Changes in Plasma Ace Activity During the Development and Reversal of One-Kidney,One Clip Hypertension in Rats

We conducted a randomized, double-blind, cross-over comparison of six weeks' treatment with 5 mg clopamide or with 25 mg hydrochlorothiazide in 17 hypertensive patients (average age 62 years). No significant differences were found between the two treatments in blood pressure control, plasma biochemical values, body weight or response to a comprehensive “quality of life” questionnaire. Despite the apparently identical performance of both drugs, significantly (x²=4.76;P<0.05) more patients expressed a preference for clopamide (12) than for hydrochlorothiazide (3). Two had no preference. Current quality of life assessments are relatively insensitive and patient preference remains a valid discriminator between otherwise comparable medications.     

The significance of brain aminopeptidases in the regulation of the actions of angiotensin peptides in the brain

From the outset, the concept of a brain renin-angiotensin system (RAS) has been controversial and this controversy continues to this day. In addition to the unresolved questions as to the means by which, and location(s) where brain Ang II is synthesized, and the uncertainties regarding the functionality of the different subtypes of Ang II receptors in the brain, a new controversy has arisen with respect to the identity of the angiotensin peptide(s) that activate brain AT₁ receptors. While it has been known for some time that Ang III can activate Ang II receptors with equivalent or near-equivalent efficacy to Ang II, it has been proposed that in the brain, only Ang III is active. This proposal, which we have named “The Angiotensin III Hypothesis” states that Ang II must be converted to Ang III in order to activate brain AT₁ receptors. This review examines several aspects of the controversies regarding the brain RAS with a special focus on brain aminopeptidases, studies that either support or refute The Angiotensin III Hypothesis, and the implications of The Angiotensin III Hypothesis for the activity of the brain RAS. It also addresses the need for further research that can test The Angiotensin III Hypothesis and definitively identify the angiotensin peptide(s) that activate brain AT₁ receptor-mediated effects.     

Enhanced Angiotensin II-Induced Activation of Na+, K+-ATPase in the Proximal Tubules of Obese Zucker Rats

Renal angiotensin II (AII) is suggested to play a role in the enhanced sodium reabsorption that causes a shift in pressure natriuresis in obesity related hypertension; however, the mechanism is not known. Therefore, to assess the influence of AII on tubular sodium transport, we determined the effect of AII on the Na⁺, K⁺-ATPase activity (NKA), an active transporter regulated by the AT₁ receptor activity, in the isolated proximal tubules of lean and obese Zucker rats. Also, we determined the levels of the tubular AT₁ receptor and associated signal transducing G proteins, as the initial signaling components that mediate the effects of AII on Na⁺, K⁺-ATPase activity. In the isolated proximal tubules, AII produced greater stimulation of the NKA activity in obese compared with lean rats. Determination of the AT₁ receptors by Scatchard analysis of the [¹²⁵I] Sar-Ang II binding and Western blot analysis in the basolateral (BLM) and brush border membrane (BBM) revealed a modest but significant increase (23%) in the AT₁ receptor number mainly in the BLM of obese compared with lean rats. The AII affinity for AT₁ receptors, as determined by IC₅₀ values of AII to displace [¹²⁵I] Sar-Ang II binding in BLM and BBM were similar in lean and obese rats. Western blot analysis revealed significant increases in Giα₁, Giα₂, Giα₃, and Gq/₁₁α in BLM and Giα₁, Giα₃, and Gq/₁₁α in BBM of obese as compared with lean rats. The increase in the levels of the AT₁ receptor and G proteins, mainly in the BLM, may be contributing to the enhanced AII-induced activation of NKA in the proximal tubules of obese rats. This phenomenon, in part, may be responsible for the increased sodium reabsorption and the development of hypertension in obese Zucker rats.     

Relationship between Insulin Resistance and the Renin-Angiotensin System: Analysis for Patients with Essential and Renovascular Hypertension

