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At least 793 records · Page 44Linked to original sources
PubMed1983

Kallikrein potentiation of angiotensin I-induced contraction on isolated mesenteric artery.

The hypotheses that glandular kallikrein (KK) potentiate the conversion of angiotensin I (AI) to angiotensin II (AII) was tested on isolated mesenteric artery from rabbit. Cumulative additions of A1 in concentrations 10(-8), 5 X 10(-8) and 10(-7) M gave dose-related contractions of the artery. Due to tachyphylaxis second dose-response run was used for comparison. KK, 0.4 U/ml, potentiated these contractions. Addition of captopril (C, 10(-5) M) to inhibit angiotensin converting enzyme (ACE) reduced the AI responses markedly and tachyphylaxis almost completely. The responses of the KK induced potentiation of AI was the same regardless of the presence of captopril. KK, 0.01 U/ml or 0.4 U/ml, produced the same effects. Saralasin (S, 10(-5) M), an AII receptor antagonist, completely abolished the responses following C+KK+AI. Thus, these results indicate that the KK induced potentiation of the AI response is due to a conversion to AII. Bradykinin (BK, 10(-7), 10(-5) M) did not mimic the KK potentiation of AI. Three different kallikrein inhibitors, S-2441 (H-D-Pro-Phe-Arg-NH-heptyl X 2HCl), Trasylol and amiloride, reduced the KK potentiation of AI. Phentolamine, an alpha-adrenergic receptor antagonist added for inhibition of AII adrenergic facilitation, also reduced the KK induced potentiation of AI. In conclusion, these results indicate that KK potentiate the conversion of AI to AII and thereby induces vasopressor effects.

Angiotensin I↗
PubMed1984

[Pharmacodynamic effects of d-nicotine--Comparison with l-nicotine].

The acute toxicity and pharmacological effects of d-nicotine were examined in several species of animals and compared with those of l-nicotine. The LD50s for intravenous administration of d- and l-nicotine were 6.15 and 0.33 mg/kg, respectively. In unanesthetized rhesus monkeys, EEG activity was not influenced by d-nicotine, 64 micrograms/kg, i.v., while the same dose of l-nicotine produced seizure-like waves with some spindles. In rats, d-nicotine increased spontaneous motor activity, and in the experiment under a DRL 20-sec schedule, it increased lever press responding, decreased the number of reinforcements and shortened interresponse time. Similar effects were also observed by administration of l-nicotine at lower doses than for the d-isomer. In anesthetized rats, d-nicotine elevated the blood pressure and increased the heart rate with a potency of about one-eighth that of the l-isomer. Further, tachyphylaxis and cross tachyphylaxis were developed to the blood pressure-raising effect in rats after repeated administration of both isomers. d-Nicotine elicited contraction of isolated rat ileum preparations, but with a potency of about one-tenth that of the l-isomer. Both isomers at the same concentration blocked transmission at the neuromuscular junction in isolated rat phrenic nerve-diaphragm muscle preparations. These results indicate that the pharmacological effects of d-nicotine are qualitatively similar to but quantitatively less potent than those of l-nicotine.

Animals↗
PubMed1978

[Effect of tyramine on the cerebrovascular resistance and arterial pressure during the action of prostaglandins E].

A resistographic study of the cerebrovascular resistance (CVR) and of the arterial blood pressure showed prostaglandins (PG), type E, to inhibit the pressor action of tyramine on the cerebral vessels and the blood pressure. Indomethacin--an inhibitor of PG biosynthesis, retarded the tyramine tachyphylaxis and restored its pressor effect. Ipraside, the monoaminooxidase inhibitor, failed to influence the speed of tyramine tachyphylaxis development under conditions of indomethacin infusion, but increased the pressor effect of tyramine. It is supposed that inomethacin influence was based on the hypersensitivity of the vascular adrenoreceptors.

Animals↗
PubMed1982

Hypotensive effects of adenosine and adenosine triphosphate compared with sodium nitroprusside.

