Effect of various beta-adrenolytic drugs on heart rate and changes in left-ventricular systolic time intervals in patients with hyperthyroidism and simple goiter

The effects of a short-term application of various beta-adrenolytic drugs on heart rate and on the changes in subperiods of left ventricle contraction have been studied in 71 patients with untreated hyperthyroidism and in 72 patients with simple goiter. The following drugs were used: propranolol, metoprolol, atenolol, pindolol, nadolol and acebutolol. It was found that those betaadrenolytic drugs which have no sympathomimetic action cause a significant decrease in heart rate both in patients with hyperthyroidism and in those with simple goiter. The effect of these drugs on heart rate was not related to the changes in blood serum concentrations of thyroxine and triiodothyronine. None of the drugs tested influenced appreciably the contraction subperiods of left heart ventricle, both in the patients with hyperthyroidism and in those with simple goiter.     

Effect of calcium channel blocker (diltiazem) on platelet aggregation

Platelet aggregation with collagen, ADP and sodium arachidonate was significantly inhibited by 0.48 and 0.24 mg/ml of diltiazem but no significant effect occurred with 0.024 mg/ml of diltiazem. It is suggested that the antiplatelet property of diltiazem may be utilized in clinical setting and diltiazem may be tried synergistically with other antiplatelet drugs.     

Acetylation phenotype and the changes in selected indicators of calcium-phosphate metabolism in patients with hyperthyroidism treated with propranolol

The occurrence of acetylation phenotype has been studied in 76 patients with untreated hyperthyroidism. In 23 of these patients having the "fast" and in 42 having the "slow" acetylation phenotype the selected parameters of calcium-phosphate metabolism have been determined before, during and after propranolol therapy lasting six days. Propranolol was administered at a dose of 160 milligrams daily. A significant decrease in the blood serum level of calcium and urinary calcium excretion following propranolol administration was found only in patients with hypercalcemia and hypercalciuria. On the other hand, a significant decrease in the urinary excretion of hydroxyproline was observed in all the patients with hyperthyroidism treated with propranolol. The effect of propranolol on the measured parameters of calcium-phosphorus metabolism was similar in hyperthyroid patients with both "fast" and "slow" acetylation phenotypes, what suggests that it does not depend on the N-acetyltransferase activity.     

A calcium channel blocker nifedipine distorts the effects of nano-zinc oxide on metal metabolism in the marsh frog Pelophylax ridibundus

Global decline of amphibian populations causes particular concern about their vulnerability to novel environmental pollutants, including engineering nanomaterials and pharmaceutical products. We evaluated the bioavailability of nanoform of zinc oxide (n-ZnO) in frog Pelophylax ridibundus and determined whether co-exposure to a common pharmaceutical, a calcium-channel blocker nifedipine (Nfd) can affect this bioavailability. Male frogs were exposed for 14 days to the tap water (Control) and n-ZnO (3.1 μM), Zn²⁺ (3.1 μM, as a positive control for n-ZnO exposures), Nfd (10 μM), and combination of n-ZnO and Nfd (n-ZnO + Nfd) in environmentally-relevant concentration. Exposure to Zn²⁺ or n-ZnO led to up-regulation of metal-binding proteins, metallothioneins (MTs) in the liver and Zn-carrying vitellogenin-like proteins in the blood plasma. Notably, upregulation of MTs by Zn²⁺ or n-ZnO exposures combined with increased binding of Zn and Cu to MTs. This was associated with the more reducing conditions in the liver tissue indicated by elevated lactate to pyruvate ratio. Nfd suppressed the binding of Zn and Cu to MTs and led to a decrease in Lactate/Pyruvate ratio and elevated protein carbonylation indicating pro-oxidant conditions. Redox status parameters were not directly related to DNA fragmentation, nuclear abnormalities or suppression of cholinesterase activity indicating that factors other than oxidative stress are involved in cytotoxicity of different pollutants and their combinations. Furthermore, activity of Phase I biotransformation enzyme (CYP450 oxidase measured as EROD) was elevated in Nfd-containing exposures and in Zn²⁺ exposed frogs. Tyrosinase-like activity in the frog liver was strongly stimulated by Zn²⁺ but suppressed by n-ZnO, Nfd and n-ZnO + Nfd. These findings show that Nfd modulates homeostasis of essential metals in amphibians and emphasize that physiological consequences of combined n-ZnO and Nfd exposures are difficult to predict based on the mechanisms of single stressors.     

