Bradykinin B<sub>2</sub> Receptor Does Not Contribute to Blood Pressure Lowering during AT<sub>1</sub> Receptor Blockade

Lefèbvre, J; Shintani, Ayumi; Gebretsadik, Tebeb; Petro, Jeffery R.; Murphey, Laine J.; Brown, Nancy J.

doi:10.1124/jpet.106.117259

Cited by 9 publications

(5 citation statements)

References 36 publications

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“…The intravenous infusion of HOE-140 decreased the basal PRA in rabbits independent of any changes in blood pressure, but it did not attenuate the furosemide-stimulated elevation in the PRA (155). HOE-140 did not alter the basal PRA or the furosemideor valsartan-induced PRA changes in humans (504,612). However, HOE-140 inhibited the increase in PRA and the decline in blood pressure observed in response to captopril in humans (251).…”

Section: Bradykininmentioning

confidence: 94%

Physiology of Kidney Renin

Castrop

Höcherl

Kurtz

et al. 2010

Physiological Reviews

232

277

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The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization. (Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The release of renin is under the control of the cAMP (stimulatory) and Ca2+(inhibitory) signaling pathways. Meanwhile, a great number of intrarenally generated or systemically acting factors have been identified that control the renin secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin II and angiotensin-( 1 – 7 ).

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Section: Bradykininmentioning

confidence: 94%

Physiology of Kidney Renin

Castrop

Höcherl

Kurtz

et al. 2010

Physiological Reviews

232

277

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“…Both animal and human studies implicate kinin peptides and/or the B 2 receptor in the actions of ARBs, possibly mediated by AT 2 receptor stimulation by the increased angiotensin II levels that accompany ARB therapy ( 116 – 124 ). However, in contrast to the attenuation of the hypotensive effects of ACE inhibition by concomitant icatibant administration (100 μg/kg/h iv for 1 h) in sodium-deplete normotensive and hypertensive subjects ( 125 ), and at a higher dose (10 mg infused iv over 15 min) in sodium replete normotensive subjects ( 126 ), a lower dose of icatibant (18 μg/kg/h iv for 6 h) did not attenuate the hypotensive effects of either acute or chronic administration of valsartan in sodium-deplete normotensive and hypertensive subjects ( 127 ).…”

Section: Lcz696 and Bradykininmentioning

confidence: 99%

Neprilysin Inhibitors and Bradykinin

Campbell

2018

Front. Med.

122

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Bradykinin has important physiological actions related to the regulation of blood vessel tone and renal function, and protection from ischemia reperfusion injury. However, bradykinin also contributes to pathological states such as angioedema and inflammation. Bradykinin is metabolized by many different peptidases that play a major role in the control of bradykinin levels. Peptidase inhibitor therapies such as angiotensin converting enzyme (ACE) and neprilysin inhibitors increase bradykinin levels, and the challenge for such therapies is to achieve the beneficial cardiovascular and renal effects without the adverse consequences such as angioedema that may result from increased bradykinin levels. Neprilysin also metabolizes natriuretic peptides. However, despite the potential therapeutic benefit of increased natriuretic peptide and bradykinin levels, neprilysin inhibitor therapy has only modest efficacy in essential hypertension and heart failure. Initial attempts to combine neprilysin inhibition with inhibition of the renin angiotensin system led to the development of omapatrilat, a drug that combines ACE and neprilysin inhibition. However, omapatrilat produced an unacceptably high incidence of angioedema in patients with hypertension (2.17%) in comparison with the ACE inhibitor enalapril (0.68%), although angioedema incidence was less in patients with heart failure with reduced ejection fraction (HFrEF) treated with omapatrilat (0.8%), and not different from that for enalapril therapy (0.5%). More recently, LCZ696, a drug that combines angiotensin receptor blockade and neprilysin inhibition, was approved for the treatment of HFrEF. The approval of LCZ696 therapy for HFrEF represents the first approval of long-term neprilysin inhibitor administration. While angioedema incidence was acceptably low in HFrEF patients receiving LCZ696 therapy (0.45%), it remains to be seen whether LCZ696 therapy for other conditions such as hypertension is also accompanied by an acceptable incidence of angioedema.

