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D W Snyder

Publications and source records attributed to D W Snyder.

54 records · Page 3Linked to original sources
PubMed1986

Pharmacology of peptide leukotrienes on ferret isolated airway smooth muscle.

The contractile activities of peptide leukotrienes (LT) on isolated spiral strips of ferret trachea were characterized pharmacologically. LTC4 and LTD4 contracted ferret tracheal strips in a concentration-related manner and were 3- to 8-fold more potent than carbachol. In contrast, high concentrations of LTE4 evoked either weak contractions or none at all, whereas LTC4 and D4 were partial agonists compared to carbachol. In tissues which were unresponsive to LTE4, this compound antagonized contractile responses to LTC4 and D4 in an apparently competitive manner: Carbachol-induced contractions were not altered by LTE4. The cyclooxygenase inhibitor, indomethacin (5 microM), LT antagonist, FPL55712 (10 microM), atropine (1 microM), phenoxybenzamine (10 microM), and LTB4 (10 microM) failed to alter LTC4 and D4 concentration-response curves. The results indicate that ferret trachea is sensitive to the contractile activity of LTC4 and LTD4 but not LTE4. The LT-induced contractions appear to be mediated by a direct action of the LT rather than indirectly through release of secondary mediators such as thromboxane, prostaglandin, or acetylcholine. LT receptors in ferret trachea are insensitive to FPL55712 but are antagonized by LTE4.

Animals↗
PubMed1986

Chemically stable homocinnamyl analogues of the leukotrienes: synthesis and preliminary biological evaluation.

The synthesis and biological characterization of a series of stable leukotriene analogues (2) are reported. They are derivatives of (5S,6R,7Z)-6-peptidyl-5-hydroxy-9-phenyl-7-nonenoic acid, in which the phenyl group is variously substituted with a heptanyl, 2-heptenyl, or hexanyloxy chain (R1) and the peptide is either glutathionyl, cysteinylglycinyl, or cysteinyl. The most potent agonist is (5S,6R,7Z)-6-S-glutathionyl-5-hydroxy-9-(4-heptanylphenyl)-7 -nonenoic acid. This analogue has an EC50 value of 74.5 nM, in the presence of 1-serine borate (45 mM), on guinea pig tracheal spirals. The agonist activity of the cysteinylglycinyl- and the cysteinyl-substituted analogues was inhibited by FPL-55712. Three of the analogues were weak leukotriene antagonists in vitro on guinea pig tracheal spirals. The most potent of these was (5S,6R,7Z)-6-S-cysteinyl-5-hydroxy-9-(2-heptanylphenyl)-7-++ +nonenoic acid. At 10 microM, this analogue inhibited by 28% the contraction induced by 8 nM LTE4.

Aminopeptidases↗
PubMed1986

Embolic stroke in a woman with mitral valve prolapse who used oral contraceptives.

A case of angiographically-documented embolism is presented in a patient using oral contraceptives (OC) with marked mitral valve prolapse (MVP) and an atrial thrombus. OC use has been shown to decrease levels of antithrombin III and increase platelet coagulant activity. This increased coagulability may increase the risk of intra-atrial thrombus formation and subsequent cerebral embolism in patients with MVP. We believe that MVP, especially when redundant valve leaflets are recognized, may be a relative contraindication to OC use.

Adult↗
PubMed1985

Mitral valve prolapse. Recognizing and treating its manifestations and complications.

Mitral valve prolapse is a common, multisystem syndrome for which the myxomatous mitral valve provides an anatomic hallmark. Symptoms are often unrelated to the valvular abnormality and rarely hazardous and should generally be handled conservatively. In contrast, cardiovascular complications are not rare and should be anticipated and treated aggressively.

Angina Pectoris↗
PubMed1984

Pharmacological evidence for a distinct leukotriene C4 receptor in guinea-pig trachea.