Hypotensive effects of the intravenous injection of adenine compounds [adenosine triphosphate (ATP), adenosine] were compared with those of sodium nitroprusside (SNP) in rabbits during light, stable halothane anesthesia. ATP and adenosine were almost equipotent in their effects on blood pressure and heart rate. The hypotensive potencies of ATP and adenosine were approximately 1/6 (bolus injection) and 1/40 (continuous infusion) that of SNP, but the adenine compounds had a more rapid onset of action and shorter recovery times than SNP. With bolus injection, SNP invariably caused a baroreceptor-mediated reflex increase in heart rate. In contrast, ATP and adenosine caused a dose-related decrease in heart rate and hypotension. With continuous infusion, ATP and adenosine produced immediate onset of hypotension without tachycardia. Blood pressure remained remarkably stable throughout the infusion; neither tachyphylaxis nor rebound hypertension were observed. Thus, the adenine compounds offer possible advantages over SNP as they are physiologic agents with little or no acute toxicity and may be devoid of tachycardia, tachyphylaxis, and rebound hypertension.

Adenosine↗
PubMed1980

Evidence against purinergic inhibitory nerves in the vagal pathway to the opossum lower esophageal sphincter.

Studies were performed on anesthetized opossums. Lower esophageal sphincter pressures were measured with waterfilled and continously perfused catheters anchored in the sphincter. Administration of adenosine 5'-triphosphate (ATP) and ADP in the left gastric artery usually produced an initial contraction followed by a more prolonged inhibition. Adenosine, on the other hand, produced only inhibition. The effect of ATP was not modified by phentolamine (1 mg/kg), propranolol (1 mg/kg) or atropine (30 micrograms/kg). Tetrodotoxin partially antagonized (P less than 0.05) the inhibitory effects of ATP and adenosine, but augmented the excitatory effect of ATP (P less than 0.05). 2-2'-Pyridylisatogen tosylate selectively antagonized the effects of ATP without modifying the effect of adenosine. This antagonist, however, did not modify the resting sphincter pressure or the vagal stimulated sphincter relaxation. Dipyridamole enhanced the inhibitory effect of adenosine, but did not augment vagal stimulates sphincter relaxation. There was no cross-tachyphylaxis between ATP and adenosine. Tachyphylaxis, either to ATP or adenosine, did not inhibit the vagal stimulated sphincter relaxation. These studies show that: (a) ATP and adenosine may act on different receptor sites to modify sphincter pressure; (b) only a small part of the inhibitory effect of ATP and adenosine is mediated by the inhibitory neurons; (c) neither ATP nor adenosine appears to be the inhibitory transmitter released by the noncholinergic, nonadrenergic inhibitory neurons in the vagal pathway to the lower esophageal sphincter.

Adenosine↗
PubMed1995

Continued benefit of lovastatin in the treatment of hypercholesterolemia in 36 patients.

After one year of treatment, low-dose (20 mg/d) lovastatin achieved continued efficacy without tachyphylaxis in 36 patients with Type IIa or IIb hyperlipoproteinemia. Six week and one year reductions in low density lipoprotein (LDL) cholesterol were significant at 33% and 31% in these patients respectively; reductions in total cholesterol were also significant at 25% and 22% respectively. Increases in high density lipoprotein cholesterol (HDL) were 6% at six weeks and 10% at one year; triglycerides were reduced 16% and 11% respectively. The cholesterol lowering effects were similar for males and females (23% and 21% respectively). Low-dose lovastatin (20 mg/d) is a good choice for reducing cholesterol in patients with primary Type IIa or IIb hyperlipoproteinemia refractory to diet therapy because it is effective in lowering LDL-cholesterol, while raising HDL-cholesterol with few side effects and without tachyphylaxis.

Aged↗
PubMed1995

Complement membrane attack complex, perforin, and bacterial exotoxins induce in K562 cells calcium-dependent cross-protection from lysis.

