The emerging recognition of the existence and potential biological significance of local tissue renin-angiotensin systems in a number of organs has fostered interest in a possible intrinsic cardiac renin-angiotensin system. Evidence for such a system was first provided by biochemical measurements of components of the renin-angiotensin system in cardiac tissue. It has recently been demonstrated that the genes coding for renin and angiotensinogen are expressed in all regions of the heart, an essential prerequisite for the postulated intracardiac biosynthesis of these proteins. Moreover, we have shown the presence of a functional and physiologically active pathway for the conversion of angiotensin I to angiotensin II in the beating mammalian heart. This conversion appears to be catalyzed by a specific cardiac converting enzyme that is susceptible to systemically administered converting-enzyme inhibitors. Evidence for the physiologic importance of the cardiac renin-angiotensin system comes from experimental data as well as indirect clinical evidence. The potent coronary vasoconstrictor properties of angiotensin II underscore its possible significance in myocardial ischemia and ischemic heart disease, in particular when viewed in the context of selective local activation. The long-known positive inotropic effects of angiotensin II are based on its direct myotropic properties and on its facilitatory effects on sympathetic neurotransmission and may be of added significance in metabolically compromised states. We have recently demonstrated that locally generated angiotensin may be a dominant etiologic factor in the pathogenesis of reperfusion arrhythmias. In addition, we have found experimental evidence for a deleterious effect of angiotensin II on myocardial metabolism in the setting of regional myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent findings suggest that the local renin-angiotensin systems, locally generated catecholamines, and possibly other locally generated peptides interact in a complex fashion to regulate the cellular biology of the myocardium, the vascular wall, and other tissues. New evidence indicates that the components of the renin-angiotensin system are synthesized in cardiovascular tissues, that the synthesis of these components can be modulated by pharmacologic agents, and that angiotensin II, the effector protein of the renin system, appears to be capable of producing hypertrophy or hyperplasia in specific tissues. In addition, recent studies suggest the participation of enhanced proto-oncogene transcriptional activity in the development of hyperplasia and hypertrophy in cardiovascular tissue. Taken together, these data raise the possibility that angiotensin and perhaps other components of the renin system can be viewed as locally active growth factors capable of acting in a fashion similar to that associated with cytokines in other systems.

Despite a dramatic fall in renal blood flow, glomerular filtration rate is usually preserved in patients with congestive heart failure until the terminal stages of the disease. This maintenance of renal function appears to be achieved in part by the synthesis of two vasoactive factors within the kidney--angiotensin II and prostaglandins--which are rapidly released whenever renal perfusion is compromised or sympathetic nerve traffic to the kidneys is increased. Although these two hormonal systems exert opposite effects on systemic and renal blood flow and sodium and water excretion, both act to preserve glomerular filtration rate: prostaglandins by a vasodilator action exerted primarily on the afferent arteriole and angiotensin II by a vasoconstrictor effect on the efferent arteriole. Consequently, when the synthesis of these hormones is experimentally blocked, renal function deteriorates, especially in subjects with marked renal hypoperfusion and sodium depletion; these two factors interact to determine the importance of intrarenal hormonal release in the modulation of renal function. Clinically, four specific factors have been identified that predispose patients with heart failure to the development of functional renal insufficiency after treatment with converting-enzyme or cyclo-oxygenase inhibitors: (1) marked renal hypoperfusion, (2) vigorous diuretic therapy, (3) diabetes mellitus, and (4) intensity of hormonal inhibition within the kidney. This last risk factor may provide the basis for differentiating among enzyme-inhibitory drugs and suggests that renal insufficiency in low-output states may be minimized by the development of therapeutic agents that block hormonal synthesis selectively at sites that are critical to the disease process but spare the homeostatic tissue-based enzyme systems that exist within the kidney.

