ABSTRACT
Both Ca-antagonistic as well as Ca-agonistic 1,4-dihydropyridines (DHPs) have become extremely important tools to investigate the role of Ca-channels under various physiological and pathophysiological conditions. While Ca-antagonists stabilize the inactivated state of the Ca-channel without influencing the voltage dependent open and closed times, Ca-agonists prolong the mean open time of the channel. We here report for the first time the effects of a novel DHP, BAY Y 5959, which modulates Ca-channel gating in a unique manner: It increases both the mean open time and the mean closed time of the Ca-channel by binding to the DHP receptor. This results in a reduced rate of Ca-current activation, an increased peak current, and a strongly prolonged tail current decay. All these effects are strongly voltage dependent. Therefore it depends on resting membrane potential and shape of the action potential whether and how the Ca-influx into the cell is influenced. This novel mode of action of BAY Y 5959 results in an interesting pharmacological profile: It has a strong positive inotropic effect in the heart without influencing vessel tone. Therefore the term Ca-promoter is suggested; it could become a new approach for the drug treatment of congestive heart failure.
Subject(s)
Calcium Channel Agonists/pharmacology , Calcium Channel Blockers/pharmacology , Dihydropyridines/pharmacology , Action Potentials , Animals , Aorta/drug effects , Aorta/physiology , Calcium Channel Agonists/chemistry , Calcium Channel Blockers/chemistry , Dihydropyridines/chemistry , Guinea Pigs , Heart/drug effects , Heart/physiology , In Vitro Techniques , Muscle Contraction/drug effects , RabbitsABSTRACT
The effect of BAY U 3405 (3 mg/kg i.v.) was tested on recombinant tissue-type plasminogen activator (rt-PA)-induced thrombolysis of an experimentally induced coronary thrombosis in anaesthetized dogs. BAY U 3405, given immediately before an rt-PA infusion, reduced time to reperfusion by more than 50% compared with vehicle-treated controls (P less than 0.01). After cessation of the rt-PA infusion, BAY U 3405 reduced the reocclusion rate compared to controls (P less than 0.05). These results show that BAY U 3405 improves rt-PA-induced coronary thrombolysis in a canine model.
Subject(s)
Carbazoles/pharmacology , Coronary Thrombosis/drug therapy , Sulfonamides/pharmacology , Thrombolytic Therapy , Tissue Plasminogen Activator/therapeutic use , Animals , Blood Pressure/drug effects , Carbazoles/metabolism , Dogs , Female , Heart Rate/drug effects , Infusions, Intravenous , Male , Recombinant Proteins/therapeutic use , Sulfonamides/metabolismABSTRACT
Organ culture of guinea pig trachea was performed in the presence of [35S]sulfate in order to characterize the sulfated glycoproteins released from the respiratory epithelium and mucosa. The sulfated macromolecules that were synthesized during a 6-h incorporation were separated by CsBr density-gradient centrifugation and gel-filtration chromatography successively. Most of the sulfated secreted macromolecules corresponded to a population of glycoproteins sensitive to reductive beta-elimination but resistant to both chondroitinase ABC and heparinase. These glycoproteins had different buoyant densities (ranging from 1.48 g/ml to 1.16 g/ml) and could be subfractionated according to molecular mass. A major part of the radioactivity was incorporated into high-molecular-mass mucins that were excluded from a Sepharose CL-2B column and did not penetrate into polyacrylamide gel in PAGE. However, a mixture of sulfated O-glycoproteins of much lower molecular mass was also characterized in addition to low amounts of chondroitin sulfate. Epithelial goblet cells are the predominant mucin-containing cells of the respiratory guinea pig trachea. Our results suggest that a wide range of sulfated O-glycoproteins are secreted by the guinea pig tracheal mucosa.
