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Biomedical subjects

M A Wasserman

Publications and source records attributed to M A Wasserman.

At least 73 records · Page 4Linked to original sources
PubMed1983

Antagonism of the pulmonary effects of the peptidoleukotrienes by a leukotriene D4 analog.

4R-hydroxy-5S-cysteinylglycine-6-Z-nonadecenoic acid (4R,5S, 6Z-2-nor-LTD1), a structural analog of leukotriene (LT) D4 (LTD4), significantly antagonized the pulmonary actions of LTD4 in several guinea pig models of LT-mediated bronchoconstriction and edema formation. In vitro, 4R,5S,6Z-2-nor-LTD1 (10(-5) and 10(-4) M) antagonized the LTD4-induced contraction of tracheal spirals and lung parenchymal strips. This antagonist action of 4R,5S,6Z-2-nor-LTD1 was specific for the LTs, in that LTC4- and LTE4-induced contractions of the trachea were also antagonized, whereas the contractions elicited by other spasmogens, e.g., histamine, carbachol, prostaglandin F2 alpha and KCl, were not antagonized. In vivo, the LTD4-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs as reflected by decreases in dynamic lung compliance and airway conductance were attenuated significantly by a 1-min pretreatment with 4R,5S,6Z-2-nor-LTD1 at 5 mg/kg i.v. Similarly, the LTD4-induced increase in tracheal microvascular permeability, as assessed by extravasation of [125I]bovine serum albumin, was blocked by pretreatment with 4R,5S,6Z-2-nor-LTD1. These results provide the first demonstration that a structural analog of the peptidoleukotrienes can pharmacologically antagonize the potent actions of these LTs.

Animals↗
PubMed1983

Effect of calcium antagonists on leukotriene D4-induced contractions of the guinea-pig trachea and lung parenchyma.

The directly mediated contractile activity of leukotriene (LT) D4 on isolated guinea-pig trachea and lung parenchyma was dependent upon the presence of calcium in the bathing buffer. Whereas 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8), a calcium antagonist believed to act intracellularly, completely antagonized the LTD4-induced contraction, the calcium channel entry blockers, nifedipine and verapamil, only partially inhibited LTD4 contractile activity; diltiazem was inactive. TMB-8, nifedipine and verapamil were more effective in blocking the contraction of the trachea elicited by KCl-induced membrane depolarization than the contraction induced by LTD4. Of the channel entry blockers, only nifedipine appeared capable of partially relaxing an established LTD4-contracted trachea, whereas TMB-8 almost completely reversed the LTD4 contraction. On the lung parenchyma, the LTD4-induced contraction was suppressed, but not abolished in Ca++-free buffer; this contraction was antagonized by meclofenamic acid, thus suggesting it could be due in part to the indirect thromboxane (Tx) A2-mediated pathway of LT action. In Ca++-free buffer, LTD4 was still capable of generating TxB2, although lower amounts were found when compared to Ca++-containing buffer. Incremental addition of calcium to the parenchyma in Ca++-free buffer containing LTD4 elicited greater than control LTD4-induced contraction and TxB2 generation. Neither the contraction of the parenchyma nor the generation of TxB2 was antagonized by nifedipine; conversely, TMB-8 blocked both completely. Thus, based upon the use of pharmacological antagonists of calcium, these results suggest that LTD4 contractile activity in the respiratory system is dependent upon calcium, with calcium of intracellular origin potentially of significance.

Animals↗
PubMed1982

The modulation of adrenergic airway tone in normal and ascaris-sensitive beagle dogs.

The airway effects of adrenergic receptor stimulation/inhibition were investigated in sets of normal (N) and natively ascaris-sensitized (S) beagle dogs. In one group, the effect of beta-adrenergic stimulation/alpha-adrenergic inhibition in airway conductance (Gaw) and dynamic lung compliance (CDYN) were observed. For both N and S dogs, thymoxamine pretreatment served to enhance an isoproterenol inhibition of PGF2 alpha-induced Gaw decreases. No effect was observed in CDYN. In another set of animals, the effects of i.v. administration of norepinephrine (NE), epinephrine (EPI) and phenylephrine (PE), before and after pretreatment with propranolol/indomethacin were observed. For N dogs, all three alpha-adrenergic agents failed to produce bronchospasm; however, propranolol/indomethacin pretreatment significantly potentiated the effects of all three alpha-agents. No significant changes were observed in the CDYN response either prior to or after pretreatment with propranolol/indomethacin. In contrast, for S dogs, all three alpha-agonists produced moderate bronchoconstriction with or without propranolol/indomethacin pretreatment. In addition, the Gaw response to i.v. PE was statistically greater in S dogs than that observed in the N group. Finally, only i.v. PE produced significant decreases in the CDYN response in the S group of animals. These data suggest the presence of alpha-adrenergic influence in the canine airways and elaboration of this action appears to occur best in propranolol/indomethacin-pretreated animals.

