icatibant and Hypotension

SARS-CoV-2 binds to ACE2 receptors and enters cells. The symptoms are cough, breathlessness, loss of taste/smell and X-ray evidence of infiltrates on chest imaging initially caused by oedema, and subsequently by a lymphocytic pneumonitis. Coagulopathy, thrombosis and hypotension occur. Worse disease occurs with age, obesity, ischaemic heart disease, hypertension and diabetes.These features may be due to abnormal activation of the contact system. This triggers coagulation and the kallikrein-kinin system, leading to accumulation of bradykinin and its derivatives, which act on receptors B1R and B2R. Receptor activation causes cough, hypotension, oedema and release of the cytokine interleukin-6 (IL-6) which recruits lymphocytes. These effects are core features seen in early SARS CoV-2 infection.. In this study, hypoxic patients with COVID-19 with symptom onset ≤7 days will be randomised to either a bradykinin inhibitor (icatibant) or placebo. Patients and investigators will be blinded. The primary outcome will be blood oxygenation, measured by arterial blood sampling. The secondary outcome will be cardiovascular status. Retinal imaging will be performed to assess vessel size. Blood samples will be taken for measurement of inflammatory analyses including IL-6. As a separate substudy, we will also take comparator blood inflammatory samples from a COVID-19-negative cohort.. The study has received the following approvals: West Midlands-Edgbaston Research Ethics Committee. Medicines and Healthcare products Regulatory Agency has issued a clinical trial authorisation. Belfast Health and Social Care Trust is the study sponsor. Results will be made available to participants upon request and findings will be presented and published.. NCT05407597.

Topics: Bradykinin; Cough; COVID-19; Edema; Humans; Hypotension; Interleukin-6; Randomized Controlled Trials as Topic; SARS-CoV-2; Treatment Outcome

The administration of protamine to patients who received heparin during cardiopulmonary bypass (CPB) induces hypotension. Protamine inhibits the carboxypeptidase N-mediated degradation of bradykinin, a peptide that causes vasodilation and tissue-type plasminogen activator (t-PA) release. This study tests the primary hypothesis that blocking the bradykinin B(2) receptor would attenuate protamine-related hypotension.. We conducted a prospective, double-blind, randomized study in 16 adult male patients undergoing elective cardiac surgery requiring CPB and taking an angiotensin-converting enzyme (ACE) inhibitor preoperatively, because ACE inhibition increases bradykinin concentrations during CPB. Subjects were randomized to receive either saline solution (N = 8) or the bradykinin B(2) receptor antagonist HOE 140 (100 mug/kg, N = 8) before the administration of protamine. Mean arterial pressure (MAP) and t-PA activity were measured intraoperatively and before and after protamine administration.. Protamine administration caused a significant increase in bradykinin concentrations in the saline solution group (from 6.0 +/- 1.3 to 10.0 +/- 1.6 fmol/mL, P = .043), as well as the HOE 140 group (from 6.5 +/- 1.8 to 14.3 +/- 4.6 fmol/mL, P = .042). Protamine significantly decreased MAP in the saline solution group (from 69.8 +/- 4.4 mm Hg to a mean individual nadir of 56.1 +/- 2.6 mm Hg, P = .031), but bradykinin receptor antagonism blunted this effect (from 74.3 +/- 3.7 mm Hg to a mean individual nadir of 69.6 +/- 1.2 mm Hg in the HOE 140 group, P = .545). Hence, during protamine infusion, MAP was significantly lower in the saline solution group compared with the HOE 140 group (P = .002). t-PA activity decreased significantly during administration of HOE 140 (from 3.59 +/- 0.31 to 1.67 +/- 0.42 IU/mL, P = .001) but not during saline solution (from 2.12 +/- 0.48 to 1.44 +/- 0.36 IU/mL, P = .214). Similarly, t-PA activity decreased significantly during protamine administration in the HOE 140 group (from 1.67 +/- 0.42 to 0.77 +/- 0.26 IU/mL, P = .038) but not in the saline solution group (from 1.44 +/- 0.36 to 0.99 +/- 0.26 IU/mL, P = .132).. Increased bradykinin contributes to protamine-related hypotension through its B(2) receptor in ACE inhibitor-treated patients.

