[ Scientific Activities - Actividades Científicas ]Senile Heart Horacio Romero Villanueva MD According to Weisfeldt and Gerstenblith  there are reasons to believe that ageing has a selective effect upon specific aspects of the cardiovascular function and upon the response to pharmacological agents. Difficulty lies in differentiating between changes caused by illness in old age and those caused by mere ageing of human cardiovascular system, due to the high prevalence of ischaemic heart disease and atherosclerosis.
Generally speaking, we should consider that changes are related to old age and not to illness when they are common to many species, when the subjects studied are healthy and when studies are longitudinal.
"Senile heart", according to a concept by Nakano and Tuzel  that we share, means that some old people without any cardiopathy have a diminished cardiac reserve. The expression is synonymous to presbicardia or myocardial senescence [Dock, 1945-1956] but not to senile cardiomyopathy or old age myocardiopathy [Burch, 1971; Schland, 1994], which are wrong as long as they imply the existence of a pathology due to old age.
On the contrary, a senile or presbicardic heart is that, which only presents changes caused by ageing.
From maturity to senescence two different processes coexist, mutually influencing one another: normal ageing and illness. Annually almost two out of every three deaths in the USA are caused by cardiovascular illness. The incidence of coronary heart disease increases from 46 % in the sixth decade of life to 84 % in the ninth [Medalia and White, 1952], and is similar in old men and women [Gordon, 1977; Kennedy, 1977].
At rest it seems that age is not a factor influencing left ventricular ejection fraction, end diastolic volume and ventricular wall regional motility [Port, 1980]. Ejection fraction was less than 0.60 during exercise in 45 % of people older than sixty but only in 2 % of those younger. The same happens with regional contraction abnormalities. Based upon this and other evidences, Fleg and Lakatta  underline that half typical Americans should be excluded from longitudinal studies of cardiovascular ageing just because they suffer from coronary heart disease, clinically silent in almost half of them.
SENILE HEART MORPHOLOGICAL ASPECTS
Heart weight can be significantly predicted either by pathological evidence of ischaemic heart disease or by myocardial infarctions. That is the reason why, when a group of old people is surveyed, ischaemic heart disease is a far more important factor than age in order to predict heart weight.
Old people hearts macroscopic aspect can change with age [Cohn, 1942]. Hearts colour becomes more deeply brown and subepicardial fat is more abundant. In the endocardium, changes are caused by continuous stress. A growing white-grey thickening can be observed focally distributed in both ventricles and in the right atrium. It is more diffuse in the left atrium. Degenerative changes or endocardial sclerosis appear in hypertrophied areas. An important elastosis, fat infiltration and loss of cohesion among collagen and elastic fibres are found in the subendocardium [Lev, 1978; McMillan, 1959]. Subepicardial and subendocardial collagen increases and becomes stiffer [Ito, 1980]. The auricular side of the mitral valve anterior leaflet becomes thicker and nodules increase in the closing line. The aortic valve leaflets are thicker in the base, the closing line and the Arancio nodule. Valves and valvular rings calcify, mitral more than aortic. The myocardium undergoes several cellular changes: increased vacuolisation and neutral fat and lipofucsin deposits in the myocyte. This is known as brown heart. Senescent myocardium shows more amiloid deposits, especially in women. This can favour heart failure and auricular fibrillation. In the elderly the exciting-conducting system sino-auricular node undergoes changes such as the loss of sinusal cells, an increase of fat, collagen, and elastic and reticular fibres.
Studies on Drosophilas heart suggest that age-related myocardial changes be not due to degenerative coronary arteries disease since there is no myocardial circulation system in this insect.
Morphological changes in mans blood vessels are a mixture of pathological and age-related changes, difficult to differentiate from one another [Camilleri, 1993]. The intima, media, and adventitia are affected at all levels of the arterial system. The intima thickens and develops a certain structure. Elastin and collagen increase, there are more cells, especially smooth muscle cells and macrophages. Endothelial macromolecule permeability increases. Between the second and third decades, fibrous plaques begin to appear in certain areas and become more numerous with age, particularly in coronary arteries. These plaques are opalescent and virtually flush with the lumen surface. They are elongated and oriented following the mainstream of blood flow. This sort of lesion differs from atherosclerotic plaques because there are no lipids in them, but smooth muscle cells, fibrous proteins and proteoglycans.
