Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study we tested the hypothesis whether an angiotensin AT2 receptor-mediated stimulation of the bradykinin (BK)/nitric oxide (NO) system can account for the effects of AT1 receptor antagonism on aortic cGMP described previously in SHRSP. Adult SHRSP were treated for 4 hours with angiotensin II (ANG II) (30 ng/kg per min IV) or vehicle (0.9% NaCl I.V.). Animals were pretreated with vehicle, losartan (100 mg/kg P.O.), PD 123319 (30 mg/kg I.V.), losartan plus PD 123319, icatibant (500 microg/kg I.V.), N(G)-nitro-L-arginine methyl ester (L-NAME; 1 mg/kg I.V.), or minoxidil (3 mg/kg I.V.). Mean arterial blood pressure (MAP) was continuously monitored over the 4-hour experimental period, and plasma ANG II and aortic cGMP were measured by RIA at the end of the study. ANG II infusion over 4 hours raised MAP by about 20 mm Hg. Losartan alone or losartan plus ANG II as well as minoxidil plus ANG II markedly reduced blood pressure when compared to vehicle-treated or ANG II-treated animals, respectively. Plasma levels of ANG II were increased 2-fold by ANG II infusion alone or by ANG II in combination with icatibant, L-NAME, or minoxidil. The increase in plasma ANG II levels was even more pronounced after losartan treatment. Aortic cGMP content was significantly increased by ANG II, losartan, losartan plus ANG II, and minoxidil plus ANG II by 60%, 45%, 68%, and 52%, respectively (P<.05). The effects of ANG II and of losartan plus ANG II on aortic cGMP content were both blocked by cotreatment with the AT2 receptor antagonist PD 123319. Icatibant and L-NAME abolished the effects of ANG II on aortic cGMP. Our results demonstrate the following: (1) ANG II increases aortic cGMP by an AT2 receptor-mediated action because the effect could be prevented by an AT2 receptor antagonist; (2) the effect of ANG II was not secondary to blood pressure increase because it remained under reduction of MAP with minoxidil; (3) losartan increased aortic cGMP most likely by increasing plasma ANG II levels with a subsequent stimulation of AT2 receptors; and (4) the effects of AT2 receptor stimulation are mediated by BK and, subsequently, NO because they were abolished by B2 receptor blockade as well as by NO synthase inhibition.
Hypertension 1998 Jan
PMID:AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. 945 27

Angiotensin II participates in the neural regulation of the heart and circulation at both central and peripheral sites. To explore the role of endogenous angiotensin II in blood pressure regulation, we conducted a randomized double-blind crossover trial in nine young healthy men (aged 33+/-3 [mean+/-SE] years) studied in the absence of salt restriction, comparing the effect of 1 week treatment with the angiotensin II receptor antagonist losartan (100 mg daily) against placebo with respect to the following variables, recorded during supine rest: intra-arterial blood pressure (BP), heart rate (HR), forearm vascular resistance and norepinephrine appearance rate, total body norepinephrine spillover, variability of BP and HR (spectral analysis), and baroreflex sensitivity for HR (gain of the transfer function from systolic BP to HR). Blood pressure was 119+/-7/66+/-4 mm Hg (systolic BP/diastolic BP) after 1 week of placebo and 112+/-6/61+/-3 mm Hg after 1 week of losartan (P<.05). Forearm vascular resistance tended to fall, from 42.3+/-6.9 U on placebo to 32.8+/-5.0 U with losartan treatment (P=.07). Losartan had no effect on HR (60+/-3 on placebo versus 59+/-2 beats per minute with losartan), total body norepinephrine spillover (3.0+/-0.8 versus 3.3+/-1.2 nmol/min), forearm norepinephrine appearance rate (3.8+/-1.1 versus 5.3+/-1.1 pmol/100 mL forearm tissue per minute), power in the high- or low-frequency components of the HR variability and BP variability spectra or on baroreflex sensitivity for HR. Endogenous angiotensin II contributes to the maintenance of supine BP in normal subjects, studied in the absence of sodium restriction. The fall in BP caused by losartan is accompanied by a resetting of the baroreflex regulation of HR and sympathetic outflow, but baroreflex sensitivity for heart rate is not altered. Therefore, the reduction in BP observed after short-term angiotensin type 1 receptor antagonism may be achieved through a direct effect on vascular tone rather than through a primary reduction in sympathetic outflow.
Hypertension 1998 Jan
PMID:Neural and hypotensive effects of angiotensin II receptor blockade. 945 32

