V. Pelouch

Thyroid control of sarcolemmal Na+/Ca2+exchanger and SR Ca2+-ATPase in developing rat heart

Thyroid hormone (TH) levels increase in the postnatal life and are essential for maturation of myocardial Ca2+ handling. During this time, the sarcolemmal (SL) Na+/Ca2+exchanger (NCX) function decreases and the sarco endoplasmic reticulum (SR) Ca2+-ATPase (SERCA2) function increases. We examined the effects of postnatal hypo- or hyperthyroidism on NCX and SERCA2 in rat hearts. Animals were rendered hypothyroid by 0.05% 6- n-propyl-2-thiouracil in drinking water given to nursing mothers from days 2 to 21 postpartum. Hyperthyroidism was induced by daily injections of 10 μg/100 g body weight of 3,3,5-triiodo-l-thyronine during this period. Ventricular steady-state mRNA and protein levels of NCX and SERCA2 were analyzed by Northern and Western blotting. These were compared with SL Na+gradient-induced and SR oxalate-supported Ca2+ transports in isolated membranes. In hypothyroidism, NCX mRNA and protein were elevated by 66 and 80%, respectively, and SERCA2 mRNA and protein were reduced to 55 and 70%, respectively ( P < 0.05 vs. euthyroid). Corresponding differences were observed in the respective Ca2+ transports. Conversely, reduced NCX (by 50%) and elevated SERCA2 (by 150%) activities were found in hyperthyroidism ( P < 0.05). The levels of NCX and SERCA2 mRNA and protein were, however, unchanged in hyperthyroidism, indicating that functional changes are not due to altered NCX and SERCA2 expression. In this case, a decline in noninhibitory phosphorylated phospholamban is a likely explanation for the elevated SR Ca2+ transport. In conclusion, physiological TH levels appear to be essential for normal reciprocal changes in the expression and function of myocardial NCX and SERCA2 during postnatal development.

Reversibility of Pulmonary Hypertension and Right Ventricular Hypertrophy Induced by Intermittent High Altitude Hypoxia in Rats

The effect of intermittent altitude hy- poxia simulated in a hypobaric chamber (7,000 m, 8 h daily, 5 days a week) on the lesser circulation and heart weight was studied in rats. A marked chronic pulm

The effect of beta adrenergic blockade on pulmonary hypertension, right ventricular hypertrophy and polycythaemia, induced in rats by intermittent high altitude hypoxia

SummaryAdult male rats were used to study the effect of a beta blocking agent on pulmonary hypertension and right ventricular hypertrophy induced by intermittent high altitude (IHA) hypoxia (8 hr daily, 5 days a week, stepwise up to the simulated altitude of 7000 m). Trimepranol was injected subcutaneously in a single dose of 10 mg/kg/b.w. one hour before each IHA exposure. Administration of the beta blocking drug caused significant changes of haematocrit values even in animals kept under normoxic conditions. The initial deep decrease was followed by a slow return to control values; prolongation of treatment led to a further significant decrease of the haematocrit curve. The polycythaemic response of IHA-exposed and Trimepranol-treated animals was, therefore, significantly less pronounced as compared with the hypoxic non-treated group. Administration of Trimepranol to IHA-exposed rats significantly decreased the values of right ventricular systolic and mean pressure, right ventricular hypertrophy as well as the degree of muscularization of pulmonary arteries.It may be assumed that the protective effect of Trimepranol is due to a) changes in pulmonary vascularization, b) reduction of polycythaemia, and c) lower cardiac output, induced by the negative inotropic and chronotropic effect of this drug.ZusammenfassungBei erwachsenen männlichen Ratten wurden die Auswirkungen einer Beta-Rezeptoren-Blockade auf die pulmonale Hypertension und die rechtsventrikuläre Hypertrophie untersucht, die durch Hypoxie unter intermittierender Höhenexposition ausgelöst wurden (8 Stunden täglich; 5 Tage pro Woche; stufenweise Steigerung bis zu einer simulierten Höhe bis zu 7000 m). Trimepranol wurde eine Stunde vor der Höhenexposition als Einzeldosis (10 mg/kg) subkutan injiziert. Die Verabfolgung des Beta-Rezeptoren-Blockers verursachte signifikante Änderungen der Hämatokritwerte selbst bei Tieren, die unter normoxischen Bedingungen gehalten wurden. Ein initialer erheblicher Abfall war gefolgt von langsamer Rückkehr zu den Kontrollwerten. Verlängerung der Behandlung führte zu weiterer signifikanter Abnahme des Hämatokrits. Die Polyzythämie nach Höhenexposition war daher bei mit Trimepranol behandelten Tieren eindeutig weniger ausgeprägt als bei der nicht behandelten “hypoxischen” Gruppe. Verabfolgung von Trimepranol reduzierte bei den Ratten mit Höhenexposition eindeutig den rechtsventrikulären systolischen Druck und Mitteldruck, die Hypertrophie des rechten Ventrikels und die Dicke der Muskelwand der Pulmonalarterie.Man kann annehmen, daß der protektive Effect von Trimepranol a) auf Änderungen der pulmonalen Vaskularisation, b) auf eine Reduktion der Polyzythämie und c) auf ein geringeres Herz-Minuten-Volumen zu beziehen ist, letzteres induziert durch die negativ inotropen und chronotropen Effekte der Substanz.

