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J Weiland

Publications and source records attributed to J Weiland.

34 records · Page 2Linked to original sources
PubMed1987

Procoagulant activity in bronchoalveolar lavage in the adult respiratory distress syndrome. Contribution of tissue factor associated with factor VII.

Alveolar fibrin deposition commonly occurs in the lungs of patients with the adult respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) from patients with ARDS, control patients with interstitial lung disease (ILD), congestive heart failure, or exposure to hyperoxia, and normal healthy subjects was studied to determine whether local alterations in procoagulant activity favor alveolar fibrin deposition in the lungs in ARDS. Procoagulant activity capable of shortening the recalcification time of plasma deficient in either factor VII or factor VIII was observed in unconcentrated BAL of all patients, but was significantly greater in BAL from patients with ARDS when compared with that of control subjects (p less than 0.001). Unconcentrated BAL from patients with ARDS shortened the recalcification time of plasma deficient in factor X, but no functional thrombin was detectable. BAL procoagulant from patients with ARDS was inhibited by concanavalin A, an inhibitor of tissue factor. The hydrolysis of purified human factor X by BAL from the ARDS and other patient groups was determined by measuring the amidolytic activity of generated factor Xa on its N-benzoyl-L-isoleucyl-L-glutamyl-glycyl-L-arginine-p-nitroanilide substrate. The procoagulant activity of BAL was associated with the development of amidolytic activity, indicating activation of factor X. BAL from patients with ARDS contained more factor X activating activity than did BAL from control groups (p less than 0.001). This activity was calcium dependent and was maximal at 1 mM ionized calcium. The BAL factor X activating activity was most active at neutral pH and was sedimented by ultracentrifugation at 100,000 x g.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Glycosidation of chlormadinol acetate alters its actions on Na+/K+-transporting ATPase and cardiac contractility: a contribution to the endogenous digitalis problem.

Compared to the progesterone derivative chlormadinol acetate 1, the arabinofuranoside 2, rhamnoside 3 and glucoside 4 of 1 are less potent in the Na/K-ATPase assay, but evoke, contrary to 1, positive inotropy in vivo. In anaesthetized cats the circulation effects of 2 and 3 appear to be more favourable than those of the digitalis glycoside digitoxin. Hence, the progestin 1 is transformed through glycosidation into an interesting cardioactive steroid.

Animals↗
PubMed1986

Origin of differences of inhibitory potency of cardiac glycosides in Na+/K+-transporting ATPase from human cardiac muscle, human brain cortex and guinea-pig cardiac muscle.

The inhibitory potency of altogether 95 steroidal compounds (including cardenolides, bufadienolides and their glycosides) on the Na/K-ATPases (Na+/K+-transporting ATPases, EC 3.6.1.37) from human cardiac muscle, human brain cortex and guinea-pig cardiac muscle was compared to probe the complementary chemotopology of the inhibitor binding site areas on the three enzyme variants. The changes of potency, resulting from systematic variations of the geometry of steroid skeleton and the character as well as the structure of side chains at C3 or/and C17 of steroid backbone, allowed the following major conclusions. With the human cardiac and cerebral enzyme forms, the paired K0.5 (K'D) values for 77 steroid derivatives, covering seven orders of ten, were highly correlated. On an average, the total of compounds showed a 1.5-fold higher affinity to the cardiac enzyme. This tiny differentiation did not appear to be connected with an important difference in the chemotopology of the complementary subsites for steroid nucleus binding on the two enzyme forms. With the human and guinea-pig cardiac enzyme variants, the K0.5 values for 69 steroid derivatives, covering six orders of ten, were determined. For 41 5 beta, 14 beta-androstane derivatives only, the paired K0.5 values showed a close correlation. Here, the human enzyme variant exhibited 27-fold higher affinity. However, the paired K0.5 values determined on both enzymes for 28 steroid derivatives of differing structural features were but poorly correlated. Essentially, the geometries of the steroid nucleus determined the differential contributions of the side chains at C3 and C17 to the integral inhibitory potency on the two enzyme variants. Thus, the species differences in the potency of cardiac glycosides were traced to species differences in the complementarity of the steroid binding subsites. Hence, estimates of the potency of new steroidal compounds obtained on the guinea-pig cardiac enzyme can be neither quantitatively nor qualitatively easily extrapolated to the human cardiac enzyme. The extrathermodynamic analysis of the data opened major new insights in the structure-activity relationships concerning the role of C14 beta-OH, the character of the lead structure in cardioactive steroid lactones, and the significance of the configuration of A/B ring junction.

Animals↗
PubMed1985

The lead structure in cardiac glycosides is 5 beta, 14 beta-androstane-3 beta 14-diol.

The purpose of the present study was to determine the lead structure in cardiac glycosides at the receptor level, i.e. the minimal structural requirement for specific and powerful receptor recognition. Accordingly 73 digitalis-like acting steroids were characterized as to the concentration effecting half-maximum inhibition of Na,K-ATPase from human cardiac muscle under standardized turnover conditions. Since the Ki value equaled the apparent KD value, K'D was expressed in terms of the apparent standard Gibbs energy change delta G degrees' of steroid interaction with Na,K-ATPase. This allowed the use of the extrathermodynamic approach as a rational way of correlating in a quantitative manner, the potency and structure of the various steroidal compounds. The results of the present analysis taken in conjunction with relevant findings reported in the literature, favour the following conclusions. Cassaine, canrenone, prednisolone- and progesterone-3,20-bisguanylhydrazone, and chlormadinol acetate are compounds that are not congeneric with digitalis. The butenolide ring of cardenolides or the analogous side-chains at C17 beta of 5 beta, 14 beta-androstane-3 beta, 14-diol are not pharmacophoric substructures, but merely amplifiers of the interaction energy of the steroid lead. All modifications of the structure, geometry and spatial relationship between the steroid nucleus and butenolide side chain of digitoxigenin all at once weaken the close fit interaction with the steroid and butenolide binding subsites of the enzyme in such way that the cardenolide derivatives interact with the receptor binding site area in whatever orientation that will minimize the Gibbs energy of the steroid-receptor-solvent system. The "butenolide carbonyl oxygen distance model" (Ahmed et al. 1983) for the interpretation of the differences in potency of the cardenolide derivatives describes the change in interaction energy through structural modification as a function of the entire molecule. 5 beta, 14 beta-androstane-3 beta, 14-diol, the steroid nucleus of cardiac glycosides of the digitalis type, is the minimum structure for specific receptor recognition and the key structure for inducing protein conformational change and thus Na,K-ATPase inhibition. It is also the structural requirement for maximum contributions of the butenolide substituent at C17 beta and the sugar substituent at C3 beta-OH to the overall interaction energy, i.e. this steroid nucleus is the lead structure.(ABSTRACT TRUNCATED AT 400 WORDS)

Androstane-3,17-diol↗