We evaluated the blood pressure-lowering activity, tolerability, and safety of losartan in 112 hypertensive (sitting diastolic blood pressure, 90 to 115 mm Hg) patients with chronic renal insufficiency including mild renal insufficiency (30 to 60 mL/min per 1.73 m2; n=51), moderate to severe renal insufficiency (10 to 29 mL/min per 1.73 m2; n=33), or hemodialysis (n=28). After a 3-week placebo period, once-daily losatan was administered for 12 weeks. The daily dose of 50 mg was increased to 100 mg after 4 weeks in patients whose sitting diastolic blood pressure remained > or = 90 mm Hg or was reduced by < 5 mm Hg. A second, non-angiotensin-converting enzyme inhibitor, antihypertensive drug was added after 8 weeks as needed. Twenty-four-hour creatinine clearance was determined and renal clearance studies of inulin and para-aminohippurate were done in a subset of 11 patients. Trough sitting blood pressures were reduced at the end of the first week in all groups. At weeks 4, 8, and 12, the reductions in systolic blood pressure/diastolic blood pressure averaged -11.9/-8.7, -10.8/-9.4, and -14.7/-12.1 mm Hg in patients with mild renal insufficiency; -7.7/-6.3, -13.1/-11.8, and -14.1/-10.6 mm Hg, in moderate to severe renal insufficiency; -17.0/-12.7, -19.1/-14.4, and -22.7/-18.0 mm Hg in hemodialysis. Creatinine clearance, glomerular filtration rate, and effective renal plasma flow were stable. Losartan was withdrawn in only 6 patients because ofa clinical or laboratory adverse experience. Hyperkalemia (> 6 mEq/L) requiring discontinuation of losartan occurred in only one (group 2) patient. We conclude that once-daily losartan, given as monotherapy at doses of 50 or 100 mg or in combination with other antihypertensive drugs, was effective in reducing blood pressure in hypertensive patients with chronic renal disease and that losartan regimens were well tolerated in all groups, including those on hemodialysis.
Hypertension 1998 Feb
PMID:Efficacy and tolerability of losartan in hypertensive patients with renal impairment. Collaborative Group. 946 Dec 41

We reported that the AT1 receptor antagonist losartan decreases arterial pressure in sodium-replete rats and that this response is attenuated in area postrema-lesioned (APx) rats (J. P. Collister, B. J. Hornfeldt, and J. W. Osborn. Hypertension 27: 598-606, 1996). In that study, food intake for the 3-wk period after sham lesion was restricted to that observed in APx rats. Food-restricted sham rats had lower arterial pressures and attenuated responses to losartan compared with control rats fed ad libitum. The present study examined whether these differences persisted months, rather than weeks after APx or sham lesions. Losartan was administered for 10 days to APx and two groups of sham rats 3 mo after APx or sham surgery. The first sham group was food restricted (SFR) for 3 wk after surgery, whereas the second sham group was allowed ad libitum (SAL) access to food. By day 8 of losartan administration, both sham groups demonstrated a marked hypotension (SFR: -38 +/- 4; SAL: -33 +/- 4 mmHg). This response was attenuated (P < 0.05) on the same day in APx rats (-17 +/- 3 mmHg). This trend continued throughout days 9 and 10. Because both sham groups responded similarly to losartan (yet significantly different from APx rats), these results demonstrate that transient decreases in food intake do not affect the response to losartan if rats are allowed an adequate recovery period. We conclude that the area postrema mediates part of the long-term hypotensive effects of AT1 receptor blockade in the conscious rat.
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PMID:Area postrema lesion attenuates the long-term hypotensive effects of losartan in salt-replete rats. 948 92

