Interstitial Cells of Cajal (ICC) are pacemaker cells that generates slow waves and drive spontaneous mechanical contractions of gastrointestinal smooth muscle. Slow waves are generated the periodic activation of spontaneous inward currents (pacemaker currents). We studied the modulation of pacemaker activities by bradykinin (10-8 M) in cultured ICC with the whole cell patch-clamp technique, and the localization of bradykinin-2 receptor-immunoreactivity using double labelling immunohistochemistry in the murine small intestine. Externally applied bradykinin produced membrane depolarization in current-clamping mode. At a -70 mV of holding potential bradykinin increased tonic inward pacemaker currents. Double labelling with bradykinin-2 receptor and and c-kit was shown that ICC expressed the bradykinin-2 receptor-immunoreactivity. These results suggest that bradykinin modulates electrical activities of ICC via bradykinin-2 receptor, which may regulate gastrointestinal motility.
Animals ; Bradykinin* ; Gastrointestinal Motility ; Immunohistochemistry ; Interstitial Cells of Cajal* ; Intestine, Small* ; Membranes ; Mice* ; Muscle, Smooth ; Patch-Clamp Techniques ; Receptors, Bradykinin*

OBJECTIVETo study the expression of bradykinin and its receptors B1R and B2R in the kidney immune injury in trichloroethylene-sensitized mouse and discuss the pathogenesis of Dermatitis Medicamentosa-like of TCE (ODMLT).

METHODSOn the first days, intradermal injection by 50% TCE and the amount of FCA mixture 100 µl for initial sensitization; on 4, 7, 10 days, painted abdominal skin by 100 µl 50% TCE for three sensitization, on 17, 19 days, painted on the back skin by 100 µl 30% TCE for initial excitation and the last challenge; 24 h before each challenge, PKSI-527+TCE group received intraperitoneal injection by inhibitor PKSI-527 (50 mg/kg); solvent control group treat without TCE and sensitization and excitation reagent the same proportion of olive oil and acetone mixture, blank control group without any treatment. Before killing the mouse, renal weight and body weight were recorded. The renals and plasma were separated at 24 h, 48 h, 72 h and 7 d after the last challenge and observed pathological of the renals. Expression of B1R and B2R in renal were examined by immunofluorescence technique. Plasma were examined by ELISA for BK.

RESULTSThe renal pathological examination revealed the apparent damage of TCE sensitized mice which compared to solvent control group showed obvious cellular infiltration, vacuolar degeneration of renal tubular epithelial cells. The renal damage of PKSI-527+TCE-sensitized groups which compared to the corresponding point of TCE-sensitized groups showed significantly reduced. The expression of BK in 24 h, 48 h and 72 h TCE-sensitized groups were significant higher than solvent control group and related TCE non-sensitized groups (P < 0.05) and 72 h point compared to the corresponding point of PKSI-527+TCE group was also increased, the difference was statistically significant (P < 0.05). The expression levels of B1R and B2R in the kidney in 24 h, 48 h, 72 h and 7 d TCE-sensitized groups were obviously higher than solvent control group and related TCE non-sensitized groups. The expression levels of B1R and B2R in the kidney in the four point of PKSI-527+TCE sensitized group were relatively lower than the corresponding point of TCE sensitized group.

CONCLUSIONKKS activation may involved in the renal immune injury of trichloroethylene-sensitized mouse and the expression change of bradykinin and its receptors B1R and B2R which may play an important role in the process.

Administration, Cutaneous ; Animals ; Bradykinin ; metabolism ; Kidney ; drug effects ; metabolism ; pathology ; Mice ; Phenylalanine ; analogs & derivatives ; Receptor, Bradykinin B1 ; metabolism ; Receptor, Bradykinin B2 ; metabolism ; Solvents ; Tranexamic Acid ; analogs & derivatives ; Trichloroethylene ; toxicity

