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This study investigates the association of 5 single nucleotide polymorphisms (SNPs) in selected genes (ABO, VEGFA, BDKRB2, NOS3, and ADRB2) with blood pressure (BP) response to enalapril. The study further assessed genetic interactions that exist within these genes and their implications in enalapril treatment response among South African adults with hypertension. A total of 284 participants belonging to the Nguni tribe of South Africa on continuous treatment for hypertension were recruited. Five SNPs in enalapril pharmacogenes were selected and genotyped using MassArray. Uncontrolled hypertension was defined as BP ≥140/90 mm Hg. The association between genotypes, alleles, and BP response to treatment was determined by fitting multivariate logistic regression model analysis, and genetic interactions between SNPs were assessed by multifactor dimensionality reduction. Majority of the study participants were female (75.00%), Xhosa (78.87%), and had uncontrolled hypertension (69.37%). All 5 SNPs were exclusively detected among Swati and Zulu participants. In the multivariate (adjusted) logistic model analysis, ADRB2 rs1042714 GC (adjusted odds ratio [AOR] = 2.31; 95% confidence interval [CI] 1.02–5.23; P = .044) and BDKRB2 rs1799722 CT (AOR = 2.74; 95% CI 1.19–6.28; P = .017) were independently associated with controlled hypertension in response to enalapril. While the C allele of VEGFA rs699947 (AOR = 0.37; 95% CI 0.15–0.94; P = .037) was significantly associated with uncontrolled hypertension. A significant interaction between rs699947, rs495828, and rs2070744 (cross-validation consistency = 10/10; P = .0005) in response to enalapril was observed. We confirmed the association of rs1042714 (ADRB2) and rs1799722 (BDKRB2) with controlled hypertension and established an interaction between rs699947 (VEGFA), rs495828 (ABO), and rs2070744 (NOS3) with BP response to enalapril. Our findings have provided substantial evidence for the use of SNPs as predictors for enalapril response among South Africans adults with hypertension.

Angioedema is a potentially life-threatening occurrence that is encountered by critical care providers. The mechanistic understanding of angioedema syndromes has improved in recent years, and novel medications are available that improve outcomes from these syndromes. This clinically focused review will describe the underlying genetics, pathophysiology, classification and treatment of angioedema syndromes, with an emphasis on the novel pharmacologic agents that have recently become available for acute treatment.A MEDLINE search was conducted with the MeSH terms angioedema, acquired angioedema, hereditary angioedema type III, and angiotensin converting enzyme inhibitor-induced angioedema.Selected publications describing angioedema, clinical trials, diagnosis, management, and genetics were retrieved (reviews, guidelines, clinical trials, case series), and their bibliographies were also reviewed to identify relevant publications.Data from the relevant publications were reviewed, summarized and the information synthesized.The data obtained were used to describe the current state of diagnosis and management of various angioedema syndromes.Angioedema is a life-threatening syndrome with multiple subtypes, each with a distinct pathophysiology. We present an evidence-based approach to the diagnosis and suggested management of various subtypes of angioedema. Securing the airway remains the most important intervention, followed by administration of both established and more novel pharmacologic interventions based on disease pathology.

Objective— Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Activity of the local kallikrein–kinin system may be important in cardiovascular disease. The effect of kinin B2 receptor (B2R) agonist and antagonist peptides on experimental AAA was investigated. Approach and Results— AAA was induced in apolipoprotein E–deficient mice via infusion of angiotensin II (1.0 μg/kg per minute SC). B2R agonists or antagonists were given via injection (2 mg/kg IP) every other day. The B2R agonist (B9772) promoted aortic rupture in response to angiotensin II associated with an increase in neutrophil infiltration of the aorta in comparison to controls. Mice receiving a B2R/kinin B1 receptor antagonist (B9430) were relatively protected from aortic rupture. Neutrophil depletion abrogated the ability of the B2R agonist to promote aortic rupture. Progression of angiotensin II–induced aortic dilatation was inhibited in mice receiving a B2R antagonist (B9330). Secretion of metalloproteinase-2 and -9, osteoprotegerin, and osteopontin by human AAA explant was reduced in the presence of the B2R antagonist (B9330). B2R agonist and antagonist peptides enhanced and inhibited, respectively, angiotensin II–induced neutrophil activation and aortic smooth muscle cell inflammatory phenotype. The B2R antagonist (B9330; 5 μg) delivered directly to the aortic wall 1 week post-AAA induction with calcium phosphate in a rat model reduced aneurysm growth associated with downregulation of aortic metalloproteinase-9. Conclusions— B2R signaling promotes aortic rupture within a mouse model associated with the ability to stimulate inflammatory phenotypes of neutrophils and vascular smooth muscle cells. B2R antagonism could be a potential therapy for AAA.

