Composition and cardioprotective effects of Primula veris L. solid herbal extract in experimental chronic heart failure.

BACKGROUND: High interest in chronic heart failure (CHF) is accounted for by its high incidence, poor prognosis, growing number of hospital admissions due to the heart failure relapse, and inadequate treatment. These facts necessitate a search for new pharmacological agents for the CHF correction. Herbal medicinal products appear to be very promising as they have a noticeable therapeutic effect and tend to be more harmless in comparison to the most of synthesized medications. PURPOSE: Our aim was to study the composition of the Primula veris L. solid herbal extract (PVSHE) and its effects on the myocardial contractile function in animals with experimental CHF. STUDY DESIGN: The study design involved the identification of the raw material composition of the P. veris L. extract. For the experimental part of our research, we used the model of CHF to elucidate the cardioprotective properties of PVSHE. METHODS: The active extract constituents were isolated by thin-layer chromatography and column chromatography; the extract components were identified by high-performance liquid chromatography, ultraviolet spectroscopy (UVS), and nuclear magnetic resonance spectroscopy (NMRS). To model CHF, L-isoproterenol at a dose of 2.5 mg/kg was intraperitoneally injected to the experimental rats twice a day for 21 days. Cardiac output was assessed with the loading test, adrenoreactivity test, and maximum isometric loading test; CHF markers adrenomedullin and copeptin were detected in blood plasma with ELISA kit for adrenomedullin and copeptin (Coud-Clone Corp., USA). RESULTS: P. veris L. solid herbal extract contains flavonoid aglycons (apigenin, quercetine, kaemferol), flavonoid glycosides (cinarozid, rutin, hyperozid), as well as polymethoxylated flavonoids acting as chemotaxonomic markers for the genus Primula (8-methoxy-flavone; 3',4'methylenedioxy-5'-methoxyflavone). The substance 3',4'methylenedioxy-5'-methoxyflavone has been isolated from the primrose herb for the first time. We showed that the PVSHE has a cardioprotective effect when it was administered at a dose of 30 mg/kg in the experimental CHF, as evidenced by a lower number of animal death, lower level of CHF markers in the blood plasma of the experimental animals, the higher increase in rate of myocardial contraction and relaxation, the higher level of left ventricular pressure (LVP) and of maximum intensity of structural performance (MISP), as compared to the control group. CONCLUSION: P. veris L. solid herbal extract contains flavonoid aglycons, flavonoid glycosides, and polymethoxylated flavonoids. The herbal agent increases the myocardial contractility in experimental CHF.

Inhibition of the Expression of Inducible NO Synthase by Neuroactive Amino Acid Derivatives Phenibut and Glufimet In Vitro and Ex Vivo.

The effects of glufimet and phenibut (glutamic acid and GABA derivatives, respectively) on concentration of inducible NO synthase and cGMP in LPS-activated mouse peritoneal macrophages and on NO end products in their culture medium were examined in vitro and ex vivo. Addition of LPS into culture medium elevated concentration of NO metabolites in this medium and increased concentration of inducible NO synthase and cGMP in the lysates of peritoneal macrophages, whereas incubation of the cells with examined agents applied at concentration of 10-5 M diminished these indices. Similar results were obtained with intraperitoneal injection of LPS, glufimet, and phenibut. In culture medium containing peritoneal macrophages from the mice injected with LPS (100 µg/kg), the concentrations of inducible NO synthase and cGMP as well as the total concentration of nitrite and nitrate ions increased, whereas in culture medium with the cells from LPS-exposed mice treated with glufimet (28.7 mg/kg) and phenibut (50 mg/kg) these indices significantly decreased.

Effect of Phenibut and Glufimet, a Novel Glutamic Acid Derivative, on Respiration of Heart and Brain Mitochondria from Animals Exposed to Stress against the Background of Inducible NO-Synthase Blockade.

Increased oxygen consumption by heart and brain mitochondria in the absence of ADP and reduced mitochondrial respiration in the presence of ADP were observed in rats exposed to stress simulated by suspension by the dorsal neck skin fold for 24 h, which attests to uncoupling of substrate oxidation and ATP synthesis and can cause electron drain from the respiratory chain, formation of ROS, and oxidative damage to cell structures. Blockade of inducible NO synthase with aminoguanidine (single intraperitoneal dose of 50 mg/kg before stress exposure) increased coupling of respiration and oxidative phosphorylation in heart and brain mitochondria of rats exposed to immobilization-painful stress, which was especially pronounced in cardiomyocytes. The test compounds glufimet (single intraperitoneal dose of 29 mg/kg before stress exposure) and phenibut (single intraperitoneal dose of 50 mg/kg before stress exposure) limited stress-induced mitochondrial damage against the background of inducible NO synthase blockade and without it, which was seen from increased respiratory control ratio in comparison with that in untreated rats exposed to stress (control).

Effect of GABA derivatives on the rate of thrombus formation, platelet aggregation, and plasma coagulation capacity in rats with experimental gestosis.

Experimental gestosis induced by replacement of drinking water with 1.8% NaCl promoted hypercoagulation, increased the rate and degree of platelet aggregation, and reduced clotting time in pregnant females. GABA derivatives, compounds RGPU-151, RGPU-152, and phenibut normalized parameters of hemostasis and platelet aggregation and the rate of thrombus formation in the animals. The efficiency of the test substances did not significantly differ from that of the reference drug sulodexide.

[Influence of RGPU-207 compound and amiodarone on ion currents in shellfish neurons].

RGPU-207 compound and amiodarone in concentrations of 1, 10, 100 and 1000 microM produce dose-dependent and reversible effects on trans-membrane sodium, calcium, and potassium ion currents of neurons in pond snail and orb snail shellfish. In concentration of 1 microM, both compounds increased the amplitude of potassium ion currents, while not affecting the amplitude of sodium and calcium ion currents. In concentrations of 100 and 1000 microM, dose-dependent suppression of all currents (with predominant potassium ion current suppression) was observed. Under the action of RGPU-207 compound, the kinetics of activation and inactivation of sodium and calcium ion currents was not changed, but the kinetics of activation of the potassium slow current was slowing down. Amiodarone decelerated the inactivation of calcium ion current and accelerated the inactivation of potassium slow current. RGPU-207 compound, in comparison to amiodarone, produces a similar membranotropic effect on the shellfish neurons.

[Effect of GABA derivative--RSMU-151 on the development of oxidative stress in rats with experimental gestosis].

Experimental gestosis induced in rats by drinking 1.8% sodium chloride solution instead of water during the entire period of pregnancy leads to activation of lipid peroxidation (LPO) process, as manifested by increased concentration of diene conjugates and malonic dialdehyde, decreased concentration of antioxidant enzymes (superoxide dismutase and glutathione peroxidase) in homogenates of rat brain, liver, uterus, and placenta. The GABA derivatives--RSMU-151 limits the damaging effect of gestosis, which is manifested by a decrease in the concentration of LPO products and by activation of the antioxidant system enzymes in all organs studied.