Insulin resistance is frequently observed in patients with essential hypertension (EHT), and the renin-angiotensin system (RAS) has been demonstrated to modulate the status of insulin resistance. The aims of present study are to investigate the relationship between systemic RAS and insulin resistance in 82 patients with EHT and compare the impact of RAS to insulin resistance with 10 renovascular hypertension (RVHT) patients who have a highly activated systemic RAS. From patients who were admitted to our hospital, patients with overt diabetes and hypertensives who had secondary HT except RVHT or chronic renal failure were excluded. Plasma renin activity (PRA) was used as an indicator of systemic RAS activity. HOMA-R as an index of insulin resistance and sum of immunoreactive insulin (IRI) during glucose tolerance test (∑IRI) and IRI at 120 minutes (IRI120) were used as indices of hyperinsulinemia. In the EHT patients, circulating PRA showed an independent relationship with IRI120 and ∑IRI after adjusting confounding factors (IRI120: t?=?2.70, p?=?0.01, ∑IRI: t?=?3.05, p < 0.001). Excluding patients who were taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blocker (ARBs), the relationship remained in univariate linear regression; after adjustment for confounding factors, PRA showed a tendency to be correlated with ∑IRI. However, there was no significant relationship between PRA and indices of insulin resistance and hyperinsulinemia in patients with RVHT. In conclusion, the systemic RAS may modulate insulin sensitivity in EHT patients.     

Potential use of DA1 and DA2 Receptor Agonists in the Treatment of Hypertension

Will dopamine (DA) agonists have a role in the treatment of hypertension? Recent advances of medicinal chemistry and receptor pharmacology have suggested a positive answer. First, the division of DA receptors into two subtypes, DA₁ and DA₂, and the differentiation of these receptors from other receptors have resulted in the synthesis of relatively selective agonists and antagonists. Second, agonists of DA₁ and DA₂ receptors have been shown to decrease blood pressure in experimental animals and hypertensive patients. Review of clinical data with DA₁, DA₂, and combination of DA₁ and DA₂ agonists not only has demonstrated efficacy, but has revealed problems in the use of these compounds. Finally, possible solutions of these problems will be discussed.     

The Place of Alpha Blockers in the Treatment of Hypertension

Alpha₁ adrenoceptor antagonists are safe, effective, well tolerated drugs which can be used alone or in combination with other drug groups in a wide range of hypertensive patients. Alpha₁ blockers not only lower blood pressure but may improve insulin sensitivity and the adverse lipid profile in many hypertensive patients. In addition to causing few side effects, alpha₁ blockers are not contra-indicated in patients with associated cardiovascular or respiratory disease. Alpha₁ blockers offer the potential to improve the risk factor profile more than conventional antihypertensive drugs.     

AT<Subscript><Emphasis Type="Italic">1</Emphasis></Subscript> Receptor Blockade Prevents Cardiac Dysfunction after Myocardial Infarction in Rats

Summary Myocardial infarction (MI) can induce severe alterations of contractile function that can, in turn, lead to heart failure. In a previous study, we have demonstrated that TNF-α was involved in cardiac contractile dysfunction 7 days after coronary artery ligation in rats. Since Angiotensin II type 1 (AT₁) receptor can be involved in TNF-α production, we have investigated whether early short-term treatment with irbesartan, an AT₁ receptor blocker, is able to limit TNF-α production within the heart and to improve cardiac function and geometry following MI in rats. Male Wistar rats were subjected to permanent coronary artery ligation and received either a placebo or irbesartan (50 mg/kg/day) per os daily from day 3 to day 6 after surgery. On day 7, cardiac TNF-α was significantly reduced in MI rats receiving irbesartan (p < 0.05). Moreover, irbesartan improved residual LV end-diastolic pressure under both basal conditions and after volume overload (p < 0.01). In addition, a significant leftward shift of the pressure-volume curve in the irbesartan-treated group was found versus placebo. Finally, infarct expansion index was also significantly improved by irbesartan (p < 0.01). In conclusion, early, short-term AT₁ receptor blockade limits post-infarct cardiac TNF-α production and diminishes myocardial alterations observed 7 days after MI in the rat.     

Insulin Receptor Gene in Hypertension

The first molecular genetic association with human essential hypertension (HT) involved the insulin receptor gene (INSR). This highly significant result in Caucasians was for an insertion/deletion polymorphism in intron 9. A polymorphism in exon 8 showed a weak association, but a microsatellite in intron 2 proved negative for HT, although has shown an association with plasma insulin in Japanese. A similar spectrum of genetic associations for variants spanning INSR has been noted for insulin-dependent diabetic patients with rapidly-progressing renal disease, a subgroup having a strong family history of essential HT. Association with HT has also been found for an INSR variant in Chinese. Insulin resistance secondary to an INSR ‘defect’, or other causes, would increase insulin, which has cardiovascular effects, and insulin can raise angiotensinogen. Also, insulin is co-secreted with amylin, which can increase renin secretion. In the spontaneously HT rat there is evidence for reduced down-regulation of INSR expression in response to NaCl-loading, consistent with a promoter effect. When combined with observations of insulin resistance in essential HT patients and their pre-HT offspring, the possibility of dys-regulation of INSR merits attention in disease etiology in a proportion of essential HT patients.     

