Studies on the mechanism underlying the influence of alanine infusion on glucose dynamics in the dog.

These experiments have been designed to study the influence of alanine infusion of glucose dynamics in the dog and to further elucidate the role of pancreatic hormones in the interaction of alanine with glucose homeostasis. The primed constant infusion of glucose-2-t was used in order to quantitate the rates of glucose production by the liver (Ra) and glucose utilization (Rd). In a first group of experiments, the intravenous infusion of alanine at the rate of 2 mg./kg./min. produced a moderate enhancement of plasma insulin (IRI), while pancreatic glucagon (IRG) increased more consistently. This different pattern of IRI and IRG response caused the insulin/glucagon molar ratio to decline progressibely throughout the experiment. Both rates of glucose turnover increased significantly during alanine infusion. Since Ra rose more rapidly thanRd did initially, hyperglycemia developed. Later, glucose production slowly decreased and, in spite of the sustained hyperglucagonemia, reached levels very close to the baseline in the second part of the experiment. A significant direct correlation between Ra and IRG was found, while the changes in Ra correlated inversely with those in I/G molar ratio. In a second group of experiments, alanine was infused at the same dose together with 0.4 microng./kg./min. of cyclic somatostatin. In the first part of the infusion, IRG fell more than IRI did, so that I/G ratio increased. Later, IRI levels maintained at low values while IRG returned slowly to the baseline and consequently I/G ratio significantly decreased. Glucose production fell rapidly soon after the beginning of the infusion, and therefore hypoglycemia developed. Later, Ra increased progressively to levels above baseline and plasma glucose returned to the preinfusion levels. As in the the first group of experiments, a significant direct correlation between Ra and IRG and an inverse correlation between the changes in Ra and I/G ratio were observed. These experiments demonstrate that alanine infusion produces an acceleration of glucose turnover and that a clear interrelationship between the release of glucose by the liver and the mobilization of pancreatic hormones exists. Finally, the experiments with somatostatin indicate that hyperglucagonemia is one of the mechanisms underlying the stimulatory effect of alanine on glucose production.

Effects of theophylline on glucose kinetics in normal and sympathectomized rats.

The influence of intraperitoneal administration of aminophylline on the rate of hepatic glucose production and peripheral uptake (Ra and Rd) was studied in normal and in adrenodemedullated and reserpinized rats by using the primed constant infusion of Glucose-2-3H. In normal rats, the dose of 100 mg. per kilogram of aminophylline produced a marked increase of Ra and Rd. Since Ra rose more rapidly than Rd did initially, hyperglycemia developed. Thereafter, glucose production and uptake increased to nearly the same extent, and a new steady state was reached at plasma glucose levels almost twice those of the baseline. Smaller and transient modifications were observed after the administration of 20 mg. per kilogram of aminophylline. With the higher dose, insulin levels markedly rose (reaching a tenfold peak above the basal value) while minor increments were observed with the lower dose. In a group of normal rats which were given glucose (10 mg. per kilogram per minute) in order to achieve a degree of hyperglycemia comparable to that brought about by the higher dose of aminophylline, an almost identical enhancement of glucose uptake was recorded. However, insulin levels were much higher in aminophylline-treated rats as compared to normal rats. From these finding it was concluded that aminophylline induces resistance to insulin effect. When aminophylline was injected into demedullated rats pretreated with reserpine, at the dose of 100 mg. per kilogram, a marked enhancement of Ra, and consequently of glycemia, was recorded initially; later, severe hypoglycemia developed depending on both a progressive exhaustion of hepatic glucose production and a marked increase of glucose utilization. Insulin levels dramatically increased in these experiments. These results suggest that aminophylline directly increases glucose production by the liver and insulin secretion. The simultaneous activation of the sympathetic system blunts the insulin response and counteracts the restraining effect of insulin on the liver and the stimulatory effect of insulin on overall glucose uptake as well.

Regional left ventricular mechanical function during isometric exercise in patients with coronary artery disease: correlation with regional coronary blood flow changes.

