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D E Clarke

Publications and source records attributed to D E Clarke.

At least 73 records · Page 4Linked to original sources
PubMed1991

Peristalsis evoked by 5-HT and renzapride: evidence for putative 5-HT4 receptor activation.

The effect of 5-hydroxytryptamine and renzapride was studied on the peristaltic reflex elicited in vitro in the guinea-pig ileum. Both agents evoked the reflex at subthreshold intraluminal pressures (50% of threshold) and were blocked by ICS 205-930 (3 microM), but not ondansetron (5 microM). This novel finding suggests strongly that the prokinetic action of renzapride and gut motility stimulating action of 5-hydroxytryptamine are mediated via agonism at the putative 5-HT4 receptor.

Animals↗
PubMed1990

5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine-induced desensitization as a discriminative tool for the 5-HT3 and putative 5-HT4 receptors in guinea pig ileum.

Agonist-induced desensitization has been utilized to discriminate and independently "isolate" the neuronal excitatory receptors to 5-hydroxytryptamine (5-HT) in the guinea pig ileum (5-HT3 and putative 5-HT4 receptors). Electrically stimulated longitudinal muscle myenteric plexus preparations, and non-stimulated segments of whole ileum were used. Exposure to 5-methoxytryptamine (10 mumol/l) inhibited completely responses to 5-HT at the putative 5-HT4 receptor without affecting 5-HT3-mediated responses. Conversely, exposure to 2-methyl-5-HT (10 mumol/l) inhibited completely responses to 5-HT at the 5-HT3 receptor without affecting putative 5-HT4-mediated responses. The inhibition with 5-methoxytryptamine and 2-methyl-5-HT, either alone or in combination, appeared selective as responses to KCl, DMPP, carbachol, histamine, and substance P were unaffected or only very slightly modified. Furthermore, the pA2 values for ICS 205-930 at the putative 5-HT4 (pA2 = 6.2 to 6.5) and 5-HT3 (pA2 = 7.6 to 8.1) receptors (estimated in the presence of 2-methyl-5-HT and 5-methoxytryptamine, respectively) were consistent with those estimated in the absence of desensitization. 5-Methoxytryptamine, but not 2-methyl-5-HT, suppressed completely but reversibly the concentration-effect curve to renzapride, suggesting that responses to this agent are mediated exclusively via agonism at the putative 5-HT4 receptor. It is concluded that 5-methoxytryptamine and 2-methyl-5-HT can be utilized as selective probes to discriminate the putative 5-HT4 receptor from the 5-HT3 receptor in guinea pig ileum. This finding is of importance as no selective antagonist exists for the putative 5-HT4 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Methoxytryptamine↗
PubMed1990

Infectious complications of indwelling long-term central venous catheters.

The long-term CVC allows patients with a variety of diseases to lead a more normal and pain-free life. The use of these catheters has become commonplace in most hospitals, and the physician caring for patients in the ICU will be caring for increasing numbers of patients with an indwelling long-term CVC. Infections of these catheters can be manifested in many different ways: tunnel infections, exit site infections, catheter-related bacteremia, and septic thrombophlebitis. The overwhelming majority of these infections are caused by coagulase-negative staphylococci, but physicians should be aware of the wide variety of organisms that can infect the long-term CVC. The diagnosis of long-term CVC sepsis can be difficult, but the use of quantitative blood cultures for catheters left in place and the Maki method for culturing those catheters that are removed will aid physicians in their quest for diagnostic certainty. The great majority of catheter infections will resolve with antibiotic therapy alone without the need for catheter removal, but there are important exceptions to this general rule. Tunnel infections and fungal long-term CVC infections often require catheter removal for their resolution; septic thrombophlebitis and CR-SCVT require the addition of anticoagulation or fibrinolytic therapy to antibiotic regimens for resolution of the infection, and surgical debridement may be warranted if these modalities fail to resolve the infection.

Catheterization, Central Venous↗
PubMed1990

Antagonist characterization of atypical beta adrenoceptors in guinea pig ileum: blockade by alprenolol and dihydroalprenolol.