Topics: Aged; Bradykinin; Bradykinin B2 Receptor Antagonists; Cardiopulmonary Bypass; Double-Blind Method; Female; Fibrinolysis; Hemodynamics; Heparin Antagonists; Humans; Hypotension; Kinins; Male; Middle Aged; Pilot Projects; Postoperative Complications; Protamines

Angiotensin-converting enzyme inhibitors are associated with deleterious hypotension during anesthesia and shock. Because the pharmacologic effects of angiotensin-converting enzyme inhibitors are partly mediated by increased bradykinin B2 receptor activation, this study aimed to determine the impact of acute B2 receptor blockade during hemorrhagic shock in angiotensin-converting enzyme inhibitor-treated mice.. In vivo study.. University research unit.. C57/Bl6 mice.. The hemodynamic effect of B2 receptor blockade using icatibant (B2 receptor antagonist) was studied using a pressure-targeted hemorrhagic shock and a volume-targeted hemorrhagic shock. Animals were anesthetized with ketamine and xylazine (250 mg/kg and 10 mg/kg, respectively), intubated using intratracheal cannula, and ventilated (9 mL/kg, 150 min). Five groups were studied: 1) sham-operated animals, 2) control shocked mice, 3) shocked mice treated with ramipril for 7 days (angiotensin-converting enzyme inhibitors) before hemorrhagic shock, 4) shocked mice treated with angiotensin-converting enzyme inhibitors and a single bolus of icatibant (HOE-140) immediately before anesthesia (angiotensin-converting enzyme inhibitors + icatibant), and 5) shocked mice treated with a single bolus of icatibant. One hour after volume-targeted hemorrhagic shock, blood lactate was measured to evaluate organ failure.. During pressure-targeted hemorrhagic shock, the mean blood volume withdrawn was significantly lower in the angiotensin-converting enzyme inhibitor group than in the other groups (p < 0.001). During volume-targeted hemorrhagic shock, icatibant prevented blood pressure lowering in the angiotensin-converting enzyme inhibitor group (p < 0.001). Blood lactate was significantly higher in the angiotensin-converting enzyme inhibitor group than in the other groups, particularly the HOE groups.. During hemorrhagic shock, acute B2 receptor blockade significantly attenuates the deleterious hemodynamic effect of angiotensin-converting enzyme inhibitor treatment in mice. This beneficial effect of B2 receptor blockade is rapidly reached and sustained with a single bolus of icatibant. This benefit could be of interest in angiotensin-converting enzyme inhibitor-treated patients during both emergency anesthesia and resuscitation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Hypotension; Mice; Mice, Inbred C57BL; Ramipril; Shock, Hemorrhagic

During 2007-2008, serious adverse events were reported following iv administration of certain batches of commercially available heparin in humans. Anaphylactoid reactions with acute hypotension were the hallmark of these cases. Subsequently, it was shown that a contaminant, oversulfated chondroitin sulfate (OSCS), was responsible for these adverse events. The present study was undertaken to further elucidate the risks related to OSCS-contaminated heparin preparations. Using an anesthetized rat hemodynamic model, marked diastolic blood pressure drops were induced with a single iv injection of a contaminated heparin (1000 IU/kg; 34% wt/wt OSCS). OSCS alone (0.8 and 20 mg/kg) or in combination (0.8-1.7 mg/kg) with uncontaminated heparin produced a similar hypotensive effect, whereas heparin spiked with 0.2 or 0.4 mg/kg OSCS produced no hemodynamic changes. In conscious rats, acute hypotensive effects were seen following single iv administration of OSCS-spiked heparin (1.7 or 3.0 mg/kg). Conversely, no hemodynamic effects were observed with same doses when administered sc. Pretreatment with a bradykinin-2 receptor antagonist (HOE140) fully abolished the hypotensive response after iv OSCS (1.7 mg/kg) administration, whereas pretreatment with the histamine (H1) receptor antagonist cetirizine did not. In vitro, OSCS (25 and 250 μg/ml) induced a robust, dose-related increase in kallikrein activity in rat and human plasma with a lower amplitude of response in dog and pig. The data suggest that the adverse events associated with OSCS-contaminated heparin are dependent upon the concentration of contaminant and its route of administration. Furthermore, the kallikrein-kinin system plays a pivotal role in the initiation of OSCS-related vascular effects.