The effects of isometric exercise on regional left ventricular mechanical function and regional coronary blood flow were evaluated in 17 patients with significant proximal stenosis of the left anterior descending coronary artery and 10 patients with normal coronary arteriograms. All patients had normal myocardial contractility in the basal condition. All performed isometric handgrip exercise at 50% of the maximal voluntary contraction for 3 min during two-dimensional echocardiographic monitoring and hemodynamic evaluation of great cardiac vein flow by thermodilution technique. During isometric exercise, 7 of the 17 patients with left anterior descending coronary stenosis developed asynergy in the anterior territory (anterior or septal segment, or both) (group I); the remaining 10 showed normal myocardial contraction during the test (group II). The 10 normal subjects manifested no regional asynergy during the test (control group). The increase in great cardiac vein flow at peak isometric exercise was significantly smaller (p less than 0.01) in group I (+15 +/- 8%) than that in group II (+98 +/- 48%) and the control group (+64 +/- 22%). Anterior coronary vascular resistance decreased in group II (-32 +/- 13%) and in the control group (-25 +/- 8%) but increased in group I (+6 +/- 8%, p less than 0.01 versus group II and control group). These data demonstrate that handgrip-induced myocardial asynergy is associated, in our study patients, with an abnormal response of the regional coronary circulation. The increase in coronary vascular resistance in group I patients with asynergy demonstrates that functional mechanisms play a dominant role in left ventricular mechanical dysfunction induced by isometric exercise.

Preconditioning does not prevent postischemic dysfunction in aging heart.

OBJECTIVES: This study was performed to investigate the effect of single or multiple brief periods of ischemia and the administration of exogenous norepinephrine before a more prolonged ischemic period and after reperfusion in adult and senescent isolated and perfused rat hearts. BACKGROUND: The mortality rate for coronary artery disease is greater in the elderly. Ischemic preconditioning has been proposed as an endogenous form of protection against ischemia-reperfusion injury. However, the role of preconditioning in aging heart is unknown. METHODS: We compared the protective effect of preconditioning transient ischemic and norepinephrine stimuli against 20 min of global normothermic ischemia and 40 min of reperfusion in isolated perfused hearts of adult (6 months old) and senescent (24 months old) rats. Norepinephrine release in coronary effluent was determined by high performance liquid chromatography. RESULTS: Final recovery of percent developed pressure was improved after single preconditioning transient ischemic and norepinephrine stimuli in adult hearts (87.7 +/- 9% and 82.3 +/- 8.7%) versus unconditioned control hearts (50.6 +/- 4.8%, p < 0.01 [mean +/-SD]). The effect of preconditioning on developed pressure recovery was not present in senescent hearts after transient ischemic stimulus (39.8 +/- 4.9% vs. 41.6 +/- 5.8%, p = NS) but was present after norepinephrine stimulus (74.3 +/- 10.5, p < 0.01). Norepinephrine release significantly increased after preconditioning transient ischemic stimulus in adult but not in senescent hearts (p < 0.01 vs. adult). Transient ischemic- and norepinephrine-induced preconditioning was blocked by alpha-adrenergic receptor antagonists in both adult and senescent hearts. Multiple transient ischemic stimuli were able to reduce postischemic dysfunction in adult but not in senescent hearts. CONCLUSIONS: Preconditioning transient ischemic stimulus significantly reduces postischemic dysfunction in adult but not in senescent hearts, whereas exogenous norepinephrine is able to mimic preconditioning in both adult and senescent hearts. Ischemic preconditioning induces an increase in norepinephrine release in adult but not in senescent hearts. Preconditioning induced by transient ischemic stimulus and norepinephrine was abolished by alpha-adrenergic receptor blockade in both adult and senescent hearts. Thus, our data demonstrate that preconditioning is absent in aging heart and is probably related to the reduction of norepinephrine release and alpha-adrenergic receptor stimulation in response to ischemic preconditioning.

Exercise training restores ischemic preconditioning in the aging heart.

