Bradykinin as a Probable Aspect in SARS-Cov-2 Scenarios: Is Bradykinin Sneaking out of Our Sight?

The new virus SARS-CoV-2 is savagely spreading out over the world. The biologic studies show that the target receptor for the virus might be angiotensin-converting enzyme 2 (ACE2). This peptide is responsible for converting angiotensin II (Ang II), which is a profoundly active peptide, into Ang 1-7 with quite a balancing barbell function. It is emphasized that the direct target of the virus is ACE2 underlining the obvious difference with ACE. Nevertheless, we hypothesized that a back load build up effect on Ang II may usurp the ACE capacity and subsequently leave the bradykinin system unabated. We think there are clinical clues for dry cough and the presumed aggravating role of ACE inhibitors like captopril on the disease process. Thereby, we speculated that inhibition of bradykinin synthesis and/or blockade of bradykinin B2 receptor using Aprotinin/ecallantide and Icatibant, respectively, may hold therapeutic promise in severe cases and these molecules can be advanced to clinical trials.

A hypothesized role for dysregulated bradykinin signaling in COVID-19 respiratory complications.

As of April 20, 2020, over time, the COVID-19 pandemic has resulted in 157 970 deaths out of 2 319 066 confirmed cases, at a Case Fatality Rate of ~6.8%. With the pandemic rapidly spreading, and health delivery systems being overwhelmed, it is imperative that safe and effective pharmacotherapeutic strategies are rapidly explored to improve survival. In this paper, we use established and emerging evidence to propose a testable hypothesis that, a vicious positive feedback loop of des-Arg(9)-bradykinin- and bradykinin-mediated inflammation â†’ injury â†’ inflammation, likely precipitates life threatening respiratory complications in COVID-19. Through our hypothesis, we make the prediction that the FDA-approved molecule, icatibant, might be able to interrupt this feedback loop and, thereby, improve the clinical outcomes. This hypothesis could lead to basic, translational, and clinical studies aimed at reducing COVID-19 morbidity and mortality.

Activation of bradykinin-sensitive pericardial afferents increases systemic venous tone in conscious rats.

Our understanding of reflex regulation of veins lags behind that of the arterial system. While the cardiac sympathetic afferent reflex (CSAR) exerts control over sympathetic outflow, its effect on venous tone is not known. We tested the hypothesis that activation of pericardial bradykinin sensitive afferents elicits systemic venoconstriction. Male and female Sprague Dawley rats were chronically instrumented for measurement of arterial pressure and mean circulatory filling pressure, an index of venous tone, and with an indwelling pericardial catheter. Mean arterial pressure, heart rate and mean circulatory filling pressure responses were assessed in conscious rats in response to graded pericardial injections of bradykinin (1.5-20 µg/kg) before and after ganglionic blockade, and to intravenous norepinephrine (0.05-0.8 µg/kg). Bradykinin B2 receptor was assessed by Western blot. Pericardial bradykinin injections caused graded increases in mean arterial pressure, heart rate and mean circulatory filling pressure. These responses were markedly attenuated after autonomic blockade. The increments in mean circulatory filling pressure were attenuated in female rats. There were no differences in the venoconstrictor responses to norepinephrine or ventricular bradykinin receptor expression between male and females. We interpret these findings to indicate that activation of bradykinin sensitive pericardial afferents elicits a sexually dimorphic, autonomically mediated systemic venoconstrictor response. Differences in venous smooth muscle responses to norepinephrine or ventricular bradykinin receptor expression do not account for the sexual dimorphism. We conclude that systemic venoconstriction contributes to the overall hemodynamic response to activation of the cardiac sympathetic afferent reflex and that this effect is sexually dimorphic.

Bradykinin system is involved in endometriosis-related pain through endothelin-1 production.