The effect of the leukotriene (LT) antagonist, FPL55712, on the contractile activity of peptide leukotrienes was evaluated in the presence and absence of enzyme inhibitors of leukotriene metabolism. L-Cysteine, an inhibitor of aminopeptidase, prevents the formation of LTE4 from LTD4 and LTC4. L-Serine borate, an inhibitor of gamma-glutamyl transpeptidase prevents the conversion of LTC4 to LTD4. L-Cysteine (3mM) enhanced the contractile activity of LTC4 and LTD4. L-Serine borate (45 mM) increased selectively the contractile activity of LTC4. FPL55712 (10 microM) antagonized the contractile activity of LTC4, LTD4 and LTE4 in the absence of enzyme inhibitors. In the presence of L-serine borate, FPL55712 (10-30 microM) failed to antagonize the contractile activity of LTC4 but did antagonize LTD4 and LTE4. However, the dissociation constant (KB) for FPL55712 against LTD4 was increased by L-serine borate whereas the KB against LTE4 was not altered. In the presence of L-cysteine, FPL55712 antagonized the contractile activity of the peptide LTs. However, FPL55712 was more effective (P less than .05) in antagonizing LTD4 and LTE4 than LTC4 in the presence of L-cysteine. The data suggest that when the conversion of LTC4 to LTD4 and subsequently to LTE4 is blocked by L-serine borate FPL55712 is ineffective in antagonizing the actions of LTC4. This would indicate that LTC4 occupies a distinct LT receptor in guinea-pig trachea which is insensitive to the actions of FPL55712.

Animals↗
PubMed1984

Pharmacological and biochemical evidence for metabolism of peptide leukotrienes by guinea-pig airway smooth muscle in vitro.

It has been demonstrated that leukotriene (LT)C4 is metabolized to LTD4 via the action of the enzyme gamma-glutamyl transpeptidase. LTD4 is, in turn, converted by the enzyme aminopeptidase to LTE4. In the present study, the pharmacological effects of the aminopeptidase inhibitor, L-cysteine and the gamma-glutamyl transpeptidase inhibitor, L-serine borate, on peptide LT concentration-response curves were evaluated in isolated guinea-pig trachea. L-Cysteine (3 mM) enhanced the contractile activity of both LTC4 and LTD4. L-Serine borate (45 mM) enhanced the contractile activity of LTC4 without altering the response to LTD4. In contrast, neither L-cysteine nor L-serine borate consistently altered the concentration-response curves to LTE4, histamine or carbachol, which rules out a nonspecific effect of these inhibitors on airway smooth muscle. In the absence of enzyme inhibitors the peptide LTs were equipotent; whereas in their presence the relative order of potency was LTC4 = LTD4 greater than LTE4. Incubation of isolated guinea-pig trachea with [3H]LTC4 resulted in the formation of [3H]LTD4 and [3H]LTE4 with a proportional decrease in [3H]LTC4. The bioconversion of [3H]LTC4 was blocked by L-serine borate in a concentration-related manner (IC50 = 3.4 +/- 0.5 mM, mean +/- S.E.M., n = 3) and the formation of LTE4 was blocked by L-cysteine (10 mM). The results suggest that LTC4 is converted to LTD4 and subsequently to LTE4 by isolated guinea-pig trachea. The potency of LTC4 and LTD4 is increased when their transformation to LTE4 is prevented.

Aminopeptidases↗
PubMed1981

Lysophosphoglycerides in ischemic myocardium effluents and potentiation of their arrhythmogenic effects.

Lysophosphoglycerides accumulate in ischemic myocardium. To determine whether lysophosphatidylcholine (LPC) concentrations increase in extracellular fluid and may be arrhythmogenic, the anterior descending coronary artery of the open-chest cat (n = 12) was perfused with a Krebs-albumin solution after 10 min of ischemia and the effluent assayed for LPC. A twofold increase in LPC (0.097 +/- 0.02 to 0.170 +/- 0.03 mM) was observed. Microelectrode intracellular recordings from from normal feline endocardium at pH 7.4 in vitro revealed little change in action potentials when superfused with feline plasma despite augmented LPC to twice normal levels (0.74 mM). However, at pH 6.7, marked changes were elicited by LPC-enriched plasma including diminished resting membrane potential (-96 +/- 1 to -35 +/- 7 mV), amplitude (102 +/- 3 to 36 +/- 8 mV), maximum rate of rise (Vmax) of phase 0 (178 +/- 24 to 26 +/- 11 V/s), and conduction velocity with fractionation of the action potential. Acidified control plasma decreased only Vmax (from 161 to 57 V/s). Thus LPC increases twofold in effluents from cat myocardium in vivo after 10 min of ischemia and, coupled with ischemia-induced acidosis, is sufficient to induce marked electrophysiological derangements in vitro.

