Lisinopril reduces left ventricular hypertrophy and cardiac polyamine concentrations without a reduction in left ventricular wall stress in transgenic Tsukuba hypertensive mice.
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This experiment was designed to determine how the angiotensin-converting enzyme inhibitor, lisinopril, acts on left ventricular wall stress and cardiac polyamine concentrations in Tsukuba hypertensive mice (THMs) carrying both human renin and angiotensinogen genes. Twelve-week-old THMs were treated with either lisinopril or hydralazine, or were left untreated, for 8 weeks. C57BL/6 mice of similar age were used as normal controls. Each group consisted of 14 mice. The systolic blood pressure of each mouse was measured once a week. Mice were euthanized at 20 weeks of age, and the left ventricular weight, left ventricular diameter, left ventricular wall stress, and left ventricular polyamine concentrations were measured. The systolic blood pressure of the untreated group was approximately 35 mmHg higher than that of the C57BL/6 mice. The left ventricular weight, left ventricular diameter, left ventricular wall stress, and left ventricular polyamine concentrations in the untreated group were significantly higher compared to those in the C57BL/6 mice. The lisinopril group had significantly decreased systolic blood pressure and other measurement items, except the left ventricular wall stress, in comparison with the untreated group. The hydralazine group also had significantly decreased systolic blood pressure and left ventricular wall stress when compared with the untreated group, but no significant differences in other measurement items when compared with the untreated group. These findings indicate that lisinopril reduces left ventricular hypertrophy and polyamine concentration without reducing left ventricular wall stress, and that simply decreasing blood pressure does not suppress left ventricular hypertrophy. (+info)
Copper-64-diacetyl-bis(N4-methylthiosemicarbazone): An agent for radiotherapy.
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Systemic administration of hypoxia-selective (64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) has increased significantly the survival time of hamsters bearing human GW39 colon cancer tumors. Radiotherapy experiments were performed in animals bearing either 7-day-old (0.5-1.0 g) or 15-day-old (1.5-2.0 g) tumors. Studies compared animals treated with a single dose of 0, 4, 6, 7, 8, or 10 mCi of (64)Cu-ATSM (1 Ci = 37 GBq) with or without the vasodilator hydralazine. A multiple dose regimen of 3 x 4 mCi at 72-h intervals was studied also. Single doses of >6 mCi of (64)Cu-ATSM and the dose-fractionation protocol significantly increased the survival time of the hamsters compared with controls. The highest dose, 10 mCi of (64)Cu-ATSM, increased survival to 135 days in 50% of animals bearing 7-day-old tumors, 6-fold longer than control animals' survival (20 days), with only transient leucopenia and thrombocytopenia but no overt toxicity. Human absorbed doses were calculated from hamster biodistribution; the dose-critical organs were the lower large intestine (1.43 +/- 0.19 rad/mCi) and upper large intestine (1.20 +/- 0.38 rad/mCi). High-resolution MRI and positron-emission tomography using a therapeutic administration of 10 mCi were used to monitor tumor volume and morphology and to assess tumor dosimetry accurately, giving a tumor dose of 81 +/- 7.5 rad/mCi. (64)Cu-ATSM has increased the survival time of tumor-bearing animals significantly with no acute toxicity and thus is a promising agent for radiotherapy. (+info)
Left ventricle and arteries: structure, function, hormones, and disease.
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The observation in the 1970s that the performance of the dysfunctional left ventricle was under the influence of aortic impedance led us to exploration of the role of the renin-angiotensin system and other hormonal systems in the progression of heart failure. The apparent efficacy of vasodilator drugs led to the first randomized, controlled trial in heart failure that demonstrated that all impedance-lowering drugs did not exert the same long-term benefit. Differences on the structural remodeling process in the myocardium and arterial vasculature were shown to account for the differential long-term response. We now recognize that the remodeling process in the left ventricle may be inhibited by nitrates, converting enzyme inhibitors, and beta-blockers, and this growth process leads to adverse outcomes. The impedance load on the left ventricle is influenced by vascular remodeling that also may be inhibited by drugs such as converting enzyme inhibitors. Thus, progression of cardiovascular disease is largely a consequence of structural changes that are hormonally mediated and may be inhibited by drug therapy. (+info)
Paradoxical regulation of short promoter human renin transgene by angiotensin ii.