The present study was undertaken to further characterize the atypical beta adrenoceptor in guinea pig ileum. Tension was developed in isolated segments of ileum using transmural electrical stimulation of enteric cholingeric nerves. The ability of isoproterenol to relax the ileum, via beta-1 adrenoceptor and atypical beta adrenoceptor agonism, was measured. Propranolol (5 x 10(-6) M) and bromoacetylaprenololmetane blocked beta-1 adrenoceptors but, at the concentrations tested, were without affinity at atypical beta adrenoceptors. (-)-Alprenolol and (-)-dihydroalprenolol, however, acted as competitive antagonists at both sites (pA2 values of 8.2 and 8.81 at beta-1 adrenoceptors and 6.47 and 6.43 at atypical beta adrenoceptors, respectively). (-)-Alprenolol also exerted agonistic activity at the atypical beta adrenoceptor. [3H](-)-Dihydroproalprenolol failed to identify beta-1 adrenoceptors or atypical beta adrenoceptors but, instead, bound to a putative lipophilic site unrelated to ileal adrenoceptors. Before this study, nadolol (pA2 = 4.7) was the only documented antagonist at the atypical beta adrenoceptor in guinea pig ileum. Thus, the present results detail two additional pharmacological probes which exhibit about a 100-fold greater affinity than nadolol for the atypical site.

Adrenergic beta-Antagonists↗
PubMed1990

Semicarbazide-sensitive amine oxidase activity in streptozotocin diabetic rats.

Semicarbazide-sensitive amine oxidase (SSAO) activity was investigated in serum and tissues of streptozotocin diabetic rats. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ, 60 mg/kg) and rats were killed at 1, 3, 7, 9, 14, 28 and 56 days after treatment. STZ increased serum glucose and serum SSAO activity at all time points with a maximal increase (2 to 3 fold) at day 7. Kidney SSAO activity showed significant increases on days 9 and 14 (2.5 and 4 fold, respectively). SSAO activity of aorta, lung and pancreas was not changed significantly. Kinetic analysis showed that the elevation in both serum and kidney SSAO activity was due to an increased Vmax with no change in Km. SSAO activity appears to be selectively increased in the serum and kidney of STZ diabetic rats which may be indicative of a relationship between serum SSAO and early renovascular damage in this animal model of diabetes mellitus.

Amine Oxidase (Copper-Containing)↗
PubMed1990

Pharmacological characterization of a neuronal receptor for 5-hydroxytryptamine in guinea pig ileum with properties similar to the 5-hydroxytryptamine receptor.

Experiments were undertaken to characterize pharmacologically a neuronal receptor to 5-HT in guinea pig ileum. Segments of longitudinal muscle myenteric plexus preparations were treated with phenoxybenzamine and exposed to submaximal electrical field stimulation to evoke the cholinergically mediated "twitch" response. The ability of 5-HT to enhance the submaximal twitch response was investigated. Results using several antagonists (metergoline, spiperone, cyanopindolol, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide, N-hexanoyl-5-hydroxytryptophyl-5-hydroxytryptophan amide, ICS 205-930, GR 38032F, MDL 72222 and cocaine) indicate that 5-HT (3 X 10(-10) to 1 x 10(-7) M) agonizes a novel 5-HT receptor site distinct from the 5-HT1, 5-HT2, 5-HT3 and 5-HT1P subtypes as well as the M receptor. The receptor site is located neuronally and is characterized positively by a low affinity for ICS 205-930 (pA2 = 6.5 vs. 5-HT) and by the following order of agonist potency: 5-HT greater than 5-methoxytryptamine greater than BRL 24924 greater than alpha-methyl-5-hydroxytryptamine greater than zacopride = cisapride = 5-carboxamidotryptamine. Agonist-independent pA2 estimates for ICS 205-930 (6.3-6.6) suggest a single site of agonism. 2-Methyl-5-hydroxytryptamine and 5-hydroxyindalpine were inactive at 1 x 10(-5) M either as agonists or antagonists. Thus, the receptor site exhibits a pharmacological profile similar to that characterizing the recently described 5-HT4 [corrected] receptor. Unlike Gaddum's M receptor, which equates with the 5-HT3 [corrected] receptor, the putative 5-HT4 [corrected] receptor site exhibits a higher sensitivity to agonism by 5-HT and is resistant to antagonism by cocaine.

Animals↗
PubMed1989

Partial agonistic activity of GR43175 at the inhibitory prejunctional 5-HT1-like receptor in rat kidney.

