Cryptosin induces backbone structural changes in cardiac Na+ and K+ dependent adenosinetriphosphatase.

Cryptosin, a new cardenolide, was found to preferentially bind to Na,K-ATPase enzyme (7), which is believed to be the ouabain binding site on cardiac sarcolemmal membrane. CD spectral studies revealed that cryptosin, in the presence of Na+ and Mg++ ions, bind to Na,K-ATPase and induce a dose-dependent change in the backbone structure of cardiac Na,K-ATPase.

Interactions of cryptosin with mammalian cardiac dihydropyridine-specific calcium channels.

Cryptosin -a new cardenolide was found to be a potent inhibitor of cardiac Na+ and K+ dependent Adenosinetri-phosphatase (7). In experiments with dog heart ex vivo, development of inotropic and toxic effect correlated with changes in the cardiac dihydropyridine-specific calcium channels as measured by the binding of 3[H]PN 200-110. A significant change in the PN 200-110 binding was observed when guinea pig and dog heart sarcolemmal membranes were pre-incubated with cryptosin in vitro. Binding analysis of 3[H]PN 200-110 (Isradipine) - -a 1,4-dihydropyridine analog with very specific calcium channel binding properties - in both in vitro and ex vivo studies were consistent and indicated a non-specific type of interaction of cryptosin with mammalian cardiac 1,4-dihydropyridine-specific calcium channels.

Interactions of cryptosin with mammalian cardiac beta-adrenoceptors.

Cryptosin - a new cardenolide from the leaves of Cryptolepis buchanani R & S was found to be a potent positive inotropic agent. In experiments with dog heart ex vivo, the rise in the cardiac rate associated with an increase in dP/dtmax and left ventricular pressure (LVP) correlated with changes in the beta-adrenoceptor densities as measured by the binding of 3H-Dihydroalprenolol (DHA). A significant change in the beta-adrenoceptor densities was observed when cryptosin was incubated with guinea pig and dog heart sarcolemmal membranes in vitro. Analysis of the binding of 3H-DHA in post-cryptosin treated membranes indicated a non-specific type of interaction of cryptosin with mammalian cardiac beta-adrenoceptors.

Dopamine and norepinephrine increase venous return by stimulating alpha and beta adrenoceptors in the dog.

The cardiopulmonary bypass technique was used to compare the effects of dopamine and norepinephrine on venous return, and to identify the adrenoceptors involved in the responses. Intraarterial boluses of dopamine and norepinephrine produced similar increases in mean arterial pressure and similar increases in venous return, but dopamine required 10-30 x larger doses than norepinephrine to produce the same effect. Phenoxybenzamine virtually abolished the venous responses to the lowest doses of both agonists and diminished the venous responses to larger doses. Propranolol had little or no effect on venous responses to the low doses but substantially diminished the responses to larger doses. These results indicate that the increase in venous return produced by dopamine or norepinephrine involves both alpha and beta adrenoceptors. To determine whether the beta adrenoceptor belonged to subtype beta 1, the "selective" beta 2 agonist, salbutamol, was used. The reported affinity of salbutamol in dogs for arterial beta 2 receptors is fivefold greater than that for cardiac beta 1 receptors. However, the dose-response curves of salbutamol on the venous and arterial systems overlapped, indicating that the increase in venous return represents a combination of properties common to both beta 1 and beta 2 adrenoceptors.

Relative cardiotoxicity and cytotoxicity of anthraquinonyl glucosaminosides.

The cardiotoxicity and cytotoxicity for tumor cells of four new synthetic anthraquinonyl glucosaminosides were compared in vitro. The nonhydroxylated anthraquinone was not cardiotoxic, and its cytotoxic activity was the weakest of the compounds in the series. Increasing the number of hydroxyl groups on the anthraquinone moiety increased the inhibition of growth of L-1210 leukemia cells and pancreatic or colonic adenocarcinomas in a soft agar colony formation assay. However, cardiotoxicity was also increased in proportion to the number of hydroxyl groups present. The adenocarcinomas were slightly more sensitive than the leukemias to the inhibitory action of the dihydroxylated anthraquinonyl glucosaminosides on cell growth.

Synthesis of anthraquinonyl glucosaminosides and studies on the influence of aglycone hydroxyl substitution on superoxide generation, DNA binding, and antimicrobial properties.

