protein kinase C inhibitor 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine (H7). TPA inhibited the AlF4(-)-induced inositol phosphate generation but stimulated both the release of arachidonic acid and the production of PGI2. H7 had opposite effects both on inositol phosphate generation and on PGI2 production. These results suggest that AlF4(-)-induced PGI2 production is mediated by a pertussis-toxin-insensitive G-protein which activates the phosphoinositide second messenger system. This production of PGI2 can be modulated by protein kinase C activation, both at the level of inositol phosphate generation and at the level of arachidonic acid release.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