Synergistic effects of combined converting enzyme inhibition and angiotensin II antagonism on blood pressure in conscious telemetered spontaneously hypertensive rats

Webb, Randy L.; Navarrete, Aida E.; Davis, Scott L.; Gasparo, Marc de

doi:10.1097/00004872-199816060-00016

Cited by 48 publications

(48 citation statements)

References 30 publications

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“…valsartan has no important effect on blood pressure is also supported by previous reports from other laboratories, 13,14 including telemetric measurements performed by Webb et al 14 These authors reported only minute effects of a somewhat higher dose of valsartan, 0.5 mg · kg…”

Section: Discussionsupporting

confidence: 76%

“…14 In the absence of telemetric measurements, we cannot exclude such minute effects in our study, but we consider it highly unlikely that the massive effects of valsartan on survival can be explained solely by lowering of the mean arterial blood pressure by some 5 mm Hg. Interestingly, blockade of the renin-angiotensin system was reported to improve survival in scleroderma renal crisis, 15 another form of thrombotic microangiopathy in the kidney.…”

Section: Discussionmentioning

confidence: 93%

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Angiotensin II Type 1 Receptor Blockade Prevents Lethal Malignant Hypertension

Hilgers¹,

Hartner²,

Porst³

et al. 2001

Circulation

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Background-Angiotensin II is elevated in malignant hypertension. We tested the hypothesis that angiotensin II type 1 receptor blockade can prevent the development of malignant hypertension even in the absence of a blood pressure-lowering effect. Methods and Results-Two-kidney, 1-clip rats were followed up for 28 days; blood pressure was measured by tail-cuff plethysmography and intra-arterially. After a 2-week run-in phase, rats received valsartan at a dose of 0.3 (nϭ14) or 3 (nϭ12) mg · kg Ϫ1 · d Ϫ1 or solvent (nϭ27). Only the higher dose of valsartan, but not the lower dose, decreased blood pressure. Both doses of valsartan prevented the development of lethal malignant hypertension. Twenty of 27 solvent-treated renovascular hypertensive rats died, but only 3 of 14 rats treated with the low dose and 1 of 12 rats treated with the high dose of valsartan died. Histological signs of malignant nephrosclerosis were found in all rats examined that had died throughout the study and in 6 of 7 surviving solvent-treated renovascular hypertensive animals. Increased expression of monocyte chemoattractant protein-1 and prominent interstitial influx of macrophages occurred in the nonclipped kidneys exposed to high pressure in solvent-treated rats. These alterations were prevented by valsartan at both doses, irrespective of blood pressure effects. Conclusions-Angiotensin II type 1 receptor blockade by valsartan prevents lethal malignant hypertension independently of blood pressure. The results suggest that reduction of angiotensin-induced inflammation in the kidney may contribute to the protective effects of valsartan.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 93%

Angiotensin II Type 1 Receptor Blockade Prevents Lethal Malignant Hypertension

Hilgers¹,

Hartner²,

Porst³

et al. 2001

Circulation

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“…However, the effects of combination therapy on cardiac gene expression have not been examined in previous reports. 6,7,22 Therefore, here, we investigated cardiac gene expressions and found that the combination of low doses of an ACE inhibitor and an AT 1 receptor antagonist (0.2 mg/kg each) decreased cardiac mRNA levels for ANF, collagen type I, and skeletal ␣-actin more potently than amlodipine alone. Furthermore, the combination of 0.05 mg/kg perindopril and candesartan cilexetil, whose hypotensive effects were similar to those of low doses of amlodipine combined with perindopril or candesartan cilexetil and were lesser than those of high doses (3 mg/kg) of amlodipine alone (Table 2), decreased left ventricular weight and ANF mRNA levels more potently than combination therapy or monotherapy with amlodipine.…”

Section: Discussionmentioning

confidence: 91%

Cardiovascular Effects of Combination of Perindopril, Candesartan, and Amlodipine in Hypertensive Rats

et al. 2000

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Abstract-The combination therapy with ACE inhibitors, angiotensin II type 1 (AT 1 ) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal ␣-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-␤ receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-␤ receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT 1 receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT 1 receptor antagonist or monotherapy with each agent. Key Words: angiotensin Ⅲ calcium Ⅲ hypertrophy Ⅲ platelet-derived growth factor Ⅲ rats, stroke-prone SHR Ⅲ antihypertensive therapy C linically, combination therapy with different types of antihypertensive drugs is very frequently used in hypertensive patients in an effort to achieve more beneficial effects than monotherapy and to diminish the incidence of unwanted side effects. Accumulating evidence indicates that ACE inhibitors and angiotensin (Ang) II type 1 (AT 1 ) receptor antagonists are effective in the treatment of cardiovascular diseases or congestive heart failure. [1][2][3][4][5] Recently, in spontaneously hypertensive rats 6 and the (mRen-2)27 transgenic rats, 7 the combination of low doses of an ACE inhibitor and an AT 1 receptor antagonist has been shown to induce greater reductions in blood pressure and cardiac weight than monotherapy with the same or higher doses. Furthermore, the combined administration of an ACE inhibitor and an AT 1 receptor antagonist decreases blood pressure in normotensive volunteers 8,9 and improves cardiac dysfunction in patients with heart failure 3,10 more than either intervention ...

