Emetic, central nervous system, and pulmonary activities of rolipram in the dog.

Rolipram was characterized for its emetic, behavioral, cardiovascular and pulmonary activities in dogs, to assess its systemic pharmacology and potential bronchodilatory selectivity. At doses > or = 0.1 mg/kg i.

Phospholipid regulation of a cyclic AMP-specific phosphodiesterase (PDE4) from U937 cells.

The regulation of phosphodiesterase-4 (PDE4) by various phospholipids was explored using PDE4s partially purified from U937 cells. Preincubation (5 min, 4 degrees C) of the large molecular weight PDE4 denoted "Peak 2 PDE4" with mixed phosphatidic acids (PAs) produced a 2-fold increase in its Vmax without changing its Km (approximately 2 microM) for cyclic AMP. This "activation" was not limited to PAs with specific fatty acid substituents: Synthetic PAs containing saturated and/or unsaturated fatty acids 16-20 carbons long produced similar effects.

Rolipram inhibition of phosphodiesterase-4 activation.

Rolipram inhibited U937 cell phosphodiesterase-4 in either the presence or absence of saturating (100 micrograms/ml) phosphatidic acid in an apparently phospholipid-independent manner, exhibiting similar kinetics (Ki values = 0.41 and 0.59 microM, respectively).

Phosphodiesterase-IV inhibition, respiratory muscle relaxation and bronchodilation by WAY-PDA-641.

The ability of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (E)-O-(aminocarbonyl) oxime) (WAY-PDA-641) to inhibit cyclic AMP-metabolizing phosphodiesterases (PDEs) and to relax respiratory muscle was explored as part of a program to identify a PDE-IV inhibitor for potential use in the treatment of asthma. WAY-PDA-641 was identified as a preferential inhibitor of PDE-IV, possessing 36 times greater potency versus canine trachealis PDE-IV than PDE-III (IC50, 4.2 x 10(-7) M and 1.

Identification and stabilization of large molecular weight PDE-IVs from U937 cells.

Cytosolic cyclic nucleotide phosphodiesterases (PDEs) from human (promonocytic) U937 cells were rapidly resolved by DEAE-Sepharose CL-6B anion exchange chromatography into two major peaks of cAMP-specific activity possessing average Kms of 1.70 microM (Peak 1) and 1.65 microM (Peak 2).

Anti-leukotriene effects of WY-50,295 tromethamine in isolated guinea pig pulmonary tissues.

The abilities of WY-50,295 tromethamine, a 5-lipoxygenase inhibitor, to inhibit antigen-induced leukotriene (LT) release from guinea pig lung fragments, and to prevent LTD4 or antigen-induced contraction of isolated guinea pig tracheal muscle were compared with the activities of zileuton and MK-886 (two selective 5-lipoxygenase inhibitors), and LY171883 (a LTD4 receptor antagonist). In fragmented guinea pig lung, WY-50,295 tromethamine inhibited antigen-induced LT release with an IC50 of 0.63 microM, and was 4.

Effects of rolipram and CI-930 on IL-2 mRNA transcription in human Jurkat cells.

Interleukin-2 (IL-2) is a major mediator of immunologic responses involved in many chronic inflammatory diseases. We have investigated the effects of rolipram, a PDE-IV inhibitor, and CI-930, a PDE-III inhibitor, on IL-2 gene expression in the Jurkat human T cell line. The immunosuppressant cyclosporin A (CsA) was included as a positive control.

Modulation of TNF alpha and IL-1 beta from endotoxin-stimulated monocytes by selective PDE isozyme inhibitors.

The effect of selective PDE isozyme inhibitors including vinpocetine (PDE-I), CI-930 and milrinone (PDE-III), rolipram and nitraquazone (PDE-IV) and zaprinast (PDE-V) on monocyte viability and production of tumor necrosis factor (TNF alpha) and interleukin-1 beta (IL-1 beta) elicited from endotoxin-stimulated human monocytes was investigated. None of the inhibitors affected monocyte viability at 10 microM or lower concentrations. PDE-IV inhibitors and to a lesser extent, PDE-III inhibitors suppressed TNF alpha production.