The angiotensin converting-enzyme inhibitors available so far are active-site directed inhibitors. They utilize all the critical binding interactions of the substrate and convert the catalytic interaction with the zinc atom into an effective binding interaction. Three chemical classes of angiotensin converting-enzyme inhibitors have been introduced into clinical use, the sulfhydryl-containing inhibitors such as captopril and its analogs and prodrugs, carboxyalkyldipeptides such as enalapril and its analogs, and phosphorus-containing inhibitors such as fosinopril and the phosphonate SQ 29,852. Within each of the three groups of inhibitors significant differences in molecular weight and polarities can be observed. These differences have a significant influence in the routes of elmination and tissue distribution of these inhibitors. Tissue distribution and intrinsic potency will determine the magnitude of angiotensin converting-enzyme inhibition at the tissue level, which could play a critical role in the clinical utilization of these inhibitors. The sulfhydryl-containing inhibitors such as captopril undergo a metabolic process significantly different from that of the other two classes. They can interact with endogenous sulfhydryl-containing compounds like glutathione and proteins, to form reversible disulfides, which can serve as depot forms of the drug. Also, because of their redox properties they might function as recyclable free radical scavengers.

The existence of a brain renin-angiotensin system (RAS) as one of various tissue RASs is now firmly established. Angiotensin-containing pathways within brain areas involved in central blood pressure regulation have been described. Evidence from biochemical, neurophysiologic, pharmacologic, and most recently, molecular genetic studies indicate that the brain RAS is regulated independently of the hormonal RAS and may contribute to blood pressure control and body fluid homeostasis. In addition, circulating angiotensin II can exert some of its action through stimulation of brain angiotensin receptors accessible from the blood. In experimental animal preparations of hypertension, especially in spontaneously hypertensive rats, an overactive brain RAS may be one of the factors involved in pathogenesis and maintenance of hypertension. In spontaneously hypertensive rats, inhibitors of the angiotensin II-generating converting enzyme (CE) have been shown to lower blood pressure by a central action when applied to the brain and to inhibit brain CE when applied systemically. The pathogenetic mechanisms underlying a particular cardiovascular disease and the characteristics of the CE inhibitor used (e.g., its lipid solubility governing penetration into tissue) may determine the degree to which CE inhibition within a given organ, such as the brain, contributes to the action of these drugs.

The large cohort of white men (317,871) 35 to 57 years old at initial screening for possible enrollment into the Multiple Risk Factor Intervention Trial (MRFIT) was examined with regard to initial blood pressure levels and subsequent coronary heart disease (CHD), stroke, and all-cause mortality. The overall prevalence of isolated systolic hypertension (ISH), defined as systolic blood pressure (SBP) greater than or equal to 160 mm Hg and diastolic blood pressure (DBP) less than 90 mm Hg, was 0.67% among white men screened for MRFIT and increased with age (0.31% among 35- to 39-year-olds to 1.7% among 55- to 57-year-olds). The 6 year CHD and all-cause mortality rates in men over 50 were highest in those with ISH compared with both subjects with diastolic hypertension and those with normal pressure. The relative risk of death from stroke in those with ISH, compared with that in those with SBP less than 160 mm Hg and those with DBP less than 90 mm Hg, was 3.0 (95% confidence interval 1.3 to 6.8). In addition, at any level of DBP, the level of SBP appeared to be the major determinant of all-cause and CHD mortality. The determinants of ISH in individuals under 60 years of age as well as the possible efficacy of its treatment should be evaluated further.

The noninvasive determination of maximal oxygen uptake or VO2max, defined as a plateau in VO2 during incremental treadmill exercise, is an objective, reproducible, and negotiable measure of the severity of chronic cardiac or circulatory failure. Moreover, this noninvasive variable predicts the exercise cardiac output response and thereby the cardiac reserve. The lactate or anaerobic threshold has been validated in these patients from the response of mixed venous lactate to incremental exercise and has been shown to be another objective measure of the severity of chronic cardiac or circulatory failure. The anaerobic threshold can be reliably assessed from the response in breath-by-breath respiratory gas exchange by the use of multiple criteria, several of which can be monitored during the exercise test itself and the remainder of which can be measured during the recovery period. We find the breath-by-breath monitoring of respiratory gas exchange and air flow to provide the best means of assessing the anaerobic threshold and for identifying the plateau in VO2, or VO2max, in response to incremental treadmill exercise.

