Age-dependent effects of ischemia and reperfusion on cardiac function and Ca2+ transport in myocardium.

Experiments on isolated hearts from adult and old rats have proved an age-dependent decrease in the resistance of contractile function and cardiac rhythm to ischemia and reperfusion. The restriction of coronary flow by 70% produced significant changes in various links of the Ca2+ transport system (an increase in sarcolemmal permeability for Ca2+ and a decrease in Ca(2+)-accumulating capacity of sarcoplasmic reticulum included). These changes, more marked in old animals, seemed to play an important role in the mechanisms of disturbances in cardiac function following coronary insufficiency.

Contractile function and Ca2+ transport system of myocardium in ageing.

Experiments with animals with various species-specific life span (rats, rabbits, cats, dogs) and different models (in situ heart, isolated perfused heart, isolated papillary muscle) have proved the reduction of functional capacity of the ageing heart. Diversely directional age-dependent shifts have been established involving myocardial Ca2+ transport system, i.e. an increase in the rate of Na+-Ca2+ exchange and passive Ca2+ transport across sarcolemma and a decrease in its Ca2+-binding capacity and a decrease in Ca2+ accumulation by sarcoplasmic reticulum and mitochondria (Ca2+ uptake). The experiments revealed a decrease in the Ca2+ ATPase myosin activity in the myocardium of aged animals and absence of age changes in the K+ ATPase activity. The findings obtained suggest that the development in the cardiac contractile function disorders in ageing largely depends on the age-related changes in the Ca2+ transport system.

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.

Contractile function, energy metabolism and myocardial structure at graded restriction of coronary blood flow.

In closed-chest dogs, 30, 50 and 70% restriction of coronary blood flow was carried out by catheterization and autoperfusion of the circumflex branch of the left coronary artery. At 70% restriction, a mild decrease in most contractility indices was observed, without simultaneous impairment of the indices of systemic haemodynamics. Changes in energy metabolism appeared already in the initial stage of coronary insufficiency. A characteristic features at suppression of aerobic oxidation was an increase of the cAMP level of glycolytic activity of the pentoso-phosphate cycle, which ensured a sufficiently high ATP level in the myocardium. A limiting factor were disturbances in the system of energy transport (creatine phosphate, creatine phosphokinase) and of the calcium pump (Ca++-ATPase of the sarcoplasmic reticulum, SPR), which evidently led to a decrease of the inotropic properties of the myocardium at 70% restriction of coronary blood flow. Signs were found of structural lesions of the myofibrils and the SPR.

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. Age-dependent differences of the vasopressin effect on the kallikrein-kinin system, adenosine metabolism, the contents of prostaglandins and cyclic AMP have been established. High sensitivity to vasopressin in combination with its increased concentration in the blood is an important factor that contributes to the development of arterial hypertension and ischemic heart disease.

Kallikrein-kinin system and adenosine metabolism system of blood and heart and their changes at hypothalamic-hypophyseal stimulation in rabbits of different age.

It was shown that kallikreinogen content was decreased in blood of old rabbits, kallikrein activity was somewhat increased, kininase activity was significantly decreased. In old animals, adenosine metabolism was activated, this being evident from the rise of 5'-nucleotidase and adenosine deaminase activity in blood and myocardium. Hypothalamic stimulation resulted in significant activation of the kallikrein-kinin system and sharp increase of kallikrein activity, the shifts being less marked in old animals than in adults. In adult animals, vasopressin administration elicited more marked activation of the kallikrein-kinin and adenosine metabolism systems.

Some myocardial factors of biological oxidation in experimental myocardial infarction.

In 175 dogs myocardial infarction was produced by high ligation of descending branch of left coronary artery. At various intervals after the intervention (1, 3, 5, 10, 30, 180 days), the activities and levels of NAD, NADH, FAD, riboflavin, cytochrome C, myoglobin, some NAD-dependent Krebs cycle enzymes, and mitochondrial succinate dehydrogenase and cytochrome oxidase were determined in the infarcted zone. It was found that in the infarcted zone there occurred substantial disturbances of various links constituting the tissue oxidative chain, in the stages of substrate dehydrogenation, electron transport to oxygen molecule, and myocardial oxygen uptake. The greatest disturbances took place in the systems of NAD and NAD-dependent enzymes, whereas the succinate oxidation system sustained substantially lesser damage. The decrease inlevels of flavonoids, which was likewise observed, participated also in the mechanism inhibiting succinate dehydrogenase. The cytochrome system activity was limited by the level of cytochrome C, whose deep decrease persisted considerably long in the infarcted zone. A certain role in disturbances of oxidative processes may have been played by the decreased concentration of myoglobin, an important myocardial reservoir of oxygen.