Blood vessels go through several changes with ageing, especially the arterial wall intima, where cells become heterogeneous in size, contour and axial orientation, so that blood intraluminal flow becomes less laminar and there are more places where lipids deposit. These changes are independent from atherosclerosis. There is also a physiological increase of cholesterol esters and phospholipids. The latter increase due to enhanced arterial wall synthesis, but higher amounts of cholesterol are due to higher plasma levels. These favour an increase of patched deposits, thicker and more irregular, which are the sign of atherosclerosis. In the media the elastic lamina becomes fragmented and the innermost layer is incorporated into the intima. There are four types of changes in the normal aorta: cystic media necrosis, elastin fragmentation, and fibrosis and medionecrosis areas. In the intermediate size arteries compliance diminishes, because of thickening of the intima and the media due to the increase of collagen and changes in elastin. Cholesterol esters and fatty acids begin to deposit and favour a calcinosis of the media layer. A high percentage of smooth muscle cells have a tetra or octaploid nucleus and their proteins are increased. Age-related changes in the adventitia are less well known. In the arterioles there are changes due to hyalinosis, especially in the renal and spleen parenchyma. All these modifications as a whole have a most important physiological consequence: the stiffening of the arterial wall with an increase of its rigidity and a decrease of its elastic properties and of the arterial lumen, what favours a physiological increase of blood pressure as the subjects become older. In the aorta, all mentioned changes can be found and with them, as a partially compensatory mechanism, an arterial dilation which indirectly accounts for the increase of cardiac impedance and the left ventricular muscle thickness. The relative percentage of collagen in the aorta and in the vena cava is constant, some 20 % of tissue weight for the first and a 37 % for the latter. With ageing, the ratio between thick and thin collagen fibres increases, which suggests an increase of crossed links and of condroitinsulphate B concentration where there is an excessive vascular stress (aortic arch) or where the vessels are injured. Collagen acid solubility decreases with age and makes these fibres more resistant to digestion by collagenase. Apparently, there are four different stages in the increase of collagen rigidity with ageing, what has been studied by determining edematisation capacity in an acid medium and denaturalisation by heat.
Ageing modifies beta-adrenergic modulation of cardiovascular function. Heart rate modifies slightly at rest, though there is a non-significant tendency to decrease as man becomes older. Intrinsic heart rate, that is to say the one which appears after denervation by sympathetic and parasympathetic blockade, decreases significantly with age. It has been demonstrated that, in many stressing situations that cause an increase in adrenergic conduction, the heart rate increase is diminished in old animals. This has been recognised since Robinson studies that show that maximal heart rate answer during dynamic exercise decreases a 20 % at 75 when compared to normal 20 year old men.
A decreased answer to catecholamines could partially explain the decrease of heart rate during maximal stress in old age. This can also be seen in the age-related difference of cardiac output at high levels of stress, which decreases when exercise is performed during beta-adrenergic blockade. In normal old men, the heart rate reflex control response to a variety of stimuli is altered. In normal men and animals the baroreceptor reflex reactivity decreases with age. Heart rate reduction is not a consequence of a decreased norepinephrine production because plasma catecholamines increase after five minutes of sustained isometric contraction and this response does not decrease with ageing but, on the contrary, increases in normal subjects. The age-related reduction of inotropic answer to catecholamines is not fundamentally mediated by beta-receptors. It has been demonstrated [Vestal, 1979] that old peoples sensitivity to isoproterenol and propranolol decreases with age, and so does their effectivity at any free plasma concentration, what coincides with the data about a reduction in beta adrenoceptors answer either to agonists or antagonists with age.
Old age is accompanied by impairment in the relations of the nervous system with the heart and blood vessels according to many experiences performed in human beings and in animals. The efficacy of beta-adrenergic modulation of cardiovascular function is what specifically decreases with old age [Xiao, 1991]. It has been observed that circulating catecholamine levels do not decrease or increase with age, particularly during stress, so that the age-related deficit in the efficacy of beta-adrenergic control is essentially post synaptic. Beta adrenergic agonist substances infusion cause less increase in heart rate, left ventricular ejection fraction and cardiac output, and a decreased vasodilator answer in old men when compared to sedentary young men. It is not probable that the impairment of cardiovascular function beta-adrenergic modulation with old age could be caused by a decrease in physical aptitude secondary to a sedentary style of life, because the age-related deficit in the answer to isoproterenol infusion persists after intense physical training.
