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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several studies have utilized the spontaneously hypertensive (SHR) diabetic rat to document the synergistic deleterious consequences of diabetes and hypertension on various organ systems. However, whether these effects are due entirely to the overlapping pathological states or partially result from a greater susceptibility of SHR rats to the diabetogenic effects of streptozotocin (STZ) is unclear. The present study was conducted to examine if strain-dependent variabilities in the STZ-induced diabetic state could also contribute to the pronounced complications previously observed in the SHR diabetic rat. To eliminate a possible modulating influence of severe hypertension on the beta-cytotoxic efficacy of STZ, SHR (SHRD), and Wistar (WisD) rats were injected with STZ (55 mg/kg i.v.) at 7-8 weeks of age, a time when there was no significant difference in systolic blood pressure between both stains. An oral glucose tolerance test was performed at 1 week following STZ and animals were killed at 2 weeks. Although both diabetic groups were equally hyperglycemic in the fed state, only SHRD rats had significantly elevated fasted glycemia at 1 week. Plasma insulin levels in the fed state or in response to oral glucose, as well as pancreatic insulin contents were diminished to a greater extent in the SHRD group relative to WisD. Fed plasma triglyceride (TG) levels were elevated only in the SHRD group, in association with a 4-fold reduction in basal circulating lipoprotein lipase (LPL) activity. However plasma TG clearance and LPL activity in response to i.v. heparin were not significantly altered in SHRD relative to SHR controls. The results in this study indicate that when evaluating the combined effects of diabetes and spontaneous hypertension, the STZ dose should be titrated to obtain an identical degree of diabetes in the SHR and a normotensive strain. In this regard, 45 (SHR) and 55 (Wistar) mg/kg STZ produced an identical milieu of diabetes.
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PMID:Susceptibility of spontaneously hypertensive rats to the diabetogenic effects of streptozotocin. 902 80

The liver plays a central role in lipoprotein metabolism. In particular, very-low density lipoprotein (VLDL) is assembled in the hepatocytes and secreted into the blood circulation. The VLDL is then catabolized to low-density lipoprotein by lipoprotein lipase and hepatic triglyceride lipase. Obese subjects, especially those with visceral fat accumulation, are frequently associated with hyperlipidemia, non-insulin-dependent diabetes mellitus (NIDDM), and hypertension. The mechanism of hyperlipidemia in visceral fat obesity has not yet been elucidated. Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model of NIDDM, characterized by obesity with visceral fat accumulation, hyperlipidemia, and late-onset insulin resistance. To elucidate the mechanism of hyperlipidemia observed in OLETF rats, we focused on the production of VLDL by the liver and investigated hepatic messenger RNA (mRNA) levels of microsomal triglyceride transfer protein (MTP), acyl-coenzyme A synthetase (ACS), and apolipoprotein B (apo B), which play important roles in VLDL synthesis and secretion. In 6-week-old OLETF rats, in which insulin resistance had not been manifested, visceral fat weight was already higher and portal free fatty acid (FFA) and VLDL-triglyceride levels were elevated compared with the control rats. Hepatic ACS activity and mRNA levels, and MTP mRNA levels were also increased in OLETF rats, whereas apo B mRNA levels were similar; these results suggest that the enhanced expression of both ACS and MTP genes associated with visceral fat accumulation before developing insulin resistance may be involved in the pathogenesis of hyperlipidemia in obese animal models with NIDDM.
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PMID:Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation. 946 57

Vascular endothelial-bound lipoprotein lipase (LPL), also known as heparin-releasable LPL, catalyzes the breakdown of the triglyceride component of lipoproteins and is rate-limiting for free fatty acid transport to tissues. We previously demonstrated that heparin-releasable LPL activity increases in diabetic Wistar rat hearts, whereas with the development of hypertension in spontaneously hypertensive rats (SHR), there is a concomitant and progressive reduction in LPL activity. The objective of the present study was to examine the regulation of cardiac LPL activity in SHR-diabetic rats. Heparin perfusion of the isolated Langendorff heart induced the release of LPL activity. SHR hearts demonstrated a reduction in peak heparin-releasable LPL activity, relative to Wistar controls. However, induction of streptozotocin-induced diabetes in SHR, as in Wistar rats, increased peak heparin-releasable LPL activity in perfused hearts. The elevated heparin-releasable LPL peak could not be accounted for by enhanced LPL synthesis in that both cellular and surface-bound LPL activities in myocytes from SHR-diabetic rats were low relative to control. Chronic (12-day) insulin treatment of SHR-diabetic rats reduced the augmented heparin-releasable LPL activity and increased cell-associated LPL activity. Moreover, acute (90-minute) treatment of SHR-diabetic rats with rapid-acting insulin also reduced the heparin-releasable LPL activity to normal, although it had no effect on the low cellular LPL activity. These results demonstrate that the diabetes-induced augmentation of cardiac LPL counteracts the reduction in enzyme activity associated with hypertension. This may serve to increase the delivery of free fatty acid to the heart, and the resultant metabolic changes may lead to the severe cardiomyopathy observed in the hypertensive-diabetic rat heart.
Hypertension 1998 Mar
PMID:Streptozotocin-induced diabetes enhances cardiac heparin-releasable lipoprotein lipase activity in spontaneously hypertensive rats. 949 76

