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1.
Am J Physiol Renal Physiol ; 306(10): F1179-89, 2014 May 15.
Article in English | MEDLINE | ID: mdl-24694588

ABSTRACT

Dual renin-angiotensin system (RAS) blockade in diabetic nephropathy is no longer feasible because of the profit/side effect imbalance. (Pro)renin receptor [(P)RR] blockade with handle region peptide (HRP) has been reported to exert beneficial effects in various diabetic models in a RAS-independent manner. To what degree (P)RR blockade adds benefits on top of RAS blockade is still unknown. In the present study, we treated diabetic TGR(mREN2)27 rats, a well-established nephropathy model with high prorenin levels [allowing continuous (P)RR stimulation in vivo], with HRP on top of renin inhibition with aliskiren. Aliskiren alone lowered blood pressure and exerted renoprotective effects, as evidenced by reduced glomerulosclerosis, diuresis, proteinuria, albuminuria, and urinary aldosterone levels as well as diminished renal (P)RR and ANG II type 1 receptor expression. It also suppressed plasma and tissue RAS activity and suppressed cardiac atrial natriuretic peptide and brain natriuretic peptide expression. HRP, when given on top of aliskiren, did not alter the effects of renin inhibition on blood pressure, RAS activity, or aldosterone. However, it counteracted the beneficial effects of aliskiren in the kidney, induced hyperkalemia, and increased plasma plasminogen activator-inhibitor 1, renal cyclooxygenase-2, and cardiac collagen content. All these effects have been linked to (P)RR stimulation, suggesting that HRP might, in fact, act as a partial agonist. Therefore, the use of HRP on top of RAS blockade in diabetic nephropathy is not advisable.


Subject(s)
Amides/pharmacology , Diabetes Mellitus, Experimental/physiopathology , Fumarates/pharmacology , Kidney/drug effects , Kidney/physiopathology , Oligopeptides/pharmacology , Receptors, Cell Surface/antagonists & inhibitors , Renin/genetics , Aldosterone/metabolism , Animals , Blood Pressure/drug effects , Blood Pressure/physiology , Cyclooxygenase 2/metabolism , Diabetes Mellitus, Experimental/chemically induced , Disease Models, Animal , Female , Male , Plasminogen Activator Inhibitor 1/metabolism , Potassium/metabolism , Rats , Rats, Sprague-Dawley , Rats, Transgenic , Receptors, Cell Surface/drug effects , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Streptozocin/adverse effects , Prorenin Receptor
2.
PLoS One ; 6(8): e23411, 2011.
Article in English | MEDLINE | ID: mdl-21858106

ABSTRACT

Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT(1)) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4(+/R)) and 4-fold (homozygous Fibulin-4(R/R)) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-ß signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-ß. Tissue levels of Ang II, a regulator of TGF-ß signaling, were increased. Prenatal treatment with the AT(1) receptor antagonist losartan, which blunts TGF-ß signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4(R/R) mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT(1) receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease.


Subject(s)
Aorta, Thoracic/physiopathology , Aortic Aneurysm/physiopathology , Extracellular Matrix Proteins/deficiency , Vasoconstriction/physiology , Angiotensin II/genetics , Angiotensin II/metabolism , Angiotensin II/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Animals, Newborn , Aorta, Thoracic/metabolism , Aorta, Thoracic/pathology , Aortic Aneurysm/genetics , Aortic Aneurysm/prevention & control , Extracellular Matrix Proteins/genetics , Female , Humans , Immunohistochemistry , In Vitro Techniques , Losartan/pharmacology , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Oligonucleotide Array Sequence Analysis , Phenylephrine/pharmacology , Pregnancy , Receptor, Angiotensin, Type 1/physiology , Smad2 Protein/genetics , Smad2 Protein/metabolism , Transcriptome , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Vasoconstriction/drug effects , Vasoconstriction/genetics , Vasoconstrictor Agents/pharmacology
3.
Hypertension ; 57(4): 852-8, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21321303

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 HRP+aliskiren 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 146±3 mm Hg and 326±4 bpm. HRP did not affect MAP, whereas aliskiren and HRP+aliskiren lowered MAP (by maximally 29±2 and 20±1 mm Hg, respectively) without affecting heart rate. Aliskiren significantly reduced MAP throughout the 3-week infusion period, whereas the blood pressure-lowering effect of HRP+aliskiren 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 HRP+aliskiren. 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.


Subject(s)
Amides/pharmacology , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Fumarates/pharmacology , Hypertension/drug therapy , Oligopeptides/pharmacology , Renin/antagonists & inhibitors , Amides/therapeutic use , Analysis of Variance , Animals , Antihypertensive Agents/therapeutic use , Bradykinin/pharmacology , Drug Interactions , Endothelium, Vascular/drug effects , Fumarates/therapeutic use , Heart Rate/drug effects , Infusion Pumps, Implantable , Male , Rats , Rats, Inbred SHR , Reverse Transcriptase Polymerase Chain Reaction , Telemetry
4.
J Hypertens ; 28(10): 2145-55, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20625318

