Nitric Oxide and Cardiac Contraction: Clinical Studies
Malcolm J. Lewis, Ajay M. Shah in Endothelial Modulation of Cardiac Function, 2020
In isolated cat papillary muscle strips, angiotensin II delayed myocardial relaxation (Meulemans, Andries and Brutsaert, 1990) and in the isolated isovolumic rat heart preparation, angiotensin II increased left ventricular end-diastolic pressure in hypertrophied but not in normal hearts (Schunkert et al., 1990). Because of these experimental findings, the angiotensin converting enzyme (ACE) inhibitor enalaprilat was infused intracoronarily in patients with left ventricular hypertrophy secondary to arterial hypertension (Haber et al., 1994) or to aortic stenosis (Friedrich et al., 1994) and resulted in improved diastolic left ventricular performance as evident from a fall in tau (= time constant of left ventricular pressure decay) or from a downward displacement of the diastolic left ventricular pressure-volume relation. These beneficial effects of ACE inhibition on myocardial relaxation were attributed to inhibition of myocardial actions of angiotensin II but recent experimental evidence in isolated ejecting guinea pig hearts suggested involvement of the bradykinin-NO pathway because similar effects were inhibited after addition of the bradykinin receptor antagonist HOE140 or of hemoglobin, which inactivates NO (Anning et al, 1995).
Phosphoinositide Metabolism
Enrique Pimentel in Handbook of Growth Factors, 2017
Activation of phosphoinositide metabolism may play an important role in the control of cellular growth under the influence of hormones, growth factors, and mitogens. It has been proposed that phosphoinositide breakdown, intracellular mobilization of Ca2+, activation of protein kinase C, and phosphorylation of distinct cell surface proteins are required for the initiation of the G1-S transition of the cell cycle and subsequent cell proliferation.250 However, several lines of evidence indicate that activation of this system does not represent a universal pathway leading to the stimulation of cell growth. Blocking of phosphoinositide turnover may not prevent specific mitogens to act through receptor tyrosine kinases to trigger DNA synthesis and cell division.268 The mechanism of action of potent mitogens such as FGF in different types of cells may be independent of phosphoinositide turnover and [Ca2+]i.248,269 Studies on the neuronal cell line NG115-401L-C3, which expresses an endogenous bradykinin receptor and was trans-fected with the mtfs/angiotensin receptor gene, indicate that neither mitogenic (angiotensin, IGF-I, TGF-β) nor nonmitogenic (bradykinin, NGF, IL-1) receptor activation may correlate with changes in the levels of phosphatidylinositol trisphosphate or with the activity of PI 3-kinase.270 Phosphatidylinositol turnover may not play a universal role in the postreceptor mechanisms of growth factor action.
Women's health—hormone replacement treatment
H. Gavras in The Year in Hypertension 2004, 2004
Emerging evidence indicates that oestrogen activates the kallikrein-kinin system (KKS) and thereby may contribute to the maintenance of normal endothelial function. There are two major subtypes of bradykinin receptor: type 1 (Bj), which is induced by tissue injury, and type 2 (B2), which is present in normal conditions. When bradykinin interacts with the B2 receptors, endothelial NO synthase, NO production, vasodilation, and natriuresis are stimulated |32,35,36|. Accordingly, the KKS has been proposed as a physiological counterbalance to the RAAS (Fig. 5.4).
The therapeutic relevance of the Kallikrein-Kinin axis in SARS-cov-2-induced vascular pathology
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Dorsa Sohaei, Morley Hollenberg, Sok-Ja Janket, Eleftherios P. Diamandis, Gennady Poda, Ioannis Prassas
Binding of SARS-CoV-2 to ACE2 not only downregulates ACE2 expression but also alters its catalytic activity, which in turn alters the ACE2-dependent regulation of the plasma kallikrein-kinin system (KKS) (Figure 2) [65,66]. The KKS produces bradykinin via proteolytic cleavage of the high-molecular-weight kininogen (HMWK or HK) by plasma kallikrein (KLK1B) or low-molecular-weight kininogen (LMWK) by tissue kallikrein (KLK1) [67]. Bradykinin is an acute-phase inflammatory hormone-like molecule [68] whose aberrant activity is physiologically controlled by ACE2 [67,69]. SARS-CoV-2-mediated ACE2 downregulation and modification of its activity can lead to aberrant bradykinin accumulation during the early stages of COVID-19. In turn, increased bradykinin can activate pro-inflammatory processes itself, driving endothelial permeability and causing vasodilating effects via bradykinin receptor 2 (BKB2R) activation. Bradykinin can also be processed further by carboxypeptidase N to produce DR9-bradykinin, which acts through bradykinin receptor 1 (BKB1R) to transmit pro-inflammatory signals [70,71]. This interplay between ACE2, the renin-angiotensin system (RAS), and the plasma KKS has been portrayed as generating a “bradykinin storm” that drives disease pathology in the setting of COVID-19 [71].
A rare presentation of angioedema with isolated retropharyngeal and supraglottic involvement
Published in Journal of Community Hospital Internal Medicine Perspectives, 2019
As the exact mechanism of ACE inhibitor induced angioedema is not established, management focuses on discontinuation of ACE inhibitor and supportive care rather than treatment with targeted reversal agents. While efficacy of epinephrine and antihistaminergic medication is not established in ACE inhibitor induced angioedema, the consensus is to initiate these therapies in patients with signs of respiratory compromise due to inability to rule out an allergic/anaphylactic reaction [7,9]. Airway assessment with direct fiberoptic visualization is recommended in the setting of oropharyngeal involvement, followed by intubation of cricothyrotomy if airway obstruction is present [7]. Corticosteroids are also used to reduce swelling and inflammation throughout the hospital admission, though there is no consensus for post discharge steroid usage [7,9]. The usage of bradykinin receptor antagonists is indicated in acute attacks of hereditary angioedema and hence these agents have been trialed in ACE inhibitor induced angioedema [21,22]. These studies have shown such agents to be inefficacious and hence their use is controversial among patients with ACE inhibitor induced angioedema [21,22].
Estradiol Alters Hippocampal Gene Expression during the Estrous Cycle
Published in Endocrine Research, 2020
Javed Iqbal, Zhi-Nei Tan, Min-Xing Li, Hui-Bin Chen, Boyu Ma, Xin Zhou, Xin-Ming Ma
The calcium signaling pathway plays an important role in E2-mediated neural plasticity and neurotransmission.58 Bdkrb2 (bradykinin receptor B2) and 5-HRr7 were regulated by E2 through the calcium signaling pathway. Intracellular Ca2+ signaling promotes hippocampal synaptic plasticity and spatial memory. Bdkrb2 provides neuroprotection59, and its receptors B1R and B2R are involved in inflammatory responses; blockage of these two receptors prevents brain injury and memory impairment.60 The regulation of 5-HTr7 and Bdkrb2 expression by E2 and Ca2+signaling plays a key role in cognition and neuropsychiatric disorders.
Related Knowledge Centers
- Adenylyl Cyclase
- Bradykinin
- Calcium
- Ligand
- Phospholipase C
- G Protein-Coupled Receptor
- Bradykinin Receptor B1
- Bradykinin Receptor B2
- Gq Alpha Subunit
- Gi Alpha Subunit