Many unknown genetic factors are involved in the pathogenesis of hypertension. Recently, the reverse genetic approach revealed that some genetic variants, such as angiotensinogen, lipoprotein lipase, and alpha-adducin gene polymorphisms, increase the risk for hypertension. Both in rat and human, the genetic predisposition to hypertension was confirmed only for angiotensinogen and alpha-adducin genes. Adducin is a membrane cytoskeletal protein, which is thought to regulate sodium transport. Abnormalities of membrane sodium transport in the kidney play an important role in hypertension. A recent report by Cusi et al showed that the Trp allele of alpha-adducin polymorphism (Gly 460 Trp) is associated with an increased risk of hypertension in whites, which led us to carry out a case-control study to examine whether the same association is observed in the Japanese population. We recruited 170 hypertensive and 194 normotensive Japanese subjects and compared the genotype distribution of alpha-adducin 460 polymorphism between cases and controls and between whites and Japanese. Trp allele frequency of controls in the Japanese subjects was twice as high as in the whites. However, no association was observed between alpha-adducin polymorphism and hypertension. Furthermore, alpha-adducin 460 polymorphism was not associated with any clinical characteristics. Accordingly, we concluded that alpha-adducin 460 polymorphism is not a major genetic risk for hypertension in Japanese people.
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PMID:No association between alpha-adducin 460 polymorphism and essential hypertension in a Japanese population. 960 91

The dyslipidemia in obese hypertensive persons may contribute to their increased vascular alpha-adrenergic receptor reactivity and tone. To further examine this notion, we conducted 2 studies of pressor sensitivity to phenylephrine, an alpha1-adrenergic receptor agonist, in lean normotensive subjects. In the first study (n=6), pressor responses to phenylephrine were obtained before and during a saline and heparin infusion. On another day, pressor reactivity to phenylephrine was measured before and during infusion of 20% Intralipid at 0.5 mL . m-2 . min-1 with heparin at 1000 U/h to increase lipoprotein lipase activity and raise nonesterified fatty acids (NEFAs). In the second study (n=8), baseline reactivity to phenylephrine was obtained on 2 separate days and repeated after raising NEFAs and triglycerides either with 0.8 mL . m-2 . min-1 of 20% Intralipid alone or together with heparin. The infusion of saline and heparin did not significantly change plasma NEFAs from baseline (516+/-90 versus 512+/-108 micromol/L, respectively; P=NS) or the dose of phenylephrine required to raise mean blood pressure by 20 mm Hg ([PD20PE]; 1.00+/-0.14 versus 0. 95+/-0.10 microg . kg-1 . min-1, respectively, P=NS). Intralipid at 0.5 mL . m-2 . min-1 with heparin raised plasma NEFAs to 793+/-30 micromol/L per liter (P<0.05 versus baseline) and reduced PD20PE from 1.01+/-0.10 to 0.80+/-0.09 microg . kg-1 . min-1 (P<0.05). Compared with baseline, Intralipid alone increased plasma NEFAs to 946+/-80 micromol/L (P<0.05), and NEFAs increased further with the addition of heparin to 2990+/-254 micromol/L (P<0.01). Despite an apparently greater increase of plasma NEFAs with Intralipid and heparin, Intralipid alone and together with heparin similarly reduced PD20PE. Across all study conditions, changes in levels of triglycerides and NEFAs correlated with changes in mean arterial pressure responses to phenylephrine, especially at the 0.4- microg . kg-1 . min-1 infusion rate of phenylephrine (r=0.64, P<0.01 and r=0. 54, P<0.01, respectively). These data suggest that raising levels of plasma NEFAs and/or triglycerides enhances alpha1-adrenoceptor mediated pressor sensitivity. The findings suggest that lipid abnormalities in obese hypertensives, which include elevated NEFAs and triglycerides, contribute to greater vascular alpha1-adrenergic reactivity.
Hypertension 1998 Oct
PMID:Intralipid enhances alpha1-adrenergic receptor mediated pressor sensitivity. 977 65