Of the 450,000 burn patients each year, 50% have a positive blood alcohol content and this predisposes them to worsened clinical outcomes. Despite high prevalence and established consequences, the mechanisms responsible for alcohol-mediated complications of post burn remote organ damage are currently unknown. To this end, mice received a single dose of alcohol (1.12 g/kg) or water by oral gavage and were subjected to a 15% total body surface area burn. Animals with a burn alone lost ~5% of their body weight in 24 hours whereas intoxicated and burned mice lost only 1% body weight (p

Purpose of review Hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (HAE-C1-INH), HAE with normal C1-INH, and acquired angioedema due to C1-INH deficiency are rare but important diseases that can be associated with significant morbidity and mortality. Research into the pathogenesis of angioedema has expanded greatly and has led to new clinical trials with novel therapeutic agents and strategies. Recent findings Strategies for managing HAE-C1-INH are aimed at treating acute attacks or preventing attacks through the use of prophylactic treatment. Agents available in Europe for treating acute attacks include plasma-derived C1-INH concentrates, a bradykinin B2 receptor (B2R) antagonist, and a recombinant human C1-INH. In the USA, a plasma-derived C1-INH concentrate, a bradykinin B2R antagonist, and a plasma kallikrein inhibitor have been approved for the treatment of acute HAE-C1-INH attacks. C1-INH concentrates and attenuated androgens are used for short-term prophylactic treatment. Long-term prophylactic treatments include attenuated androgens, a plasma-derived C1-INH concentrate, and antifibrinolytics. Plasma-derived C1-INH and a bradykinin B2R antagonist are approved for self-administration at home. Summary The number of management options for HAE-C1-INH and similar conditions has increased considerably within the last few years, thus helping to alleviate the burden of these rare diseases.

OBJECTIVE The role of bradykinin (BK) receptors in activating and sensitizing peripheral nociceptors is well known. Recently, we showed that spinal dynorphin was pronociceptive through direct or indirect BK receptor activation. Here, we explored the potential role of BK receptors in pain associated with persistent pancreatitis in rats. METHODS Experimental pancreatitis and abdominal hypersensitivity were induced by intravenous administrations of dibutyltin dichloride (DBTC). [des-Arg-Leu]BK (B1 antagonist) and HOE 140 (B2 antagonist) were given by intraperitoneal or intrathecal injection. Dynorphin antiserum was given intrathecally. Reverse transcription-polymerase chain reaction was used to detect spinal mRNA for BK receptors. RESULTS Dibutyltin dichloride-induced pancreatitis upregulated B1 and B2 mRNA in the thoracic dorsal root ganglion and B2, but not B1, in the pancreas. No changes in spinal B1 or B2 mRNA were observed. Intraperitoneal or intrathecal administration of HOE 140 dose dependently abolished DBTC-induced abdominal hypersensitivity, whereas [des-Arg-Leu]BK was without effect by either route of administration. Antiserum to dynorphin (intrathecal) abolished DBTC-induced hypersensitivity. CONCLUSIONS These results suggest that blockade of peripheral or spinal BK B2 receptors may be an effective approach for diminishing pain associated with pancreatitis. Moreover, it is suggested that spinal dynorphin may maintain pancreatitis pain through direct or indirect activation of BK B2 receptors in the spinal cord.