高血压病的胰岛素抵抗

对 17例治疗的 ,2 0例未治疗的高血压病人和 2 5例正常对照者 ,测定空腹及 75 g葡萄糖刺激后血浆葡萄糖和胰岛素浓度、红细胞胰岛素受体、血脂及脂蛋白。结果表明 :治疗和未治疗的高血压病人 ,血糖和胰岛素对葡萄糖刺激后的反应及胰岛素释放指数均显著高于对照组 ,血甘油三酯 (TG)、低密度脂蛋白(L DL )显著增高 ,高密度脂蛋白 (HDL )显著降低 ,红细胞胰岛素受体分析各组间差异无显著性。葡萄糖刺激后血浆胰岛素反应曲线下面积 (AIA )与收缩期和舒张期血压呈显著正相关 ,与TG,TC,L DL 也呈显著正相关 ,调整年龄、体重指数和血糖后 ,其相关性依然存在 ,说明高血压病存在着胰岛素抵抗 ,后者在高血压病因和临床中起重要作用     

牛磺酸对大鼠胰岛素抵抗高血压的影响

目的探讨牛磺酸对胰岛素抵抗高血压大鼠的影响。方法在输注胰岛素和葡萄糖引起动物胰岛素抵抗高血压模型上，测量平均动脉压、心率、血糖，放射免疫法测定血浆胰岛素和内皮素及主动脉组织内皮素，用２－脱氧葡萄糖摄取评估骨骼肌葡萄糖转运活性，用乙醇沉淀法测定肌糖原合成，测定肝胰岛素清除。结果胰岛素抵抗高血压大鼠血压升高，心率加快，血糖和血浆胰岛素含量增加（Ｐ＜０．０１）。牛磺酸治疗可明显改善上述指标，并增加骨骼肌葡萄糖转运活性，促进肌糖原合成和肝胰岛素清除，同时减轻血浆和主动脉内皮素含量。结论牛磺酸治疗胰岛素抵抗高血压大鼠是有效的。     

胰岛素抵抗高血压大鼠血小板L—精氨酸／一氧化氮系统的改变

目的 观察胰岛素抵抗高血压大鼠血小板Ｌ－精氨酸／一氧化氮系统的改变。方法 自发性高血压大鼠（ＳＨＲ）自第５周至第１０周喂信果糖,制备胰岛素抵抗高血压大鼠（ＩＲ）模型。在此模型上,检测血小板一氧化氮合酶（ＮＯＳ）活性、一氧化氮（ＮＯ）产生量及Ｌ－精氨酸（Ｌ－Ａｒｇ）转运特征,同时观察了血浆Ｌ－Ａｒｇ水平、心纳素（ＮＡＰ）、ＮＯ水平及ｃＧＭＰ水平。结果 ＳＨＲ大鼠收缩压（ＳＢＰ）（Ｐ〈０．０１）,血浆     

高血压患者血脂异常与红细胞胰岛素受体的关系

探讨血清脂质水平与胰岛素受体及胰岛素抵抗的关系。方法以１３例健康体检者为对照组，研究３７例原发性高血压患者红细胞胰岛素受体和血清脂质水平的变化。结果与对照组相比，原发性高血压患者红细胞胰岛素受体较少，血清总胆固醇（ＴＣ）、低密度脂蛋白胆固醇（ＬＤＬＣ）、低密度脂蛋白胆固醇／高密度脂蛋白胆固醇（ＬＤＬ／ＨＤＬ）均显著较高，载脂蛋白Ａ１（ＡｐｏＡ１）、ＡｐｏＡ／ＡｐｏＢ较低，高亲和力型红细胞胰岛素受体数目（Ｒ１）与ＴＣ、ＴＧ、ＬＤＬＣ呈显著负相关，与ＨＤＬＣ、ＡｐｏＡ１呈显著正相关。结论血脂导常可能与胰岛素受体减少有关。     

原发性高血压胰岛素抵抗与红细胞胰岛素受体的关系

目的探讨胰岛素受体和胰岛素敏感性指数之间的关系。方法用改良Ｇａｍｂｈａｉｒ法检测定３７例原发性高血压患者和１３例正常人的红细胞胰岛素受体，并以胰岛素敏感性指标作对照。结果高血压患者的红细胞胰岛素受体明显降低，和胰岛素敏感指数之间呈明显的负相关，而健康人的两者之间呈明显的正相关。结论高血压患者的胰岛素受体的减少在胰岛素抵抗发病上起重要作用。     

Dopamine D5 Receptor Expression is Unchanged in Peripheral Blood Lymphocytes in Essential Hypertension

The present study was designed to investigate possible changes in the expression of lymphocyte dopamine receptor in essential hypertension. The expression of dopamine D₅ receptor was evaluated by radioligand binding techniques using [³H]-SCH 23390 as ligand. Plasma catecholamines, aldosterone levels and plasma renin activity were also measured.