1. The pharmacological effect of the selective 5-HT receptor agonist GR43175 has been studied in the isolated perfused rat kidney with particular reference to the inhibitory prejunctional 5-HT1-like receptor. 2. GR43175 (1 x 10(-8) to 1 x 10(-5) M) inhibited the electrically evoked release of tritium from renal noradrenergic nerves but did not affect the basal (non-stimulated) release of tritium or perfusion pressure. 3. The inhibitory prejunctional action of GR43175, as well as that of 5-HT, was blocked by methiothepin, suggesting that both agonists act at the inhibitory 5-HT1-like site. 4. GR43175, relative to 5-HT, acted as a weak partial agonist at the inhibitory prejunctional 5-HT1-like receptor and antagonized 5-HT-induced inhibition of tritium release, suggesting again that a common site of action is involved. 5. The results support the conclusion that the 5-HT1-like receptor activated by GR43175 in the rat kidney is very similar to that identified in dog saphenous vein and certain other tissues.

Animals↗
PubMed1989

Factors involved in nurses' teaching breast self-examination.

It has been demonstrated that breast self-examination (BSE) is a reliable method for early detection of breast abnormalities when practiced regularly and correctly. In addition, it has been found that a woman is likely to be more proficient if she has been taught BSE by a physician or nurse. In a hospital-based study, nurses were surveyed regarding both their personal practice and their teaching of BSE to patients. Although the nurses revealed themselves to be highly compliant in terms of performing the procedure themselves, only 40% included BSE in their patient teaching. The nurses' teaching of BSE was found to be unrelated to their age, BSE practice, or personal risk for breast cancer. Nurses agreed that BSE was a valuable tool in the prevention of deaths from breast cancer. They also believed themselves to be susceptible to breast cancer despite good health and low-to-medium risk sources. We suggest that nurses' ambivalent attitudes towards breast cancer and BSE may influence their teaching behavior.

Adult↗
PubMed1989

Unsurmountable antagonism to 5-hydroxytryptamine in rat kidney results from pseudoirreversible inhibition rather than multiple receptors or allosteric receptor modulation.

Experiments were conducted in the isolated perfused rat kidney to determine the mechanism of unsurmountable antagonism by metergoline toward the vasoconstrictor response to 5-hydroxytryptamine (5-HT). Three possible mechanisms were investigated: 1) multiple receptors for 5-HT; 2) pseudoirreversible inhibition; and 3) allosteric modulation of 5-HT receptors. Metergoline and six other 5-HT antagonists acted as potent unsurmountable antagonists, only (-)-propranolol acted competitively (pA2 = 6.5). Multiple receptors for 5-HT were ruled out as the mechanism of unsurmountable antagonism because 5-HT and four 5-HT analogs gave similar pA2 values with (-)-propranolol. In addition, the KA value for 5-HT (185 nM) and the order and relativity of agonist potency suggest the presence of a single 5-HT2 receptor. Pseudoirreversible inhibition, over allosteric modulation of the 5-HT2 receptor, is suggested from experiments in which reversal of metergoline-induced inhibition by (-)-propranolol (studied in the presence of metergoline) was matched, in magnitude, by wash-out of metergoline. (-)-Propranolol is suggested to mimic wash-out by occupying and protecting receptors from which metergoline has dissociated. This is accomplished by virtue of its faster kinetics, on-off the 5-HT receptor, allowing restoration of 5-HT responses via a competitive interaction. Pseudoirreversible antagonism, over allosteric receptor modulation, offers an explanation that does not involve the postulation of allosteric effector sites or changes in the state of the 5-HT2 receptor.

Allosteric Regulation↗
PubMed1988

Agonist and antagonist characterization of a putative adrenoceptor with distinct pharmacological properties from the alpha- and beta-subtypes.