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“…Changes in blood pressure from baseline were analyzed by comparison of the areas over the curve, as calculated by the trapezoidal method (millimeters of mercuryϫdays). 17,18 Data obtained with the Langendorff preparation were recorded and digitalized using WinDaq waveform recording software (Dataq Instruments). After manual selection of the desired signals preinjection and postinjection, data were analyzed using Matlab (Mathworks Inc).…”

Section: Discussionmentioning

confidence: 99%

Handle Region Peptide Counteracts the Beneficial Effects of the Renin Inhibitor Aliskiren in Spontaneously Hypertensive Rats

et al. 2011

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Abstract-To investigate whether the putative (pro)renin receptor blocker, the handle region peptide (HRP), exerts effects on top of the blood pressure-lowering and cardioprotective effects of the renin inhibitor aliskiren, spontaneously hypertensive rats were implanted with telemetry transmitters to monitor heart rate and mean arterial pressure (MAP). After a 2-week recovery period, vehicle, aliskiren, HRP (100 and 1 mg/kg per day, respectively), and HRPϩaliskiren were infused for 3 weeks using osmotic minipumps. Subsequently, the heart was removed to study coronary function according to Langendorff. Baseline MAP and heart rate in vehicle-treated rats were 146Ϯ3 mm Hg and 326Ϯ4 bpm. HRP did not affect MAP, whereas aliskiren and HRPϩaliskiren lowered MAP (by maximally 29Ϯ2 and 20Ϯ1 mm Hg, respectively) without affecting heart rate. Aliskiren significantly reduced MAP throughout the 3-week infusion period, whereas the blood pressure-lowering effect of HRPϩaliskiren returned to baseline within 2 weeks of treatment. In comparison with vehicle, aliskiren increased the endothelium-dependent response to bradykinin and decreased the response to angiotensin II in the coronary circulation, whereas these responses were not altered after treatment with HRP or HRPϩaliskiren. HRP did not alter plasma renin activity, plasma angiotensin levels, or the renal angiotensin content, either alone or on top of aliskiren, nor did it alter the aliskiren-induced decrease in renal Ang II type 1 receptor expression. Yet, it did reverse the aliskiren-induced reduction in cardiomyocyte area, without affecting this area when given alone. In conclusion, HRP counteracts the beneficial effects of aliskiren on blood pressure, coronary function, and cardiac hypertrophy in an angiotensin-independent manner. (Hypertension. 2011;57:852-858.)Key Words: handle region peptide Ⅲ (pro)renin Ⅲ aliskiren Ⅲ spontaneously hypertensive rat Ⅲ angiotensin T he renin inhibitor aliskiren exerts beneficial effects in the heart of spontaneously hypertensive rats (SHRs) 1 and in the mouse heart postmyocardial infarction. 2 Among others, it improved coronary endothelial function, diminished the responsiveness to angiotensin (Ang) II (most likely because of a downregulation of Ang II type 1 [AT 1 ] receptor density), reduced cardiomyocyte area, and prevented remodeling. These observations parallel findings in humans, where aliskiren reduced left ventricular mass reduction at least as effectively as other blockers of the renin-Ang system (RAS). 3 However, although the suppression of cardiac Ang II by aliskiren was superior to that induced by Ang-converting enzyme inhibition, Ang II levels did not decrease to 0.

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Synergistic effects of combined converting enzyme inhibition and angiotensin II antagonism on blood pressure in conscious telemetered spontaneously hypertensive rats

Cited by 48 publications

References 30 publications

Angiotensin II Type 1 Receptor Blockade Prevents Lethal Malignant Hypertension

Angiotensin II Type 1 Receptor Blockade Prevents Lethal Malignant Hypertension

Cardiovascular Effects of Combination of Perindopril, Candesartan, and Amlodipine in Hypertensive Rats

Handle Region Peptide Counteracts the Beneficial Effects of the Renin Inhibitor Aliskiren in Spontaneously Hypertensive Rats

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