Topics: Anaphylaxis; Animals; Bradykinin; Chondroitin Sulfates; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Contamination; Female; Heparin; Humans; Hypotension; Kallikrein-Kinin System; Male; Rats; Rats, Sprague-Dawley; Swine

The anti-hypertensive peptide Arg-Ile-Tyr, which was isolated based on its inhibitory activity (IC(50)=28microM) for angiotensin I-converting enzyme (ACE) from the subtilisin digest of rapeseed protein, exhibited vasorelaxing activity (EC(50)=5.1microM) in an endothelium-dependent manner in the mesenteric artery of spontaneously hypertensive rats (SHRs). We named the peptide rapakinin. ACE inhibitors are reported to induce nitric oxide (NO)-dependent vasorelaxation by elevating the endogenous bradykinin level; however, the vasorelaxation induced by 10microM of rapakinin was blocked only insignificantly by HOE140 or N(G)-nitro-l-arginine methyl ester (l-NAME), antagonists of bradykinin B(2) receptor and an inhibitor of NO synthase, respectively. On the other hand, the vasorelaxation induced by 10microM rapakinin was significantly blocked by indomethacin and CAY10441, a cyclooxygenase (COX) inhibitor and an antagonist of the IP receptor, respectively. The vasorelaxing activity of rapakinin was also blocked by lorglumide, an antagonist of the cholecystokinin (CCK) CCK(1) receptor, although rapakinin has no affinity for the IP and CCK(1) receptors. The vasorelaxation induced by 10microM iloprost, an IP receptor agonist, was also blocked by lorglumide, suggesting that CCK-CCK(1) receptor system is activated downstream of the PGI(2)-IP receptor system. The anti-hypertensive activity of rapakinin after oral administration in SHRs was also blocked by CAY10441 and lorglumide. These results suggest that the anti-hypertensive activity of rapakinin might be mediated mainly by the PGI(2)-IP receptor, followed by CCK-CCK(1) receptor-dependent vasorelaxation.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Bradykinin B1 Receptor Antagonists; Brassica rapa; Hypotension; Indomethacin; Male; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Peptides; Plant Proteins; Proglumide; Quinazolinones; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Bradykinin B1; Receptor, Cholecystokinin A; Receptors, Prostaglandin; Vasodilation

We have tested the activity of 4-(S)-amino-5-(4-[4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl] piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132), a novel nonpeptide kinin B(2) receptor antagonist, on bradykinin (BK)-induced inflammatory responses, bronchoconstriction, and hypotension in guinea pigs. After i.v. (1-10 nmol/kg i.v.), intratracheal (i.t.) (10-100 nmol/kg i.t.), or aerosol (0.01-0.1 mM/5 min) administration, MEN16132 inhibited in a dose-dependent manner the bronchoconstriction induced by BK (10 nmol/kg i.v.). MEN16132 was more potent and possessed a longer duration of action as compared with the peptide B(2) receptor antagonist icatibant (HOE140; H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH trifluoroacetate). After i.v. administration, its inhibitory effect on bronchoconstriction lasted more than 8 h at 30 nmol/kg. When administered by i.v. or i.t. routes, the dose completely inhibiting bronchoconstriction also partially reduced the hypotensive response to BK, whereas after aerosol administration, the inhibitory effect was limited to respiratory level. Intranasal (i.n.) administration of MEN16132 (0.01-0.3 nmol/nostril) reduced, in a dose-dependent and long-lasting manner, the nasal mucosa plasma protein extravasation induced by BK (100 nmol/nostril), and it exerted a complete inhibition at about 30-fold lower dose than icatibant. At 1 nmol/nostril, MEN16132 activity was significant for at least 6 h with no systemic effect measured as inhibition of BK-induced hypotension, and at 10 nmol/nostril, the inhibitory effect lasted for more than 15 h with only a weak effect on hypotension. These findings indicate that in vivo MEN16132 is a potent kinin B(2) receptor antagonist with long duration of action, both after i.v. and local administration. A complete and prolonged inhibition of BK-induced bronchoconstriction or nasal inflammation can be achieved with MEN16132 topical administration (aerosol or i.n.) at doses devoid of systemic effects.

Topics: Anesthesia; Animals; Blood Pressure; Blood Proteins; Bradykinin; Bradykinin B2 Receptor Antagonists; Bronchoconstriction; Capillary Permeability; Dose-Response Relationship, Drug; Guinea Pigs; Hypotension; In Vitro Techniques; Injections, Intravenous; Male; Microcirculation; Nasal Mucosa; Ornithine; Regional Blood Flow; Sulfonamides