1. Experiments were done to characterize a putative adrenoceptor which functions to inhibit longitudinal muscle tension development in the guinea-pig ileum. Several phenylethylamine based agonists were investigated: BRL 37344, (-)-isoprenaline, (+)-isoprenaline, noradrenaline, adrenaline, and fenoterol. Propranolol and nadolol were tested as antagonists. Agonist-induced inhibition of the contractile response to histamine was measured under equilibrium conditions with alpha-adrenoceptors and muscarinic cholinoceptors inhibited. 2. Inhibitory responses were obtained to (-)-isoprenaline and BRL 37344 that were resistant to beta-adrenoceptor blockage with propranolol (5 microM) and nadolol (10 microM). These resistant responses were antagonized by much higher concentrations of nadolol (30 to 1000 microM) yielding apparent pA2 values for nadolol of 4.31 with (-)-isoprenaline as the agonist, and 4.68 with BRL 37344 as the agonist. Similar apparent pA2 values for nadolol at the putative adrenoceptor were obtained with noradrenaline (4.79), adrenaline (4.68), and fenoterol (4.38). 3. The order and relative potency of agonists at the putative adrenoceptor was: BRL 37344 (20) greater than (-)-isoprenaline (8) greater than noradrenaline (1) greater than adrenaline (0.5) greater than fenoterol (0.35) greater than (+)-isoprenaline (0.27). 4. The resistance to blockade by propranolol (5 microM), the low affinity of nadolol, and the order and relative potency of agonists, suggest the presence of an adrenoceptor with distinct pharmacological characteristics from currently defined alpha- and beta-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1987

A response to isoprenaline unrelated to alpha- and beta-adrenoceptor agonism.

The hypothesis that beta-adrenoceptor agonism might explain a reported lack of competitive antagonism between alpha 2-adrenoceptor antagonists and agonists of the phenylethylamine class was tested in the electrically field stimulated ileum of the guinea-pig. The beta-adrenoceptor agonist, isoprenaline, was used as the phenylethylamine and inhibition of 'twitch' response evoked by cholinergic stimulation was measured. In the presence of idazoxan (3 microM), to block inhibitory alpha 2-adrenoceptors, propranolol (0.1 to 5.0 microM) failed to act competitively toward isoprenaline. Isoprenaline responses totally resistant to inhibition by propranolol were obtained. As inhibitory alpha 1-adrenoceptors are absent from guinea-pig ileum, a recognition site distinct from the currently defined alpha- and beta-adrenoceptors is postulated. Agonism by phenylethylamine based agonists at this site may explain their inability to act competitively with alpha- and beta-adrenoceptor antagonists.

Adrenergic alpha-Antagonists↗
PubMed1986

Evidence for a receptor mediated action of norepinephrine distinct from alpha- and beta-adrenoceptors.

The mode of action of (-) norepinephrine (NE) and UK-14,304-18 has been investigated using the cholinergically-evoked 'twitch' response of the electrically stimulated guinea-pig ileum. St 587 and benextramine were employed as antagonists. St 587 acted as a competitive antagonist toward UK-14,304-18, yielding an apparent pA2 value of 7.3. In contrast, St 587 failed to act competitively toward NE. Similarly, benextramine (1 X 10(-5) mol/l) blocked the inhibitory responses to UK-14,304-18 but was considerably less active toward NE. Remaining responses to NE after benextramine were not antagonized by St 587, even at a concentration of 3 X 10(-5) mol/l. It is postulated that NE acts to inhibit the 'twitch' response be evoking two different receptor-mediated events: 1. agonism at the alpha 2-adrenoceptor and 2. agonism at a site which is distinct from the alpha- and beta-subtypes. In the concentrations studied, UK-14,304-18, St 587 and benextramine are postulated to lack affinity for the proposed site. The effect of NE and UK-14,304-18 was also investigated on the contractile responses to exogenously applied histamine. These experiments were done in the presence of muscarinic cholinergic and adrenoceptor blockade. NE inhibited responses to histamine but UK-14,304-18 was inactive. Furthermore, the inhibitory action of NE was stereoselective with the (-) form being 25 times more potent than the (+) enantiomer. These findings suggest the presence of a receptor site for NE which is distinct from cholinergic mechanisms and established alpha and beta-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1986

An inhibitory prejunctional 5-HT1-like receptor in the isolated perfused rat kidney. Apparent distinction from the 5-HT1A, 5-HT1B and 5-HT1C subtypes.