Brain edema following subarachnoid hemorrhage (SAH) is a result of impairment of cerebral autoregulation and breakdown of the blood-brain barrier. We investigated the role of bradykinin B2 receptors (BrdB2Rs) on brain edema formation after SAH.In vivo and ex vivo animal study.University research laboratory.Male Sprague-Dawley rats.Rats were subjected to an endovascular perforation of the circle of Willis and were randomly assigned to a) vehicle, b) immediate treatment (30 minutes before and 300 minutes post-SAH) or c) delayed treatment (30 and 300 minutes post-SAH) with the B2 receptor antagonist Anatibant (LF 16-0687 Ms), and d) sham surgery. BrdB2R, kininogen (Kng1), and kallikrein mRNA expression was determined 6 hours after SAH or sham surgery.SAH resulted in a significant increase in brain water content (vehicle: 80.3% +/- 1.2% vs. sham: 79.1% +/- 0.2%, p0.01) after 24 hours. Blockade of BrdB2Rs before SAH significantly prevented brain edema formation (79.0% +/- 0.3%, p0.05) and significantly improved neurologic recovery. BrdB2Rs and Kng1 mRNA were significantly increased 6 hours post-SAH (BrdB2R: 216%; Kng1: 2729%; p0.02 vs. sham). Delayed treatment regimen failed to reduce brain water content and neurologic impairment.Our results indicate that BrdB2Rs play a key role in the initial phase after SAH contributing to brain edema formation. Inhibition of B2 receptors in a posttreatment regimen did not influence brain edema formation. Delayed pathophysiologic processes after SAH seem to be independent of B2 receptors.

Background and Purpose— Brain edema is detrimental in ischemic stroke and its treatment options are limited. Kinins are proinflammatory peptides that are released during tissue injury. The effects of kinins are mediated by 2 different receptors (B1 and B2 receptor [B1R and B2R]) and comprise induction of edema formation and release of proinflammatory mediators. Methods— Focal cerebral ischemia was induced in B1R knockout, B2R knockout, and wild-type mice by transient middle cerebral artery occlusion. Infarct volumes were measured by planimetry. Evan’s blue tracer was applied to determine the extent of brain edema. Postischemic inflammation was assessed by real-time reverse-transcriptase polymerase chain reaction and immunohistochemistry. To analyze the effect of a pharmacological kinin receptor blockade, B1R and B2R inhibitors were injected. Results— B1R knockout mice developed significantly smaller brain infarctions and less neurological deficits compared to wild-type controls (16.8±4.7 mm 3 vs 50.1±9.1 mm 3 , respectively; P 3 vs 50.1±9.1 mm 3 , respectively; P Conclusions— These data demonstrate that blocking of B1R can diminish brain infarction and edema formation in mice and may open new avenues for acute stroke treatment in humans.

Animal models suggest a vasomotor role for the B1 kinin receptor in cardiovascular disease states. In patients with heart failure treated with angiotensin-converting enzyme inhibition (ACEi), or combined B1/B2 receptor antagonism, but not B2 receptor antagonism alone, causes vasoconstriction. However, B1 agonism has no effect on vasomotor or fibrinolytic function. Findings from transgenic animals lacking the B2 receptor suggest that these conflicting data may be explained by cross-talk between B1 and B2 receptors. We hypothesized that B1 stimulation causes vasodilatation and tissue plasminogen activator release in the human forearm when B2 receptor signaling is inhibited. Forearm blood flow was measured in 16 patients with heart failure receiving ACEi. In double-blinded crossover studies, intrabrachial Lys-[Leu8]-des-Arg9-bradykinin (B1 antagonist), lys-des-Arg9-bradykinin (B1 agonist), bradykinin (B2 agonist), and sodium nitroprusside (endothelium-independent vasodilator) were infused alone or with HOE-140 (B2 antagonist). HOE-140 did not affect basal vascular tone or t-PA release, but it abolished bradykinin-induced vasodilatation and t-PA release (P < 0.0001). Blood flow and t-PA release were unaffected by B1 agonism or antagonism in the presence and absence HOE-140. Our findings do not support a role for crosstalk between the B1 and B2 kinin receptors in the human peripheral circulation.

Angiotensin-converting enzyme (ACE) is an ectoprotein able to modulate the activity of a plethora of compounds, among them angiotensin I and bradykinin. Despite several decades of research, new aspects of the mechanism of action of ACE have been elucidated, expanding our understanding of its role not only in cardiovascular regulation but also in different areas. Recent findings have ascribed an important role for ACE/kinin B 2 receptor heterodimerization in the pharmacological properties of the receptor. In this work, we tested the hypothesis that this interaction also affects ACE enzymatic activity. ACE catalytic activity was analyzed in Chinese hamster ovary cell monolayers coexpressing the somatic form of the enzyme and the receptor coding region using as substrate the fluorescence resonance energy transfer peptide Abz-FRK(Dnp)P-OH. Results show that the coexpression of the kinin B 2 receptor leads to an augmentation in ACE activity. In addition, this effect could be blocked by the B 2 receptor antagonist icatibant. The hypothesis was also tested in endothelial cells, a more physiological system, where both proteins are naturally expressed. Endothelial cells from genetically ablated kinin B 2 receptor mice showed a decreased ACE activity when compared with wild-type mice cells. In summary, this is the first report showing that the ACE/kinin B 2 receptor interaction modulates ACE activity. Taking into account the interplay among ACE, ACE inhibitors, and kinin receptors, we believe that these results will shed new light into the arena of the controversial search for the mechanism controlling these interactions.