Certain evidences suggest that the impairment of the beta-adrenergic response could be caused by a decrease in cardioacceleration, myocardial contractility and cardiac dilation, which happen during maximal exercise in old people.
Old peoples hearts incapacity to increase ejection fraction at the same level that young peoples do after beta-adrenergic infusion or during exercise is due to an insufficient end systolic volume. This could be caused by an age-related decrease in beta-adrenergic stimulation, or to an age-associated increase to either the vascular or the cardiac afterload components. Heart size is related to the cardiac afterload component, which can be increased with age, or to the end diastolic volume, at rest and during exercise. The vascular afterload component is also increased with age due to an augmentation in vascular stiffness reflected by the pulse wave, and sometimes by an increase in peripheral resistance in old people. The measure in which the myocardial contractility index and systolic heart pressure upon end systolic volume increase during exercise decrease with age. This deficit is reduced during exercise in presence of beta-adrenergic blockade.
According to what we know, beta adrenergic response is very impaired with age, due to a decrease in the regulation and in the union of agonists to beta1 receptors, lack of coupling to beta2 receptors and an abnormal transduction signal mediated by protein G.
As to the vascular response, let us say that in maximal exercise the decrease of telesystolic volume and the increase in ejection fraction values compared to those obtained at rest are lower in old than in young people. During exercise the charge caused by arterial vessels on the left ventricle increases with age due to a decreased vasodilatation mediated by beta-adrenoceptors. This could be demonstrated because, in young animals, vasodilatation prevents an increase of impedance to left ventricle ejection during exercise, but in older ones the increase of impedance to ejection is higher as long as exercise goes on, what could be caused by an insufficiency in arterial vasodilatation induced by beta adrenergic stimulation. After beta-adrenergic pharmacological blockade, young as well as old animals showed an increase of impedance to blood ejection during exercise.
Beta-adrenergic stimulation has two consequences upon myocardial contraction: it increases strength and decreases duration. Catecholamines are less effective to increase old hearts contractility but they can decrease contraction duration never mind the age. All this makes think that intrinsic inotropic catecholamines response decreases in senescent myocardium, and this is not due to tachifilaxia, catecholamine tissue uptake or contractile proteins capacity to answer to an increase in calcium concentration, but to a decrease in catecholamines capacity to increase disposable intracellular calcium to contraction.
SENILE HEART HAEMODYNAMICS
It is a difficult task to be sure of senile hearts haemodynamic results valuation. Many times, studies were performed on patients who had not been well selected and had a hidden coronary artery disease. Originally invasive methods were used, which could by themselves produce an increase in cardiac output in young people. This must not be considered an age-dependent phenomenon but rather caused by the very invasive procedure. This can now be avoided with radioisotope gamma camera and echocardiograph studies.
Left ventricular ejection fraction does not decrease in old people, in spite that stroke volume does. When it is measured with the gamma camera, it is about 70 %. According to the findings of studies performed in man, normal ageing is associated to alterations in the left ventricle diastolic filling, to an increase in the aortic arch diameter and to a left ventricular hypertrophy, but all that does not alter the contractile capacity at rest.
Left ventricular diastolic function in healthy subjects was evaluated through Doppler echocardiography, studying the changes in the mitral inflow pattern [Miyatake, 1984]. With ageing, the speed peak in the fast filling stage tends to decrease and both the auricular contraction and the fast ventricular filling increase significantly. It could also be interpreted as if the mean left ventricular distensibility in the early diastole were impaired or decreased with ageing and the increase of the auricular contraction contribution to the ventricular filling were compensatory.
Finally, let us add that with ageing peripheral resistance increase even in the absence of any cardiovascular illness.
At rest [van Tosh, 1980] there was no difference at all in heart rate, systolic blood pressure and shortening speed measures by bidimensional echocardiography. During exercise, the increase was also similar in young and old subjects. But, at similar submaximal charges, cardiac performance increased in young, but not in old people. End systolic area decreased in the first, but it was end diastolic area that did the same in the second. According to this, the increase in performance in older people depends very much on the use of the Frank-Starling mechanism.