Differential regulation of TNF-alpha and IL-1beta production from endotoxin stimulated human monocytes by phosphodiesterase inhibitors.

The effect of selective PDE-I (vinpocetine), PDE-III (milrinone, CI-930), PDE-IV (rolipram, nitroquazone), and PDE-V (zaprinast) isozyme inhibitors on TNF-alpha and IL-1beta production from LPS stimulated human monocytes was investigated. The PDE-IV inhibitors caused a concentration dependent inhibition of TNF-alpha production, but only partially inhibited IL-1beta at high concentrations. High concentrations of the PDE-III inhibitors weakly inhibited TNF-alpha, but had no effect on IL-1beta production.

Bronchial vs. cardiovascular activities of selective phosphodiesterase inhibitors in the anesthetized beta-blocked dog.

This study was undertaken to determine whether isozyme-specific inhibitors of cAMP-selective phosphodiesterases (PDEs) induce bronchodilation without the cardiovascular side effects known to be produced by nonselective PDE inhibitors. The abilities of PDE inhibitors to reverse the bronchoconstriction induced by serotonin in a beta-blocked anesthetized dog were compared simultaneously with their effects on cardiac contractile force (+dP/dt), heart rate and blood pressure. Aminophylline and enprofylline, two antiasthma drugs with nonselective PDE inhibitory activity, produced dose-dependent (ED50S = 2.

WY-50, 295 tromethamine: an orally active 5-lipoxygenase inhibitor with anti-allergic activity.

WY-50,295 tromethamine inhibited antigen-induced peptidoleukotriene (pLT) release from fragmented sensitized guinea pig lung (IC50 = 0.63 microM), antagonized LTD4-induced contractions of isolated guinea pig trachea (pA2 = 6.06), and suppressed antigen-induced contraction of sensitized guinea pig trachea over the 0.

Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst.

Modulation of the human polymorphonuclear leukocyte (PMN) respiratory burst by selective cyclic 3',5' adenosine monophosphate (cAMP) phosphodiesterase (PDE) inhibitors was studied with respect to PDE isozyme characteristics. Zaprinast, an inhibitor of a cyclic guanosine monophosphate (cGMP)-specific PDE (PDE I), at concentrations up to 100 mumol/L, had no significant effect on the respiratory burst. Milrinone and imazodan, inhibitors of cAMP-metabolizing, cGMP-sensitive PDE (PDE III), reduced the respiratory burst to 60% of control magnitude but only had significant effects when they were introduced at high (100 mumol/L) concentrations.

Evidence that prostaglandins can contract the rat aorta via a novel protein kinase C-dependent mechanism.

The effects of prostaglandin (PG) F2 alpha and PGB2 on isolated rat aortic strips were studied in calcium-free 1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid buffer to explore the mechanisms of PG-induced smooth muscle contraction. In the absence of extracellular calcium, PGF2 alpha and PGB2 induced sustained contractions that were similar to those induced by activators of protein kinase C (PKC) or norepinephrine. These sustained contractions were apparently induced via a pharmacomechanical coupling mechanism because they could be elicited repeatedly in the absence of extracellular calcium and were not affected by changes in buffer concentrations of potassium, magnesium or phosphate.

Structure-activity relationships of 1H-indole-7-carboxamides as a novel series of selective alpha 1-adrenoceptor agonists.

The present isolated tissue study was designed to quantitate the alpha-adrenoceptor agonist activity of AY- 30,191 (5-(1-hydroxy-2-amino-ethyl)-1H-indole-7-carboxamide) and a series of related compounds. AY-30,191 induced contractions in the rabbit aorta, which were blocked by prazosin. In the rat vas deferens, while clonidine inhibited the electrically induced twitch response, AY-30,191 caused a prazosin-sensitive augmentation.