Eleven borderline hypertensive patients, 15 patients with mild essential hypertension, 7 patients with moderate essential hypertension and 5 patients with severe essential hypertension were examined. Plasma catecholamine levels were assayed by high pressure liquid chromatography with electrochemical detection. Dopamine D₅ receptor was measured by radioligand binding techniques. Plasma aldosterone levels and renin activity were determined by radio immunoassay.

[³H]-SCH 23390 was specifically bound to human peripheral blood lymphocytes. The binding was time-, temperature- and concentration- dependent with a dissociation constant (Kd) value of 0.59 nM and a maximum density of binding sites (Bmax) of 223 pmol/ 10⁶ cells.

Dopamine competed with [3H]-SCH 23390 binding in the submicromolar range suggestin the labelling of a dopamine D5 receptor. No changes in peripheral blood lymphocytes between essential hypertensive patients and normotensive subjects. Also catecholamines, plasma renin activity and aldosterone levels were unchanged.

In spite of the availability of a sensitive technique for measuring dopamine receptors in human peripheral lymphocytes, no change in their expression was noticeable in essential hypertension. This suggests that dopamine receptor analysis in essential hypertension is not a useful marker for investigating hypertension-dependent changes of the peripheral dopaminergic system. the density of [9 HI-SCH 23390 binding sites were observed in human     

Upregulation of the Vascular Alpha-1 Receptor in Malignant Doca-salt Hypertension

In this investigation we describe regulation of the vascular alpha-1 receptor and functional properties of resistance vessels in malignant hypertensive DOCA-salt rats (DOCA-salt). Uninephrectomized control and DOCA-salt rats were maintained for 6 weeks; microscopic renal morphology provided an index of vascular injury. Radioligand binding studies indicated a striking increase in the density of mesenteric alpha-1 binding sites in DOCA-salt (542 ± 44 fm/mg) vs. salt control (206 ± 4 fm/mg) and water control (223 +31 fm/mg) P < .01. The affinity of the receptor for the radioligand [¹²⁵I] (±) BE 2254 was reduced in DOCA-salt rats. Electrical nerve stimulation and agonist dose response curves were performed on isolated perfused mesenteric arteries. A singular correlation between increased receptor density and vascular responses in DOCA-salt rats could not be demonstrated. The norepinephrine (NE) content of mesenteric arteries was reduced in DOCA-salt (1001 ± 32 ng/g) vs. water control (1522 ± 44 ng/g) and saline control (1538 ± 30 ng/g) P < .01. Our results indicate, upregulation of the mesenteric alpha-1 receptor occurs in DOCA-salt rats, however, additional factors participate in the vascular response to adrenergic stimulation in this model.     

Myocardial electrophysiological properties in the presence of an AT1 angiotensin II receptor antagonist

Introduction Blockade of the AT₁ angiotensin II (Ang II) receptor has been shown to provide antihypertensive effects. However, whether AT₁ Ang II receptor antagonists influence myocardial electrophysiological properties remains unclear.Methods and results Accordingly, atrial and ventricular myocardial electrophysiological properties were examined in adult rat (n=13) and guinea pig (n=9) myocardial preparations in the presence of the specific AT₁ Ang II receptor antagonist, valsartan (CGP 48933; 0.5, 5, or 500 mol/L). These concentrations reflect up to 100 fold higher drug concentrations than those observed in clinical trials. Transmembrane potential data were recorded using standard microelectrode techniques at baseline and following superfusion with valsartan. The lower concentrations of valsartan (0.5 and 5 mol/L) had minimal effects on myocardial electrophysiology. In the presence of 500 mol/L of valsartan, resting membrane potential increased from baseline in both rat (–82.3±4.1 vs –76.8±5.8 mV, p<0.05) and guinea pig (–81.6±2.9 vs –76.9±2.0 mV, p<0.05) atrial myocardium. Action potential duration at 90% repolarization was increased in guinea pig atrial (91.7±1.4 vs 80.0±5.6 ms, p<0.05) and ventricular (131.1±8.1 vs 118.7±8.3 ms, p<0.05) myocardium following exposure to 500 mol/L of valsartan. In a separate series of experiments Ang II (1.0 mol/L) had no effect on atrial or ventricular action potential characteristics in either species.Conclusion Thus, the effects of valsartan, which were observed only at concentrations 100 fold higher than those reported in clinical trials, may be due to non-specific drug interactions with the myocyte sarcolemma.     