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We previously reported the generation of transgenic mice containing the entire human renin gene with a 900-bp promoter. To determine whether all the required elements for angiotensin II-mediated suppression of human renin are present in these mice, angiotensin II was chronically infused by means of osmotic minipump at both low and high doses, 200 and 1000 ng/kg per minute, respectively. Blood pressure was measured by tail-cuff, and kidney renin mRNA levels were quantitated using ribonuclease protection assays. Blood pressure was unchanged in mice receiving either vehicle or low-dose angiotensin II infusion but was increased by approximately 40 mm Hg with the higher dose of angiotensin II. Mouse renin mRNA decreased by >60% during both pressor and nonpressor angiotensin II infusion. Human renin mRNA was not suppressed by nonpressor angiotensin II and was paradoxically increased 1.9-fold by pressor angiotensin II. The lack of upregulation during nonpressor angiotensin II suggested that the increase might be pressure-mediated. To test this, the angiotensin II-induced increase in blood pressure was prevented by coadministration of the vasodilator, hydralazine (15 mg/kg per day). Hydralazine alone decreased blood pressure (-27+/-3 mm Hg) and increased mouse renin mRNA 2.4-fold. Human renin mRNA was unresponsive to this vasodilator-induced fall in pressure and despite the normalization of blood pressure by hydralazine, high-dose angiotensin II still caused a 2.1-fold increase in human renin mRNA. Thus, the first 900 bp of the human renin promoter does not contain all the elements required for appropriate angiotensin II-mediated suppression of human renin mRNA. (+info)
AT1 receptor antagonist combats oxidative stress and restores nitric oxide signaling in the SHR.
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The tubuloglomerular feedback (TGF) responses of the spontaneously hypertensive rat (SHR) are under exaggerated regulation by angiotensin II (Ang II) type 1 receptors (AT1-R). Since AT1-Rs enhance oxygen radical (O2-) generation, we tested the hypothesis that the exaggerated TGF was due to a diminished blunting by macula densa (MD)-derived nitric oxide (NO) because of excessive AT1-R-dependent generation of O2-. Groups of SHR and control Wistar-Kyoto (WKY) rats received vehicle (Veh), the AT1-R antagonist candesartan (Cand; 3 mg. kg-1. day-1), or nonspecific therapy with hydralazine + hydrochlorothiazide + reserpine (HHR) for two weeks. Compared with WKY rats, the elevated mean arterial pressure of SHR (WKY 125 +/- 2 vs. SHR 163 to 779 mm Hg, P < 0.001) was reduced (P < 0.001) similarly in SHR by Cand and HHR (121 +/- 5 and 116 +/- 5 mm Hg, P = NS). The SHR had an increased maximal TGF response (change in stop flow pressure during luminal perfusion of fluid: SHR 11.2 +/- 0.5 vs. WKY 8.3 +/- 0.4 mm Hg, P < 0.01) and a reduced TGF response to blockade of neuroneal NO synthase (nNOS) in the MD with luminal 7-nitroindazole (7-NI: DeltaTGF in WKY 2.8 +/- 0.4 vs. SHR 1.1 +/- 0.6 mm Hg, P < 0.05). Although the elevated TGF responses of SHR were normalized by both HHR and Cand, only Cand restored a normal TGF response to luminal perfusion of the MD with 7-NI (DeltaTGF with 7-NI in SHR: Veh + 1.8 +/- 0.4 vs. Cand + 3.4 +/- 0.5 mm Hg, P < 0.05). To abrogate the local effects of O2-, tempol (a membrane-permeable superoxide dismutase mimetic) was perfused into the efferent arteriole. During tempol, SHR given vehicle or HHR had a much increased response to blockade of nNOS with 7-NI (DeltaTGF in SHR with 7-NI during tempol: Veh 6.3 +/- 1.0 and HHR 4.5 +/- 0.8 mm Hg, P < 0.01 vs. no tempol for both), implying that the effects of NO had been prevented because of excessive O2-. In contrast, the TGF response to 7-NI in SHR given Cand was unaffected by tempol (DeltaTGF with 7-NI during tempol: 2.9 +/- 0.9, P = NS, compared with no tempol). In conclusion, TGF responses of SHR are exaggerated because of the effects of hypertension and AT1-R. AT1-R blockade specifically diminishes oxidative stress and restores NO signaling in the juxtaglomerular apparatus of the SHR. (+info)
Temporary treatment of prepubescent rats with angiotensin inhibitors suppresses the development of hypertensive nephrosclerosis.