The complement membrane attack complex (MAC), the cytolytic granule protein of cytotoxic lymphocytes perforin, the streptococcal exotoxin streptolysin O (SLO), and the bee venom polypeptide melittin utilize a similar mechanism to incorporate into cell membranes, induce a Ca2+ influx and a rise in intracellular Ca2+ concentration, and produce cell lysis. At sublytic concentrations, these proteins trigger several cellular activities, including protein phosphorylation and synthesis. We have recently demonstrated that human leukemic cells treated with sublytic doses of human complement become more resistant to lytic complement doses. The study has now been extended to include three other pore-formers: murine perforin, SLO and melittin. As shown here, sublytic MAC induces in the K562 human erythroleukemic cells protection from lytic perforin, and vice versa, sublytic perforin induces protection from complement. Also, sublytic SLO and melittin increase resistance of K562 cells to lytic complement and perforin doses. The capacity of Ca2+ ionophores to induce resistance to the lytic proteins has been examined. Exposure of K562 cells to sublytic concentrations of ionomycin or A23187 for 1 h at 37 degrees C confers on them resistance to complement- and perforin-mediated lysis. The protective effects of the ionophores can be abrogated by chelation of extracellular Ca2+ and by inhibition of RNA or protein synthesis in the cells. These results indicate the following: 1) nucleated cells exposed to sublytic complement MAC, perforin, SLO, or melittin may become resistant to the four pore-formers. Physiologically, this may be regarded as an immunologic tachyphylaxis. 2) Ca2+ influx induced by these pore-formers is an essential and sufficient factor to produce this tachyphylaxis.

Bacterial Proteins↗
PubMedDate not supplied

Calcium modulation of the effects of serotonin, carbachol, and histamine on rabbit ileal ion transport.

In mammalian intestine, a number of secretagogues have been shown to work through either cyclic nucleotide or calcium mediated pathways to elicit ion secretion. Because excessive intestinal electrolyte and fluid secretion is central to the pathogenesis of a variety of diarrheal disorders, understanding of these processes is essential to the development of future clinical treatments. In the current study, the effects of serotonin (5HT), histamine, and carbachol on intestinal ion transport were examined in in vitro preparations of rabbit ileum. All three agonists induced a rapid and transient increase short-circuit current (delta Isc) across ileal mucosa. Inhibition of the delta Isc response of all three agents in chloride-free solution or in the presence of bumetanide confirmed that chloride is the main electrolyte involved in electrogenic ion secretion. Pretreatment of tissue with tetrodotoxin or atropine did not effect secretagogue-mediated electrolyte secretion. While tachyphylaxis of delta Isc response was shown to develop after repeated exposure of a secretagogue to tissue, delta Isc responses after sequential addition of different agonists indicate that cross-tachyphylaxis between agents did not occur. Serotonin, histamine, and carbachol have previously been reported to mediate electrolyte secretion through calcium-dependent pathways. To access the role of extracellular calcium in regulating ion secretion, the effect of verapamil on each agent was tested; verapamil decreased 5HT-induced delta Isc by 65.2% and histamine response by 33.5%, but had no effect on carbachol-elicited chloride secretion. An additive secretory effect was found upon simultaneous exposure of 5HT and carbachol to the system; no other combination of agents produced a significant additive effect. Findings from this study support previous work which has suggested that multiple calcium pathways may be involved in mediating chloride secretion in mammalian intestine.

Animals↗
PubMed1977

The role of calcium in the response of rabbit aorta to angiotensin.

The role of Ca++ in the stimulus-contraction coupling of the response of the isolated rabbit aorta to angiotensin II was investigated. Angiotensin was found to have lower intrinsic activity than epinephrine and to be more sensitive to acute exposure of the organ to Ca++-free medium. Two minutes after removal of Ca++, the maximal responses to angiotensin and epinephrine were reduced by 40% +/- 8% and 7% +/- 5%, respectively. Further loss of response for the two agonists followed parallel time courses. In another series of experiments, angiotensin tachyphylaxis was obtained in the rabbit aorta by administration of either [1-sarcosine]angiotensin or betainyl-angiotensin. The intrinsic activity of [1-sarcosine]angiotensin was lower than that of angiotensin and was not affected by removal of Ca++. It is concluded that the low intrinsic activity and the tachyphylaxis may be dependent on a strong binding of the molecule's positively charged N-terminus to sites responsible for release of Ca++ into the cell.

Angiotensin II↗
PubMed1996

Airway hyperresponsiveness to acetylcholine induced by aerosolized arachidonic acid metabolites in guinea-pigs.