Adrenergic alpha-Agonists↗
PubMed1982

The synthesis of 6,9-deepoxy-6,9-N-phenylimino-delta 6,8-prostaglandin I1. A novel inhibitor of leukotriene C and D synthesis.

The pyrrole analog of prostacyclin, 6,9-deepoxy-6,9-N-phenylimino-delta 6,8-prostaglandin I1 was synthesized from PGF2 alpha methyl ester. This pyrroloprostacyclin (U-60,257) and its methyl ester (U-56,467) have been shown to inhibit leukotriene C/D biosynthesis and antagonize leukotriene C/D contractions in vitro. Antigen induced bronchopulmonary changes in monkeys and guinea pigs are inhibited by U-60,257 in vivo.

Animals↗
PubMed1982

Effects of intravenous and aerosol nifedipine on prostaglandin F2 alpha and histamine-induced bronchoconstriction in anesthetized dogs.

The effect of nifedipine, a calcium slow channel blocking drug, was investigated by varying routes of administration in a canine model of pharmacologically induced bronchoconstriction. Control bronchopulmonary responses, i.e., increases in pulmonary resistance (RL) and decreases in dynamic lung compliance were accomplished by aerosols of prostaglandin F2 alpha and histamine in normal pentobarbital-anesthetized beagles. When infused i.v. within the range 200 to 400 micrograms/kg, nifedipine afforded significant protection vs. RL changes due to prostaglandin F2 alpha (84--89% inhibition). Aerosol pretreatment by nifedipine (0.1 and 1.0%) also produced significant inhibition in RL changes caused by prostaglandin F2 alpha. A single i.v. injection (200 micrograms/kg) of nifedipine provided significant protection against RL changes due to a histamine challenge for 240 min. The onset of protection occurred within 15 min and maximum protection occurred during the 60 to 90-min period after the single injection of nifedipine. A single aerosol pretreatment of nifedipine (0.1%) significantly blocked RL changes against successive histamine aerosol challenges at 15-, 30- and 60-min time periods. Infused nifedipine failed to have any relaxant effect on the resting base line of either RL or dynamic lung compliance, whereas aerosolized nifedipine did decrease resting airway tone intrinsically, although not significantly. In addition, cardiovascular side effects by the aerosol route were slight compared to those observed by the i.v. route of nifedipine. Therefore, delivery of a calcium channel antagonist by either the aerosol or i.v. route can inhibit pharmacologically induced bronchoconstriction.

Aerosols↗
PubMed1980

Bronchodilator effects of prostacyclin (PGI2) in dogs and guinea pigs.

prostacyclin (PGI2), a recently discovered unstable product in the biosynthetic conversion of prostaglandin endoperoxides, was examined for bronchopulmonary actions. in anesthetized dogs, PGI2 given i.v. (0.3-30.0 microgram/kg) and by aerosol (0.002-0.2%) inhibited significantly PGF2 alpha-induced increases in pulmonary resistance and decreases in dynamic lung compliance in a dose-related fashion. Intrinsically, PGI2 affected resting bronchopulmonary and cardiac functions minimally, but decreased peripheral and pulmonary vascular pressures. PGI2 (0.1-10 mg/kg, i.p.) afforded protection against histamine-induced asphyxial collapse in normal guinea pigs and ovalbumin-induced anaphylaxis in sensitized animals. Cumulative concentrations of PGI2 (1.0 x 10(-9)--3.0 x 10(-4) M) relaxed contractions of the isolated guine pig trachea produced by carbachol. These bronchodilator and hemodynamic effects could not be ascribed to the stable metabolic product of PGI2, because 6-keto-PGF1 alpha was inactive or markedly less active than PGI2 in these test systems. The results of this investigation suggest that PGI2 possesses considerable bronchodilator and vasodilator activity in experimental animal systems.

6-Ketoprostaglandin F1 alpha↗
PubMed1980

Potent bronchoconstrictor effects of aerosolized prostaglandin D2 in dogs.