The physiological effects of ACE inhibitors may act in part through a kinin-dependent mechanism. We investigated the effect of chronic ACE-inhibitor treatment on functional kinin B(1)- and B(2)-receptor expression, which are the molecular entities responsible for the biological effects of kinins.. Rats were subjected to different 6-week treatments using various mixtures of the following agents: ACE inhibitor, angiotensin AT(1)-receptor antagonist, and B(1)- and B(2)-receptor antagonists. Chronic ACE inhibition induced both renal and vascular B(1)-receptor expression, whereas B(2)-receptor expression was not modified. Furthermore, with B(1)-receptor antagonists, it was shown that B(1)-receptor induction was involved in the hypotensive effect of ACE inhibition. Using microdissection, we prepared 10 different nephron segments and found ACE-inhibitor-induced expression of functional B(1)-receptors in all segments. ACE-inhibitor-induced B(1)-receptor induction involved homologous upregulation, because it was prevented by B(1)-receptor antagonist treatment. Finally, using B(2)-receptor knockout mice, we showed that ACE-inhibitor-induced B(1)-receptor expression was B(2)-receptor independent.. This study provides the first evidence that chronic ACE-inhibitor administration is associated with functional vascular and renal B(1)-receptor induction, which is involved in ACE-inhibitor-induced hypotension. The observed B(1)-receptor induction in the kidney might participate in the known renoprotective effects of ACE inhibition.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Dinoprostone; Drug Administration Schedule; Enzyme Activation; Hypotension; Irbesartan; Kidney; Male; Mice; Mice, Knockout; Nephrons; Organ Specificity; Ramipril; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; RNA, Messenger; Tetrazoles; Time

We have compared the in vivo activity of the bradykinin B(2) receptor peptide antagonists MEN 11270 and Icatibant versus the nonpeptide antagonist FR 173657, after intravenous (i.v.) and intratracheal (i.t.) administration, on the bradykinin (BK)-induced bronchoconstriction and hypotension in anesthetized guinea pigs. We have also assessed the affinity of these antagonists for B(2) receptors in guinea pig lung membranes by radioligand binding and the metabolic stability of peptide antagonists in guinea pig plasma and tissue homogenates. The i.v. administration of MEN 11270, Icatibant, or FR 173657 induced a dose-dependent (10-100 nmol/kg) inhibition of both hypotension and bronchoconstriction induced by bradykinin (10 nmol/kg i.v.). The inhibitory effect of MEN 11270 and Icatibant was comparable both in terms of potency and time course, whereas FR 173657 was less potent and shorter acting. After i.t. administration MEN 11270 and Icatibant (10-100 nmol/kg) dose dependently inhibited both bronchoconstriction and hypotension, whereas FR 173657 (10-100 nmol/kg) reduced bronchoconstriction without affecting hypotension. The antibronchoconstrictor effect of MEN 11270 was more prolonged than that of Icatibant and FR 173657, whereas no differences were found between the peptide antagonists in inhibiting hypotension. These findings indicated that, in vivo, the peptide antagonists are more potent and longer lasting than FR 173657 acting on bradykinin B(2) receptors in guinea pig airways and in the vascular system. The greater efficacy of the antagonists in blocking airway compared with vascular B(2) receptors after topical administration suggests that they can block airway B(2) receptors with little systemic effects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Bronchoconstriction; Cell Membrane; Disease Models, Animal; Drug Interactions; Drug Stability; Guinea Pigs; Hypotension; Infusions, Intravenous; Lung; Male; Oligopeptides; Peptides, Cyclic; Quinolines; Receptor, Bradykinin B2; Tritium

The induction of B(1) receptors (B(1)Rs) and desensitization or down-regulation of B(2) receptors (B(2)Rs) as a consequence of the production of endogenous kinins has been termed the autoregulation hypothesis. The latter was investigated using two models based on the rabbit: kinin stimulation of cultured vascular smooth muscle cells (SMCs) and in vivo contact system activation (dextran sulphate intravenous injection, 2 mg kg(-1), 5 h). Rabbit aortic SMCs express a baseline population of B(1)Rs that was up-regulated upon interleukin-1beta treatment ([(3)H]-Lys-des-Arg(9)-BK binding or mRNA concentration evaluated by RT - PCR; 4 or 3 h, respectively). Treatment with B(1)R or B(2)R agonists failed to alter B(1)R expression under the same conditions. Despite consuming endogenous kininogen (assessed using the kinetics of immunoreactive kinin formation in the plasma exposed to glass beads ex vivo) and producing hypotension mediated by B(2)Rs in anaesthetized rabbits, dextran sulphate treatment failed to induce B(1)Rs in conscious animals (RT - PCR in several organs, aortic contractility). By contrast, lipopolysaccharide (LPS, 50 microg kg(-1), 5 h) was an effective B(1)R inducer (kidney, duodenum, aorta) but did not reduce kininogen reserve. We tested the alternate hypothesis that endogenous kinin participate in LPS induction of B(1)Rs. Kinin receptor antagonists (icatibant combined to B-9858, 50 microg kg(-1) of each) failed to prevent or reduce the effect of LPS on B(1)R expression. Dextran sulphate or LPS treatments did not persistently down-regulate vascular B(2)Rs (jugular vein contractility assessed ex vivo). The kinin receptor autoregulation hypothesis is not applicable to primary cell cultures derived from a tissue known to express B(1)Rs in a regulated manner (aorta). The activation of the endogenous kallikrein-kinin system is ineffective to induce B(1)Rs in vivo in an experimental time frame sufficient for B(1)R induction by LPS.