OBJECTIVES: To investigate the effects of ischemic preconditioning in hearts from adult and both sedentary and trained senescent rats. BACKGROUND: Ischemic preconditioning does not prevent postischemic dysfunction in the aging heart, probably because of reduction of cardiac norepinephrine release. Exercise training can reverse the age-related decrease of norepinephrine production. METHODS: We investigated the effects on mechanical parameters of ischemic preconditioning against 20 min of global ischemia followed by 40 min of reperfusion in isolated perfused hearts from adult (six months) and sedentary or trained (six weeks of graduated swim training) senescent (24 months) rats. Norepinephrine release in coronary effluent was determined by high-performance liquid chromatography. RESULTS: Final recovery of percent-developed pressure was significantly improved after preconditioning in adult hearts (91.6+/-9.6%) versus unconditioned controls (54.2+/-5.1%, p<0.01). The effect of preconditioning on developed pressure recovery was absent in sedentary but present in trained senescent hearts (39.6+/-4.1% vs. 64.3+/-7.1%, p<0.05). Norepinephrine release significantly increased after preconditioning in adult and in trained but not in sedentary senescent hearts. The depletion of myocardial norepinephrine stores by reserpine abolished preconditioning effects in adult and trained senescent hearts. CONCLUSIONS: In adult and trained but not in sedentary senescent hearts, preconditioning reduces postischemic dysfunction and is associated with an increase in norepinephrine release. Preconditioning was blocked by reserpine in both adult and trained senescent hearts. Thus, exercise training may restore preconditioning in the senescent heart through an increase of norepinephrine release.

Effects of histamine on coronary hemodynamics in humans: role of H1 and H2 receptors.

To evaluate whether histamine exerts a direct effect on coronary hemodynamics in humans, and to investigate the role played by H1 and H2 receptors in this response, intracoronary saline solution or histamine (4 micrograms) was administered in 10 patients with normal coronary arteries during diagnostic cardiac catheterization. Histamine injection was repeated after intravenous cimetidine (400 mg) and diphenhydramine (10 mg). The electrocardiogram, arterial pressure and thermodilution coronary blood flow were continuously monitored during and for 40 seconds after each injection. Immediately after histamine injection there was a significant increase in coronary blood flow (65 +/- 6%) and a decrease in coronary vascular resistance (-40 +/- 3%) (both p less than 0.001), with minor changes in the RR interval and the mean arterial pressure. H2 receptor blockade with cimetidine did not affect these changes, while H1 receptor blockade with diphenhydramine significantly reduced the histamine-induced increase in coronary blood flow and the decrease in coronary vascular resistance (26 +/- 6%, p less than 0.005 and -18 +/- 5%, p less than 0.001, respectively). Twenty to 30 seconds after histamine injection, a significant decrease in mean arterial pressure (-17 +/- 2%, p less than 0.001) and in the RR interval (-4 +/- 1%, p less than 0.01) was observed. These changes persisted after H2 receptor blockade with cimetidine, but were completely abolished after H1 receptor blockade with diphenhydramine. In each case coronary and systemic hemodynamics returned to normal within 40 seconds of the injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina-induced protection against myocardial infarction in adult and elderly patients: a loss of preconditioning mechanism in the aging heart?

OBJECTIVES: The present study examined whether angina 48 h before myocardial infarction provides protection in adult and elderly patients. BACKGROUND: The mortality rate for coronary artery disease is greater in elderly than in young patients. In experimental studies, ischemic preconditioning affords an endogenous form of protection against ischemia-reperfusion injury in adult but not in senescent hearts. Angina before myocardial infarction, a clinical equivalent of experimental ischemic preconditioning, has a protective effect in adult patients. It is not known whether angina before myocardial infarction is also protective in aged patients. METHODS: We retrospectively verified whether antecedent angina within 48 h of myocardial infarction exerts a beneficial effect on in-hospital outcomes in adult (< 65 years old, n = 293) and elderly (> or = 65 years old, n = 210) patients. RESULTS: In-hospital death was more frequent in adult patients without than in those with previous angina (10% vs. 2.6%, p < 0.01), as were congestive heart failure or shock (10.7% vs. 3.3%, p < 0.02) and the combined end points (in-hospital death and congestive heart failure or shock) (20.7% vs. 5.9%, p < 0.0003). In contrast, the presence or absence of previous angina before acute myocardial infarction in elderly patients seems not to influence the incidence of in-hospital death (14.4% vs. 15.2%, p = 0.97), congestive heart failure or shock (11.0% vs. 11.9%, p = 0.99) and the combined end points (25.4% vs. 27.1%, p = 0.89). Logistic regression analysis models for in-hospital end points show that previous angina is a positive predictor in adult but not in elderly patients. CONCLUSIONS: The presence of angina before acute myocardial infarction seems to confer protection against in-hospital outcomes in adults; this effect seemed to be less obvious in elderly patients. This study suggests that the protection afforded by angina in adult patients may involve the occurrence of ischemic preconditioning, which seems to be lost in senescent patients.