BACKGROUND: Endometriosis is a gynaecological disease exhibiting severe pelvic pain, but the mechanism of pain production remains unknown. Bradykinin (BK) is known as an inflammatory mediator, and shows elevated levels in inflammatory diseases such as rheumatoid arthritis. In the present study, we evaluated whether BK is involved in endometriosis-related pain. METHODS: Endometriotic lesions were used for immunohistochemistry. Primary cultures of endometriotic stromal cells (ESC) were stimulated with IL-1ß and/or BK. Quantitative RT-PCR was used to evaluate the mRNA expressions of BK receptors (BKR) and endothelin-1 in ESC. The concentration of endothelin-1 in cystic fluid of endometrioma or non-endometrioma was measured with ELISA. The conditioned medium of ESC stimulated with IL-1ß and/or BK was injected intraplantarly in mice, and evaluated whether pain-related licking behaviour was elicited. RESULTS: The expressions of BK and BKR in endometriotic lesions were observed by immunohistochemistry. In vitro experiments showed that IL-1ß induced BKR-B1 and B2 on ESC. Activation of these receptors by BK significantly induced endothelin-1 expression in ESC, which was negated completely by HOE-140, a BKR-B2 antagonist. The cystic fluid of endometrioma contained higher amount of endothelin-1 compared to non-endometrioma. Intraplantar injection of the conditioned medium of ESC treated with IL-1ß and BK significantly induced licking behaviour, which was suppressed with BQ-123, an endothelin type-A receptor antagonist. CONCLUSIONS: The present study demonstrated the presence and the function of the BK axis in endometriosis, and established a potential new therapy target for endometriosis-related pain. SIGNIFICANCE: The present study demonstrated (1) the presence and the function of the BK system in endometriosis, (2) activation of BKR induced endothelin-1 in endometriotic lesion and (3) blocking endothelin-1 was effective to decrease pain.

Indomethacin can downregulate the levels of inflammatory mediators in the hippocampus of rats submitted to pilocarpine-induced status epilepticus.

OBJECTIVE: Refractory status epilepticus is one of the most life-threatening neurological emergencies and is characterized by high morbidity and mortality. Additionally, the use of anti-inflammatory drugs during this period is very controversial. Thus, this study has been designed to analyze the effect of a low dose of indomethacin (a COX inhibitor) on the expression of inflammatory molecules. METHOD: The hippocampus of rats submitted to pilocarpine-induced long-lasting status epilepticus was analyzed to determine the expression of inflammatory molecules with RT-PCR and immunohistochemistry. RESULTS: Compared with controls, reduced levels of the kinin B2 receptors IL1ß and TNFα were found in the hippocampus of rats submitted to long-lasting status epilepticus and treated with indomethacin. CONCLUSIONS: These data show that low doses of indomethacin could be employed to minimize inflammation during long-lasting status epilepticus.

Indomethacin can downregulate the levels of inflammatory mediators in the hippocampus of rats submitted to pilocarpine-induced status epilepticus

OBJECTIVE: Refractory status epilepticus is one of the most life-threatening neurological emergencies and is characterized by high morbidity and mortality. Additionally, the use of anti-inflammatory drugs during this period is very controversial. Thus, this study has been designed to analyze the effect of a low dose of indomethacin (a COX inhibitor) on the expression of inflammatory molecules. METHOD: The hippocampus of rats submitted to pilocarpine-induced long-lasting status epilepticus was analyzed to determine the expression of inflammatory molecules with RT-PCR and immunohistochemistry. RESULTS: Compared with controls, reduced levels of the kinin B2 receptors IL1β and TNFα were found in the hippocampus of rats submitted to long-lasting status epilepticus and treated with indomethacin. CONCLUSIONS: These data show that low doses of indomethacin could be employed to minimize inflammation during long-lasting status epilepticus. .

Balance between the two kinin receptors in the progression of experimental focal and segmental glomerulosclerosis in mice.