Topics: Anesthesia; Animals; Aorta; Bradykinin; Bradykinin Receptor Antagonists; Captopril; Cells, Cultured; Dextran Sulfate; Dose-Response Relationship, Drug; Gene Expression Regulation; Hypotension; Interleukin-1; Kininogens; Ligands; Lipopolysaccharides; Male; Muscle, Smooth, Vascular; Rabbits; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Vasoconstriction

Footshocks increases mean arterial pressure and heart rate. Systemic or intracerebroventricular (IVT) administration of losartan, a specific angiotensin AT1 receptor antagonist, not only inhibited the pressor response to footshocks but resulted in vasodepression. Peripheral or IVT administration of PD 123319, a specific angiotensin AT2 receptor antagonist, did not alter the haemodynamic response to footshocks. However, simultaneous blockade of angiotensin AT1 and AT2 receptors by combined systemic or central administration of losartan and PD 12319, eliminated the vasodepressor response to footshocks unmasked in losartan pretreated rats. Our data suggest that activation of peripheral or brain angiotensin AT2 receptor mediated the vasodepressor response to footshocks in the presence of angiotensin AT1 receptor antagonist. We studied the role of kinins and nitric oxide in the vasodepressor response observed after footshocks. The decrease in mean arterial pressure observed after footshocks in losartan treated rats was blunted by systemic or IVT administration of icatibant (HOE 140) or N(G)-nitro-L-arginine-methyl ester, indicating that peripheral or brain kinins and nitric oxide are involved in the hypotensor response to footshocks during angiotensin AT1 receptor blockade. Our results suggest a role for angiotensin AT2 receptor in the regulation of arterial blood pressure, possibly through the release of vasodilator autacoids such as bradykinins and nitric oxide.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Drug Administration Routes; Enzyme Inhibitors; Hot Temperature; Hypertension; Hypotension; Imidazoles; Losartan; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Shock; Vasodilation

Previous studies have shown that an intravenous infusion of dextran sulfate (DXS) causes arterial hypotension via release of bradykinin (BK) and stimulation of bradykinin B2 receptors in pigs. The bradykinin B1 receptor is not physiologically present but its expression can be induced by bacterial lipopolysaccharide (LPS). This study was designed to assess the relative roles of bradykinin B2 and B1 receptors in the hypotensive response produced by DXS in LPS-treated pigs. In LPS-treated pigs a continuous infusion of DXS produced a progressive drop in blood pressure that peaked at approximately 30 min after onset of the infusion and returned to baseline after another 30 min. In animals receiving the selective B2 receptor antagonist Hoe-140 a significant attenuation of the peak fall in blood pressure to DXS was observed. In pigs treated with Hoe-140 and the selective B1 receptor antagonist CP-0298 (Lys(0)-Leu(8)-des-Arg(9)-bradykinin) DXS infusion had no effect on blood pressure. This is the first demonstration in vivo that following activation of the contact system both B2 and B1 receptors are involved in the resulting hypotensive response. This would be consistent with the production of BK (which stimulates B2 receptors) that is subsequently converted to the biologically active metabolite des-Arg(9)-BK in sufficient concentrations to activate B 1 receptors. The significance of these observations to pathophysiology remains to be determined.

Topics: Adrenergic beta-Antagonists; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Dextran Sulfate; Endotoxemia; Hypotension; Lipopolysaccharides; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Swine; Up-Regulation