BACKGROUND AND OBJECTIVE: To investigate the role of arachidonic acid (AA) metabolites in airway hypersensitivity. METHOD: We studied the change in airway responsiveness to acetylcholine (ACh) after inhalation of some AA metabolites in guinea-pigs. RESULTS: Exposure to prostaglandin (PG) D2, thromboxane (TX) A2 mimetic U-46619, leukotriene (LT) D4 or LTE4 at concentrations which did not influence bronchial tone and blood pressure dose-dependently caused airway hyperresponsiveness. However, the change was not observed after challenge with a high concentration of PGF2 alpha. Furthermore, PGD2 and U-46619 induced an acute and short-lived increase in responsiveness, while LTD4 and LTE4 induced a slow-onset and longer-lived increase. In the tachyphylaxis study, although the tachyphylaxis for airway hyperresponsiveness provoked by PGD2 and U-46619 was not observed, airway hyperresponsiveness induced by the second LTD4 tended to decrease, and the second LTE4-induced airway hyperresponsiveness obviously diminished. In the study using antagonists and inhibitors, TX-receptor antagonist BM-13177 inhibited PGD2- and U-46619-, but not LTD4- and LTE4-induced airway hyperresponsiveness. TX synthase inhibitor OKY-046 had no effect on PGD2-, U-46619- and LTD4-induced airway hyperresponsiveness, while LTE4-induced airway hyperresponsiveness tended to be inhibited by these inhibitors. However, the LT-receptor antagonist ONO-1078 inhibited both LTD4- and LTE4-, but not PGD2- or U-46619-induced airway hyperresponsiveness. 5-lipoxygenase inhibitor AA-861 tended to prevent LTE4-induced airway hyperresponsiveness, but had no effect on PGD2-, U-46619- and LTD4-induced enhanced responses. CONCLUSION: These findings indicate that the local existence of PGD2, TXA2, LTD4 and LTE4 in the guinea-pig airway may act as an airway hyperresponsiveness-inducing factor rather than as a bronchoconstrictor. In addition, PGD2/U-46619 may stimulate the TX receptor to induce an acute and short-lived airway hyperresponsiveness, and LTD4 and LTE4, which may involve secondary mediator release, may act at the LT receptor to induce a slow-onset and longer-lived airway hyperresponsiveness, which may be associated with the induction, the development and the long duration of airway hyperreactivity.

Acetylcholine↗
PubMed1979

Development of new antiallergic drugs (cromolyn sodium, lodoxamide tromethamine). What is the role of cholinergic stimulation in the biphasic dose response?

The antiallergy drugs, cromolyn sodium and lodoxamide tromethamine (U-42,585E) show in vitro dose responses which are bell-shaped or biphasic in mast cells. The nature of the biphasic dose response is poorly understood; however, through the use of specific antagonists, it has been possible to show that at the high concentrations of these drugs leading to enhanced histamine release or multiple high-dose tachyphylaxis, a cholinergic receptor is stimulated in the cell. This receptor is muscarinic in nature and can be blocked by atropine or quinuclidinyl benzilate (QNB). Prevention of multiple dose tachyphylaxis to either drug can be modulated by pretreatment with atropine or QNB. High concentrations of both drugs cause the cell accumulation of cyclic-guanosine monophosphate through stimulation of guanyl cyclase and prevention of cGMP breakdown by inhibition of the phosphodiesterase (PDE) for cGMP.

Animals↗
PubMed1964

POTENTIATION OF THE ACTION OF BRADYKININ ON SMOOTH MUSCLE BY CHYMOTRYPSIN, CHYMOTRYPSINOGEN AND TRYPSIN.

Chymotrypsin, chymotrypsinogen and trypsin sensitized the guinea-pig isolated ileum and rat isolated uterus preparations to the action of bradykinin, whilst the responses to histamine, acetylcholine and 5-hydroxytryptamine were unaffected. Chymotrypsin caused a quick contraction of the guinea-pig ileum which was abolished by mepyramine and therefore probably mediated by histamine. Trypsin contracted the rat uterus as well as the guinea-pig ileum; the latter contraction was slow, resistant to mepyramine and gave rise to tachyphylaxis. It is suggested that isolated smooth muscle preparations should be treated with chymotrypsin for use in the estimation of minute amounts of bradykinin.

Acetylcholine↗
PubMed2003

Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies.