Focal and segmental glomerulosclerosis (FSGS) is one of the most important renal diseases related to end-stage renal failure. Bradykinin has been implicated in the pathogenesis of renal inflammation, whereas the role of its receptor 2 (B2RBK; also known as BDKRB2) in FSGS has not been studied. FSGS was induced in wild-type and B2RBK-knockout mice by a single intravenous injection of Adriamycin (ADM). In order to further modulate the kinin receptors, the animals were also treated with the B2RBK antagonist HOE-140 and the B1RBK antagonist DALBK. Here, we show that the blockage of B2RBK with HOE-140 protects mice from the development of FSGS, including podocyte foot process effacement and the re-establishment of slit-diaphragm-related proteins. However, B2RBK-knockout mice were not protected from FSGS. These opposite results were due to B1RBK expression. B1RBK was upregulated after the injection of ADM and this upregulation was exacerbated in B2RBK-knockout animals. Furthermore, treatment with HOE-140 downregulated the B1RBK receptor. The blockage of B1RBK in B2RBK-knockout animals promoted FSGS regression, with a less-inflammatory phenotype. These results indicate a deleterious role of both kinin receptors in an FSGS model and suggest a possible cross-talk between them in the progression of disease.

Impact of kinins in the treatment of cardiovascular diseases.

In recent years, ACE Inhibitors (ACEIs) and Angiotensin II receptor antagonists (also known as AT1 receptor antagonists (AT1-RAs), angiotensin receptor blockers (ARBs), or Sartans), have become the drugs of choice for the treatment of hypertension, heart and renal failure, coronary artery diseases, myocardial infarction and diabetes. By suppressing angiotensin and potentiating bradykinin effects, ACEIs and ARBs activate hemodynamic, metabolic and cellular mechanisms that not only reduce high blood pressure, but also protect the endothelium, the heart, the kidney and the brain, namely the target organs which are at risk in cardiovascular diseases. Major therapeutic benefits of these drugs are the reduction of cardiovascular events and the amelioration of the quality of life and of the patient survival. Results from large clinical trials have established that ACEIs and ARBs are efficient and safe drugs, suitable for the chronic treatments of cardiovascular diseases. Side effects are rare and easily manageable in most cases. The following is a brief review of the basic actions and mechanisms by which two opposing systems, the renin-angiotensin (RAS) and the kallikrein-kinin (KKS), interact in the regulation of cardiovascular and fluid homeostasis to keep the balance in healthy life and correct the imbalance in pathological conditions. Here we discuss how and why imbalances created by overactive RAS are best corrected by treatments with ACEI or AT1-RAs.

Role of spinal neurotransmitter receptors in itch: new insights into therapies and drug development.

Targets for antipruritic therapies are now expanding from the skin to the central nervous system. Recent studies demonstrate that various neuronal receptors in the spinal cord are involved in pruritus. The spinal opioid receptor is one of the best-known examples. Spinal administration of morphine is frequently accompanied by segmental pruritus. In addition to µ-opioid receptor antagonists, κ-opioid receptor agonists have recently come into usage as novel antipruritic drugs, and are expected to suppress certain subtypes of itch such as hemodialysis- and cholestasis-associated itch that are difficult to treat with antihistamines. The gastrin-releasing peptide receptor in the superficial dorsal horn of the spinal cord has also received recent attention as a novel pathway of itch-selective neural transmission. The NMDA glutamate receptor appears to be another potential target for the treatment of itch, especially in terms of central sensitization. The development of NMDA receptor antagonists with less undesirable side effects on the central nervous system might be beneficial for antipruritic therapies. Drugs suppressing presynaptic glutamate-release such as gabapentin and pregabalin also reportedly inhibit certain subtypes of itch such as brachioradial pruritus. Spinal receptors of other neuromediators such as bradykinin, substance P, serotonin, and histamine may also be potential targets for antipruritic therapies, given that most of these molecules interfere not only with pain, but also with itch transmission or regulation. Thus, the identification of itch-specific receptors and understanding itch-related circuits in the spinal cord may be innovative strategies for the development of novel antipruritic drugs.

Abnormal bradykinin signalling in fibroblasts deficient in the PIP(2) 5-phosphatase, ocrl1.