Previously, we demonstrated that prostaglandin D2 (PGD2), a natural product of the endoperoxide PGH2, evoked bronchoconstriction when given I.V. to dogs (PROSTAGLANDINS 13:255-269, 1977). The present investigation in anesthetized dogs demonstrated that aerosols of PGD2 (0.001-0.1%) produced concentration-dependent increases in pulmonary resistance (RL) and decreases in dynamic lung compliance(CDYN) which were short-lived and equipotent to PGF2 alpha. These alterations in pulmonary mechanics were partially, yet significantly, inhibited by atropine, thereby suggesting that at least a portion of the bronchoconstriction may be cholinergically mediated. Concomitant cardiovascular depressant effects of both PGD2 and PFG2 alpha aerosols were much less and more variable than their bronchopulmonary effects. These results demonstrate a potent bronchoconstrictor effect of aerosolized PGD2 in dogs. PGD2 warrants further attention as a possible mediator of the bronchospasm seen in acute, reversible airways obstruction.

Aerosols↗
PubMed1980

Inhibition of bronchoconstriction by aerosols of prostaglandins E1 and E2.

The proposal that some naturally occurring prostaglandins (PGs) or their by-products may be implicated in the pathogenesis of the asthmatic bronchospasm has been suggested. Other PGs may be potentially useful in the treatment of this lung disease. The present investigation compared the bronchodilator effects of PGE1 and PGE2 in pharmacologically constricted experimental animals. In pentobarbital-anesthetized, spontaneously breathing dogs, aerosols of PGE1 and PGE2, 0.0002 to 0.2%, effectively inhibited the increases in pulmonary resistance (RL) and decreases in dynamic lung compliance (CDYN) produced by PGF2 alpha (3.0 micrograms/kg i.v.). PGE2 was found to be more effective than PGE1 in preventing RL responses to PGF2 alpha; however, both bronchodilators were equally effective vs. CDYN changes. These agents inhibited central airway constriction more than peripheral. Transient decreases in systemic arterial pressure and increases in heart rate occurred especially at the higher concentrations. In a group of trained conscious dogs, effective concentrations did not evoke adverse subjective discomfort or irritation. Higher concentrations, i.e., 1.0%, did produce coughing, breathholding, restlessness and altered patterns of breathing. In normal or sensitized guinea pigs, PGE aerosols were effective in reducing the bronchopulmonary provocation produced by histamine or specific antigen. These in vivo results suggest that aerosols of the classical PGEs are effective bronchospasmolytics in laboratory animals and that irritation may be related to concentration.

Aerosols↗
PubMed1977

Bronchopulmonary and cardiovascular effects of prostaglandin D2 in the dog.

The effects of intravenously administered prostaglandin D2 (PGD2) on bronchopulmonary and cardiovascular functions were examined in the dog. PGD2 (0.03-1.0 microng/kg) was shown to be more active than PGF2alpha, a known bronchoconstrictor, in decreasing dynamic lung compliance, tidal volume, and expiratory airflow rate, as well as in elevating lung resistance. PGD2 demonstrated a potency approximately 4-6 times that of PGF2alpha on pulmonary mechanics. Atropine sulfate infusions reduced significantly the resistance and compliance responses to PGF2alpha, but only the resistance responses to PGD2, thereby suggesting that part of the bronchoconstrictor activities of these agents involved a cholinergic component. In another series of anesthetized dogs, PGD2 (0.1-10.0 microng/kg) increased pulmonary arterial pressure (comparable to PGF2alpha) and heart rate (greater than PGF2alpha, but less than PGE2), while concomitantly decreasing systemic arterial pressure in a dose-related manner (1/10 that of PGE2). Qualitatively similar alterations in cardiovascular parameters were obtained for PGD2 in conscious dogs. Therefore, potent biologic activity of PGD2 has been shown in the dog. No physiologic or pathologic role for PGD2 has yet been demonstrated, but nonetheless, since it is a naturally occurring PG derived from arachidonic acid, further studies are warranted.

Animals↗
PubMed1976

Bronchopulmonary pharmacology of some prostaglandin endoperoxide analogs in the dog.

This investigation examined quantitatively the bronchopulmonary effects of two prostaglandin endoperoxide analogs (cyclic ethers) in the spontaneously breathing, anesthetized dog. Responses to these agents were measured by computer analyses and compared to those produced by prostaglandin F2alpha (PGF2alpha). In a dose range of 0.03-1.0 mug/kg i.v., both cyclic ethers produced dose-related alterations in pulmonary airway resistance dynamic lung compliance, expiratory airflow rate, tidal volume and respiratory frequency. These pulmonary changes were significantly greater than those observed for PGF2alpha (0.3-3.0 mug/kg). The onset of activity was prompt (less than 1 min) and recovery was complete within 5-10 min. Atropine pretreatment greatly reduced the airway resistance effects of all three test agents, thus suggesting some cholinergic component to their potent bronchoconstrictor activities. These cyclic ethers are stable forms of prostaglandin endoperoxides and may represent invaluable pharmacologic tools for the further study of intermediates in prostaglandin synthesis.

Atropine↗