During exercise, cardiac output suffers no modification at all with age [Rodeheffer, 1984]. Heart rate decreases with ageing, so that cardiac output can only remain the same if ejection stroke volume increases. This augmentation comes through the left ventricular end diastole increase thanks to the Frank-Starling mechanism. This is not what happens in young people, who adapt to effort by increasing heart rate and inotropism and decreasing afterload. That is the reason why end systolic volume is decreased in them. The opposite happens in the old because inotropism is less efficient and the answer to the adrenergic stimulation is impaired. In old people, on the other hand, end diastolic volume increases during exercise and this allows them to increase ejection fraction in spite of the lack of augmentation of the end systolic volume, compensating in that way their incapacity to reach high heart rates. We can conclude that, with mild or moderate exercise, old people ejection fraction answer is similar to that of young people but, when exercise is intense, the increase is smaller.
A decrease in physical activity has been observed in human beings and in animals as they grow older, but it has also been proved that the parameters that define senile heart can be modified, at least in animals, through chronic physical training. These include the disappearance of the prolonged contraction, the decrease of active dynamic rigidity, etc. In rats, physical training has caused an increase of the actomyosin ATPase and of the Ca++ recapture by the sarcoplasmic reticulum, what improves diastolic relaxation. Let us say that the characteristic contraction prolongation in old rats becomes normal after a mild training [Takemoto, 1992]. In sedentary rats [Farrar, 1988] from middle age to senescence, the heart shows a significant deviation in the isozyme myosin V1 composition to the isozyme V3, accompanied by a decline in the Ca++ activating activity of the actomyosin ATPase. This age-related deviation in the myosin composition happened in spite of a chronic training program performed at about 75 % of O2 maximal consumption, what demonstrates that the improvement of cardiac capacity through training is not accompanied by an attenuation of the myosin isozyme composition deviation.
We could conclude that contraction prolongation in senescence is not definitive and can be experimentally reduced. Chronic physical training can improve the proportion of the uptake steady state in the isolated sarcoplasmic reticulum and, therefore, it could be speculated that a chronic exercise protocol could prevent or even reverse the decline of the Ca++ pumping proportional ratio in the old hearts sarcoplasmic reticulum. When old long distance runners were compared to sedentary old people [Takemoto, 1992] Doppler echocardiograph diastolic filling indices proved significantly different. In the runners, the late diastolic peak (A) was proportionally lower than in sedentary people. And the early diastolic filling peak E/late A ratio was higher in the trained than in the untrained group. After the age of 25, VO2 maximal consumption decreases approximately in a 10 % every decade in sedentary subjects. Old people have a decreased O2 maximal consumption but a relative increase in the exercise resistance performance. This could be due to a selective atrophy of fast fibres in skeletal muscle that causes a relative increase in the slow contraction fibres, which produces less lactate. The lower heart rate during exercise in old people has been attributed to a beta-adrenergic decreased cardiac sensitivity. It has been proved [Fagard, 1984] that beta adrenergic block did not either avoid the consequences of training in persons older than sixty or the exercise capacity in hypertensive people treated with atenolol and labetalol. Old cyclers have a greater resistance than sedentary controls at the same age. It has also been proved [Levy, 1996] that the decreased healthy old subjects early diastolic filling time at rest could be improved after a six-month physical training.
According to Weisfeldt and Gerstenblith  there is nowadays an incomplete knowledge of the peripheral vessels physiological answer in old people. It is not known in detail how ageing affects the skeletal muscle capacity to vasodilate and increase its perfusion either. That is the reason why they suggest that the decrease in the blood flow redistribution from the splanchnic to the renal beds and to the active muscles could be an important factor in the decreased physical capacity of old people. Thus studies on animals which are resistant to atheroma and normotensive are extremely important. Michel  reports as a fundamental macroscopic finding in rats an age-related increase in the arterial size. This structural phenomenon is related to an age-dependent increase in functional arterial stiffness and to increases in medial and intimal thickness. It was also related to a significant cardiac hypertrophy, increased auricular natriuretic factor and decreased plasma renin activity. Significantly, ACEI could decrease several parameters, such as the already mentioned intimal and medial thickening and cardiac hypertrophy, without preventing the arterial size increase or the age-related matrix-dependent arterial stiffening.
EXPERIMENTAL CARDIAC HYPERTROPHY AND SENILE HEART
It has been repeatedly demonstrated that the heart becomes bigger during senescence, and slightly hypertrophied. In that sense, a senescent myocardium is similar in many aspects, functional and structural, to that observed in animals, which have got experimentally a cardiac hypertrophy. Changes can be observed in catecholamine content, in the action potential configuration, in the Ca++ accumulation ratio in the sarcoplasmic reticulum, in the myophilaments ATPase and in the passive viscoelastic proprieties.