OBJECTIVE: To find out wheather the substance P takes part in the pain mediating system of uterus, and to ascertain the role of substance P in the hypersensitivity of hypogastric nerve to bradykinin during the uterine inflammation. METHODS: The uterus has two sensory innervations, which are the hypogastric nerve and the pelvic nerve. Since the hypogastric nerve is known to show increased sensitivity to bradykinin, a pain mediator, when the uterus is in inflammatory state, the hypogastric nerve recording was done for electrophysiological study of uterine pain-mediating mechanism in female SD rats (200-250 g). NK1 receptor antagonist (L-703,606) was injected through uterine artery before injecting bradykinin while uterus was under inflammation. RESULTS: The NK-1 receptor antagonist (L-703,606) decreased the spontaneous nerve impulse during inflammation, and it also decreased the hypersensitivity of the hypogastric nerve to bradykinin during the uterine inflammation. CONCLUSION: Substance P mediates the pain sense of hypogastric nerve, and it also plays a role in increased sensitivity of hypogastric nerve to bradykinin while uterus is in inflammatory state.
Action Potentials ; Animals ; Bradykinin* ; Female ; Humans ; Hypersensitivity ; Inflammation ; Mustard Plant* ; Negotiating ; Rats* ; Receptors, Neurokinin-1* ; Substance P ; Uterine Artery ; Uterus*

Pharmacotherapy for the treatment of heart failure has advanced considerably in recent years, and clinical trials have demonstrated the favorable long-term effects of angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers on the morbidity and mortality. Although the current guidelines recommend ACEI and beta-blockers as standard therapy for heart failure, as they have demonstrated benefits in terms of mortality, only one third of patients with heart failure are receiving both classes of drug due to concern over their adverse effects. The benefit of ACEI has been attributed largely to blockade of angiotensin II production, but also to the accumulation of bradykinin. The accumulation of bradykinin however, has been implicated as contributing to adverse effects, such as a dry cough, associated with ACEI treatment, and has also been suggested to result in prejunctional norepinephine release. Recently, many clinical trials have shown that angiotensin receptor blockers (ARBs) had similar effect on the mortality and morbidity of patients with heart failure. The side effects, notably the cough, are significantly less than with ACE inhibitors. ARBs could also be recommended for patients who can not tolerate ACE inhibitors for symptomatic treatment. In combination with ACEI, ARBs may improve the symptoms of heart failure, and reduce hospitalizations due to heart failure deterioration. Whether concomitant beta-blockade negatively affects the effect of ARB will require further evaluation. In this paper, recent large clinical trials of ARBs therapy in heart failure, and the ongoing clinical trials, were reviewed for the recommendation of the optimal conditions for ARBs treatment in heart failures.
Angiotensin II* ; Angiotensin Receptor Antagonists* ; Angiotensin-Converting Enzyme Inhibitors ; Angiotensins* ; Bradykinin ; Cough ; Drug Therapy ; Estrogens, Conjugated (USP)* ; Heart ; Heart Failure* ; Hospitalization ; Humans ; Mortality ; Receptors, Angiotensin*

The present study was undertaken to investigate the effect of bradykinin on secretion of catecholamines (CA) evoked by stimulation of cholinergic receptors and membrane depolarization from the isolated perfused model of the rat adrenal glands, and to elucidate its mechanism of action. Bradykinin (3 X 10 (-8) M) alone produced a weak secretory response of the CA. however, the perfusion with bradykinin (3 X 10 (-8) M) into an adrenal vein of the rat adrenal gland for 90 min enhanced markedly the secretory responses of CA evoked by ACh (5.32 X 10 (-3) M), excess K+ (5.6 X 10 (-2) M, a membrane depolarizer), DMPP (10 (-4) M, a selective neuronal nicotinic agonist) and McN-A-343 (10 (-4) M, a selective M1-muscarinic agonist). Moreover, bradykinin (3 X 10 (-8) M) in to an adrenal vein for 90 min also augmented the CA release evoked by BAY-K-8644, an activator of the dihydropyridine L-type Ca2+ channels. However, in the presence of (N-Methyl-D-Phe7) -bradykinin trifluoroacetate salt (3 X 10 (-8) M), an antagonist of BK2-bradykinin receptor, bradykinin no longer enhanced the CA secretion evoked by Ach and high potassium whereas the pretreatment with Lys- (des-Arg9, Leu8) -bradykinin trifluoroacetate salt (3 X 10 (-8) M), an antagonist of BK1-bradykinin receptor did fail to affect them. Furthermore, the perfusion with bradykinin (3 X 10 (-6) M) into an adrenal vein of the rabbit adrenal gland for 90 min enhanced markedly the secretory responses of CA evoked by excess K+ (5.6 X 10 (-2) M). Collectively, these experimental results suggest that bradykinin enhances the CA secretion from the rat adrenal medulla evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) and membrane depolarization through the activation of B2-bradykinin receptors, not through B1-bradykinin receptors. This facilitatory effect of bradykinin seems to be associated to the increased Ca2+ influx through the activation of the dihydropyridine L-type Ca2+ channels.
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride ; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester ; Adrenal Glands ; Adrenal Medulla* ; Animals ; Bradykinin* ; Catecholamines ; Dimethylphenylpiperazinium Iodide ; Membranes ; Neurons ; Perfusion ; Potassium ; Rats* ; Receptors, Bradykinin ; Receptors, Cholinergic ; Trifluoroacetic Acid ; Veins