The effects of N-type calcium channel inhibition with omega-conotoxin GVIA (omega-CTX) on cardiovascular parameters and vagally mediated autonomic reflexes and the role of the renin-angiotensin system were assessed in conscious rabbits. Omega-CTX (10 microg/kg, i.v.) resulted in hypotension, tachycardia, and attenuation of the sympathetic and vagal components of the baroreceptor-heart rate reflex (baroreflex). In the control group (no pretreatment), the peak decrease in mean arterial pressure (MAP) of 13 +/- 3 mm Hg from 72 +/- 2 mm Hg occurred after 33 +/- 3 min, with a corresponding tachycardia of 80 +/- 20 beats/min (n = 6). The tachycardia was due to vagal withdrawal, as a similar increase in heart rate (84 +/- 8 beats/min) after omega-CTX was observed after pretreatment with the beta-adrenoceptor antagonist, propranolol (n = 6). Angiotensin-converting enzyme (ACE) inhibition with enalaprilat revealed a larger, more rapid decrease in MAP in response to omega-CTX (-19 +/- 4 mm Hg from 65 +/- 1 mm Hg after 18 +/- 2 min; n = 6) compared with the control group. Similar larger decreases in MAP were also observed in the presence of the AT1-receptor antagonist, losartan, or the bradykinin B2 receptor antagonist, HOE-140 (n = 5-6). Pretreatment with enalaprilat, losartan, or HOE-140 caused a 50% decrease in the reflex tachycardia after omega-CTX compared with that observed in the control group, and omega-CTX caused a greater attenuation of the vagal component of the baroreflex and a decrease in the bradycardia evoked by the Bezold-Jarisch-like reflex. Also, there was a significant decrease in the bradycardia induced by the nasopharyngeal reflex after omega-CTX in the presence of ACE inhibition and HOE-140. Thus in the conscious rabbit, angiotensin II and bradykinin have a role in attenuating and slowing the hypotensive effect of N-type calcium channel inhibition. Vagolytic effects of omega-CTX on the baroreflex are augmented, and on other vagal reflexes are unmasked, via inhibition of the renin-angiotensin system. The complexity and mechanism of the interaction between N-type calcium channels and the renin-angiotensin system remain to be elucidated.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Baroreflex; Blood Pressure; Bradykinin; Calcium Channel Blockers; Dose-Response Relationship, Drug; Enalaprilat; Heart Rate; Hypotension; Losartan; Nasopharynx; omega-Conotoxin GVIA; Peptides; Pressoreceptors; Propranolol; Rabbits; Renin-Angiotensin System

Bradykinin binds to its receptor at target organs and exerts a wide spectrum of biological activities including vasodilation, smooth muscle contraction and relaxation, pain, and inflammation. To gain a better insight into the physiological function of this potent vasoactive peptide, we created transgenic mice that harbor the human bradykinin B2 receptor transgene under the control of the Rous sarcoma virus 3'-LTR promoter (RSV-cHBKR). Expression of HBKR in these transgenic mice was identified in the aorta, brain, heart, lung, liver, kidney, uterus, and prostate gland by reverse transcription-polymerase chain reaction Southern blot analysis. Two transgenic mouse lines expressing the human B2 receptor resulted in a significant reduction of blood pressure (84.2 +/- 0.6 mm Hg, n = 28; 76.9 +/- 0.8 mm Hg, n = 24; P < .001) compared with the control littermates (96.9 +/- 0.4 mm Hg, n = 52). Administration of Hoe 140, a bradykinin B2 receptor antagonist, restored the blood pressure of the transgenic mice to normal levels within 1 hour, and the effect diminished within 4 hours. The transgenic mice displayed enhanced blood pressure-lowering effect induced by a bolus intra-aortic injection of kinin and showed increased response in kinin-induced uterine smooth muscle contractility compared with control littermates. These studies show that overexpression of human bradykinin B2 receptor causes a sustained reduction of blood pressure in transgenic mice. They also suggest that the B2 receptor-mediated signal transduction pathway plays a role in blood pressure regulation.

Topics: Adrenergic beta-Antagonists; Animals; Avian Sarcoma Viruses; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cell Line; Female; Humans; Hypotension; Mice; Mice, Transgenic; Muscle, Smooth; Phenotype; Receptor, Bradykinin B2; Receptors, Bradykinin; Repetitive Sequences, Nucleic Acid; Transfection; Uterine Contraction

This study has investigated the oral activity, following intragastric administration, of three potent and long-acting peptide-based bradykinin antagonists, HOE-140, B9430, and CP-0597, in the anesthetized rat, using bradykinin-induced hypotension. Two of the three bradykinin antagonists, B9430 and HOE-140, but not CP-0597, were found to be active following intragastric administration, producing dose-dependent (1, 3, and 10 mg/kg) and selective inhibition of bradykinin-induced hypotension. At a dose of 10 mg/kg, the inhibition of bradykinin-induced hypotension occurred within 15 min and lasted for at least 2 h, which was the duration of the experiment. HOE-140 and CP-0597, 10 micrograms/kg i.v., produced significant inhibition of bradykinin-induced responses that lasted for 60 min. B9430, 10 micrograms/kg i.v., produced a significantly greater inhibition than HOE-140 and CP-0597, this inhibition being significant for the duration of the experiment (2 h) compared with saline controls. Considering the close chemical structure of CP-0597 compared with HOE-140 and B9430, it is not clear as to why CP-0597 was inactive via the intragastric route. This is the first demonstration of the oral activity of peptide-based bradykinin antagonists following intragastric administration in the rat.