The oculocerebrorenal syndrome of Lowe (Lowe syndrome) is an X-linked disorder of phosphatidylinositol metabolism characterized by congenital cataracts, renal proximal tubulopathy and neurological deficits. The disorder is due to the deficiency of the phosphatidylinositol 4,5-bisphosphate (PIP(2)) 5-phosphatase, ocrl1. PIP(2) is critical for numerous cellular processes, including cell signalling, actin reorganization and protein trafficking, and is chronically elevated in patients with Lowe syndrome. The elevation of PIP(2) cells of patients with Lowe syndrome provides the unique opportunity to investigate the roles of this phospholipid in fundamental cellular processes. We previously demonstrated that ocrl1 deficiency causes alterations in the actin cytoskeleton. Since actin remodelling is strongly activated by [Ca(+2)], which increases in response to IP(3) production, we hypothesized that altered calcium signalling might contribute to the observed abnormalities in actin organization. Here we report a specific increase in bradykinin-induced Ca(+2) mobilization in Lowe fibroblasts. We show that the abnormal bradykinin signalling occurs in spite of normal total cellular receptor content. These data point to a novel role for ocrl1 in agonist-induced calcium release.

Lipopolysaccharide activates the kallikrein-kinin system in mouse choroid plexus cell line ECPC4.

Regulation of the kallikrein-kinin system in cerebral inflammation is still unclear. Here, we used reverse-transcription polymerase chain reaction (RT-PCR) techniques to show that lipopolysaccharide (LPS) activates the kallikrein-kinin system by enhancing liberation of bradykinin (BK), and alters mRNA levels of kallikrein-kinin system components, including high molecular weight (H-) and low molecular weight (L-) kininogens, in ECPC4 cells, a cell line of mouse choroid plexus epithelium. LPS treatment increased liberation of immunoreactive bradykinin in the supernatant of ECPC4 cells, and addition of LPS (500 ng/ml) to cultures resulted in elevation of H- and L-kininogen mRNA levels in ECPC4 cells within 24-48 h. Furthermore, LPS treatment elevated bradykinin type 2 and type 1 receptor mRNA levels within 4h, but did not change tissue kallikrein or plasma kallikrein mRNA levels. On the other hand, expression of pro-inflammatory mediators interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and cyclooxygenase-2 mRNA increased within 4-8h after addition of LPS to ECPC4 cells. The addition of IL-1beta and TNF-alpha to investigate the major mediator for kininogen expression in ECPC4 cells remarkably induced expression of H- and L-kininogen mRNAs in ECPC4 cells. These results suggest that LPS activates the kallikrein-kinin system in the choroid plexus via autocrine induction of IL-1beta and TNF-alpha.

Neuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microglia.

Bradykinin (BK) has been reported to be a mediator of brain damage in acute insults. Receptors for BK have been identified on microglia, the pathologic sensors of the brain. Here, we report that BK attenuated lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta from microglial cells, thus acting as an anti-inflammatory mediator in the brain. This effect was mimicked by raising intracellular cAMP or stimulating the prostanoid receptors EP2 and EP4, while it was abolished by a cAMP antagonist, a prostanoid receptor antagonist, or by an inhibitor of the inducible cyclooxygenase (cyclooxygenase-2). BK also enhanced formation of prostaglandin E(2) and expression of microsomal prostaglandin E synthase. Expression of BK receptors and EP2/EP4 receptors were also enhanced. Using physiological techniques, we identified functional BK receptors not only in culture, but also in microglia from acute brain slices. BK reduced LPS-induced neuronal death in neuron-microglia co-cultures. This was probably mediated via microglia as it did not affect TNF-alpha-induced neuronal death in pure neuronal cultures. Our data imply that BK has anti-inflammatory and neuroprotective effects in the central nervous system by modulating microglial function.

Synergistic actions of enalapril and tempol during chronic angiotensin II-induced hypertension.