BACKGROUNDS: Pain can occur following acute noxious stimuli and tissue damage. The duration of such pain may outlast the stimulus and its amplitude may be exaggerated (hyperalgesia). This response comes from a sensitization of the peripheral nociceptor. Traditional thought has associated the antinociceptive effects of opiates with the activation of opioid receptors located in the central nervous system. Recently, however, opiate receptors in the peripheral nervous system have led to the hypothesis that analgesic action might, in part, result from a reduction in the response of peripheral nerve fibers thought to be concerned with signaling pain. METHODS: Twenty units were recorded from the strands of the hypogastric nerve innervating the urinary bladder of the cat. Nerve activity and intravesical pressure were monitored before and after the onset of an acute inflammation induced by the intravesical instillation of 2% mustard oil. The responses of afferent units to chemical stimuli by intra-arterially injected bradykinin (10 microgram/0.2 ml., i.a.) and potassium chloride (0.3 M/0.2 ml, i.a.) were compared each time at control, after inflammation, and after administration of morphine (2.5 mg/kg) and naloxone (5 microgram/kg) respectively. RESULTS: Polymodal receptors in the urinary bladder showed excitatory response to algesic substances such as bradykinin, potassium chloride and the urinary bladder contracted simultaneously, both the responses of the nerve impulse and bladder contraction to bradykinin and potassium chloride increased significantly after bladder inflammation induced by 2% mustard oil and the sensitization of the sensory receptors attenuated by morphine and naloxone reversed the effect of morphine. CONCLUSIONS: These observations suggest that morphine might have a peripheral effect.
Action Potentials ; Administration, Intravesical ; Animals ; Bradykinin ; Cats ; Central Nervous System ; Inflammation ; Morphine* ; Mustard Plant ; Naloxone ; Nociceptors ; Peripheral Nerves ; Peripheral Nervous System ; Potassium Chloride ; Receptors, Opioid ; Sensory Receptor Cells* ; Urinary Bladder*

The memory of pain can be more damaging than its initial experience. Several factors are related the directions of pain memory; current pain intensity, emotion, expectation of pain, and peak intensity of previous pain. The possible mechanisms of memory of pain are neuroplastic changes of nervous system via peripheral and central sensitization. Peripheral sensitization is induced by neurohumoral alterations at the site of injury and nearby. Biochemicals such as K+, prostaglandins, bradykinin, substance P, histamine and serotonin, increase transduction and produce continuous nociceptive input. Central sensitization takes place within the dorsal horn of spinal cord and amplifies the nociceptive input from the periphery. The mechanisms of central sensitization involve a variety of transmitters and postsynaptic mechanisms resulting from the activations of NMDA receptors by glutamate, and activation of NK-1 tachykinnin receptors by substance-P and neurokinnin. The clinical result of peripheral and central sensitization is hyperalgesia, allodynia, spontaneous pain, referred pain, or sympathetically maintained pain. These persistent sensory responses to noxious stimuli are a form of memory. The hypothesis of preemptive analgesia is that analgesia administered before the painful stimulus will prevent or reduce subsequent pain and analgesic requirements in comparison to the identical analgesic intervention administered after the painful stimulus, by preventing or reducing the memory of pain in the nervous system. Conventionally, pain management was initiated following noxious stimuli such as surgery. More recently, many have endorsed preemptive analgesia initiated before surgery. Treatments to control postsurgical pain are often best started before injury activates peripheral nociceptors and triggers central sensitization. Such preemption is not achieved solely by regional anesthesia and drug therapy but also requires behavioral interventions to decrease anxiety or stress. Although the benefit of preemptive analgesia is not obvious in every circumstance, and in many cases may not sufficient to abolish central sensitization, it is an appropriate and human goal of clinical practice.
Analgesia* ; Anesthesia, Conduction ; Animals ; Anxiety ; Bradykinin ; Central Nervous System Sensitization ; Drug Therapy ; Glutamic Acid ; Histamine ; Horns ; Humans ; Hyperalgesia ; Memory* ; Nervous System ; Nociceptors ; Pain Management ; Pain, Referred ; Prostaglandins ; Receptors, N-Methyl-D-Aspartate ; Serotonin ; Spinal Cord ; Substance P