Comparison of the beta-adrenoceptor affinity and selectivity of cetamolol, atenolol, betaxolol, and ICI-118,551.

The objective of the present study was to compare the quantitative differences in the beta 1- vs. beta 2-adrenoceptor affinity and selectivity of cetamolol and its enantiomers to the reference compounds atenolol, betaxolol, and ICI-118,551, using isolated tissues obtained from the dog, guinea pig, and rat. Cetamolol antagonized the beta-adrenoceptor-mediated responses induced by isoproterenol, epinephrine, norepinephrine, and salbutamol, in tissues from both the dog and guinea pig, in a concentration-dependent manner.

Intracellular mechanisms of contraction in the hypertensive and normotensive rat aortas.

The roles of intracellular mechanisms of contraction were compared in aortas from genetically hypertensive and normotensive rats by investigating the contractile activities of prostaglandin F2 alpha (PGF2 alpha) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in the absence of extracellular calcium. PGF2 alpha induced a greater amount of tension in aortic strips from hypertensive than normotensive rats. Furthermore, in hypertensive but not normotensive rat aortas, PGF2 alpha- and TPA-induced contractions were additive and were capable of sustaining a near maximum degree of muscle activation.

Interaction of neutrophils with vascular smooth muscle: identification of a neutrophil-derived relaxing factor.

Experiments were designed to study the interaction of rat peritoneal neutrophils with the vascular smooth muscle of the rat aorta. Rings of aorta, suspended in 10-ml organ chambers containing a physiologic salt solution, were precontracted with phenylephrine. Neutrophils (1 X 10(5) -4 X 10(7) cells/organ chamber) caused a cell number-dependent relaxation of the rat aorta that was augmented by superoxide dismutase (100 U/ml) or changing the oxygen content from 95 to 21%.

Co-regulation of tracheal tone by cyclic AMP- and cyclic GMP-dependent mechanisms.

The regulation of guinea pig tracheal muscle tone by cyclic AMP-dependent and cyclic GMP-dependent relaxant mechanisms was investigated by studying the tracheal relaxant activities of forskolin, nitroprusside, N6-2'-O-dibutyryl-cyclic AMP and 8-bromoguanosine-cyclic GMP. In carbachol (3 X 10(-6) M)-contracted isolated tracheal rings, N6-2'-O-dibutyryl-cyclic AMP and 8-bromoguanosine-cyclic GMP each caused biphasic relaxation responses, which consisted of an acute relaxation followed by a sustained but lesser degree of relaxation. The biphasic nature of this response is suggested to result from a functional counter-balancing of cyclic nucleotide-dependent relaxant mechanisms and the contractile mechanisms stimulated by carbachol.

In vitro isolated tissue studies with atiprosin (AY-28,228): a new antihypertensive compound.

Using in vitro isolated tissue and binding studies we have defined a receptor activity profile for atiprosin. The most prominent action of the compound was significant alpha-adrenoceptor antagonist activity (pA2 = 8.11) that was less potent than prazosin (pA2 = 8.

Demonstration of the beta 2-adrenoceptor intrinsic efficacy of AY-28,925 using the PGF2 alpha-contracted guinea-pig trachea.

The abilities of AY-28,925, labetalol and medroxalol to relax the PGF2 alpha-contracted isolated guinea-pig trachea have been investigated to compare their activities at beta 2-adrenoceptors. Maximum relaxation induced by AY-28,925 was significantly greater than that induced by either labetalol or medroxalol. This relaxation occurred in a concentration-dependent manner over a range of concentrations consistent with the previously determined affinity of AY-28,925 for beta-adrenoceptors.

In vitro characterization of the adrenoceptor activity of AY-28,925.

The adrenoceptor activity of AY-28,925 (5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-1 H-indole-7-carboxamide) was evaluated on various isolated vascular and nonvascular tissues. Based upon pA2 values derived from either the antagonism of the effect of isoproterenol on paced guinea pig left atria (pA2 = 7.3), spontaneously beating guinea pig right atria (pA2 = 7.