There is a close similarity between what happens to a left ventricular hypertrophied myocardium on the edge of decompensation and what can be observed in that of healthy senescent animals. The first one has been described like a "complex of extenuation and failure in the hypertrophied heart", and the second is nothing else but the senile heart. Similarities consist in a myocardial fibres hypertrophy, a marked myocardial fibrosis with proliferation of fibrillar connective tissue, a decrease of protein synthesis, a decrease to half or to a third in the normal concentration of ADN in the myocardial tissue, an increase in the ARN/ADN ratio, a decrease in the oxidative phosphorylation in the senile heart, a decrease of 10 to 20 % in the ATP and the creatin phosphate in the hypertrophied myocardium and a narrowing in the adaptation range of cardiac activity. On this ground is based the concept of "accelerated ageing" of the heart in those cases of hypertrophy experimentally induced.
It has been suggested [Lakatta, 1987] that the vascular stiffening causes an increase in blood pressure, essentially in the systolic, even in those ranges considered normal. That is the reason why "vascular ageing" can be considered a "mute arterial hypertension" or hypertension an "accelerated ageing". This makes think that there is a continual process as long as myocardial effects are considered, for instance of the type of increased cardiac mass, between chronic hypertension and what happens in the advanced age in man. We must consider that in hypertensive as much as in normotensive old people, systolic pump function remains without alterations at rest, while in normotensive subjects between 20 and 80 years, the percentage of fast ventricular filling alters in a 50 %, and even more in hypertensive subjects, and that volumes decrease. This last abnormality can be attributed to cardiac hypertrophy and to isometric relaxation, which can be observed in men and animals and in certain types of hypertension. In old people, it is thought that the prolongation of relaxation can be caused by an increase in the transitory myoplasmic Ca++ with excitation, which is accompanied by an important prolongation of the transmembrame potential action, a decrease in the percentage of Ca++ pumped by the sarcoplasmic reticulum and an alteration in the myosin isozyme. Similar changes can be observed in young animals with a cardiac hypertrophy caused by chronic experimental overcharge in the postcharge.
When the findings determining the extension of myocardial hypertrophy in old rats are analysed, be it caused by aortic constriction or in other ways, it can be concluded that there would be many factors within the very cardiac cell, which modulate the process relating the increase in the circulatory demand and the process of synthesis and degradation of proteins. As myocytes cannot multiply, the senescent heart capacity to adapt to different types of haemodynamic overcharges depends critically on the capacity of hypertrophy. Therefore, when these functional demands go beyond the adaptive limits, heart failure appears. Old people heart fails with overcharges that can be well tolerated by young people. This has been explained on the basis of an impaired capacity to hypertrophy in the senescent heart when the exigency passes certain limits.
The capacity to develop a left ventricular hypertrophy as an answer to a pressure or volume overcharge decreases with ageing. This could also show that cardiac adaptations to different types of haemodynamic overcharges imply altered patterns in genetic expression.
Therefore, senescent myocardium is able to answer when submitted to an acute pressure overcharge with a molecular genetic pattern and a protein synthesis that causes hypertrophy just like young animals do. Heart can answer to an overcharge stepwise, first by altering the expression of a whole family of multigenes of myosin heavy chains and then through the alteration of other genes expression, like that of the reticular sarcoplasmic ATPase, an enzyme related to the coupling between excitation and contraction.
ROLE OF VASCULAR ENDOTHELIUM IN AGEING PROCESSES
Vascular endothelium interacts with cellular factors present in the blood. In the most important blood vessels this structure behaves as a selective barrier. From the point of view of metabolism, VE absorbs and transforms different substances such as norepinephrine, different sorts of prostaglandins or even serotonin released by platelets. A converting enzyme can be found in the endothelial membrane, which on the one hand converts angiotensin I in angiotensin II and on the other metabolise different kinins, among which bradikinin can be found, transforming them in inactive peptides.
