Study of antiatherogenic properties of indapamide in a pharmacologic model.

A localized atheromatous plaque was induced in rabbits after transmural electrical stimulation of the carotid and a cholesterol-rich diet (1.33% cholesterol) for 4 weeks. This model was used to investigate the antiatherogenicity of indapamide. The treatment given per os started 14 days before the stimulation period. Animals were divided into six groups: group 1 (control) received gelatin 2%, group 2 received hydrochlorothiazide at 20 mg/kg/day, group 3 was treated with flunarizine at 25 mg/kg/day, and groups 4, 5, and 6 received indapamide at 0.3, 1, and 3 mg/kg/day, respectively. During the experimental period, all rabbits showed similar weight gain, regardless of the treatment. Image analysis showed an antiatherogenic effect for indapamide (0.3 mg/kg/day) characterized by a reduction in the number of cell layers (NCL; 10.5 +/- 1.8 vs. 18.0 +/- 2.9; p < 0.05) and in the intima/media area ratio (I/M; 17.5 +/- 4.5 vs. 42.7 +/- 7.0%; p < 0.01). Indapamide appeared to be more active than the reference drug flunarizine (NCL = 14.2 +/- 2.5, N.S.; I/M = 24.5 +/- 4.3, p < 0.05). The maximum effect occurred at the lowest dose tested (0.3 mg/kg/day). The reason for the loss of antiatherogenic activity of indapamide at higher doses is discussed. Hydrochlorothiazide did not show any effect on the formation of the atheromatous plaque.

Vasoactivity of trimetazidine on guinea-pig isolated ductus arteriosus.

The effect of trimetazidine (TMZ), an anti-anginal drug, on the mechanical response of the guinea-pig ductus arteriosus placed under conditions of mild hypoxia (PO2 approximately equal to 75 mmHg) was investigated. When the PO2 of the bathing solution was 75 mmHg, TMZ caused a dose-dependent increase in tension. The median effective dose (ED50) for the drug was 8 X 10(-5)M. TMZ-induced increase in tension was not significantly affected by pretreatment of the preparation with adrenoceptor blocking agents, or indomethacin. The amplitude of the PO2-dependent tension was significantly augmented by exposure of the strip to TMZ 10(-4)M, whereas neither the resting tone (low PO2), nor the oxygen-induced contraction (high PO2) were altered. This ability of TMZ to increase the tension response during hypoxia was dependent on the external calcium concentration. Under low PO2 conditions, a contractile activity of 10(-4)M TMZ was unmasked in preparations perfused with 18 mM K+-PSS medium. This response to TMZ disappeared after the removal of calcium from the bath. At the maximally effective dose of 10(-3)M, and during low PO2, the TMZ-induced contractile response changed to a relaxation response when the external K+ concentration was raised more than five fold. The possibility that TMZ stimulates the mechanism by which oxygen normally controls the concentration of free intracellular calcium in the ductus arteriosus is proposed.

Oxygen-induced contraction in the guinea pig neonatal ductus arteriosus.

We investigated the mechanism of oxygen-induced contractions in ductus arteriosus isolated from neonatal guinea pig. A preparation equilibrated at low Po2 (less than 40 mm Hg) displayed a steady membrane potential of -54.8 mV. Application of oxygen (Po2 (less than approximately or equal to 300 mm Hg) resulted in: (1) stepwise development of tension coupled to action potentials and (2) sustained membrane depolarization to -32.9 mV associated with tonic contraction. Mechanical sensitivity to oxygen persisted at any[K]o up to 126 mM, and tension was always larger at a given [K]o or a given membrane potential with high Po2 than with low Po2. The change in membrane potential per decade change in [K]o was 35 mV at low Po2 and 16 mV at high Po2. Oxygen contractions occurred when the ductal strips were bathed in K-free media or exposed to ouabain. We conclude that oxygen caused a conductance change in the sarcolemma resulting in depolarization, which is coupled to contraction. There is also evidence of a membrane potential-independent contraction mechanism.

Correlation of prostaglandin-induced mitochondrial calcium release with contraction in bovine intrapulmonary vein.

The effects of prostaglandins A2, A1, F2 alpha, E2, E2, F1 beta and an analog of PGH2 upon calcium release from mitochondria isolated from bovine intrapulmonary vein and contraction of helical strips of the same tissue were determined. The order of activity of the prostaglandins for calcium release was similar to that for contraction with the exception of the PGH2 analog. It is suggested that prostaglandin A2, F2 alpha, E2 and A1 induced release of mitochondrial calcium may influence the contractile state of bovine intrapulmonary vein. However, the PGH2 analog has a subcellular mechanism other than or in addition to mitochondrial calcium release and is different from the other prostaglandins.

Transmembrane calcium movements and excitation-contraction coupling in myocardial cells.

It has been realized for a century that Ca2+ is important in the initiation and the control of mechanical activity. The present paper does not cover the field of excitation-contraction coupling in heart but mainly reports some modern and controversial aspects about the regulation of the internal Ca concentration by the sarcolemma while the role of internal stores is only discussed. The first part deals with flux experiments; the second with the slow inward current mainly carried by Ca ions. An analysis of the mechanical activity reveals that only a part of tension is triggered by this slow current; besides, a second component of tension is demonstrated and an exchange mechanism of Na and Ca ions is described in detail. This countertransport, during depolarization, facilitates an influx of Ca ions (coupled to an efflux of Na ions). During hyperpolarization, or even at the resting membrane potential, it promotes an efflux of Ca ions. Thus, the same mechanism may account in part for the development or for the relaxation of tension according to the membrane potential.

Control of the frog heart relaxation by Na-Ca exchange.

Frog heart relaxation was analysed under voltage clamp conditions as the tension decay observed after membrane potential had been stepped back to its resting value. It appeared mostly exponential with a time constant of about 190 msec. Relaxation rate decreased with the external Na concentration. It fell to 1/10 in a Na-free solution. Relaxation rate decreased also following an increase in the intracellular Na content by application of veratrine. When switching from a high to a low Na-containing solution the relaxation rate reached rapidly a value transiently higher than the steady-state's (and vice versa). In Na-free solution, adrenaline accelerated tension decay, an effect not noticeable on frog heart in Ringer solution. In frog myocardium, part of the intracellular Ca concentration decrease which occurs during each cardiac cycle directly results from a calcium extrusion carried out by the Na-Ca exchange. Such a Ca decrease, besides internal Ca storage, should play a primary role in the relaxation of contractile tissues whose cells have a large surface/volume ratio.

Relaxation of frog myocardium.

Tension fall of frog heart contraction was analyzed under voltage-clamp conditions. It appears mostly exponential. The rate of relaxation depends upon the extracellular and intracellular Na concentrations. This suggests that the relaxation is under the control of Na-Ca exchange. The speeding up of relaxation by adrenaline in frog heart is revealed by low Na solution, while it is hidden by the primordial Na-Ca exchange in Ringer's solution.