Influence of genetic predisposition to diabetes and obesity on mitochondrial function

Inbred mice with the mutation diabetes C57BL/KsJ db+/db+ and the mutation obese C57BL/6J ob/ob displayed a total liver mitochondrial capacity to oxidize glutamate or succinate which was approximately eight times greater than the capacity of the C57BL/6J +/+ control mice. This increase in oxidation capacity was estimated by multiplying the observed twofold increase in each of the following components: total liver weight, the mitochondrial protein content per gram of liver, and glutamate or succinate respiration activity per milligram of liver mitochondrial protein. No significant difference in liver mitochondrial function and capacity for oxidation was observed between db+/db+ and ob/ob mutants, which indicated that these results may be primarily mediated by the genetic factors responsible for obesity and hyperphagia in these mutants, and not by the genetic traits associated with diabetes. These findings may provide a biochemical foundation in support of the thrifty gene hypothesis.     

Thermal biofeedback as an effective substitute for sympatholytic medication in moderate hypertension: A failure to replicate

Thirty-three moderate hypertensives were converted to a 2-drug regimen of metoprolol and diuretic and BPs stabilized at a well-controlled level. They then completed one of three conditions over an 8-week interval: (I) 16 sessions of TBF (hand and foot warming); (II) 16 sessions of frontal EMG-BF; (III) regular home monitoring of BP. Attempts were then made to withdraw the patients from the sympatholytic medication. Those successfully withdrawn were followed up for one year. There were no significant advantages for TBF over the other two conditions in the short term or with long-term follow-up. Only 27% of treated patients (including Condition III failures who were remedicated and treated with TBF) were successfully off of the sympatholytic at a one-year follow-up. The generally poor results on clinical outcome were confirmed by clinic BPs, home BPs by patients, and 24-hour ambulatory BPs.This research was supported by grant No. HL-27622 from NHLBI. The authors wish to thank Dr. Guy C. McCoy for his role in the initial conceptualization of the study, Dr. Jim Jaccard and Barbara Greene for their assistance in the analyses of the 24-hour ambulatory BP data, and Annabel Prins, Bruce Steffek, and Debra Belkin, who served as therapists for a portion of the study.     

Ultrastructure and histochemistry of rat myocardial capillary endothelial cells in response to diabetes and hypertension

INTRODUCTIONThe streptozotocin [STZ]-induced diabetes and NO-deficient hypertension are widely used experimental modelsfor the investigation of heart failure [1-4]. Cardiac dys-function in both models is consequence of different sig-nal and metabolic dera…     

郴州市高血压患者中药物抵抗型高血压的筛查和城乡比较研究

目的：通过调查郴州市城区和乡村高血压患者用药现状,筛查出药物抵抗型高血压患者,以提高药物抵抗型高血压患者的治疗率和控制率,为高血压患者个体化降压治疗方案和健康教育方案的制定提供依据。方法：随机选择郴州市区及乡村地区各200名高血压患者,以问卷的形式进行调查。结果：郴州市区药物抵抗型高血压在高血压患者中所占比例及知晓比例分别为6%、9.5%,乡村地区所占比例及知晓比例分别为7%、4%。结论：郴州市药物抵抗型高血压在高血压患者中所占比例为6.5%,农村药物抵抗型高血压患者知晓比例较低;药物抵抗型高血压患者个体化降压治疗方案有待于改进。     