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“…BK also acts directly on the sino-atrial node, via the BK B 2 receptor, to lower HR [37]. In BK B 2 receptor knockout mice basal HR is elevated compared with littermate controls [38], and pharmacological blockade by the BK B 2 receptor antagonist HOE 140 increases HR in both rats [39] and humans [40]. A second potential explanation for the slower HR observed in rats with intact adrenal glands is that β-FXIIa induced increases in PACAP [13], which lowers HR by liberating acetylcholine from postganglionic parasympathetic nerves [41].…”

Section: Discussionmentioning

confidence: 99%

Activated plasma coagulation β-Factor XII-induced vasoconstriction in rats

et al. 2012

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By inducing BK (bradykinin)-stimulated adrenomedullary catecholamine release, bolus injection of the β-fragment of activated plasma coagulation Factor XII (β-FXIIa) transiently elevates BP (blood pressure) and HR (heart rate) of anaesthetized, vagotomized, ganglion-blocked, captopril-treated bioassay rats. We hypothesized that intravenous infusion of β-FXIIa into intact untreated rats would elicit a qualitatively similar vasoconstrictor response. BN (Brown Norway) rats received for 60 min either: (i) saline (control; n=10); (ii) β-FXIIa (85 ng/min per kg of body weight; n=9); or (iii) β-FXIIa after 2ADX (bilateral adrenalectomy; n=9). LV (left ventricular) volume and aortic BP were recorded before (30 min baseline), during (60 min) and after (30 min recovery) the infusion. TPR (total peripheral resistance) was derived from MAP (mean arterial pressure), SV (stroke volume) and HR. Saline had no haemodynamic effects. β-FXIIa infusion increased its plasma concentration 3-fold in both groups. In adrenally intact rats, β-FXIIa infusion increased MAP by 6% (5±2 mmHg) and TPR by 45% (0.50±0.12 mmHg/ml per min), despite falls in SV (−38±8 μl) and HR [−18±5 b.p.m. (beats/min)] (all P<0.05). In 2ADX rats, β-FXIIa had no HR effect, but decreased SV (−89±9 μl) and MAP (−4±1 mmHg), and increased TPR by 66% (0.59±0.15 mmHg/ml per min) (all P<0.05). After infusion, adrenally intact rats exhibited persistent vasoconstriction (MAP, 10±1 mmHg; TPR, 0.55±0.07 mmHg/ml per min; both P<0.05), whereas in 2ADX rats, MAP remained 5±1 mmHg below baseline (P<0.05) and TPR returned to baseline. End-study arterial adrenaline (epinephrine) concentrations in the three groups were 1.9±0.6, 9.8±4.1 and 0.6±0.2 nmol/l respectively. Thus, in neurally intact lightly anaesthetized untreated rats, β-FXIIa infusion induces both adrenal catecholamine-mediated and adrenally independent increases in peripheral resistance.

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Bradykinin B₂ Receptor Does Not Contribute to Blood Pressure Lowering during AT₁ Receptor Blockade

Cited by 9 publications

References 36 publications

Physiology of Kidney Renin

Physiology of Kidney Renin

Neprilysin Inhibitors and Bradykinin

Activated plasma coagulation β-Factor XII-induced vasoconstriction in rats

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Bradykinin B2 Receptor Does Not Contribute to Blood Pressure Lowering during AT1 Receptor Blockade

Cited by 9 publications

References 36 publications

Physiology of Kidney Renin

Physiology of Kidney Renin

Neprilysin Inhibitors and Bradykinin

Activated plasma coagulation β-Factor XII-induced vasoconstriction in rats

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Product

Resources

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Bradykinin B₂ Receptor Does Not Contribute to Blood Pressure Lowering during AT₁ Receptor Blockade