The Authors report, in this article, about pathophysiology mechanism that is to the base of the vascular injury mediate from the Angiotensin II able of modulate the primer, the acceleration and the progression of the atherosclerosis. Afterward is considered the importance of the administration of the inhibiting of the receptors AT-1 (Losartan) in the control of the hypertension and of the atherosclerosis.
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PMID:[Physiopathology of angiotensin II and vascular lesion]. 949 56

1. Desensitization of the myocardial beta-adrenergic signal transduction pathway is an important mechanism which is involved in the progression of hypertensive heart disease. The aim of the present study was to evaluate the differential effects of chronic pharmacotherapy with an angiotensin converting enzyme (ACE)-inhibitor, an AT1-receptor antagonist and a direct vasodilator on blood pressure, cardiac hypertrophy and the beta-adrenergic signal transduction. Therefore, transgenic TG(mREN2)27 (TG) rats overexpressing the mouse renin gene were used. This strain is characterized by the development of fulminant hypertension with cardiac hypertrophy. 2. Seven week old heterozygous TG(mREN2)27 rats were treated for 11 weeks with the AT1-receptor antagonist losartan (10 mg kg[-1]), the ACE-inhibitor quinapril (15 mg kg[-1]) and the direct vasodilator hydralazine (30 mg kg[-1]). Untreated TG and normotensive Sprague-Dawley rats (SD) served as controls. 3. TG(mREN2)27-rats were characterized by arterial hypertension (TG 194+/-3.2 mmHg vs SD 136+/-2.9 mmHg systolic blood pressure), increased left ventricular weights (TG 4.3+/-0.3 vs SD 3.0+/-0.1 mg g(-1) body weight), decreased myocardial neuropeptide Y (NPY) concentrations (TG 1143+/-108 vs SD 1953+/-134 pg g(-1) wet weight), reduced beta-adrenoceptor densities (TG 51.1+/-1.9 vs SD 63.4+/-3.7 fmol mg[-1]) as assessed by [125I]-cyanopindolol binding studies, and increased Gi(alpha)-activities (TG 4151+/-181 vs SD 3169+/-130 densitometric units) as assessed by pertussis toxin catalyzed [32P]-ADP-ribosylation. Downregulation of beta-adrenoceptors and increased Gi(alpha) were accompanied by significantly reduced isoprenaline-, Gpp(NH)p- and forskolin-stimulated adenylyl cyclase activity. Catalyst activity as determined by forskolin plus Mn2+ co-stimulation of adenylyl cyclase did not differ between TG(mREN2)27- and SD control-rats. 4. Losartan and quinapril significantly restored systolic blood pressures, left ventricular weights, beta-adrenoceptor densities, myocardial neuropeptide Y-concentrations, adenylyl cyclase activities and Gi(alpha)-activities towards the values in Sprague-Dawley-controls. No differences were observed between the effects of quinapril- and losartan-treatment. In contrast, hydralazine had only minor effects on blood pressure reduction, regression of left ventricular hypertrophy and neuroeffector defects in TG(mREN2)27. 5. In conclusion, direct vasodilatation is not able to overcome the pathophysiological alterations in TG caused by transgene overexpression. In contrast, ACE-inhibitors and AT1-receptor antagonists, which inhibit the renin angiotensin system, equally exert beneficial effects on blood pressure, myocardial hypertrophy and neuroeffector mechanisms. Modulation of the sympathetic tone and resensitization of the beta-adrenergic signal transduction system may contribute to the special effectiveness of these drugs in the treatment of the hypertensive cardiomyopathy.
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PMID:Effects of quinapril, losartan and hydralazine on cardiac hypertrophy and beta-adrenergic neuroeffector mechanisms in transgenic (mREN2)27 rats. 950 80