A series of anthraquinonyl glucosaminosides (10a-e) were synthesized by Koenigs-Knorr glycosidation of the corresponding aglycones (11a-e) with bromo sugar 12 followed by saponification. These glycosides were intended to serve as models to study the role played by the hydroxyl substituents on the aglycone portion of the antitumor anthracycline antibiotics. Superoxide generation as measured in rat heart sarcosomes was found to increase with the addition of successive hydroxyl groups to the anthraquinone nucleus. The 1,8-dihydroxy pattern was determined to generate significantly less superoxide than the 1,4-dihydroxy pattern. Hydroxyl substitution was also observed to stabilize the complex formed between the anthraquinones and DNA and was required for antibacterial activity against a number of Gram-positive organisms.

Histamine receptor activation by unsaturated (allyl and propargyl) homologs of histamine.

The spectrum of agonist activity for three new homologs of histamine (cis- and trans-imidazolylallylamine and imidazolylpropargylamine) was evaluated in the isolated guinea pig ileum and right atrium. The homologs were about three log units less potent than histamine in stimulating contractions of the longitudinal muscles of the ileum, but they were histamine-like, pharmacologically, because they were sensitive to blockade by pyrilamine and resistant to blockade by atropine. In the right atrium, these weak agonists were partially sensitive to blockade by cimetidine. The agonist activity of the cis-isomer in particular was completely blocked by a combination of cimetidine and propranolol, but resistant to reserpine treatment (neuronal catecholamine depletion). Therefore, these homologs of histamine have the ability to stimulate H1- and H2-histamine receptors and beta-adrenoreceptors in vitro.

DNA binding, cardiac superoxide production and cytotoxicity of daunomycin analogs.

Pyridoanthraquinones are potent antibacterial agents especially against gram-positive organisms. We tested two major biologic actions of these compounds: DNA intercalation and superoxide (O2-) production in sarcosomes. Using the bathochromic and hypochromic shifts induced by intercalation, followed by Scatchard analysis, we calculated dissociation constants and the number of binding sites per base pair for several analogues. We compared O2- production using cytochrome c reduction. Unsubstituted compounds do not bind to DNA or change its melting temperature (Tm). Placing a morpholino or piperidyl group at C-5 enhances the binding to DNA. The tetracyclic compounds were equipotent at producing O2- and were 20-fold more active than daunomycin. These compounds were unusual in their solid tumor cytotoxicity.

Optically active catecholimidazolines: a study of steric interactions at alpha-adrenoreceptors.

The optical isomers and deoxy form of 2-(3,4, alpha-trihydroxybenzyl)imidazoline hydrochloride were examined for their alpha-adrenergic activity on rat aorta. The rank order of stimulant activity was deoxy (2) congruent to (R)-(-)-1 greater than (S)-(+)-1. This is in contrast to catecholamines in which the order of activity is (R)-(-)-epinephrine greater than (S)-(+)-epinephrine = epinine (deoxyepinephrine). The relative order of potency for the isomers of 2-(3,4, alpha-trihydroxybenzyl)imidazoline is different than that predicted by the Easson--Stedman theory for stereoisomers of catecholamines. Also, substitution of the deoxy compound 2 with substituents, methyl or benzyl, in the 4-position lowers the alpha-adrenergic agonist activity, and differences observed between optical isomers were small.

A pharmacological study of two bisbenzylisoquinoline alkaloids, thalistyline and obamegine.

Thalistyline, a monoquaternary bisbenzylisoquinoline alkaloid isolated from Thalictrum sp. inhibited respiration in anesthetized dogs. Thalistyline is about one-fourth as potent as d-tubocurarine in blocking neuromuscular transmission in the rat hemidiaphragm preparation. The pharmacological mechanism of action of the alkaloid is similar to that of d-tubocurarine. Obamegine did not exhibit curare-like activity. On the isolated rabbit aorta, contractions induced by an alpha-adrenoreceptor agonist, phenylephrine, were antagonized by both alkaloids. Increasing concentrations of thalistyline produced parallel shifts to the right in the dose-response curves of phenylephrine. The pA2 value for the competitive pharmacological antagonism was 6.33. Obamegine also antagonized the effects of phenylephrine on the aorta, line and obamegine lowered blood pressure in normotensive dogs. The effect was transient. Repeated injections of the alkaloids resulted in tachyphylaxis to blood pressure lowering effects. Although alkaloids exhibited alpha adrenergic blockade in the vascular preparation, the mechanism for the hypotensive effect remains to be established.