A calcium channel blocker activates both ecto-5(')-nucleotidase and NO synthase in HUVEC

Since amlodipine, a long-acting Ca channel blocker, increases both NO and adenosine production in canine hearts, we investigated that amlodipine activates both ecto-5(')-nucleotidase responsible for adenosine production and NO synthase (NOS) for NO production in human umbilical venous endothelial cells (HUVECs), and its cellular signaling. We measured activities of ecto-5(')-nucleotidase and NOS in HUVECs in the condition with additions of xanthine (100 microM)+xanthine oxidase (1.6 x 10(-3)U/ml) in the presence or absence of amlodipine (1 x 10(-9)-1 x 10(-6)M). Amlodipine increased both ecto-5(')-nucleotidase and NOS activities. Xanthine+xanthine oxidase deactivated both NOS and ecto-5(')-nucleotidase, and amlodipine increased both activities of NOS and ecto-5(')-nucleotidase by 117+/-33% and 48+/-6%, respectively. Amlodipine phosphorylated p38MAP kinase and that an inhibitor of p38MAP kinase inhibited the amlodipine-induced activation of both NOS and ecto-5(')-nucleotidase. Furthermore, amlodipine increased both adenosine and NO production in the canine ischemic hearts. We concluded that amlodipine activates both NOS and ecto-5(')-nucleotidase via p38MAP kinase in vitro and enhances both NO and adenosine production in vivo.     

The effect of a new calcium channel blocker (TA-3090) on lipoprotein profile and intestinal lipid handling in rodents.

Recent interest has focused on findings that drugs used to lower blood pressure may adversely modify plasma lipids and lipoprotein metabolism. This observation may explain why pharmacologic control of hypertension has failed to reduce the incidence of morbidity and mortality from coronary artery disease. The present study aims to evaluate the effect of TA-3090, a new calcium channel blocker, on fasting plasma lipids and lipoproteins, as well as on processes of intestinal fat absorption. Rats were treated by gavage with TA-3090 (10 mg/kg twice daily) for 4 days and compared with controls (n = 6 per group). Plasma cholesterol was increased in the treated group to (mean +/- SE) 74 +/- 2 vs 60 +/- 4 mg/dl (P less than 0.01), due mainly to an increased high density lipoprotein-cholesterol level (50 +/- 2 vs 37 +/- 3 mg/dl, P less than 0.005). Notably plasma triglycerides (TG) and low density lipoprotein-cholesterol were not significantly affected. Another group of TA-3090-treated animals was given an intraduodenal fat meal, and the rise in plasma TG and chylomicrons followed over 4 hr. Postprandial hypertriglyceridemia and chylomicronemia were significantly lower at 2 hr (P less than 0.05) and 3 hr (P less than 0.01) compared with controls. In a separate group of animals, the addition of TA-3090 to a 2% intralipid infusion intraduodenally was associated with significantly reduced TG and chylomicron-TG transport into lymph (P less than 0.05). Furthermore, experiments in rats pretreated with TA-3090 intraperitoneally and then given 2% intralipid intraduodenally were shown to have a significant decrease in mean flow rate (27%), TG transport (31%) and chylomicron-TG output (37%), when compared with controls. In vitro studies using jejunal organ culture to examine the effect of TA-3090 on intracellular lipid synthesis and secretion revealed that the addition of the drug to the medium resulted in significantly decreased TG synthesis and secretion. These data suggest that TA-3090 could be effective in increasing HDL-cholesterol and reducing postprandial chylomicronemia. Our findings support a role for TA-3090 directly on enterocyte absorption and/or intracellular lipid transport, and thus indicate the importance of intracellular calcium on these processes.     