Acidosis↗
PubMed1981

Reductions in blood pressure, heart rate and renal sympathetic nervous discharge after imidazole-4-acetic acid: mediation through central gamma-aminobutyric acid (GABA) receptor stimulation.

Intracerebroventricular administration of imidazole-4-acetic acid (IAA) (0.3--10 microgram/kg) significantly reduced mean arterial pressure, heart rate and renal sympathetic nerve discharge in chloralose-anesthetized cats. In contrast, i.v. administration of IAA did not lower arterial pressure or heart rate. This would suggest that the hypotensive and bradycardic effects of IAA were centrally mediated. The cardiovascular effects of IAA were attenuated by the central administration of bicuculline methiodide (15 microgram/kg), a gamma-aminobutyric acid receptor antagonist. Reflex bradycardia evoked during the pressor response to norepinephrine (0.03--1.0 microgram/kg i.v.) was reversed to tachycardia after only the central administration of IAA. The vasoconstrictor response evoked during a 20-sec period of bilateral occlusion of carotid arteries was not altered by IAA. These results suggest that the cardiovascular effects of IAA are mediated through the activation of central gamma-aminobutyric acid receptors, to inhibit sympathetic vasomotor outflow.

Animals↗
PubMed1980

Premature ventricular complexes: therapeutic dilemmas and decisions.

Adult subjects with high-grade VEA have an increased risk of sudden death. In all likelihood, the risk reflects a predisposition to VF with concomitant but possibly independently caused VEA. Among patients sustaining acute myocardial infarction, the severity of VEA late after infarction appears to depend primarily on the extent of underlying coronary artery disease and the extent of tissue damage sustained, as does the likelihood of sudden death. It is not yet clear whether suppression of one manifestation of severe coronary artery disease, namely VEA, confers protection against more serious manifestations - particularly sudden death. Although increased mortality among patients with and without overt coronary artery disease is associated with high-grade VEA and although the absolute frequency of PVCs is strongly correlated with severity defined with conventional classification schemes, frequent, unifocal PVCs in the absence of high-grade VEA appear to carry only a small associated risk of sudden death [56]. Furthermore, even though early PVCs may be particularly hazardous soon after the onset of acute myocardial infarction, they do not appear to be malignant during the hospital phase or among ambulatory patients with or without coronary artery disease. The temptation to suppress even low-grade VEA is strong because even a single PVC can initiate VF in the ischemic heart, and it is of course possible that suppression could prevent a single PVC from occurring after the onset of ischemia and initiating VF. However, suppression of PVCs, even if successful in an ambulatory patient, will not necessarily suppress VEA initiated by a new bout of ischemia. Accordingly, based on currently available information, low-grade VEA does not require treatment in our view in ambulatory patients without specific indications.

Anti-Arrhythmia Agents↗
PubMed1978

Regional distribution of blood flow during arterial hypertension produced by lesions of the nucleus tractus solitarii in rats.

Changes in the fractional distribution of cardiac output (FF), organ blood flow, and regional vascular resistance were measured by the isotope dilution technique of Sapirstein using 86Rb as indicator in unanesthetized rats during acute arterial hypertension produced by bilateral lesions of the nucleus tractus solitarii (NTS). After NTS lesions, the FF was significantly reduced in skin, muscle, and colon, increased in ventricular myocardium, spleen, and adrenal glands, and was unchanged elsewhere. Because of a marked reduction in cardiac output (CO) during hypertension, the absolute organ blood flow (FF X CO) was reduced in lesioned rats to 30-40% of control in skin, muscle, and colon and between 60% and 75% of control in most of the remainder of the gastrointestinal tract and renal cortex; it was unchanged in myocardium and endocrine glands. Resistance was substantially increased (4- to 6-fold) in skin, muscle and colon but was only moderately increased (1.5- to 2.5-fold) in the remaining organs. The results indicate that, while NTS lesions will increase resistance in most vascular beds, the response is unequally distributed, influencing skin, muscle, and colon disproportionately to other tissues. Because of an interaction between a reduction in CO and little autoregulation, blood flow is reduced primarily in skin, muscle, and colon. The pattern of redistribution of CO was consistent with the interpretation that NTS hypertension results from interrupting baroreceptor reflexes centrally. The pattern of redistribution of blood flow in rats with NTS lesions differs from that produced by deoxycorticosterone acetate-salt and renal ischemia.

Animals↗