Peptide kinins are potent vasoactive agents in the microcirculation that might be released after burn injury. The present study was designed to test the hypothesis that Icatibant (JE 049), a potent, selective peptidomimetic bradykinin-B2 receptor antagonist, would reduce the cardiovascular pathology occurring in sheep exposed to 40% total body surface area (TBSA), third-degree burn. Female sheep were surgically prepared for chronic study. After 5 to 7 days' recovery from the operative procedure, they were randomized to five groups: sham (n = 6, noninjured, nontreated), medicated sham (n = 4, noninjured, treated with 20 microg kg h Icatibant), control (n = 7, 40% TBSA third-degree burn, nontreated), Icatibant-4 (n = 6, 40% TBSA third-degree burn, treated with 4 microg kg h Icatibant [low dose]), Icatibant-20 (n = 8, 40% TBSA third-degree burn, treated with 20 microg kg h Icatibant [high dose]). Prefemoral lymph flow (milliliters per hour) remained constant in the sham and medicated sham groups but increased after injury: control (0 h, 3.9 +/- 0.5; 24 h, 28 +/- 4.2; 48 h, 33.0 +/- 8.1). The increased fluid flux was associated with enhanced protein flux. Both low and high doses of Icatibant significantly reduced the microvascular fluid flux: Icatibant-4 (0 h, 5.3 +/- 0.6; 24 h, 17.5 +/- 3.5; 48 h, 20.3 +/- 3.4); Icatibant-20 (0 h, 5.3 +/- 1.1; 24 h, 15.2 +/- 2; 48 h, 17.6 +/- 4.1). Total prefemoral protein leak was reduced in all treatment groups. The low dose of Icatibant significantly reduced prefemoral lymph flow without adversely affecting the hemodynamic changes observed after burn injury in sheep, suggesting that the bradykinin antagonist would reduce edema formation and improve fluid management of thermally injured patients.

Objective This study was designed to investigate the ability of a chronic blockade of angiotensin II type 1 receptors with losartan to reverse the endothelial dysfunction present in Nω-nitro-L-arginine methyl ester (L-NAME)-treated hypertensive rats and the possible dependence of this effect on bradykinin B2-receptor activation. Methods Rats treated with L-NAME alone (60 mg/kg per day for 8 weeks) or with L-NAME + losartan, L-NAME + icatibant (a bradykinin B2-receptor antagonist) and L-NAME + losartan + icatibant were studied. Losartan, icatibant or losartan + icatibant were co-administered with L-NAME during the last 4 weeks of the experiment. Endothelial nitric oxide synthase gene expression in aortic tissues, plasma nitrite/nitrate concentrations, the relaxant effect of acetylcholine on norepinephrine-precontracted aortic rings and 6-keto-PGF1α release from aortic rings were used as markers of the endothelial function. Results Rats treated with L-NAME alone and L-NAME + icatibant showed, as compared with untreated animals, a clear-cut increase in systolic blood pressure and a decrease of all the markers of endothelial function evaluated. In L-NAME-rats, administration of losartan reduced the systolic blood pressure and restored endothelial nitric oxide synthase gene expression, plasma nitrite/nitrate levels, the relaxant activity of acetylcholine on aortic rings and the generation of 6-keto-PGF1α from the aortic tissues. Co-administration of icatibant with losartan blunted the stimulatory effect of losartan on the markers of endothelial function evaluated. Conclusion These results demonstrated that losartan is capable of reversing the endothelial vasodilator dysfunction in L-NAME-induced hypertensive rats, and that the beneficial effect of losartan is mediated by bradykinin B2-receptor activation.