Experiments were designed to test the hypothesis that antioxidant treatment would increase the anti-hypertensive actions of endogenous kinins during angiotensin converting enzyme (ACE) inhibition. Four groups of rats, all given angiotensin II (Ang II) for 2 weeks, were studied: 1) control, 2) enalapril, 3) tempol or 4) both tempol and enalapril. Ang II significantly increased systolic blood pressure (BP) when compared with the baseline (170+/-8 vs. 128+/-4 mm Hg, P<0.05). Neither enalapril nor tempol alone was able to attenuate the elevation in BP (165+/-7 and 164+/-6 mm Hg, respectively). In contrast, combined administration of tempol and enalapril prevented the increase in BP (137+/-5 mm Hg). Plasma 8-isoprostane increased in Ang II-infused rats when compared with control untreated rats (69+/-14 vs. 23+/-0.5 pg/ml, P<0.05). Tempol alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane (29+/-6 and 34+/-7 pg/ml, respectively). In additional experiments, we used the bradykinin B(2) antagonist, icatibant to determine if increased B(2) receptor contributes to the anti-hypertensive effect of combined tempol and enalapril in Ang II-infused rats. Icatibant decreased the ability of this combination to lower arterial pressure. Additionally, a significant increase in B(1) receptor protein expression in renal cortex of Ang II-infused rats was observed compared to control suggesting that bradykinin receptor activation could account for the effect of enalapril to enhance the actions of tempol. These data support the hypothesis that combined reduction of superoxide along with enhanced endogenous kinins may facilitate blood pressure lowering in Ang II hypertension.

Activation of splanchnic and pelvic colonic afferents by bradykinin in mice.

BACKGROUND: Lumbar splanchnic (LSN) and sacral pelvic (PN) nerves convey different mechanosensory information from the colon to the spinal cord. Here, we determined whether these pathways differ also in their chemosensitivity to bradykinin. METHODS: Using a novel in vitro mouse colon preparation, serosal afferents were recorded from the LSN and PN and distinguished based on their mechanosensitivity to von Frey filaments (70-4000 mg) and insensitivity to colonic stretch (1-5 g) or fine mucosal stroking (10 mg). Bradykinin was applied into a ring around mechanoreceptive fields. RESULTS: The LSN and PN afferents had different dynamic responses to mechanical stimuli: PN afferents required lower intensity stimuli, evoked larger responses, and displayed more maintained responses than LSN afferents. Bradykinin (1 micromol L-1) excited 66% (27 of 41) of LSN afferents. Responses to probing were potentiated after bradykinin. The concentration-dependent (EC50: 0.16 micromol L-1) response was reversed by the B2-receptor antagonist HOE-140 (10 nmol L-)). Twelve bradykinin responsive afferents were mechanically insensitive. More LSN serosal afferents responded to bradykinin than PN afferents (11%, P<0.001) , with larger responses (P<0.05). No mechanically insensitive PN afferents were recruited by bradykinin. CONCLUSIONS: Bradykinin potently stimulates most splanchnic serosal afferents via B2-receptors, but few pelvic afferents. Mechanically insensitive afferents recruited by bradykinin are exclusive to the LSN.

Expression of metallopeptidases and kinin receptors in swine oropharyngeal tissues: effects of angiotensin I-converting enzyme inhibition and inflammation.

Angiotensin I-converting enzyme inhibitors (ACEi) cause both chronic and acute side effects, including rare but potentially life-threatening angioedema (AE). The main hypothesis to be tested in this study was that metallopeptidases and kinin receptors are present in oropharyngeal tissues and that their expression is modulated by ACEi and inflammation. Novel real-time polymerase chain reaction analysis was developed and allowed the relative quantification of tissue's gene expression for neprilysin, membrane-bound aminopeptidase P (mAPP), and both B1 and B2 kinin receptor subtypes in tongue, parotid gland, and laryngeal tissue (areas especially involved in the gravest clinical forms of AE) and in kidney in a porcine model (single injection or 7-day ACEi oral treatments applied or lipopolysaccharide injected as a positive inflammatory control). The results provide evidence of the expression and activities of kininases in oropharyngeal tissues in the swine. ACEi treatment modulated the expression of neutral endopeptidase and mAPP mRNA, but the corresponding enzyme activities and that of angiotensin I-converting enzyme (ACE) were generally stable in tissues. The 7-day ACEi treatment up-regulated both kinin receptor mRNAs in the oropharynx and the B1 receptor mRNA in the lingual vascular endothelium (immunohistochemistry). The inhibition of ACE in plasma is responsible for an accumulation of bradykinin and des-arginine9-bradykinin generated during activation of the contact system with glass beads. The expression of critical components of the kallikrein-kinin system in the oropharyngeal tissues supports the role of kinins in ACEi-induced AE.