High level of physical activity preserves the cardioprotective effect of preinfarction angina in elderly patients.

OBJECTIVES: The study investigated the effects of physical activity on preinfarction angina, a clinical equivalent of ischemic preconditioning (PC), in adult and elderly patients with acute myocardial infarction (AMI). BACKGROUND: Preinfarction angina seems to confer protection against in-hospital mortality in adult but not in elderly patients. However, it has been experimentally demonstrated that exercise training restores the protective effect of PC in the aging heart. METHODS: We retrospectively verified whether physical activity preserved the protective effect of preinfarction angina against in-hospital mortality in 557 elderly patients with AMI. Physical activity was quantified according to the Physical Activity Scale for the Elderly (PASE). RESULTS: In-hospital mortality was 22.2% in elderly patients with preinfarction angina and 27.2% in those without (p = 0.20). When the PASE score was stratified in quartiles (0 to 40, 41 to 56, 57 to 90, >90), a high score was strongly associated with reduced in-hospital mortality (30.8%, 32.2%, 17.2% and 15.3%, respectively, p < 0.001 for trend). Interestingly, a high level of physical activity reduced in-hospital mortality in elderly patients with preinfarction angina (35.7%, 35.4%, 12.3% and 4.23%, respectively, p < 0.001 for trend) but not in those without (23.0%, 27.2%, 26.0% and 35.0%, respectively, p = 0.35 for trend). Accordingly, the protective role of preinfarction angina on in-hospital mortality was present only in elderly patients showing a high level of physical activity (adjusted odds ratio, 0.09; 95% confidence interval, 0.01 to 0.57; p < 0.05). CONCLUSIONS: Physical activity and not preinfarction angina protects against in-hospital mortality in elderly patients with myocardial infarction. Nevertheless, the protective effect of preinfarction angina is preserved in elderly patients with a high level of physical activity.

Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart.

Ischemic preconditioning (IP) has been proposed as an endogenous form of protection against ischemia reperfusion injury. IP, however, does not prevent post-ischemic dysfunction in the aging heart but may be partially corrected by exercise training and food restriction. We investigated the role of exercise training combined with food restriction on restoring IP in the aging heart. Effects of IP against ischemia-reperfusion injury in isolated hearts from adult (A, 6 months old), sedentary 'ad libitum' fed (SL), trained ad libitum fed (TL), sedentary food-restricted (SR), trained- and food-restricted senescent rats (TR) (24 months old) were investigated. Norepinephrine release in coronary effluent was determined by high performance liquid cromatography. IP significantly improved final recovery of percent developed pressure in hearts from A (p<0.01) but not in those from SL (p=NS) vs unconditioned controls. Developed pressure recovery was partial in hearts from TL and SR (64.3 and 67.3%, respectively; p<0.05 vs controls) but it was total in those from TR (82.3%, p=NS vs A; p<0.05 vs hearts from TL and SR). Similarly, IP determined a similar increase of norepinephrine release in A (p<0.001) and in TR (p<0.001, p=NS vs adult). IP was abolished by depletion of myocardial norepinephrine stores by reserpine in all groups. Thus, IP reduces post-ischemic dysfunction in A but not in SL. Moreover, IP was preserved partially in TR and SR and totally in TR. Complete IP maybe due to full restoration of norepinephrine release in response to IP stimulus.