The vascular kallikrein-kinin system contributes to about one third of flow-dependent dilation in mice carotid arteries, by activating bradykinin B 2 receptors coupled to endothelial nitric oxide (NO) release. Because the bradykinin/NO pathway may mediate some of the effects of angiotensin II AT 2 receptors, we examined the possible contribution of AT 2 receptors to the kinin-dependent response to flow. Changes in outer diameter after increases in flow rate were evaluated in perfused arteries from wild-type animals (TK +/+ ) and in tissue kallikrein-deficient mice (TK −/− ) in which the presence of AT 2 receptor expression was verified. Saralasin, a nonselective angiotensin II receptor antagonist, impaired significantly flow-induced dilation in TK +/+ , whereas it had no effect in TK −/− mice. In both groups, blockade of AT 1 receptors with losartan or candesartan did not affect the response to flow. Inhibition of AT 2 receptors with PD123319 reduced significantly flow-induced dilation in TK +/+ mice, but had no significant effect in TK −/− mice. Combining PD123319 with the bradykinin B 2 receptor antagonist HOE-140 had no additional effect to AT 2 receptor blockade alone in TK +/+ arteries. Flow-dependent-dilation was also impaired in AT 2 receptor deficient mice (AT 2 −/− ) when compared with wild-type littermates. Furthermore, HOE-140 significantly reduced the response to flow in the AT 2 +/+ , but not in AT 2 −/− mice. In conclusion, this study demonstrates that the presence of functional AT 2 receptors is necessary to observe the contribution of the vascular kinin-kallikrein system to flow-dependent dilation.

Abdominal aortic banding induces upregulation of the angiotensin II (Ang II) type-2 (AT 2 ) receptor, thereby decreasing the contractile response to Ang II in the thoracic aorta of the rat. The aim of this study was to use a mouse model to clarify the mechanisms by which the banding elicits upregulation of the aortic AT 2 receptor and the subsequent attenuation of Ang II responsiveness. Concomitantly with the elevation in blood pressure and plasma renin concentration after banding, AT 2 -receptor mRNA levels in the thoracic aorta rapidly increased in mice within 4 days. Upregulation of the AT 2 receptor, as well as blood pressure elevation after banding, was abolished by losartan administration. The contractile response to Ang II was depressed in aortic rings of banding mice but not of sham mice, and was restored by either the AT 2 -receptor antagonist PD123319 or the bradykinin B 2 -receptor antagonist icatibant. cGMP content in the thoracic aorta of banding mice was 9-fold greater than that of sham mice, and the elevation was reduced to sham levels 1 hour after intravenous injection of PD123319 or icatibant. When aortic rings were incubated with Ang II, cGMP content increased in banding rings but not in sham rings; the pretreatment with PD123319 or icatibant inhibited Ang II-induced cGMP production. These results suggest that aortic banding induces upregulation of the AT 2 receptor through increased circulating Ang II via the AT 1 receptor, thereby activating a vasodilatory pathway in vessels through the AT 2 receptor via the kinin/cGMP system.

Angioedema of the intestinal tract is an infrequent but well-described cause of abdominal pain that can occur because of inherited, acquired, allergic, or drug-induced causes. Hereditary angioedema (HAE) is a genetic disorder that causes recurrent attacks of severe edema of various body parts, including the intestinal tract. Moderate to severe abdominal pain occurs in 43-93% of such attacks due to intestinal edema. Laryngeal edema is a potentially life-threatening manifestation. Failure to recognize and diagnose HAE or other causes of intestinal angioedema can lead to years of delay in diagnosis, and in the case of HAE, often to unnecessary abdominal surgeries. Recognizing the typical history of recurrent attacks of abdominal pain, oropharyngeal/laryngeal angioedema or cutaneous angioedema, family history of similar symptoms, association of attacks with stress or menses, and exacerbation of attacks after administration of estrogens or angiotensin-converting enzyme inhibitors will increase diagnostic accuracy. Interdisciplinary treatment is often necessary after the diagnosis of HAE, first with acute management in the emergency room or the intensive care unit, followed by either drug prophylaxis against future attacks using a C1-esterase inhibitor concentrate or attenuated androgens and discontinuation of medications known to trigger attacks. Newer drugs approved for treatment of acute attacks may have future roles in the prevention of attacks if further studies support their efficacy. Gastroenterologists in particular should maintain a high index of suspicion for the possibility of HAE or other causes of intestinal angioedema in patients with a history of recurrent abdominal pain.