In the chronic phase of coarctation hypertension (CH) we have shown both reduction in baroreceptor sensitivity (Hypertension. 1992;19[suppl II]:II-198-II-201.) and normalization of the depressed baroreceptor reflex control of heart rate, even with the persistence of hypertension in losartan-treated animals (Am J Physiol. 1995;269:H812-H818). In the present study we analyzed the effects of angiotensin II blockade on afferent aortic nerve activity of CH and sham-operated groups treated chronically with vehicle or losartan (10 mg/kg per day p.o.). CH was induced by subdiaphragmatic aortic coarctation, and the treatments lasted 8 days (4 control and 4 experimental days). Aortic pressure (conscious rats) and aortic nerve activity simultaneous to pressure (anesthetized rats) were recorded on the fourth day of the experimental period. Losartan-treated rats showed reduced tail pressure (104+/-3 versus 117+/-3 mm Hg in the vehicle group). In both groups, aortic coarctation caused a significant increase in pressure (25% and 28%, respectively) and a depression of the aortic nerve activity/pressure relationship when compared with sham-operated coarcted animals. In the physiological range of pressure changes, the depression was significantly smaller after losartan treatment (3.30+/-0.33 versus 2.18+/-0.37%/mm Hg in the losartan- and vehicle-treated CH groups, respectively, versus 5.05+/-0.33%/mm Hg in the sham-operated vehicle-treated group). Angiotensin type 1 (AT1) receptor blockade was also accompanied by reduced variability of the afferent discharge. The data suggested that apart from its pressure effect, angiotensin II acts at AT1 receptors to decrease the sensitivity of aortic afferents during physiological (+/-10 mm Hg) increases and decreases in pressure. Thus, angiotensin II may contribute to reductions of baroreceptor gain in chronic hypertension.
Hypertension 1998 Apr
PMID:Chronic AT1 receptor blockade alters aortic nerve activity in hypertension. 953 23

Oleic acid and angiotensin II (Ang II) are elevated and may interact to accelerate vascular disease in obese hypertensive patients. We studied the effects of oleic acid and Ang II on growth responses of rat aortic smooth muscle cells (VSMCs). Oleic acid (50 micromol/L) raised thymidine incorporation by 50% at 24 hours and cell number by 55% at 6 days (P<.05). Ang II (10(-11) to 10(-6) mol/L) did not significantly increase thymidine incorporation or VSMC number. Combining Ang II and 50 micromol/L oleic acid doubled thymidine incorporation and VSMC number. Losartan, an angiotensin type 1 (AT1) receptor antagonist, blocked the synergistic interaction between Ang II and oleic acid, whereas the AT2 receptor antagonist PD 123319 did not. Protein kinase C inhibition and downregulation, as well as inhibition of extracellular signal-regulated kinase (ERK) activation by PD 98059, eliminated the rise of thymidine incorporation in response to oleic acid and the synergistic interaction with Ang II. However, the response to 10% fetal bovine serum was unaffected. An antisense oligodeoxynucleotide to ERK-1 and ERK-2 reduced ERK protein expression and activation by 83% and 75%, respectively. Antisense prevented the rise of thymidine incorporation in response to oleic acid and the synergy with Ang II. Antisense reduced but did not prevent increased thymidine incorporation in response to serum. The data indicate that oleic acid and Ang II exert a synergistic mitogenic effect in VSMCs and suggest an important role for the AT1 receptor, PKC, and ERK in this synergy. The observations raise the possibility that a synergistic mitogenic interaction between oleic acid and Ang II accelerates vascular remodeling in obese hypertensive patients.
Hypertension 1998 Apr
PMID:Oleic acid and angiotensin II induce a synergistic mitogenic response in vascular smooth muscle cells. 953 24