BACKGROUND: The duration of action of the immediate-release formulation of methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of methylphenidate had reduced efficacy compared with immediate-release methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance. METHODS: Children with attention-deficit/hyperactivity disorder were evaluated in a laboratory school to characterize onset and duration of the effect of a variety of methylphenidate regimens. In a proof-of-concept study, an experimental ascending profile was established by an initial bolus followed by small increasing doses of immediate-release methylphenidate in capsules administered every 30 minutes for 8 hours. Two proof-of-product studies of a new oral once-a-day formulation to deliver methylphenidate by an osmotic pump process based on OROS (ALZA Corp, Mountain View, Calif) technology (hereafter referred to "OROS-methylphenidate") were conducted: a pharmacokinetic study and a pharmacodynamic study. RESULTS: The experimental ascending profile matched the effect of the standard regimen of methylphenidate, 3 times daily. In the pharmacokinetic study, OROS-methylphenidate treatment produced a rapid rise followed by increasing plasma concentrations that peaked 7 to 9 hours after administration. In the pharmacodynamic study, OROS-methylphenidate treatment matched the 3 times daily dosing of methylphenidate for onset and duration of efficacy. CONCLUSIONS: These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of methylphenidate) into clinical application (the selection of a new drug delivery pattern for methylphenidate). This approach produced a new product (OROS-methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy (10-12 hours) after a single administration in the morning.

Administration, Oral↗
PubMed1980

Atenolol 4% eyedrops in glaucoma simplex.

The single-dose response to local administration of atenolol 4% is compared in normal eyes and 3 groups of eyes with glaucoma simplex. The reduction in intraocular pressure is seen to be greater in eyes with glaucoma than in normal eyes. The usefulness of atenolol 4%, whether or not combined with other local therapy, seems to be limited by tachyphylaxis.

Atenolol↗
PubMed1984

Bronchopulmonary effects of elliptinium in anesthetized dogs.

The bronchoconstrictor effect of elliptinium already demonstrated in the guinea-pig is shown in the dog. It is less intense and its onset is prompter. Successive administration of identical doses of elliptinium attenuates the bronchospasm induced, suggesting tachyphylaxis. The previously described indirect bronchoconstrictor effect involving endogenous mediators seems also to be active in these circumstances.

Alkaloids↗
PubMed1977

The intraocular pressure response of glaucomatous eyes to topically applied bupranolol. A pilot study.

Bupranolol 0.5% oily solution applied topically lowered intraocular pressure of glaucomatous eyes significantly. The pressure decrease is related to pretreatment pressure levels. The maximum effect occurred within 4 hours and lasted for more than 24 hours. No objective or subjective irritation could be attributed to the ophthalmic preparation. There was no significant effect on outflow facility, on blood pressure or tear flow. However, bupranolol produces local anesthesia on the eye. The problem of tachyphylaxis is discussed in the treatment of glaucoma with bupranolol eye drops.

Administration, Topical↗
PubMed1979

Longitudinal contraction of isolated guinea-pig ileum induced by rapid cooling.

1. Rapid change of bath temperature from 37 degrees C to 27 degrees C and vice versa caused longitudinal contraction of the isolated guinea-pig ileum. 2. Tetrodotoxin, tropicamide, noradrenaline, isoprenaline, morphine, and the met-enkephalin analogue FK 33-824 depressed the responses or accelerated the fade of the contraction induced by rapid cooling when added after the response had reached its maximum. 3. Hexamethonium had no influence on the responses. 4. Physostigmine potentiated all responses and reversed the fade of contraction induced by rapid cooling when added after this contraction had reached its maximum. 5. The effects of rapid cooling or warming were not altered in preparations made tachyphylactic to substance P; the response to rapid warming, but not cooling, was partially inhibited under tachyphylaxis to 5-hydroxytryptamine. 6. Antazoline, phentolamine, naloxone, and indomethacin did not block the responses. 7. Capsaicin firt potentiated and subsequently depressed the responses to both rapid cooling and warming. 8. The results indicate that rapid change of bath temperature induces longitudinal contraction by excitation of postganglionic cholinergic fibres.

Animals↗
PubMed1988

Reproducibility of heart rate changes following adenosine infusion in man.

The change in heart rate following infusion of adenosine in healthy human subjects was studied on two occasions. Adenosine produced a significant, dose-related increase in heart rate. Tachyphylaxis to this effect of the naturally occurring nucleoside did not occur. There was a tendency for prolonged infusion to cause a greater increase in heart rate, but this did not reach significance.

Adenosine↗