In the endothelium these substances perform a dynamic role in the normal vascular response especially in the regulation or modulation of the vascular smooth muscle function. Endothelium functions can be performed through releasing of substances by autocrine or paracrine ways. These substances are nitric oxide, endothelins and others. It has been possible to demonstrate a direct contact between the cellular unions on the endothelial surface and those of the vascular smooth muscle. It is possible that VE cells transduce signals for others, which are within the vessels wall. This would regulate the smooth muscle cells functions through receptors. Particularly, endothelial substances modulate the vascular tone and structure.
Furchgott and Zawadzki  discovered that VE presence was obligatory to provoke isolated artery dilation as an answer to acetylcholine stimulus. Acetylcholine stimulates the releasing of a great number of other neurohormonal mediators, which intervene in the maintenance of vascular tone. The administration of acetylcholine induces the VE to release nitric oxide, which activates a cytosolic enzyme, the guanilatocyclase, accelerating thereby the formation of cyclic monophosphate of guanosine. It is the latter that inhibits vasoconstriction.
ON participates in many physiological cardiovascular mechanisms besides regulating vascular tone: myocardial contractility, vascular integrity and permeability, vascular cellular proliferation and the interaction between monocytes, platelets and the endothelium. It also has antithrombotic effects. Under physiological conditions, ON releasing by the VE cells in high quantities produce a vasodilating answer. In the most important vessels ON activity should be predominant because they are under the influence of mechanical changes such as pulsatile blood flow and shear stress, but ON releasing is greater in the smallest vessels, that is to say in those of resistance. In both vascular segments ON seems to be implicated in the autoregulation of blood flow and can therefore determine a relative distribution of it among the different vascular segments.
Human endothelial cell presents what could be called a phenomenon of biological obsolescence genetically programmed, because their normal span of life is about thirty years. Then they die and are replaced by neighbour cells. These, nevertheless, seem not to have the same releasing capacities, especially when they must answer to platelet adhesiveness and trombin because, in whole animals without VE in their coronary arteries, the regeneration process and the characteristics of the endothelium-dependent answers were controlled during months, and it was not only found that the regenerated VE was satisfactory, but the number of cells in the renovated area was almost twice more than in control areas; and yet, they were not able to prevent the contraction induced by platelet adhesiveness, and the answer to the stimulus generated by serotonin, alfa2 adrenergic agonists and other substances, which stimulate the releasing of endothelium-dependent relaxing factors was very poor.
In normal human beings, the endothelium-dependent vasodilatation of resistance vessels in the forearm is impaired with ageing [Gerhard, 1996]. Studies with venous occlusion pletismography, through the injection of metacholine to investigate endothelium-dependent vasodilatation, and nitroprussiate for that independent of it, showed that the first gets progressively impaired with age, what can be perfectly evident after the fourth decade of life. Many regression analyses demonstrated that age is still the best predictor of endothelium-dependent impairment. On the other hand, endothelium-independent vasodilatation did not change with age.
Normo and hypertensive patients have also been compared [Taddei, 1995]. Pletismography was used to assess the forearm blood flow, through acetylcholine injection as an endothelium-dependent vasodilator and nitroprussiate as an endothelium-independent one. Acetylcholine produced a dose-dependent vasodilatation significantly lower in patients with essential hypertension than in normotensive subjects, but there was also a significant negative correlation between acetylcholine-induced vasodilatation and age, in normo and in hypertensive patients. Vasodilatation caused by nitroprussiate was equally similar in both groups of patients.
Causes of age-related endothelial dysfunction were also evaluated in normal and hypertensive patients [Taddei, 1997], confirming that ageing is an important factor which alters endothelium-dependent vasodilatation in both. The mechanisms affected in this answer would be a defect in the L-arginine/ON via and in the ciclooxigenase-dependent production of endothelium-derived constrictive factor.
These facts, that is to say the impairment of the ON formation secondary to ageing and that seen in hypertension, in which an early impairment of the L-arginine/ON via and of the vasoconstrictor prostanoid happen, would suggest that the mechanism through which an endothelial dysfunction is produced in hypertension would be the acceleration of changes that can normally be seen with mere ageing. The information that could confirm this hypothesis is in fact multiple and very abundant. Atkinson  comes to the conclusion that norepinephrine response, measured when the endothelium is functional, apparently increases with age. But when it is studied when VE is disrupted, the a1-adrenergic mechanism appears as age-dependently impaired. A possible explanation is the existence of an age-related decrease in agonist-induced endothelium dependent relaxing factor release, which can be postponed in very old rats by ACEI treatment.
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