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D C Manning

Publications and source records attributed to D C Manning.

13 recordsLinked to original sources
PubMed1992

The effects of bradykinin and sequence-related analogs on the response properties of cutaneous nociceptors in monkeys.

The endogenous peptide bradykinin is found in plasma and inflammatory exudates and has been implicated as a chemical mediator of inflammatory pain and hyperalgesia. Two subtypes of bradykinin receptors, B1 and B2, have been described, and antagonists for the receptor subtypes have been synthesized. The bradykinin analogs [desArg9,Leu8]BK and DArg[Hyp3,DPhe7]BK have been reported to have antagonist activity at the B1 and B2 bradykinin receptors in smooth muscle, respectively. Behavioral studies in rats indicate that the bradykinin analogs can block the algesic effects of bradykinin. We wished to determine the effects of bradykinin and the bradykinin analogs (B1 and B2 analogs, respectively) on cutaneous nociceptors in the monkey. In addition, we wished to determine the type of bradykinin receptor that mediates the sensitizing effects of bradykinin. Recordings were made from single C-fiber and A-fiber nociceptive afferents (CMHs and AMHs) that innervated hairy skin. Heat sensitivity before and after the injections was determined with a heat test sequence consisting of stimuli that ranged, in 1 degree C increments, from 41 degrees to 49 degrees C. Intradermal injections of vehicle (neutral normal saline) failed to alter the heat response of CMHs. Bradykinin (10 nmol in 10 microliters) evoked activity in 6 of 10 CMHs and sensitized all the fibers to heat stimuli. After the bradykinin injection, the mean heat threshold of the CMHs decreased from 44 +/- 0.5 degrees to 42.7 +/- 0.5 degrees C (mean +/- SEM, p less than 0.02), and the total response to the heat test sequence increased by 87% (p less than 0.002). In a related psychophysical study in human volunteers, the same dose of bradykinin resulted in a comparable (115%) increase in ratings of pain (Manning et al., 1991). Bradykinin also evoked activity in 10 of 17 AMHs and sensitized 8 AMHs to heat stimuli. Bradykinin failed to alter the threshold for activation of CMHs to mechanical stimuli as measured by application of von Frey hairs to the receptive field. In contrast to bradykinin, intradermal injection of the B1 and B2 analogs (10 nmol in 10 microliters) evoked activity in 2 of 6 and 0 of 5 CMHs, respectively. A noteworthy finding was that both analogs enhanced the response of CMHs to heat stimuli by 50% (B1 analog, 1.5 +/- 0.1; B2 analog, 1.5 +/- 0.2). The B1 (n = 10) and B2 (n = 5) analogs did not evoke activity in any of the 15 AMHs tested.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1992

Characterization of kinin receptors on human synovial cells and upregulation of receptor number by interleukin-1.

Bradykinin has been implicated in the pathogenesis of inflammatory arthritis by virtue of its potent proinflammatory properties. We have previously shown bradykinin to be a potent stimulus for the release of prostanoids from interleukin-1 (IL-1)-treated, but not untreated, human synovial cells. We hypothesize that one mechanism by which IL-1 induces responsiveness to bradykinin is by upregulation of number or affinity of kinin receptors on human synovial cells. We performed [3H]bradykinin binding studies in intact human synovial tissue and in cultured human synovial cells. Specific, saturable [3H]bradykinin binding sites in intact synovia were identified by autoradiographic localization and were present in much higher density in rheumatoid, than in osteoarthritis, synovia. In untreated human synovial cells in culture, a single (B2) class of kinin binding sites with a Kd of 2.3 nM and Bmax of 58 +/- 9 fmol/10(6) cells was demonstrated. In matched experiments, IL-1 treatment enhanced specific [3H]bradykinin binding 1.5- to 2.0-fold above that observed in untreated cells. This enhancement was attributable to an increase in Bmax (53 +/- 4 vs. 105 +/- 24 fmol/10(6) cells in untreated and IL-1-treated cells, respectively), rather than an alteration in Kd (1.7 and 1.4 nM, respectively). The potencies of a series of kinin analogs and antagonists and unrelated peptides in displacing [3H]bradykinin from IL-1-treated cells correlated well with their abilities to induce prostanoid release. These studies provide novel information regarding the nature of kinin receptors in intact human synovia and in cultured human synovial cells, their regulation by IL-1 and their role in IL-1-treated cells in kinin-mediated prostaglandin E2 production.

Autoradiography↗
PubMed1991

Pain and hyperalgesia after intradermal injection of bradykinin in humans.

Pain and hyperalgesia, the perceptual campanions of tissue injury and inflammation, are thought to be in part attributable to the sensitization of primary afferent nociceptors by endogenously released chemicals, such as bradykinin. Bradykinin (0.1 to 10 nmol in 10 microliters) evoked a dose-dependent pain, hyperalgesia to heat stimuli, and wheal and flare when injected in a double-blind manner into the volar forearm intradermally. Though hyperalgesia to mechanical stimuli is a conspicuous feature of inflammatory pain, none was measurable for any of the bradykinin doses in response to graded nylon monofilament probes. A second injection of bradykinin (5- or 30-minute intervals) at the same site produced markedly less pain and hyperalgesia to heat stimuli, indicating that the algesic and hyperalgesic effects of bradykinin undergo tachyphylaxis. These findings suggest that bradykinin alone cannot account for all aspects of the hyperalgesia that occurs after inflammation.