ABSTRACT

BACKGROUND: The blood pressure-lowering effect of the renin inhibitor aliskiren equals that of angiotensin-converting enzyme (ACE) inhibitors and angiotensin (Ang) II type 1 (AT1) receptor blockers. Whether aliskiren offers end-organ protection remains to be investigated. Here, we compared the cardiac effects of aliskiren, the AT1 receptor blocker irbesartan and the ACE inhibitor captopril in spontaneously hypertensive rats (SHR) at equi-hypotensive doses. METHODS AND RESULTS: SHR were treated for 1-3 weeks with vehicle, aliskiren, captopril or irbesartan (100, 3 and 15 mg/kg per day, respectively) using an osmotic minipump, and compared to vehicle-treated Wistar-Kyoto (WKY) controls. All drugs lowered (but not normalized) mean arterial pressure in SHR equi-effectively, as monitored by radiotelemetry, without altering heart rate. All drugs also reduced the increased cardiomyocyte area in SHR, and tended to normalize the elevated brain natriuretic peptide plasma levels. In the Langendorff set-up, all drugs normalized the diminished endothelium-dependent vasodilator response to bradykinin in SHR. Moreover, aliskiren and irbesartan, but not captopril, decreased the enhanced coronary Ang II response in SHR. Aliskiren reduced plasma renin activity and the plasma and tissue angiotensin levels at 1 week of treatment; yet, after 3 weeks of aliskiren treatment only the cardiac angiotensin levels remained suppressed, whereas no tissue angiotensin reductions were seen with captopril or irbesartan. CONCLUSION: For a given decrease in blood pressure, aliskiren improves coronary endothelial function and decreases cardiac hypertrophy in SHR to at least the same degree as ACE inhibition and AT1 receptor blockade. In addition, aliskiren diminishes the enhanced Ang II response in the coronary circulation of SHR and offers superior long-term cardiac angiotensin suppression.


Subject(s)
Amides/pharmacology , Blood Pressure/drug effects , Fumarates/pharmacology , Heart/drug effects , Hypertension/physiopathology , Renin/antagonists & inhibitors , Amides/therapeutic use , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensins/blood , Animals , Biphenyl Compounds/pharmacology , Blood Pressure/physiology , Captopril/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Fumarates/therapeutic use , Heart/physiopathology , Heart Ventricles/pathology , Hypertension/blood , Hypertension/drug therapy , Hypertrophy/drug therapy , Irbesartan , Male , Natriuretic Peptide, Brain/blood , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Renin/blood , Tetrazoles/pharmacology
5.
Eur J Pharmacol ; 640(1-3): 185-9, 2010 Aug 25.
Article in English | MEDLINE | ID: mdl-20462506

ABSTRACT

To verify the recently proposed concept that mast cell-derived renin facilitates angiotensin II-induced bronchoconstriction bronchial rings from male Sprague-Dawley rats were mounted in Mulvany myographs, and exposed to the mast cell degranulator compound 48/80 (300 microg/ml), angiotensin I, angiotensin II, bradykinin or serotonin (5-hydroxytryptamine, 5-HT), in the absence or presence of the renin inhibitor aliskiren (10 micromol/l), the ACE inhibitor captopril (10 micromol/l), the angiotensin II type 1 (AT1) receptor blocker irbesartan (1 micromol/l), the mast cell stabilizer cromolyn (0.3 mmol/l), the 5-HT2A/2C receptor antagonist ketanserin (0.1 micromol/l) or the alpha1-adrenoceptor antagonist phentolamine (1 micromol/l). Bath fluid was collected to verify angiotensin generation. Bronchial tissue was homogenized to determine renin, angiotensinogen and serotonin content. Compound 48/80 contracted bronchi to 24+/-4% of the KCl-induced contraction. Ketanserin fully abolished this effect, while cromolyn reduced the contraction to 16+/-5%. Aliskiren, captopril, irbesartan and phentolamine did not affect this response, and the angiotensin I and II levels in the bath fluid after 48/80 exposure were below the detection limit. Angiotensin I and II equipotently contracted bronchi. Captopril shifted the angiotensin I curve approximately 10-fold to the right, whereas irbesartan fully blocked the effect of angiotensin II. Bradykinin-induced constriction was shifted approximately 100-fold to the left with captopril. Serotonin contracted bronchi, and ketanserin fully blocked this effect. Finally, bronchial tissue contained serotonin at micromolar levels, whereas renin and angiotensinogen were undetectable in this preparation. In conclusion, mast cell degranulation results in serotonin-induced bronchoconstriction, and is unlikely to involve renin-induced angiotensin generation.


Subject(s)
Bronchoconstriction , Cell Degranulation , Mast Cells/cytology , Mast Cells/metabolism , Renin/metabolism , Serotonin/metabolism , Amides/pharmacology , Angiotensinogen/metabolism , Animals , Biphenyl Compounds/pharmacology , Bronchi/cytology , Bronchi/physiology , Bronchoconstriction/drug effects , Captopril/pharmacology , Cell Degranulation/drug effects , Fumarates/pharmacology , In Vitro Techniques , Irbesartan , Male , Mast Cells/drug effects , Methacholine Chloride/pharmacology , Rats , Rats, Sprague-Dawley , Renin/antagonists & inhibitors , Tetrazoles/pharmacology , p-Methoxy-N-methylphenethylamine/pharmacology
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