Relative organ blood flow in rats exposed to intermittent high altitude hypoxia.

SummaryCirculating blood volume, cardiac output and relative organ perfusion changes were studied, using the Sapirstein method of86Rb tissue uptake, in male 75-day-old rats exposed to intermittent high altitude hypoxia (gradually up to 7000 m, 4 h daily, 5 days a week; the total number of exposures was 24).Intermittent hypobaric exposure caused a significant rise of the erythrocyte volume, whereas the plasma volume remained unchanged. The relative perfusion of the left and particularly of the right ventricular myocardium, as well as of the spleen, liver, lung, small intestine and skeletal muscle, was significantly higher. The cardiac output determined in other experimental animals similarly treated was significantly higher after 24 exposures to the intermittent high altitude hypoxia. We suggest that these changes are triggered by tissue hypoxia and a greater blood flow demand.

Comparison of cardiopulmonary response to intermittent high-altitude hypoxia in young and adult rats.

Haemodynamic and heart weight parameters were compared in male rats exposed to intermittent high-altitude (IHA) hypoxia (barochamber, 8 h/day, 5 days/week, total of 24 exposures stepwise up to 7,000 m) starting either from the 4th day or the 12th week of postnatal life. Systemic arterial pressure and heart rate increased in adult IHA acclimatized animals only. Marked chronic pulmonary hypertension and right ventricular enlargement were found in both age groups. Right ventricular weight increased linearly with a rise of pulmonary blood pressure in animals exposed to IHA from the 4th day of life (r = 0.72); no significant relation was found in adult rats (r = 0.16). The close correlation between both variables in young hypoxic rats may be due to the ability of the developing heart to respond to chronic hypoxia by both hypertrophy and hyperplasia of myocytes.

Effect of Verapamil on Pulmonary Hypertension and Right Ventricular Hypertrophy Induced in Rats by Intermittent High Altitude Hypoxia

Adult male Wistar rats were used for studying the effect of Ca2+ antagonist verapamil on pulmonary hypertension, right ventricular hypertrophy and the medial thickness of pulmonary arterioles, induced by intermittent high altitude (IHA) hypoxia. This was simulated in a hypobaric chamber (7,000, 8 h daily, 5 days a week, 24 exposures). Verapamil was injected subcutaneously in a single dose of 8 mg/kg before each IHA exposure. Administration of verapamil to IHA-exposed animals significantly reduced right ventricular systolic pressure, right ventricular hypertrophy and pulmonary arteriolar medial thickness. Our results support the hypothesis that the transmembrane influx of extracellular calcium is an important component of the mechanisms of hypoxic pulmonary vasoconstriction.

Ontogenetic differences in cardiac sensitivity to verapamil in rats.

SummaryThe degree of a negative inotropic response of the isolated right ventricle to verapamil as well as the mortality rate were studied in rats during their postnatal development. Male Wistar rats aged 3, 15, 30, and 90 days were used. The isolated right ventricle was incubated in a glucose-free solution with a mixture of 95% O2 and 5% CO2 and electrically stimulated. The amplitude of isotonic contractions (AIC) was registered. In 90-day-old rats, AIC was 74.1±6.2% of initial amplitude 45 min after administration of verapamil; in 30-day-old, 41.1±6.4%; in 15-day-old, 38.2±4.1%; and in 3-day-old rats, only 2.6±1.5. The difference between the 3-day-old rats and all older groups was statistically highly significant. The mortality rate of verapamil-treated rats increased with decreasing age of animals. It is concluded that the sensitivity of the rat myocardium to verapamil is age dependent: the negative inotropic effect of this drug increases with decreasing age of the animal. This indicates a possible risk in the therapeutic use of verapamil when given to newborns and infants.

The effect of isoprenaline on the phospholipid content of the compact and spongious musculature of the carp ventricular myocardium

1. After a single injection of 40 mg kg-1 of isoprenaline to the carp, lysophospholipids appear in the tissue of the heart ventricle, ethanolamine plasmalogens increase and choline plasmalogens decrease; phosphatidylinositol is lowered in the spongious layer only. 2. Daily administration of 5 mg kg-1 of the drug leads, after 5 doses, to a dramatic decrease of the diphosphatidylglycerol content; during the subsequent 5 and 10 doses a return to normal values occurs. Shifts in plasmalogens are similar to those found after a single high dose. Some other phospholipids change significantly. 3. All changes reveal that the spongious musculature is more sensitive to the drug than the compact one.

Structural Remodeling and Functional Changes in Chronic Hypoxia-Induced Right Ventricular Hypertrophy

Myocardial hypertrophy is a positive adaptive process allowing temporary compensation of raised demands on blood circulation. Not only does the amount of contractile elements increase, but the heart itself undergoes complete remodeling at the organ, cellular, and subcellular level. Positive signs of adaptation are, however, accompanied by the development of pathological changes that may lead to cardiac failure.

Function of the Hypertrophic Right and Left Ventricles in Experimental Conditions

The heart responds to a chronically increased load by an important adaptive mechanism, myocardial hypertrophy. The condition involves comprehensive and dynamic transformation of the heart at the level of organ, cells, and subcellular structures. However, the adaptive process, in addition to its positive aspects, includes adverse changes that may be associated with functional impairment and the development of cardiac failure.