Normalization of deranged signal transduction in lymphocytes of COPD patients by the novel calcium channel blocker H-DHPM

Investigations on the role of intracellular Ca²⁺ ion concentration in the mechanism of development of COPD in smokers and non-smokers were carried out. The intracellular Ca²⁺ levels were found to be increased in human lymphocytes in patients with COPD as compared to non-smokers and smokers without COPD. The investigations reveal an association in altered intracellular Ca²⁺ regulation in lymphocytes and severity of COPD, by means of significant activation of Protein kinase C and inducible nitric oxide synthase (iNOS). The effect of a novel calcium channel blocker ethyl 4-(4′-heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (H-DHPM) as a potential candidate for the treatment of COPD was also investigated. H-DHPM treated cells showed a decrease in intracellular Ca²⁺ level as compared to the control cells. Molecular studies were carried out to evaluate the expression profile of NOS isoforms in human lymphocytes and it was shown that H-DHPM decreases the increased iNOS in COPD along with reestablishing the normal levels of endothelial nitric oxide synthase (eNOS). The results of H-DHPM were comparable with those of Amlodipine, a known calcium channel blocker. Calcium channel blocker H-DHPM proves to be a potential candidate for the treatment of COPD and further clinical studies are required to prove its role in the treatment of pulmonary hypertension (PH).     

Effect of a calcium channel blocker on the hypophyseal secretion of luteinizing hormone in intact and castrated rats of both sexes

The effect of verapamil on luteinizing hormone secretion by pituitary body was studied in normal and castrated male and female rats. Intragastric verapamil administration at a dose of 10 mg/g body weight two hours prior to decapitation decreased luteinizing hormone serum and pituitary levels in female rats only in proestrus. It is suggested that preovulatory luteinizing hormone secretion depends partially on estradiol-stimulated calcium transport.     

Effect of intravenous methimazole on serum levels of thyroid hormones in patients with hyperthyroidism resistant to oral thyrostatic drugs

The effectiveness of therapy involving intravenous administration of methimazole applied in patients with hyperthyroidism resistant to oral thyrostatic drugs has been investigated. Methimazole (Favistan, Asta) was administered intravenously to 3 patients (two women and one man, of ages 21, 24 and 67 years, respectively) in whom there was no remission of the disease after oral methimazole therapy lasting at least two months. Blood serum concentrations of thyroxine (T4), triiodothyronine (T3), reverse++ triiodothyronine (rT3) and triiodothyronine binding index (T3I) have been measured and free thyroxine index (FT4I) calculated before the treatment and on the 4-th, 7-th, 11-th, 14-th and 17-th day of the treatment. The mean value of T4 concentration decreased from 17.0 micrograms/dl before the treatment to 9.7 micrograms/dl after the treatment. T3 from 352 to 177 ng/dl, rT3 from 114 to 103ng/dl the value of T3I from 183 to 161%, and that of FT4I from 30 to 17, respectively. A significant fall of T3 level was observed on the 11-th day of the therapy, that of rT3 on the 14-th day, and that of FT4I on the seventh day. It was concluded that the resistance of some patients with hyperthyroidism to the oral thyreostatic therapy may be caused by the defective absorption of these drugs from the intestinal tract.     

Pre- and postsynaptic effects of the calcium channel blocker verapamil in the nerve-muscle preparation

Verapamil did not change the amplitude of the miniature and multiquantal end-plate currents, synchronicity of the transmitter release and repetitive firing at the motor nerve endings. Verapamil shortened the decay of multiquantal currents, the effect being enhanced after acetylcholinesterase inhibition. In muscles with inhibited acetylcholinesterase, verapamil promoted the depression of successive end-late currents in rhythmic nerve stimulation. The data suggest that in skeletal muscles verapamil-sensitive calcium channels do not take part in physiological transmitter release or in chemical potentiation of the secretion after treatment with potassium channels blocking agents.