Renin Secretion in Lyon Hypertensive Rats

In genetically hypertensive rats of Lyon strain (LH), both development and maintenance of hypertension are extremely sensitive to the chronic blockade of the renin-angiotensin system. However, LH rats exhibit a low renin secretory profile as indicated by (1) low basal plasma renin concentration; (2) blunted renin responses to reductions of renal perfusion pressure and β-adrenoceptor stimulation both in vitro (isolated perfused kidney) and in vivo (conscious rat). None of the latter abnormalities are corrected by chronic sodium deprivation or when hypertension is prevented by hydralazine or perindopril treatment. Future studies will therefore have to elucidate the ‘renin paradox’ in LH rats.     

Dopamine-1 Receptor G-Protein Coupling and the Involvement of Phospholipase A2 in Dopamine-1 Receptor Mediated Cellular Signaling Mechanisms in the Proximal Tubules of SHR

Dopamine-induced natriuretic response which results from the activation of tubular dopamine₁ (DA₁) receptors is diminished in spontaneously hypertensive rats (SHR). This may be a result of alterations occurring at the receptor level and within the cellular signaling pathway which ultimately causes inhibition of Na⁺,K⁺-ATPase. There have been reports showing that DA, receptor induced inhibition of Na⁺,K⁺-ATPase is abolished in SHR which is due to a decreased activation of PLC and PKC by dopamine. Of the mechanisms, adenylyl cyclase and phospholipase C are two known enzymes linked to DA₁ receptors via G proteins. Furthermore, the involvement of phospholipase A2 (PLA2) has also been reported in this process. However, the site of defect in DA₁ receptor signaling pathway in SHR is still not well understood. This report will (i) review the coupling of DA₁ receptor with G proteins and their levels in Wistar Kyoto (WKY) rats and SHR and (ii) discuss studies dealing with the role of PLA2 in dopamine-induced inhibition of Na⁺,K⁺-ATPase in WKY rat and SHR kidneys. Fenoldopam, DA₁ receptor selective agonist stimulated [³⁵S]GTP_γ S binding in a concentration (10^?9-10^?4 M)-dependent manner in WKY rats which was attenuated in SHR. Fenoldopam (10 μM)-induced stimulation of [³⁵S]GTP_γ S binding was significantly reduced by a DA₁ receptor selective antagonist, SCH 23390 suggesting the involvement of DA, receptor. Furthermore, the specific antipeptides Gsa, and Gq/l la significantly blocked fenoldopam-stimulation of [35S]GTPrS binding suggesting the coupling of DA, receptor with both the G proteins. Western analysis revealed a significant decrease in Gq/lla but no changes in Gsa in SHR compared to WKY rats. Dopamine inhibited Na′,K+-ATPase activity in a concentration (lo5 M)-dependent manner in WKY rats while it failed to inhibit the enzyme activity in SHR. Dopamine (10 &I)-induced inhibition in Na′,K'′ATPase activity was significantly blocked by mepacrine (a PLA2 inhibitor) suggesting the involvement of PLA2 in dopamine-mediated inhibition of Na′,K′-ATPase. Arachidonic acid (AA), a PLA2 product, inhibited Na′,K′-ATPase in a concentration (1-100 &I)-dependent manner in WKY rats while the inhibition in SHR was significantly attenuated (IC5,: 7.5, A4 in WKY and 80 &I in SHR). Furthermore, lower concentration (1 pM) of AA stimulated the enzyme activity in SHR. This suggests a defect in the metabolism of AA in SHR. Proadifen (10 pM), an inhibitor of cytochrome P-450 monoxygenase (an arachidonic acid metabolizing enzyme) significantly blocked the inhibition produced by arachidonic acid in WKY rats and abolished the difference in arachidonic acid inhibition of Na′,K+-ATPase between WKY rats and SHR. These data suggest that (i) the reduced activation of G proteins following DA, receptor stimulation, (ii) reduced amount of Gq/l l a and (iii) a defect in the AA metabolism may be responsible for the reduced dopaminergic inhibition of sodium pump activity and a diminished natriuretic response to dopamine in SHR.     

Pathogenesis of Hypertension in Diabetes

Reviews in Endocrine and Metabolic Disorders -