Angioedema is a non-pitting edema that occurs in the skin and mucus membranes. It is known that major etiologies include hereditary deficiency of C1 esterase inhibitor, temperature extreme, trauma, food sensitivity, and medications such as penicillin, aspirin, NSAIDS and ACE inhibitors. ACE inhibitors are blocking the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and increasing local levels of bradykinin, a potent vasodilator. This increased bradykinin has been theorized to cause angioedema and cough in patients on ACE inhibitors. However, there has been very few causes of angioedema induced by angiotensin II receptor blocker. This is the first report of a patient presenting angioedema induced by losartan -angiotensin II receptor blocker- in this century.
Angioedema* ; Angiotensin I ; Angiotensin II ; Angiotensin-Converting Enzyme Inhibitors ; Anti-Inflammatory Agents, Non-Steroidal ; Aspirin ; Bradykinin ; Cough ; Edema ; Hereditary Angioedema Types I and II ; Humans ; Losartan* ; Membranes ; Mucus ; Penicillins ; Receptors, Angiotensin ; Skin

In 1965, Melzack and Well proposed the gate-control theory which is based on modern neurophysiological principles. Its clinical application in western medicine remains in the area of pain control to relieve pain in certain diseases such as in the neck, scapula, elbow, wrist, knee, ankle joint pain, low back pain, facial palsy, headache, etc. Recent study, gradually developed in the western countries, has reported that the mechanism of action is by the method of the opiate receptor binding -sites and the release of intrinsic morphine like substances two related pentapeptides, 5HT (5-Hvdr oxyltriptamine), Na-glutamate, and by bradykinine, serotonine, histamine and prostaglandine E, etc. by peripheral nerve stimulation. It seems that the mechanism of stimulation involves neuropliysiological and neurohumoral inhibitory effects at the level of the spinal cord, brain stem (thalamus) and cortex. As yet it is not clear, but further study will improve the understanding of pain mechanisms in developed countries in the near future. Since 1976, the pain clinic in Hanyang University Hospital has used peripheral electrical acupuncture stimulation and found it to relieve pain which had not responded to various drugs and other methods. Here, the techinic and procedure of the treatment are described. The results for the forty-seven cases showed: marked improvement in 27 cases(57. 4%), improvement in 17 cases (36. 2%) and transient improvement in 3 cases (6. 4%).
Acupuncture ; Ankle Joint ; Bradykinin ; Brain Stem ; Developed Countries ; Elbow ; Facial Pain ; Headache ; Histamine ; Knee ; Low Back Pain ; Morphine ; Neck ; Pain Clinics ; Paralysis ; Peripheral Nerves* ; Receptors, Opioid ; Scapula ; Serotonin ; Spinal Cord ; Wrist

Injury or inflammation induces release of a range of inflammatory mediators. Bradykinin is one of the most important inflammatory mediators and plays a crucial role in mediating inflammatory pain. It is well known that multiple ion channels located in the nociceptors participate in pain sensation. Recent studies demonstrate an important role of bradykinin in regulating the function and expression of pain-related ion channels. This paper summarizes the recent advances in the understanding of the role of bradykinin in modulation of the channels and discusses future possibilities in the treatment of inflammatory pain.
Acid Sensing Ion Channels ; Animals ; Bradykinin ; pharmacology ; physiology ; Humans ; Inflammation ; complications ; Inflammation Mediators ; pharmacology ; physiology ; Ion Channels ; KCNQ Potassium Channels ; metabolism ; physiology ; Nerve Tissue Proteins ; metabolism ; Pain ; etiology ; metabolism ; physiopathology ; Receptors, AMPA ; metabolism ; Receptors, N-Methyl-D-Aspartate ; metabolism ; Receptors, Purinergic P2X3 ; metabolism ; Sodium Channels ; metabolism ; TRPA1 Cation Channel ; TRPV Cation Channels ; metabolism ; physiology ; Transient Receptor Potential Channels ; metabolism ; physiology