Adolescent↗
PubMed1989

Bradykinin receptors localized by quantitative autoradiography in kidney, ureter, and bladder.

We have localized high affinity [3H]bradykinin receptor binding sites by in vitro autoradiography in kidney, ureter, and bladder of the guinea pig. The peptide pharmacology of the binding sites corresponds to that of high affinity physiological bradykinin receptors previously described (Manning, D. C., R. Vavrek, J. M. Stewart, and S. H. Snyder. J. Pharmacol. Exp. Ther. 237:504-512, 1986). In the kidney, receptors are concentrated in the medulla with negligible binding in the cortex. Medullary receptors are localized to the interstitium just beneath the basal membrane of collecting tubule cells and between tubules. In the ureter and bladder, receptors are confined to the lamina propria just beneath the epithelial layer. Localizations in the kidney may relate to the diuretic and natriuretic actions of bradykinin. Ureteral and bladder receptors may be associated with a role of bradykinin in pain and inflammation.

Animals↗
PubMed1988

Bradykinin as a pain mediator: receptors are localized to sensory neurons, and antagonists have analgesic actions.

Autoradiographic studies localize [3H]bradykinin receptor binding sites to the substantia gelatinosa, dorsal root, and a subset of small cells in both the dorsal root and trigeminal ganglia of the guinea pig. [3H]Bradykinin labeling is also observed over myocardial/coronary visceral afferent fibers. The localization of [3H]bradykinin receptors to nociceptive pathways supports a role for bradykinin in pain mediation. Several bradykinin antagonists block bradykinin-induced acute vascular pain in the rat. The bradykinin antagonists also relieve bradykinin- and urate-induced hyperalgesia in the rat paw. These results indicate that bradykinin is a physiologic mediator of pain and that bradykinin antagonists have analgesic activity in both acute and chronic pain models.

Analgesia↗
PubMed1988

Bradykinin analogues: differential agonist and antagonist activities suggesting multiple receptors.

Bradykinin analogues with specific antagonist activity in several bioassays were evaluated for effects on [3H]-bradykinin receptor binding sites and inositol phosphate production in neuroblastoma N1E-115 cells. The analogues varied in their affinities for bradykinin receptors in guinea-pig ileum and N1E-115 cell membranes, in their effects on uterine and ileal contractions and in their agonist or antagonist activity on phosphoinositide turnover in N1E-115 cells. These tissue specific effects suggest the presence of multiple bradykinin receptor subtypes.

Animals↗
PubMed1986

3H-bradykinin binding site localization in guinea pig urinary system.

Bradykinin (BK) causes vasodilation and increases free water and sodium excretion in the kidney and stimulates smooth muscle contraction in the ureter and bladder. Several proposed sites of action for BK include the renal medullary collecting duct, renal blood vessels and the ureter and bladder smooth muscle. This study employs 3H-BK autoradiography to localize the sites of BK action. 3H-BK binding sites in the kidney are localized in the medullary interstitium where BK may produce prostaglandins which mediate its blood flow, natriuretic and diuretic effects. 3H-BK binding sites in the ureter and bladder are localized in the lamina propria below the basal epithelial layer and absent over the muscle layers suggesting an indirect action on urinary tract smooth muscle.

Animals↗
PubMed1986

Two bradykinin binding sites with picomolar affinities.

Bradykinin (BK) and related peptides exert a wide range of effects on several organ systems. We have attempted to sort out these effects by studying the binding interaction of [3H]BK at the membrane level with in vitro receptor binding techniques. High specific activity [3H]BK and an enzyme inhibitor "cocktail" has enabled us to label two BK binding sites with different affinity and peptide specificity in several guinea-pig tissues. In the guinea-pig ileum the high-affinity site has an equilibrium dissociation constant (Kd) for [3H]BK of 13 pM and a maximal number of binding sites of 8.3 pmol/g of tissue wet weight. The low-affinity guinea-pig ileum site displays a Kd of 910 pM, a maximum number of binding sites of 14 pmol/g of tissue wet weight and shows a greater selectivity for BK analogs over Lysyl-BK analogs. Two similar sites can also be discriminated in kidney and heart. The potencies of a series of BK analogs at the high-affinity guinea-pig ileum site correlate well with their potencies in contracting ileal smooth muscle. The binding of [3H]BK in the guinea-pig ileum is inhibited by physiological concentrations of monovalent and divalent cations.

Animals↗
PubMed1981

[3H]Bradykinin receptor binding in mammalian tissue membranes.

[3H]Bradykinin binds to membranes from a variety of mammalian tissues in a saturable fashion with a dissociation constant of about 5 nM. Highest levels of binding are detected in guinea pig ileum, colon, and duodenum and in the oestrus rat uterus. The relative potencies of bradykinin derivatives in competing for these binding sites in guinea pig ileum membranes correlate with their contractile potencies in the ileum better than with contractile effects in the uterus. Thus, receptor recognition sites may differ in ileum and uterus. Monovalent and divalent cations at physiological concentrations reduce [3H]bradykinin binding. Of the monovalent cations, medium lowers binding 50% at about 80 mM. Among the divalent cations, calcium lowers binding about 50% at 5 mM, suggesting a link to the calcium conductance channel.

Animals↗