Influence of hypertension and of antihypertensive drugs on the arterial wall

This paper reviews some of the experimental data regarding the effects of hypertension and antihypertensive drugs on the arterial wall. Hypertension induces major changes in both the arterial media and intima. Experimental studies from our own and other laboratories have demonstrated that medial smooth muscle cells in several forms of hypertension in the rat undergo hypertrophy and nuclear polyploidy which contribute, along with connective tissue alterations, to a large increase in medial mass. Our studies in the deoxycorticosterone/salt-hypertensive rat indicate that such changes may be difficult to regress, despite prolonged control of the hypertension. In the arterial intima, major alterations in the endothelium are induced by hypertension in association with increase in arterial permeability. Marked enhancements of adherence of circulating white blood cells to the endothelium can also be demonstrated along with penetration of blood monocytes and their accumulation in the subendothelial space. Hypertension also appears to stimulate the migration and proliferation of smooth muscle cells in the intima, and evidence is beginning to accumulate that endogenous growth factors within the artery may be involved in this process. Essentially all of the intimal changes which we have observed as a result of arterial hypertension are also present with cholesterol feeding although intimal accumulation of lipid and formation of atherosclerotic plaques do not occur with hypertension alone. On the other hand, in hypercholesterolemic animals, hypertension appears to act as a promoter of atherogenesis. Several antihypertensive drugs may influence the atherosclerotic process. The experimental data regarding the effects of beta blockers and calcium antagonists in the cholesterol-fed rabbit are discussed. Though of considerable interest, the clinical relevance of the findings remains uncertain.     

Erythrocyte ouabain binding and intracellular Na+ in normotensive obese women and obese women receiving medication for hypertension

People with "primary obesity" may be hypertensive because they have lost their ability to compensate for the effect of low Na+-K+-ATPase levels on blood pressure. In obese patients receiving hypertensive medication (n = 13), but not in normotensive nonmedicated patients (n = 42), diastolic blood pressure was inversely correlated with erythrocyte ouabain binding (P less than 0.02) and directly correlated with intracellular Na+ concentration (P less than 0.01). Moreover, there was a stronger inverse relationship between ouabain binding and intracellular Na+ in patients receiving medication for hypertension (P less than 0.01) than in normotensive patients (P less than 0.05). These data suggest that patients receiving hypertensive medication may be less able to compensate than normotensive patients, (a) for the potential effect of Na+-K+-ATPase levels on intracellular Na+ and (b) for the potential effect of intracellular Na+ concentration on diastolic blood pressure. We propose that obese people with low levels of ouabain binding (primary obesity) may have an increased risk of developing hypertension if their compensatory mechanisms fail.     

Comparative effectiveness of guidelines for the management of hyperlipidemia and hypertension for type 2 diabetes patients

Background

Several guidelines to reduce cardiovascular risk in diabetes patients exist in North America, Europe, and Australia. Their ability to achieve this goal efficiently is unclear.

Methods and Findings

Decision analysis was used to compare the efficiency and effectiveness of international contemporary guidelines for the management of hypertension and hyperlipidemia for patients aged 40–80 with type 2 diabetes. Measures of comparative effectiveness included the expected probability of a coronary or stroke event, incremental medication costs per event, and number-needed-to-treat (NNT) to prevent an event. All guidelines are equally effective, but they differ significantly in their medication costs. The range of NNT to prevent an event was small across guidelines (6.5–7.6 for males and 6.5–7.5 for females); a larger range of differences were observed for expected cost per event avoided (ranges, $117,269–$157,186 for males and $115,999–$163,775 for females). Australian and U.S. guidelines result in the highest and lowest expected costs, respectively.

Conclusions

International guidelines based on the same evidence and seeking the same goal are similar in their effectiveness; however, there are large differences in expected medication costs.     