Essential hypertension is, at least in many subjects, associated with a decrease in insulin sensitivity, whereas glycemic control is (still) normal. Metaanalyses of hypertension intervention studies revealed different efficacy of treatment on cerebral (cerebrovascular accidents [CVA]) and cardiac (coronary heart disease [CHD]) morbidity and mortality. Although CVA were reduced to an extent similar to that anticipated, the decrease in CHD was less than expected. These differences are likely to be caused by the different impact of concomitant cardiovascular risk factors, such as dyslipidemia, impaired glucose tolerance, and non-insulin-dependent diabetes mellitus on CHD and CVA. Frequently these cardiovascular risk factors are ineffectively controlled in hypertensive patients, and moreover, some of the widely used antihypertensive agents have unfavorable side effects and further deteriorate these particular metabolic risk factors. Therefore, the metabolic side effects of antihypertensive treatment have received more attention. During the past few years, studies demonstrated that most antihypertensive agents modify insulin sensitivity in parallel with alterations in the atherogenic lipid profile. Alpha1-blockers and angiotensin converting enzyme inhibitors were shown to either have no impact on or even improve insulin resistance and the profile of atherogenic lipids, whereas most of the calcium channel blockers were found to be metabolically inert. The diuretics and beta-adrenoreceptor antagonists further decrease insulin sensitivity and worsen dyslipidemia. The mechanisms by which beta-adrenoreceptor antagonist treatment exert its disadvantageous effects are not fully understood, but several possibilities exist: significant body weight gain, reduction in enzyme activities (muscle lipoprotein lipase and lecithin cholesterol acyltransferase), alterations in insulin clearance and insulin secretion, and, probably most important, reduced peripheral blood flow due to increase in total peripheral vascular resistance. Recent metabolic studies found beneficial effects of the newer vasodilating beta-blockers, such as dilevalol, carvedilol and celiprolol, on insulin sensitivity and the atherogenic risk factors. In many hypertensive patients, elevated sympathetic nerve activity and insulin resistance are a deleterious combination. Although conventional beta-blocker treatment was able to take care of the former, the latter got worse; the newer vasodilating beta-blocker generation seems to be capable of successfully treating both of them.
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PMID:Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents? 979 45

Exercise training improves cardiovascular disease risk, but individual responses are highly variable. We hypothesized that common polymorphic gene variations would affect these responses. Sedentary obese hypertensive older men who had undergone exercise training were typed at the apolipoprotein (apo) E, angiotensin-converting enzyme (ACE), and lipoprotein lipase (LPL) loci. Individuals of all genotype subgroups were generally similar before training; they also changed body weight, body composition, and &f1;O(2)max similarly with training. ACE insertion/insertion (II) and insertion/deletion (ID) genotype individuals (n=10) tended to reduce systolic blood pressure more with training than deletion/deletion (DD) individuals (n=8) (-10 versus -5 mm Hg, P=0. 16). ACE II and ID individuals decreased diastolic blood pressure more with training than DD individuals (-10 versus -1 mm Hg, P<0. 005). Systolic blood pressure reductions with training were also larger in apoE3 and E4 (n=15) than apoE2 men (n=3) (-10 versus 0 mm Hg, P<0.05). The same trend was evident for diastolic blood pressure (-7 versus -3 mm Hg), but the difference was not significant. Systolic (14 versus -6 mm Hg, P=0.08) and diastolic (-9 versus -5 mm Hg, P=0.10) blood pressure reductions tended to be greater in LPL PvuII +/+ (n=4) than +/- and -/- individuals (n=14). Systolic (-10 versus 3 mm Hg, P<0.05) and diastolic (-9 versus 2 mm Hg, P<0.05) blood pressure reductions were larger in LPL HindIII +/+ and +/- (n=15) than -/- persons (n=3), respectively. LPL PvuII -/- individuals (n=3) had larger increases in HDL cholesterol (11 versus 2 mg/dL, P<0.05) and HDL(2) cholesterol (8 versus 0 mg/dL, P<0.05) than LPL PvuII +/- and +/+ individuals (n=15). These results are consistent with the possibility that apoE, ACE, and LPL genotypes may identify hypertensives who will improve blood pressure, lipoprotein lipids, and cardiovascular disease risk the most with exercise training.
Hypertension 1999 Jul
PMID:Exercise training-induced blood pressure and plasma lipid improvements in hypertensives may be genotype dependent. 1040 18