The present study has identified a receptor for 5-hydroxytryptamine (5-HT) which functions to inhibit the stimulus-induced release of [3H] noradrenaline following sympathetic periarterial nerve stimulation to the isolated perfused rat kidney. In addition to 5-HT (IC30 = 4.5 X 10(-8) mol/l), both 5-carboxamidotryptamine (IC30 = 8 X 10(-9) mol/l) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl) indole (RU-24969, IC30 = 2.5 X 10(-7) mol/l) acted as agonists whereas 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was inactive. The inhibitory effect of 5-HT on the electrically-evoked release of tritium was antagonized in a concentration-dependent manner by methiothepin (IC50 = 4 X 10(-9) mol/l), metergoline (IC50 = 4 X 10(-8) mol/l) and methysergide (IC50 = 1.3 X 10(-7) mol/l) but not by cyproheptadine, ketanserin, mesulergine, (-)-propranolol, (+/-)-pindolol, (+/-)-cyanopindolol, metoclopramide or phentolamine. It is concluded that the receptor to 5-HT conforms to general criteria defining 5-HT1-like receptors but at the present time the receptor site cannot be fitted to the designated 5-HT1A, 5-HT1B or 5-HT1C subtypes.

Animals↗
PubMed1986

Responses to norepinephrine resistant to inhibition by alpha and beta adrenoceptor antagonists.

The mode of action of clonidine and norepinephrine (NE) has been investigated in the isolated transmurally stimulated guinea-pig ileum preparation using rauwolscine, idazoxan and benextramine as antagonists. Both clonidine and NE produced concentration-dependent inhibition of the cholinergically induced twitch response and were antagonized by rauwolscine and idazoxan, but only clonidine was antagonized in a truly competitive fashion. Benextramine, an irreversible alpha adrenoceptor antagonist, in a concentration of 10(-5) M, inhibited the effect of clonidine completely but only partially antagonized the inhibitory action of NE. The antagonism of NE by rauwolscine and benextramine was most pronounced after reserpine pretreatment and blockade of neuronal and extraneuronal uptake. Under these conditions, the concentration-effect curve to NE remaining after treatment with benextramine showed an IC50 of about 3 X 10(-7) M and an intrinsic activity of 0.6. This curve was resistant to further inhibition by clonidine (10(-5) M), phentolamine (3 X 10(-6) M), rauwolscine (3 X 10(-6) M), prazosin (10(-6) M) and propranolol (1.2 X 10(-5) M). Thus, alpha and beta adrenergic receptors do not appear to be involved. It is postulated that NE-induced inhibition of the guinea-pig ileum twitch response is mediated by two distinct sites: one is the classical alpha-2 adrenoceptor (the site of action of clonidine and the alpha adrenoceptor antagonists) whereas the other is a site seemingly unrelated to the alpha and beta subtypes.

Adrenergic alpha-Antagonists↗
PubMed1985

Benzylamine oxidase activity in spontaneously hypertensive rats.

Benzylamine oxidase (BzAO) activity was assayed in aorta, atria and serum from 20 week old spontaneously hypertensive (SH) rats and Wistar Kyoto (WKY) control rats. Atrial BzAO activity was reduced by 50% in SH rats compared with WKY control. Aorta and serum BzAO activity did not differ significantly between the two groups. Thus, BzAO activity of serum and cardiovascular tissues appears unrelated to pressure-induced changes in connective tissue production.

Animals↗
PubMed1984

Cardiac norepinephrine releasing action of kynuramine, an endogenous diamine derived from L-tryptophan.

Kynuramine, an endogenous metabolite of L-tryptophan, was found to function as an indirectly acting sympathomimetic amine in rat atria in vitro. Kynuramine released tritium from atria preloaded with [3H]norepinephrine (NE), an effect which was blocked completely by pretreatment with reserpine or 6-hydroxydopamine. Release by kynuramine was calcium-independent and was potentiated by inhibition of monoamine oxidase but was only partially sensitive (50%) to inhibition by cocaine (10(-4)M). The ability of kynuramine to enter cardiac cells was demonstrated in whole atria by measuring its intracellular deamination rate by monoamine oxidase. Blockade of neuronal uptake (cocaine) and extraneuronal uptake (SKF 550) had no effect upon this measure. It is concluded that knyuramine releases cardiac NE, in part, by a cocaine-sensitive mechanism but that the process operating for the membrane transport of kynuramine in both neuronal and non-neuronal cells remains uncertain. The data are discussed in relation to the possible cardiac consequences of L-tryptophan ingestion in man.

Animals↗