Influence of the cGMP analog 8-PCPT-cGMP on agonist-induced increases in cytosolic ionized Ca2+ and on aggregation of human platelets.

The present study was undertaken to compare inhibitory effects of the cGMP analog 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate (8-PCPT-cGMP) on increases in cytosolic ionized Ca2+ and on aggregation in human platelets induced via diverse agonists. Fura-2-loaded and gel-filtered platelets were stimulated by either ADP (8 microM), thrombin (0.025 IU/ml) or collagen (1-3 micrograms/ml), respectively.

Blocking of the receptor-stimulated calcium entry into human platelets by verapamil and nicardipine.

Verapamil (ED50 = 3 x 10(-6) M) and nicardipine (ED50 = 10(-6) M) inhibited the platelet activating factor (PAF)-induced increase of free cytosolic calcium concentration [( Ca2+]i) in quin2-loaded human platelets. In a Ca-free medium containing 5 mM BaCl2, PAF stimulated the inflow of Ba2+ ions which is completely abolished by verapamil and nicardipine. Simultaneous determination of quin2 fluorescence and 45Ca absorption showed that the action of verapamil is accounted for by blocking of the Ca2+ entry.

Platelets as a model for studying the action of antihypertensive drugs.

The action of different antihypertensive drugs on Ca2+ concentration in human platelets was studied under in vitro conditions and during the treatment of hypertensive persons. Several calcium antagonists (verapamil, nifedipine, and nicardipine) acted to block an increase of Ca2+ concentration in platelets which was induced by platelet activating factor (PAF), adenosine diphosphate, and U46619, the stable analog of thromboxane A2. All calcium antagonists suppressed dose-dependent calcium responses induced by each agonist.

The hypertensive heart: pathogenesis, variants, and prognostic value.

We examine the heart's involvement in arterial hypertension, reporting on several studies of hypertensive patients showing that left ventricular myocardial mass is a significant prognostic indicator of essential hypertension and that left ventricular hypertrophy (LVH) correlates with an induced increase in Ca2+ concentration in platelets. We also consider the LVH variant of asymmetric hypertrophy and the role of the hypertensive heart in coronary insufficiency, and we speculate on the significance of the degree of LVH and asymmetric hypertrophy as risk factors for predicting cardiac complications of essential hypertension.

Calmodulin and troponin C as targets for drug action.

In this study, ligands from various chemical classes were investigated with respect to their relative affinities to calmodulin (CaM) and troponin C (TnC), using the fluorescent dye 3,3'-dipropylthiocarbocyanine iodide (diS-C3-5'). In parallel, functional tests were carried out determining the effects of the ligands on the CaM activated cyclic nucleotide phosphodiesterase (PDE) activity and the TnC mediated Ca-sensitivity of skinned myocardial fibres and cardiac myofibrils. The following results were obtained: 1) As a rule, most of the ligands tested had higher affinities to CaM than to TnC.

Decrease of platelet aggregation and spreading via inhibition of the cAMP phosphodiesterase by trapidil.

Trapidil (N,N-diethyl-5-methyl[1,2,4]triazolo[1,5-alpha]pyrimidine-7-amine ) inhibits platelet spreading and aggregation induced by arachidonic acid (AA), a stable analogue of prostaglandin (PG) endoperoxides (U46619), ADP, and low concentrations of thrombin, but not by A23187 and high concentrations of thrombin. Trapidil does not affect platelet adenylate cyclase but inhibits the cAMP PDE by approx. 50%.