Blood pressure (BP) is heritable and finding quantitative trait loci that influence BP is an important step in identifying genes responsible for BP regulation. Sixty-six pairs of dizygotic (DZ) twin subjects and their parents were used in a sib-pair analysis to look for linkage of selected candidate genes to the quantitative trait BP. Microsatellite markers were tested in the vicinity of the gene loci for insulin-like growth factor-1 (IGF-1), Liddle syndrome, autosomal-dominant hypertension with brachydactyly, angiotensinogen, angiotensin II type 1 receptor, angiotensin-converting enzyme, renin, and lipoprotein lipase. BP was measured in a standardized manner. Heart size was determined echocardiographically. Significant linkage was found at the IGF-1, Liddle syndrome, and AT1 receptor gene for systolic BP. Linkage for diastolic BP was found at the autosomal-dominant hypertension with brachydactyly locus. Both systolic and diastolic BP were linked to the renin gene locus. The linkage was most consistent for the IGF-1 gene locus and systolic BP. Linkage was also found between the IGF-1 gene locus and posterior cardiac wall thickness, septal thickness, and left ventricular mass index. It is suggested that these quantitative trait loci may be important for the subsequent detection of allelic variants for elevated BP. Furthermore, these results linking the IGF-1 gene locus to both BP and cardiac dimensions underscore the importance of the IGF-1 gene as a candidate gene for cardiovascular disease.
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PMID:Quantitative trait loci for blood pressure exist near the IGF-1, the Liddle syndrome, the angiotensin II-receptor gene and the renin loci in man. 1044 38

We investigated the possibility that the DNA HindIII polymorphism of human lipoprotein lipase (LPL) is associated with the severity of coronary artery disease (CAD) determined by angiography in young patients who survived a myocardial infarction (MI). Conflicting studies have explored the relationship linking CAD severity to the HindIII restriction site polymorphism at the LPL gene locus, and to our knowledge, no data are available from Italy. The patients were aged less than 45 years (mean age, 40.1 +/- 3.9 years); 83 were male and four were female. The 87 case-patients had a Q-wave or non-Q-wave infarction (67.3% and 32.7%, respectively); the MI was anterior (50.5%), lateral (41.7%), or inferior (7.8%). Analysis of coronary angiograms showed the absence of critical stenosis in 13.8% and the presence of monovessel disease in 50.6% and multivessel disease in 35.6% of the case-patients. The allelic frequency of the HindIII H(-) and H(+) allele was 0.37 and 0.63, respectively. There was a striking association between the HindIII polymorphism and the number of diseased vessels. The patients with HindIII(+/+) genotypes were significantly more likely to have double- or triple-vessel disease and less likely to have no significantly diseased vessels. In this study, we demonstrated that the homozygous form of the LPL HindIII(+) allele increases the risk of multivessel disease by a factor of 4 in an Italian group of young MI survivors. This association was independent from the smoking status and a positive family history for CAD and hypertension, which are known to predict CAD severity. The discrepancies in the results of these studies are difficult to explain. The lack of homogeneity in the study populations (age at which CAD occurred, number of enrolled patients, and geographical origin) and differences in the assessment of CAD severity may account for these conflicting results.
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PMID:Human lipoprotein lipase HindIII polymorphism in young patients with myocardial infarction. 1048 57

There is mounting evidence that inflammation plays a role in the development of coronary heart disease (CHD). Observations have been made linking the presence of infections in the vessel wall with atherosclerosis, and epidemiological data also implicate infection in remote sites in the aetiology of CHD. In this article we propose a key role for the proinflammatory cytokine interleukin-6 (IL-6) in several mechanisms that contribute to the development of CHD. IL-6 is a powerful inducer of the hepatic acute phase response. Elevated concentrations of acute phase reactants, such as C-reactive protein (CRP), are found in patients with acute coronary syndromes, and predict future risk in apparently healthy subjects. The acute phase reaction is associated with elevated levels of fibrinogen, a strong risk factor for CHD, with autocrine and paracrine activation of monocytes by IL-6 in the vessel wall contributing to the deposition of fibrinogen. The acute phase response is associated with increased blood viscosity, platelet number and activity. Furthermore, raised serum amyloid A lowers HDL-cholesterol levels. IL-6 decreases lipoprotein lipase (LPL) activity and monomeric LPL levels in plasma, which increases macrophage uptake of lipids. In fatty streaks and in the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smooth muscle cells (SMC) express IL-6, suggesting a role for this cytokine along with interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), in the progression of atherosclerosis. Both these cytokines induce the release of IL-6 from several cell types, including SMC. During vascular injury SMC are exposed to platelets or their products, and cytokine production by SMC further contributes to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis, activation of which is associated with central obesity, hypertension and insulin resistance. Thus we propose a role for IL-6 in the pathogenesis of CHD through a combination of autocrine, paracrine and endocrine mechanisms. This hypothesis lends itself to testing using interventions to influence IL-6 secretion and actions.
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PMID:Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? 1065 56


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