The stimulation of autocrine and paracrine factors such as basic fibroblast- (bFGF) and platelet-derived (PDGF) growth factors mediates many of the growth-promoting actions of angiotensin II. The aim of this study was to evaluate the effect of chronic AT1-receptor blockade on plasma endothelin-1 (ET-1) and growth factors levels, and on left ventricular mass, in essential hypertension (EH). The study population consisted of 16 patients with mild-moderate EH, and 25 normotensive controls. In the EH patients under basal conditions, and after 3 and 6 months of chronic therapy with Losartan 50 mg/day, we measured serum levels of ET-1, bFGF and PDGF, and tumor necrosis factor (TNF). At the same time, all patients underwent 24-h ambulatory blood pressure monitoring and an echocardiographic evaluation to measure the thickness of the posterior wall (PWT) of the left ventricle and of the interventricular septum (IVS). The healthy controls underwent the same analyses, under basal conditions, at baseline and after 3 and 6 months of observation. In the EH patients, after 3 months of AT1-receptor blockade bFGF was reduced from 13.6 +/- 0.7 to 10.9 +/- 0.7 pg/mL (P < .004), and both TNF and PDGF were significantly decreased (P < .006 and P < .007, respectively). After 6 months of therapy, ET-1 was significantly diminished in comparison with baseline (6.9 +/- 0.8 v 5.5 +/- 0.1 fmol/mL; P < .05), and the reduction in the levels of growth factors were even more significant than at 3 months of treatment. Both PWT and IVS were significantly changed after 6 months of therapy with losartan after basal evaluation (P < .05, respectively). Systolic and diastolic 24-h blood pressures declined significantly after 3 and 6 months of therapy with losartan (P < .01, respectively). It seems likely that the inhibition of the action of angiotensin II by the specific AT1-receptor blockade, by reducing circulating levels of ET-1 and those of some growth factors, may offer an advantage regarding the effect on hypertensive cardiovascular changes in human hypertension.
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PMID:Changes of plasma endothelin and growth factor levels, and of left ventricular mass, after chronic AT1-receptor blockade in human hypertension. 963 90

Hypertension is a known risk factor for the development of atherosclerosis. However, in most of the studies, no effect of blood pressure reduction was demonstrated on the incidence of coronary artery disease, except in the SHEP study in which it was shown that in older persons, with isolated systolic hypertension, antihypertensive stepped-care drug treatment reduced the incidence of total stroke and major cardiovascular event. In hypertensive patients with elevated plasma renin activity, a 5-fold increased incidence of myocardial infarction was demonstrated. As oxidation of low density lipoprotein (LDL) was suggested to be a major risk factor for atherosclerosis, we studied the relationship between hypertension and LDL oxidation. We demonstrated increased propensity of LDL obtained from hypertensive patients to oxidative modification, in comparison with LDL obtained from normotensive subjects and suggested that angiotensin II (Ang-II) may be involved in this effect. Ang-II was shown to enhance macrophage lipid peroxidation both in vivo and in vitro. This effect was dose-dependent and involved the binding of Ang-II to its receptor on the macrophage surface. In addition, these lipid peroxidized Ang-II-treated macrophages could substantially oxidize LDL. Ang-II was shown to possess additional atherogenic properties such as increasing the activity of the macrophage oxidized LDL receptors. It also binds to LDL, thus leading to the formation of a modified lipoprotein, which is taken up by macrophages at enhanced rate through the scavenger receptor. Inhibition of Ang-II formation by angiotensin converting enzyme inhibitors reduced LDL peroxidation in hypertensive patients as well as in the atherosclerotic apo E deficient mice. The reduction in LDL peroxidation in these mice was accompanied by a 70-90% reduction in the atherosclerotic lesion area. A similar effect in these mice was demonstrated with the Ang-II receptor antagonist, Losartan. Thus, we suggest that Ang-II is involved in the development of atherogenesis in hypertensive patients and inhibition of Ang-II formation or prevention of its interaction with its receptor may attenuate the atherosclerotic process.
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PMID:Angiotensin, LDL peroxidation and atherosclerosis. 966 59


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