Dataset Information

Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema.

ABSTRACT:

Background and purpose

Inhibition of bradykinin metabolizing enzymes (BMEs) can cause acute angioedema, as demonstrated in a recent clinical trial in patients administered the antihypertensive, omapatrilat. However, the relative contribution of specific BMEs to this effect is unclear and confounded by the lack of a predictive pre-clinical model of angioedema.

Experimental approach

Rats were instrumented to record blood pressure and heart rate; inhibitors were infused for 35 min and bradykinin was infused during the last 5 min to elicit hypotension, as a functional marker of circulating bradykinin and relative angioedema risk.

Key results

In the presence of omapatrilat bradykinin produced dose-dependent hypotension, an effect abolished by B(2) blockade. In the presence of lisinopril (ACE inhibitor), but not candoxatril (NEP inhibitor) or apstatin (APP inhibitor), bradykinin also elicited hypotension. Lisinopril-mediated hypotension was unchanged with concomitant blockade of NEP or NEP/DPPIV (candoxatril+A-899301). However, hypotension was enhanced upon concomitant blockade of APP and further intensified in the presence of NEP inhibition to values not different from omapatrilat alone.

Conclusions and implications

We demonstrated that bradykinin is degraded in vivo with an enzyme rank-efficacy of ACE>APP>>NEP or DPPIV. These results suggest the effects of omapatrilat are mediated by inhibition of three BMEs, ACE/APP/NEP. However, dual inhibition of ACE/NEP or ACE/NEP/DPPIV elicits no increased risk of angioedema compared to ACE inhibition alone. Thus, novel BME inhibitors must display no activity against APP to avoid angioedema risk due to high prevalence of ACE inhibitor therapy in patients with diabetes and cardiovascular disease.

SUBMITTER: Fryer RM

PROVIDER: S-EPMC2267285 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema.

Fryer R M RM Segreti J J Banfor P N PN Widomski D L DL Backes B J BJ Lin C W CW Ballaron S J SJ Cox B F BF Trevillyan J M JM Reinhart G A GA von Geldern T W TW

British journal of pharmacology 20071217 5

<h4>Background and purpose</h4>Inhibition of bradykinin metabolizing enzymes (BMEs) can cause acute angioedema, as demonstrated in a recent clinical trial in patients administered the antihypertensive, omapatrilat. However, the relative contribution of specific BMEs to this effect is unclear and confounded by the lack of a predictive pre-clinical model of angioedema.<h4>Experimental approach</h4>Rats were instrumented to record blood pressure and heart rate; inhibitors were infused for 35 min an ...[more]

PMID: 18084312

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Project description:Deep brain stimulation (DBS) of the subthalamic nucleus (STN) antidromically activates the motor cortex (M1), and this cortical activation appears to play a role in the treatment of hypokinetic motor behaviors (Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K. Science 324: 354-359, 2009; Yu C, Cassar IR, Sambangi J, Grill WM. J Neurosci 40: 4323-4334, 2020). The synchronous antidromic activation takes the form of a short-latency cortical evoked potential (cEP) in electrocorticography (ECoG) recordings of M1. We assessed the utility of the cEP as a biomarker for STN DBS in unilateral 6-hydroxydopamine-lesioned female Sprague Dawley rats, with stimulating electrodes implanted in the STN and the ECoG recorded above M1. We quantified the correlations of the cEP magnitude and latency with changes in motor behavior from DBS and compared them to the correlation between motor behaviors and several commonly used spectral-based biomarkers. The cEP features correlated strongly with motor behaviors and were highly consistent across animals, whereas the spectral biomarkers correlated weakly with motor behaviors and were highly variable across animals. The cEP may thus be a useful biomarker for assessing the therapeutic efficacy of DBS parameters, as its features strongly correlate with motor behavior, it is consistent across time and subjects, it can be recorded under anesthesia, and it is simple to quantify with a large signal-to-noise ratio, enabling rapid, real-time evaluation. Additionally, our work provides further evidence that antidromic cortical activation mediates changes in motor behavior from STN DBS and that the dependence of DBS efficacy on stimulation frequency may be related to antidromic spike failure.NEW & NOTEWORTHY We characterize a new potential biomarker for deep brain stimulation (DBS), the cortical evoked potential (cEP), and demonstrate that it exhibits a robust correlation with motor behaviors as a function of stimulation frequency. The cEP may thus be a useful clinical biomarker for changes in motor behavior. This work also provides insight into the cortical mechanisms of DBS, suggesting that motor behaviors are strongly affected by the rate of antidromic spike failure during DBS.

Dataset Information

Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema.

Similar Datasets

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