Pharmacological characterization of ligand-receptor interactions at the zebrafish bradykinin receptor.

Ligand interactions of a piscine bradykinin (BK) receptor expressed in vitro have been characterized for the first time by measuring inositol phosphate accumulation. The ligands were analogues of zebrafish BK with serial substitutions by D-amino acids or alanine. Substitutions at residues Arg(1), Gly(4), Ser(6), Pro(7), Leu(8) and Arg(9) caused greatly reduced potency and maximum response. The Pro(3) --> Ala analogue had higher potency but lower maximum response. The peptide HOE140 was a weak partial agonist although it is an antagonist at the human B2 receptor and a potent agonist at chicken B2.Thus, cloned zebrafish BK receptor reveals a ligand-interaction profile that is distinct from mammalian B1 and B2 receptors and from the previously characterized BK receptor in trout stomach, but similar to the receptor in cod intestine. These results increase our understanding of the evolution of BK receptors and the functions of the kallikrein-kinin system.

Omapatrilat limits infarct size and lowers the threshold for induction of myocardial preconditioning through a bradykinin receptor-mediated mechanism.

Bradykinin is an important endogenous trigger of myocardial ischemic preconditioning (IPC). Through simultaneous inhibition of neutral endopeptidase and angiotensin converting enzyme, omapatrilat prevents enzymatic degradation of bradykinin. The aim of this study was to investigate if omapatrilat, through its ability to augment bradykinin levels, can augment a subthreshold IPC stimulus (Sub-IPC) and to compare the action of omapatrilat with the angiotensin-converting enzyme inhibitor, captopril. Langendorff perfused rat hearts were subjected to 35 min left coronary artery occlusion and 120 min reperfusion. Full IPC was induced with 5 min global ischemia/10 min reperfusion and substantially limited infarct size (21.5 +/- 3.5% of risk zone vs 53.4 +/- 2.0% in controls, P < 0.01). Sub-IPC (2 min global ischemia/10 min reperfusion) did not limit infarct size (48.4 +/- 3.8%). Omapatrilat (10 micromol/L) or captopril (200 micromol/L) were administered alone or in conjunction with Sub-IPC. Reduced infarct size comparable to that observed with the full IPC protocol was seen when sub-IPC was combined with either omapatrilat (19.7 +/- 2.5%) or captopril (20.3 +/- 4.9%). Omapatrilat alone caused modest reduction of infarct size (34.6 +/- 1.5%, P < 0.01 v control), an effect not observed with captopril. Hoe140, a selective kinin B(2) receptor antagonist, eliminated the cardioprotective effect of omaptrilat alone or in combination with sub-IPC. We conclude that omapatrilat elicits cardioprotection via inhibition of bradykinin degradation and that dual inhibition of angiotensin-converting enzyme and neutral endopeptidase may have beneficial effects beyond standard angiotensin-converting enzyme inhibitor therapy in patients with acute coronary syndromes who are at risk of myocardial infarction.

Autoradiographic localization of [125I-Tyr0]bradykinin binding sites in brains of Wistar-Kyoto and spontaneously hypertensive rats.