Topics: Administration, Oral; Animals; Biological Availability; Bradykinin; Dose-Response Relationship, Drug; Hypotension; Male; Oligopeptides; Rats; Rats, Sprague-Dawley

Topics: Anesthesia; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Guinea Pigs; Hypotension; Naphthalenes; Organophosphorus Compounds; Rabbits; Receptor, Bradykinin B2; Receptors, Bradykinin

Inhibition of angiotensin-converting enzyme (ACE) inhibits formation of angiotensin II and, by inhibition of kinin metabolism, may also increase vascular bradykinin. The present experiments were done in sodium-depleted, conscious, unrestrained marmosets (n = 5-11) to examine the contribution of bradykinin to ACE inhibitor-induced hypotension. Aortic blood pressure and heart rate (HR) were monitored via telemetry. After sodium depletion (low-sodium diet and furosemide), captopril (1 mg/kg po) caused a significant (P < 0.05) decrease in mean arterial blood pressure (MABP) (-34 +/- 3 mmHg, maximally, from 79 +/- 2 mmHg) but no change in HR compared with vehicle treatment. The bradykinin receptor antagonist HOE-140 (1 mg/kg sc) significantly inhibited the hypotensive response to captopril and caused marked tachycardia (+133 +/- 14 beats/min from 214 +/- 8 beats/min). HOE-140 (1 mg/kg sc) followed by vehicle administration had no effect on MABP but increased HR similarly. The hypotensive response to captopril was inhibited by HOE-140 regardless of the order of administration or the route of captopril administration (by mouth vs. subcutaneously). The hypotensive response to a renin inhibitor, A-72517 (3 mg/kg sc), was not inhibited by prior HOE-140 administration despite a similar HOE-140-induced tachycardia. These data suggest that the hypotensive effect of captopril in sodium-depleted, conscious marmosets is dependent on functional bradykinin B2 receptors. Also, blockade of B2 receptors uncovers marked tachycardia in this model, suggesting a tonic effect of bradykinin on control of HR in marmosets.

Topics: Administration, Oral; Animals; Blood Pressure; Bradykinin; Callithrix; Captopril; Female; Hypotension; Injections, Subcutaneous; Male; Piperazines; Renin; Sodium; Thiazoles

1. The aim of this study was to clarify the role of endogenous bradykinin (BK) in the hypotensive response induced by lipopolysaccharide (LPS) by comparing the degree of hypotension caused by LPS in a strain of specific pathogen-free (SPF) Brown Norway (B/N), kininogen-deficient mutant Katholiek rats with that of B/N normal Kitasato rats. 2. The dose-dependent hypotensive responses caused by intravenous injection of BK (1-100 nmol kg-1) or platelet-activating factor (PAF, 0.003-1 microgram kg-1), were not different in the two strains of rats used. However, there was a strong difference in the hypotensive response induced by LPS in kininogen-deficient and normal rats; in normal rats the hypotensive response was composed of two phases (15 min and 70-80 min after LPS injection), but in kininogen-deficient rats LPS caused a delayed (second phase), but not an acute (first phase) hypotension. 3. We demonstrate that Hoe 140 (1 mg kg-1, i.v.) is a potent, selective, and long-lasting antagonist of the hypotensive effects of BK. Hoe 140 diminished the hypotension caused by LPS in normal rats to the level observed in kininogen-deficient rats, but had no effect on the hypotension caused by LPS in kininogen-deficient rats. 4. TCV309 (0.1 mg kg-1, i.v.) selectively inhibited the hypotension caused by repetitive injection of PAF for up to 180 min. Pretreatment with TCV309 caused a near complete inhibition of the LPS-induced hypotension in kininogen-deficient and normal B/N rats. 5. In the normal rats, dexamethasone (0.5 mg kg-1, i.p.) inhibited the second phase of the hypotension induced by LPS, but not the first phase of the hypotension. 6. A small amount of BK (0.1 nmol kg-1) potentiated the hypotensive action of PAF (0.01 microg kg-1),when they were injected simultaneously.7. In conclusion, we demonstrate that formation of endogenous BK contributes primarily to the acute,but not to the delayed hypotension afforded by endotoxin in the rat. In contrast, formation of endogenous PAF contributes to both the acute and the delayed hypotension afforded by endotoxin in vivo.