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Hypertensive nephrosclerosis is a leading cause of end-stage renal disease; therefore, strategies to prevent the development of renal disease require close study. Here it is demonstrated that transient treatment of prepubescent rats with angiotensin inhibitors attenuated their susceptibility to the development of hypertensive nephrosclerosis after maturation. Stroke-prone spontaneously hypertensive Izumo strain rats were divided into four groups, treated with vehicle, the angiotensin-converting enzyme inhibitor (ACEI) delapril (40 mg/kg per d), the angiotensin receptor antagonist (AT1R-Ant) candesartan cilexetil (1 mg/kg per d), or the vasodilator hydralazine (25 mg/kg per d) from weaning to puberty (3 to 10 wk of age), and then monitored without treatment for 6 mo. BP in the ACEI- and AT1R-Ant-treated groups remained significantly decreased, compared with the untreated and hydralazine-treated groups. Moreover, marked proteinuria and nephrosclerosis developed in the untreated and hydralazine-treated groups at 30 wk but were suppressed in the ACEI- and AT1R-Ant-treated groups. Of interest, plasma renin activity, plasma angiotensin II concentrations, and renal renin mRNA levels were reduced by >50% in the ACEI- and AT1R-Ant-treated rats, suggesting that the treatments may have attenuated the development of nephrosclerosis by overcoming the susceptibility of stroke-prone spontaneously hypertensive rats to overactivation of the renin-angiotensin system. (+info)
Abnormal platelet function and calcium handling in Dahl salt-hypertensive rats.
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The effect of dietary salt on platelet function and Ca(2+) homeostasis was studied in Dahl (DS) rats, a genetic model of salt-sensitive hypertension. DS rats were fed a high-salt (DSHS) or a low-salt diet (DSLS) for up to 4 weeks, and the effects of salt loading on systolic blood pressure, platelet P-selectin expression, and platelet Ca(2+) homeostasis were measured. The high-salt diet increased blood pressure and markedly increased the amount of ionomycin (IM)-releasable Ca(2+) in platelet intracellular stores (Ca(2+)/IM). The alteration in Ca(2+) stores was not prevented when the hypertension was prevented by treatment with hydralazine and reserpine. The Ca(2+) store filling during platelet exposure to 1 mmol/L Ca(2+) for 5 minutes and the rate of sarcoplasmic/endoplasmic Ca(2+) ATPase-dependent Ca(45) uptake were higher in DSHS compared with that in DSLS. There was a decrease in thrombin-induced Ca(2+) influx in platelets from DSHS; consistent with this, agonist-induced P-selectin expression was decreased. In DSLS, nitric oxide accelerated reloading of platelet Ca(2+) stores after their emptying by thrombin but failed to do so in DSHS. These results indicate that in DS rats, a high-salt diet increases sarcoplasmic/endoplasmic Ca(2+) ATPase activity and the Ca(2+)/IM but decreases the reuptake of Ca(2+) caused by nitric oxide. Decreases in Ca(2+) influx and platelet P-selectin expression might be explained by changes in intracellular Ca(2+) stores in DSHS rats, which apparently is a heritable response to a high-salt diet. (+info)
Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice.
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Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1-/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1-/- mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1+/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1+/+ and Npr1-/- mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control. (+info)