Effects of diabetes and hypertension on myocardial Na+-Ca2+ exchange

Abnormalities in cardiac function have been extensively documented in experimental and clinical diabetes. These aberrations are well known to be exaggerated when hypertension and diabetes co-exist. The objective of the present study was to examine whether alterations in the activity of the myocardial Na+-Ca2+ exchanger (NCX) can account for the deleterious effects of diabetes and (or) hypertension on the heart. To this aim, the following experimental groups were studied: (i) control; (ii) diabetic; (iii) hypertensive; and (iv) hypertensive-diabetic. Wistar rats served as the control group (C) while Wistar rats injected with streptozotocin (STZ, 55 mg/kg) served as the diabetic (D) group. Spontaneously hypertensive (SH) rats were used as the hypertensive group (H) while SH rats injected with STZ served as the hypertensive-diabetic (HD) group. Sarcolemma was isolated from the ventricles of the C, D, H, and HD groups and NCX activity was examined using rapid quenching techniques to study initial rates over a [Ca2+]o range of 10-160 microM. The Vmax of NCX was lower in the D group when compared with the C group (D, 2.96 +/- 0.26 vs. C, 4.0 +/- 0.46 nmol x mgprot(-1) x s(-1), P < 0.05), however combined diabetes and hypertension (HD) did not affect the Vmax of NCX activity (HD, 3.84 +/- 0.88 vs. H, 3.59 +/- 0.24 nmol x mgprot(-1) x s(-1), P > 0.05). However, analysis of the Km values for Ca2+ indicated that both the D and HD groups exhibited a significantly lower Km when compared with their respective control groups (D, 42 +/- 4 vs. C, 56 +/- 4 microM, P < 0.05; HD, 33 +/- 7 vs. H, 51 +/- 8 microM, P < 0.05). Immunoblotting using polyclonal antibodies (against canine cardiac NCX) exhibited the typical banding of 160, 120, and 70 kDa. The 120 kDa band is believed to represent the native exchanger with its post-translational modifications. Examination of the blots revealed a lower intensity of the 120 kDa band in the D group when compared with the C group, however, no significant difference in the HD group was observed. We speculate that the lower Vmax in the D group may be due to a reduced concentration of exchanger protein in the membrane. The absence of this defect in the HD group may be a result of compensatory mechanisms to the overall hemodynamic overload, however, this remains to be determined. The increased affinity for Ca2+ in both the D and HD groups (determined by the lower Km values) is an interesting finding and may be due to changes in sarcolemmal lipid bilayer composition secondary to diabetes-induced hyperlipidemia.     

Nitric oxide may be required to prevent hypertension at the onset of diabetes

Nitric oxide (NO) plays an important role in the regulation of vascular tone, and evidence suggests that endothelial-dependent relaxation, possibly mediated via NO, is impaired in diabetes. However, the role of the endothelium in arterial pressure control early in diabetes, before dysfunction develops, is not known. This was evaluated in the present study by comparing the responses to induction of diabetes in vehicle-treated rats (D, n = 7) vs. rats chronically treated with N(G)-nitro-L-arginine methyl ester (L-NAME; D+L, n = 8). A nondiabetic group also was treated with L-NAME (L, n = 7) to control for L-NAME effects over time, independent of diabetes. After baseline measurements, rats were given either vehicle or L-NAME (10 microg. kg(-1). min(-1) iv) infusion throughout the experiment. Six days later, streptozotocin (60 mg/kg iv) was administered, followed by a 3-wk diabetic study period. Induction of diabetes in the D+L rats caused a marked and progressive increase in mean arterial pressure throughout the diabetic period, averaging approximately 70 mmHg greater than in the D rats and approximately 20 mmHg greater than in the L rats. Glomerular filtration rate and renal plasma flow tended to increase during diabetes, but this trend was reversed in the D+L rats. In addition, plasma renin activity increased in the D and D+L rats during week 1 of diabetes but then returned to control in the D rats, while continuing to increase in the D+L rats. These results suggest that, in the early stages of diabetes, NO synthesis is important to prevent hypertension from developing, possibly through actions to maintain glomerular filtration and suppress renin secretion.     

Evaluating diabetes and hypertension disease causality using mouse phenotypes

Background  

Genome-wide association studies (GWAS) have found hundreds of single nucleotide polymorphisms (SNPs) associated with common diseases. However, it is largely unknown what genes linked with the SNPs actually implicate disease causality. A definitive proof for disease causality can be demonstration of disease-like phenotypes through genetic perturbation of the genes or alleles, which is obviously a daunting task for complex diseases where only mammalian models can be used.