[Organ Bath Experiments on Human Pulmonary Vessels: Assessment of Drug Efficacy for Treatment of Pulmonary Arterial Hypertension].

Various vasodilator medications are used in the treatment of pulmonary arterial hypertension (PAH), such as endothelin receptor antagonists (ERA) or phosphodiesterase-5-(PDE-5-)inhibitors. In a human ex vivo model, we investigated whether the combination of two substance classes could achieve a higher effect or - without loss of vasodilatation - a lower dosage of the individual substances might be sufficient. We established an ex vivo organ bath model to evaluate the dose-dependent effects of ERA and PDE-5-inhibitors on pulmonary vessels harvested from patients who underwent surgery (lung resection/transplantation).

Evaluation of the combination of endothelin receptor antagonists (ERA) and phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension (PAH) in pathologic human pulmonary arteries in an ex-vivo organ bath model.

Purpose: Medical combination therapy of pulmonary arterial hypertension (PAH) may alleviate the drawbacks of monotherapy by avoiding drug tolerance and by increasing effectiveness, as shown by the combination of ambrisentan and tadalafil (AMBITION trial). The present ex-vivo study evaluated the combination of the endothelin receptor antagonists (ERA) macitentan and bosentan with the phosphodiesterase-5 (PDE-5) inhibitor vardenafil in pulmonary arteries from patients suffering from terminal lung disease as a model of PAH.

Methods: Segments of the pulmonary vessels were excised from resected lungs of patients requiring lung transplantation (LTX).

Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage.

According to the general understanding, the chondrocyte lineage terminates with the elimination of late hypertrophic cells by apoptosis in the growth plate. However, recent cell tracking studies have shown that murine hypertrophic chondrocytes can survive beyond "terminal" differentiation and give rise to a progeny of osteoblasts participating in endochondral bone formation. The question how chondrocytes convert into osteoblasts, however, remained open.

Deletion of beta catenin in hypertrophic growth plate chondrocytes impairs trabecular bone formation.

In order to elucidate the role of β-catenin in hypertrophic cartilage zone of the growth plate, we deleted the β-catenin gene ctnnb1specifically from hypertrophic chondrocytes by mating ctnnb1(fl/fl) mice with BAC-Col10a1-Cre-deleter mice. Surprisingly, this resulted in a significant reduction of subchondral trabecular bone formation in BACCol10Cre; ctnnb1(Δ/Δ) (referred to as Cat-ko) mice, although Cre expression was restricted to hypertrophic chondrocytes. The size of the Col10a1 positive hypertrophic zone was normal, but qRT-PCR revealed reduced expression of Mmp13, and Vegfa in Cat-ko hypertrophic chondrocytes, indicating impaired terminal differentiation.

Antioxidants as antiarrhythmic drugs.

Experiments on rats and rabbits using models of arrhythmias induced by vasopressin, epinephrine, strophanthin, and CaCl2 showed that antioxidants derived from 1,4-dihydropyridines, dibunol, and alpha-tocopherol possessed antiarrhythmic effects. Administration of these antioxidants decreased the occurrence of extrasystoles, disturbances of atrioventricular conductivity and ventricular fibrillation. These drugs also prevented changes in membrane phospholipid composition, inhibited activation of peroxidation, decreased phospholipase activity, prevented a decrease of Ca2+ ATPase and Ca2+ binding and uptake by sarcoplasmic reticulum, and increased sarcolemmal Na+, K+-ATPase, sarcoplasmic reticulum creatine phosphokinase.

[Anti-arrhythmic action of preparations of the dihydropyridine series].

The derivatives of the dihydropyridine series, sodium salt of 2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydronicotinic acid (drug I) and disodium salt of 2,6-dimethyl-1,4-dihydropyridine-3,6-bis-carbonyloxyacetic acid (drug II), reduce or completely prevent (depending on the dose) arrhythmias of different types (disturbances of atrioventricular conduction, extrasystoles, heart fibrillation) induced by vasopressin, calcium chloride and strophantine. Study of the lipid composition and activity of lipid-dependent enzymes of sarcoplasmic reticulum membranes has demonstrated that the antiarrhythmic effect of the drugs under study is linked with their antioxidant action favouring the preservation of enzymes involved in Ca2+ transport.

Vasopressin and cardiovascular system in aging.

The studies concerned age-dependent peculiarities of the vasopressin effect on the hemodynamics and tone of the coronary vessels in dogs, the contraction of the isolated vascular strip in rats, and the hemodynamic and ECG indices in rabbits and in rats. The data obtained indicate the great sensitivity of old vessels to vasopressin. In aging, both humans and animals show a rise of vasopressin concentration in the blood.

[Blood vasopressin and the kallikrein-kinin system in chronic ischemic heart disease].

The blood vasopressin content and kinin system activity were studied in 83 patients with chronic ischemic heart disease of various severity. It was established that the blood vasopressin concentration increases with an increase in the severity of the disease. A high degree of correlation between changes in vasopressin content and in components of the kinin system was revealed: increase in the concentration of vasopressin is attended by activation of the kallikrein-kinin system.

[Blood vasopressin concentration is patients of different ages with hypertension].

The concentration of blood vasopressin was investigated in apparently healthy persons and in patients with I--II degree hypertension, aged from 20 to 80 years. Vasopressin concentration was determined by the biological method according to the antidiuretic effect of ethanol-anesthetized and constantly hydrated rats on an original 5-channel apparatus. The results obtained showed the blood vasopressin concentration to increase with age.

[Hormonal regulation of the heart in aging].

It was established in experiments on adult (8--12 month) and old (26--32 month) rats that in ageing the sensitivity of the cardiovascular system to certain hormones--adrenaline, vasopressin, insulin, thyroxine, estradiol dipropionate--grows while its reactivity to them diminishes. The administration of these hormones causes significant changes in hemodynamics and myocardial contractility. Adrenaline and thyroxine lead to an increase in the blood minute and stroke volume, arterial pressure, cardiac index and left ventricular work index, maximum rate of intraventricular pressure growth, maximum rate of myocardial fiber shortening, and in the contrastility index.

[E1Age and the development of coronary insufficiency under the influence of vasopressin].

Experimental results showed that the ECG changes (elevation of T wave, a shift of the S-T segment and disturbances of the atrio-ventricular conduction) under the effect of vasopressin occurred in rats aged 24-26 months after lower doses of vasopressin than in the animals aged 10-12 months. With the administration of the same doses coronary insufficiency was more pronounced in the old animals (more frequent disturbances of the atrio-ventricular conduction, grade II or III, and greater derangement of general hemodynamics).

[Vasopressin concentration in the blood and sensitivity of the cardiovascular system to it during aging].

With aging the content of the blood vasopressin increases. In old animals smaller doses of vasopressin induce coronary insufficiency (rise of T wave, shift of S-T segment, disorders of the atrio-ventricular conductivity). On continuous administration of vasopressin (during a month), arterial hypertension appears only in old animals due to increase in cardiac output, stroke volume at unchanged cardiac rhythm, and to some decrease in the total peripheral resistance.