phosphorus-radioisotopes and Hypertrophy

Cardiac hypertrophy occurs in as many as 47% of normotensive individuals who chronically use cocaine. We investigated the effects of cocaine, in concentrations commonly found in chronic cocaine users, on calcium/calmodulin kinase (CaMK), and whether cocaine can activate CaMK, increase cardiac myocyte protein expression, and cause cardiac hypertrophy in this manner. In series I to III, 0 (control) or cocaine in concentrations of 10 to 10 mol/L was added to cultured adult rat cardiac ventricular myocytes to determine by Western blots and by P incorporation the optimal treatment time and the optimal dose for CaMK activation. In series I, cocaine, 10 mol/L, increased myocyte CaMKII translocation from myocyte soluble to particulate fractions by > or =73 +/- 9% (P < 0.01) in comparison with controls but did not cause the translocation of CaMKI or CaMKIV. In series II and III, cocaine treatment of myocytes for 15 minutes increased maximal CaMKII activity by 86.5 +/- 13.3% (P < 0.001) and a cocaine dose of 5 x 10 mol/L increased CaMKII activity by 169.5 +/- 18.1% (P < 0.001). In series IV we measured by silver staining beta-myosin heavy chain protein (beta-MHC) expression in myocytes before and after cocaine and also CaMK inhibition with KN-62 (1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine). In these experiments, cocaine, 5x10 mol/L, increased myocyte protein concentration by 29.2 +/- 2.8%, and beta-MHC by 93.2 +/- 8.8% (P < 0.001). In series V and VI, cocaine effects on calcium currents (ICa) and intracellular Ca ([Ca]i) were determined before and after CaMK inhibition with KN-62 in rat myocytes. Cocaine, 10 mol/L, enhanced ICa peak amplitude in a voltage-dependent manner (by 173.9 +/- 14.9% at -20 mV and by 38.4 +/- 6.9% at 0 mV P < 0.01). Cocaine, 10 to 10 mol/L, in series VI promoted Ca transients from myocyte sarcoplasmic reticulum and increased [Ca]i to 607 +/- 141 x 10 mol/L (P < 0.05). KN-62 decreased cocaine-induced myocyte protein expression by 76.6%, and beta-MHC by 66.2% (P < 0.01) and significantly decreased cocaine-induced Ca transients and [Ca]i. We conclude that CaMKII activation is an important mechanism whereby cocaine can cause myocyte hypertrophy.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Adenosine Triphosphate; Animals; Calcium Channels; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Cocaine; Dose-Response Relationship, Drug; Heart Ventricles; Hypertrophy; Male; Membrane Potentials; Myocytes, Cardiac; Myosin Heavy Chains; Patch-Clamp Techniques; Peptides; Phenylephrine; Phosphorus Radioisotopes; Phosphorylation; Rats; Rats, Sprague-Dawley; Sarcolemma

Effects of radiophosphorus, at the dose rate of 1.0 muCi/g body weight, was studied on the development of anterior pituitary in mice. P-32 injected to pregnant female 7 days after fertilization did not influence substantially the pituitary either of fetuses or younger borns. 1-day-old mice injected with P-32 reveal hypertrophy of acidophils. In mice injected at the 7th day, signs of cell death followed by an increase in the number of acidophils were found. Following injection of 14 and 21-day-old mice the decrease in the number of acidophils was very clearly visible. In 21 and 28-day-old injected groups, there is a difference in the reactivity of male and female pituitary to P-32. There may be individual variation in relation to radiation effects in pituitary, with advent of age.

Topics: Age Factors; Animals; Cell Survival; Female; Hypertrophy; Male; Mice; Phosphorus Radioisotopes; Pituitary Gland; Pituitary Gland, Anterior; Radiation Dosage; Sex Factors