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

Abstract

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.

Renin- and Prorenin-Induced Effects in Rat Vascular Smooth Muscle Cells Overexpressing the Human (Pro)Renin Receptor

“…This has been noted before 7,15 and raises the possibility that the beneficial effects of these drugs 19,20 involve other, as-yetundefined targets. 22 Bafilomycin also did not affect the effect of renin and prorenin on DNA synthesis, suggesting that this phenomenon, unlike acidification, 12 does not involve V-ATPase.…”

“…It has even been claimed that HRP also prevents renin binding to the (P)RR, acts as an agonist of the (P)RR, and/or has (P)RR-independent effects. 16,21,22 To obtain a better understanding of the apparent discrepancy between the in vitro and in vivo consequences of (pro)renin-(P)RR interaction, we carefully compared the concentration dependency of the effects of human renin and prorenin via the human (P)RR (h[P]RR) in aortic vascular smooth muscle cells (VSMCs) obtained from rats overexpressing the h(P)RR in VSMCs and their wild-type controls. 3 We focused on Ang II formation and signaling, making use of putative blockers of the (P)RR (human and rat HRP) and V-ATPase (bafilomycin), in addition to knocking down the (P)RR with small interfering (si) RNA.…”

Biochemical, Structural and Pathophysiological Aspects of Prorenin and (Pro)renin Receptor

“…Chronic HRP treatment did not improve target organ damage in renovascular Goldblatt hypertensive rats with high renin, prorenin and PRA that lead to Ang-II dependent target organ damage rather HRP counteracts the beneficial effects of aliskiren (van Esch et al, 2011). Also, HRP had no effects on the activation of signal transduction mediated by prorenin-(P)RR interaction (Feldt et al, 2008a).…”

Cardiac remodeling during and after renin–angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats

“…The first cocktail contained ethylenediaminetetraacetic acid (EDTA) and aprotinin for the determination of plasma renin and pro-renin activity by enzyme-kinetic assay, as described by Van Esch et al 16 A second cocktail consisted of EDTA, phenanthroline, lisinopril, ethanol, neomycin sulfate and a renin inhibitor for the determination of plasma Ang II levels by radioimmunoassay as described before. 16 All RAScomponents were measured in a subset of plasma samples (n=4-6 for each group). Samples of young IHR at the age of 8 and 12 weeks and adult IHR at the age of 34 and 38 weeks were analyzed to check whether the sustained elevation in BP in young IHR might have been due to prolonged elevation of circulating RAS-components.…”