Topics: Amino Acid Sequence; Animals; Bradykinin; Dose-Response Relationship, Drug; Endotoxins; Hypotension; Isoquinolines; Kininogens; Lipopolysaccharides; Male; Molecular Sequence Data; Platelet Activating Factor; Pyridinium Compounds; Rats; Rats, Inbred BN; Rats, Mutant Strains; Rats, Sprague-Dawley; Reference Values; Tetrahydroisoquinolines

The involvement of bradykinin and nitric oxide (NO) in the early (within 1 h) hemodynamic effects of bacterial lipopolysaccharide (LPS) were investigated in anaesthetised rats. Infusion of rats with LPS (14 mg/kg/h) produced a transient hypotension (nadir at 20 min) and reduced pressor responses to noradrenaline (NA,.1-1 microgram/kg, intravenously (i.v.)). Pretreatment of rats with NG-nitro-L-arginine methylester (L-NAME, 1 mg/kg, i.v.) produced a hypertension which counteracted but did not abolish the hypotension induced by LPS, although it entirely prevented LPS-induced hyporeactivity to NA. In control rats, the bradykinin B2 receptors antagonist HOE 140 (10 nmol/kg, i.v.) produced a transient hypotension, but it did not modify the reactivity to NA. In rats pretreated with HOE 140, subsequently infused with LPS, the drop in blood pressure and its time course after the onset of LPS infusion were not different from those elicited by HOE 140 or LPS separately. In addition, HOE 140 partially prevented the onset of hyporesponsiveness to NA induced by LPS. These results support the view that both bradykinin and NO are involved in the early hyporesponsiveness to NA. They suggest that other mechanisms than NO release are involved in the early hypotensive effects of LPS.

Topics: Animals; Arginine; Bradykinin; Bradykinin Receptor Antagonists; Hemodynamics; Hypotension; Lipopolysaccharides; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Norepinephrine; Rats; Rats, Wistar; Receptor, Bradykinin B2; Shock, Septic

1. In a previous investigation, Hoe 140, a specific and potent bradykinin B2 receptor antagonist, prevented the pancreatic oedema and the hypotension observed during acute experimental pancreatitis; however, it augmented the associated rises in the serum activities of pancreatic enzymes. Therefore, we have now investigated the consequences of the pancreatic oedema for the fate of activated enzymes released into the tissue during the course of acute pancreatitis. 2. Acute oedematous pancreatitis was induced in rats, pretreated with captopril (50 mumol kg-1, i.p.), by hyperstimulation of the exocrine function of the pancreas with the cholecystokinin analogue, caerulein (4 nmol kg-1 h-1, i.v.), for up to 120 min. 3. Pancreatic oedema began to develop 10 min after the start of the caerulein infusion, reached a maximum within about 45 min, and then declined slightly. The development of the oedema parallelled the second phase of the caerulein-induced fall in blood pressure found in earlier experiments. No further extravasation of plasma proteins occurred during the 2nd hour of the caerulein infusion. The oedema formation was completely blocked in animals pretreated with the bradykinin receptor antagonist, Hoe 140 (100 nmol kg-1, s.c.). Pretreatment with aprotinin or soy bean trypsin inhibitor did not result in a significant inhibition of the oedema. 4. The haematocrit of animals with experimental pancreatitis showed a pronounced increase which started 10 min after the start of the caerulein infusion and reached maximal values at 60 min. The changes in haematocrit showed a reduction in total blood volume of 28% due to a 48% loss of plasma. This effect was completely blocked by Hoe 140. 5. In rats with caerulein-induced pancreatitis, there was a time-dependent increase in the activities of amylase and lipase in blood serum as well as in the pancreas. Pretreatment with Hoe 140 greatly augmented the caerulein-induced rise in enzyme activities in blood serum but potently attenuated it in the pancreas. The activities of trypsin in both the blood serum and the pancreas were below or near the limit of detection in all experimental groups.6. It is concluded that the second phase of hypotension in this model of acute pancreatitis is due to the liberation of kinins which cause a massive loss of blood plasma into the pancreas and into the retroperitoneal space. Activated enzymes are trapped in the pancreas, at least in part, by the oedema of the gland. Treatment with Hoe 1

Topics: Acute Disease; Animals; Bradykinin; Edema; Female; Hematocrit; Hypotension; Pancreas; Pancreatitis; Protease Inhibitors; Rats; Rats, Sprague-Dawley

Topics: Bradykinin; Humans; Hypotension; Kallidin; Kallikreins; Muscle Contraction; Muscle, Smooth; Oligopeptides