1. The present study was undertaken to localize and characterize bradykinin (BK) binding sites in brains from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2. Serial sections of brains were cut from adult WKY and SHR and specific [125I-Tyr0]bradykinin ([125I-Tyr0]BK) binding was determined using in vitro quantitative receptor autoradiographic techniques. 3. Specific binding of [125I Tyr0]BK was localized in the medulla oblongata to the regions of the nucleus of the solitary tract (NTS), area postrema (AP), dorsal motor nucleus of the vagus (X), and caudal subnucleus of the spinal trigeminal nucleus in both strains of rat. The specific binding (85-90% of total binding) was of high affinity and saturable with KD values in the range of 100 pM and a B(max) of 0.75 fmol per mg tissue equivalent in the NTS-X-AP complex of both the WKY and SHR. In competition studies, the rank order of potencies was similar in both strains with BK = Lys-BK > icatibant >>> DesArg9-BK. The B2 receptor antagonist icatibant inhibited [125I-Tyr0]BK binding with a Ki value of 0.63 +/ 0.19 nM in WKY and 0.91 +/- 0.73 nM in SHR, while Ki values for the B1 receptor agonist DesArg9-BK were 1475 +/- 1055 and 806 +/-362 nM in WKY and SHR, respectively. 4. Our finding of specific high-affinity [125I-Tyr0]BK B2 binding sites in the NTS, AP, and the X of WKY and SHR is important because these brain areas are associated with central cardiovascular regulation. However, alterations in BK B2 receptors in the medulla that could contribute to the hypertensive state in the SHR were not detected.

Facilitation of drug entry into the CNS via transient permeation of blood brain barrier: laboratory and preliminary clinical evidence from bradykinin receptor agonist, Cereport.

One novel approach of transporting drugs into the central nervous system (CNS) involves the activation of receptors on the endothelial cells comprising the blood brain barrier (BBB). Recently the selective B(2) bradykinin receptor agonist, Cereport (also called RMP-7), has been shown to transiently increase permeability of the BBB. Although initially developed to increase the permeability of the vasculature feeding glioma, recent studies have demonstrated that Cereport also increases the delivery of pharmacological agents across the normal (i.e. nontumor) BBB. In this review paper, we discuss evidence of enhanced CNS delivery of carboplatin, loperamide, and cyclosporin-A, which are accompanied by enhanced chemotherapeutic, analgesic and neuroprotective effects, respectively. These observations suggest feasibility of Cereport as an adjunct therapy to pharmacological treatments that require drug availability in the CNS to exert therapeutic efficacy. Because many potential drugs for CNS disorders normally do not cross the BBB, Cereport-induced transient permeation of BBB stands as an efficacious strategy for enhancing pharmacotherapy.

Actions of bradykinin on electrical and synaptic behavior of neurones in the myenteric plexus of guinea-pig small intestine.

1. Electrophysiologic methods were used to study actions of bradykinin (BK) in neurones of the myenteric plexus of guinea-pig small intestine in vitro. Exposure to BK depolarized the membrane potential and elevated excitability in AH- and S-type neurones. Neuronal input resistance associated with the depolarizing responses was either decreased or unchanged in S-type and increased in AH-type neurones. 2. The selective B(2) BK receptor antagonist HOE-140, but not the selective B(1) receptor antagonist des-arg(10)-HOE-140, suppressed the BK-evoked responses. RT-PCR confirmed the expression of B(2) receptor mRNA, but not B(1) receptor mRNA. 3. Binding of fluorescently- labeled HOE-140 (HOE741) was localized to ganglion cells in whole-mount preparations. BK B(2) receptors were coexpressed with immunoreactivity for calbindin or nitric oxide synthase. 4. Exposure to BK suppressed the amplitude of both fast and slow excitatory postsynaptic potentials. Depolarizing responses evoked by application of serotonin or substance P and nicotinic responses to acetylcholine were not reduced by BK. This suggested that BK action on neurotransmission was presynaptic suppression of neurotransmitter release. Presence of HOE-140 in the bathing solution suppressed or abolished the presynaptic inhibitory action of BK. 5. The cyclooxygenase inhibitor, piroxicam, suppressed both the direct excitatory action of BK and its presynaptic inhibitory action. Application of prostaglandin E(2), D(2), F(2alpha) or I(2) mimicked the BK-evoked responses. 6. The results suggest that BK acts at B(2) BK receptors on myenteric neurones to stimulate the formation of prostaglandins. Once formed and released, the prostaglandins act to elevate the excitability of ganglion cells in the myenteric plexus and to suppress the synaptic release of neurotransmitters.