Engagement in muscular exercise involves complex local and nervous adjustments of the circulation. In the active muscles, including cardiac muscle, the resistance vessels relax in response to local chemical changes to provide an increase in blood flow adequate for their metabolic requirements. There is increased release of norepinephrine from the sympathetic nerve endings as a result of increased sympathetic outflow; the resultant alpha-receptor activation leads to constriction of both systemic resistance and capacitance vessels outside the active muscles, and the beta-receptor activation leads to an increase in heart rate, shortening of the refractory period, and enhancement of myocardial contractility. As a consequence, the filling pressure of the heart and arterial blood pressure are maintained, and the increase in left ventricular output is directed primarily to the active muscles. During upright exercise, the action of the leg muscle pump contributes to the maintenance of the cardiac filling pressure. As exercise continues and body temperature rises, the skin flow increases to dissipate heat from the body. Static exercise causes a greater increase in arterial blood pressure than dynamic exercise. This is due to the combination of an increase in cardiac output and in total systemic vascular resistance as a consequence of increase sympathetic outflow and mechanical compression of the vessels in the active muscles. The hemodynamic changes result from activation of ergoreceptors in the contracted muscles and from central command. The increase in pressure helps to oppose the mechanical compression. The arterial baroreceptors are reset so that they operate normally around the higher blood pressure.

During exercise, the level of oxygen consumption (VO2) above which aerobic energy production is supplemented by anaerobic mechanisms causing a sustained increase in lactate and metabolic acidosis is termed the anaerobic threshold. The VO2 at which the anaerobic threshold occurs is influenced by the factors that affect oxygen delivery to the tissues, being increased when oxygen flow is enhanced and decreased when oxygen flow is diminished. The anaerobic threshold is an important functional demarcation since the physiologic responses to exercise are different above the anaerobic threshold as compared with below the anaerobic threshold. Above the anaerobic threshold, in addition to the development of metabolic acidosis, exercise endurance is reduced, VO2 kinetics are slowed so that a steady state is delayed, and minute ventilation increases disproportionately to the metabolic requirement and a progressive tachypnea develops. The anaerobic threshold can be measured directly from lactate concentration with good threshold detection from a log-log transformation of lactate and VO2. This threshold defines the VO2 at which the lactate/pyruvate ratio increases. As bicarbonate changes reciprocally with lactate, its measurement can also be used to estimate the lactate threshold. But most conveniently, changes in gas exchange caused by the physical-chemical event of buffering of lactic acid by bicarbonate can be used to detect the anaerobic threshold during exercise.

Power outputs that are below the anaerobic threshold (theta an) may be sustained for prolonged durations, whereas power outputs that are greater than theta an result in a significant reduction in the tolerable duration to fatigue. The theta an may therefore be considered to demarcate exercise intensity into moderate (below) and heavy (above) domains. O2 uptake (VO2) responds with linear first-order dynamics for sub-theta an power outputs with a time constant of approximately equal to 25 to 35 sec and a "delay" of 15 to 20 sec. A steady state is therefore normally achieved within 3 min. For supra-theta an exercise an additional, slower component of VO2 delays the steady state (if attainable). This slow phase of the VO2 response causes the VO2 to rise to values above the steady-state level attainable by fitter subjects at that work rate. The magnitude of this "excess" VO2 correlates highly with the increased arterial blood lactate [L-] and becomes marked when [L-] exceeds 4 to 5 meq/liter. The theta an may therefore be considered a crucial index for sustainable physical activity that is not--or is modestly--fatiguing.

Exercise testing has assumed a position of growing importance in the assessment of patients with chronic congestive heart failure. The hemodynamic and neurohumoral adjustments that occur during dynamic exercise are very complex, but are basically designed to ensure that oxygen delivery is commensurate with oxygen demand. These responses are clearly altered in the presence of certain types of heart disease. Patients with chronic congestive heart failure have an attenuated heart rate and blood pressure response throughout exercise, but this is most clearly evident when the data are expressed as a percent of peak oxygen consumption (VO2) rather than as a function of absolute VO2. Likewise, the sympathetic response to exercise is altered in patients with heart failure. Plasma norepinephrine is normally augmented as a function of VO2 during exercise, but this augmentation occurs during the later stages (beyond 50% of peak VO2). Patients with congestive heart failure show a greater than normal augmentation of plasma norepinephrine during exercise when the data are expressed in terms of absolute VO2. However, when the data are expressed as a percent of peak VO2, there appears to be a relative attenuation of the sympathetic response to exercise. Current information suggests that increased plasma norepinephrine and renin activity during exercise in patients with heart failure are not directly related to a decrement in nutritive blood flow to skeletal muscles. The mechanisms responsible for exercise intolerance in patients with heart failure are not known, but do not seem directly related to a decrement in cardiac output or an increase in left ventricular filling pressure.(ABSTRACT TRUNCATED AT 250 WORDS)