Upper gastrointestinal symptoms and therapies in elderly out-patients, users of non-selective NSAIDs or coxibs.

BACKGROUND: The association between coxib or non-steroidal anti-inflammatory drug use with gastrointestinal symptoms and drug prescriptions in ambulatory elderly patients is not well defined. AIM: To evaluate the association between non-steroidal anti-inflammatory drug NSAID and coxib use with gastrointestinal symptoms and therapies in elderly subjects managed by their general practitioner. MATERIALS: The study was carried out by 133 general practitioners in Italy. By using a structured interview, sex, age, physical function, current medications, new drug prescriptions and upper gastrointestinal symptoms were registered from all elderly subjects who were referred to their general practitioners during a 2-week period. The numbers of hospitalizations, gastrointestinal bleeding events and gastrointestinal diagnostic procedures occurring during the last 6-month period were recorded. RESULTS: Included in this study were 5515 elderly subjects. The overall prevalence of drug use was 92%. Musculo-skeletal drugs were taken by 15% of patients; NSAIDs were taken by 6%, and coxibs by 3% of patients. A significantly higher prevalence of upper gastrointestinal symptoms was observed in elderly NSAID users compared with coxib users and non-users of musculo-skeletal drugs (44% vs. 33% vs. 32% respectively, P = 0.001). The prescriptions of drugs for acid-related disorders were significantly higher in patients who were concomitantly taking NSAID rather than coxibs (13% vs. 6%, P < 0.01). The prescriptions of drugs for acid-related disorders were significantly associated with the presence of upper gastrointestinal symptoms (OR = 1.7, 95% CI = 1.6-1.9), previous gastrointestinal disorders (OR = 1.1, 95% CI = 1.0-1.3) and NSAID use (OR = 1.5, 95% CI = 1.0-2.2), but no coxib use. CONCLUSION: In this elderly population, upper gastrointestinal symptoms and prescriptions for gastroenterological drugs were higher in non-steroidal anti-inflammatory drug users than coxib users and non-users of musculo-skeletal drugs.

Role of increased cholinergic activity in reperfusion induced ventricular arrhythmias.

The effect of increased cholinergic activity on reperfusion induced ventricular arrhythmias was studied in alpha chloralose anaesthetised dogs by administering neostigmine during a 25 min occlusion of the anterior left descending coronary artery. The dogs were divided into five groups, each of 10 animals: the control group received only saline solution; group 1 neostigmine 0.03 mg.kg-1 iv at 20 min of coronary occlusion (that is, 5 min before reperfusion); group 2 atropine 0.4 mg.kg-1 iv at 10 min of coronary occlusion and neostigmine 0.03 mg.kg-1 iv at 20 min; and group 3 neostigmine 0.03 mg.kg-1 iv at 20 min of coronary occlusion and at the same time underwent atrial pacing at the same rate as that of the sinus node just before neostigmine administration. In group 4 heart rate was slowed (junctional rhythm) by destroying the sinus node at 20 min of coronary occlusion. The results obtained showed that ventricular tachycardia and fibrillation, which occur at the beginning of reperfusion, were significantly less frequent in group 1 (p less than 0.001) and in group 4 (p less than 0.001). The protective action of neostigmine was abolished by previous administration of atropine (group 2) and modified by preventing the decrease in the heart rate by atrial pacing (group 3). In group 3 ventricular tachycardia was more frequent but the incidence of ventricular fibrillation was reduced significantly compared with the control and atropine groups. Thus cholinergic activity has a protective role in reperfusion arrhythmias by decreasing the heart rate before release of the coronary occlusion and therefore reduces the incidence of ventricular fibrillation.

Baroreflex responsiveness in borderline hypertensives: a study with neostigmine.

The baroreflex response to changes in transmural pressure throughout the arterial tree or limited to the carotid sinus was evaluated in ten borderline hypertensives and compared with that observed in ten normal subjects and in ten established hypertensives. Baroreceptor sensitivity was tested by evaluating both heart rate response to phenylephrine-induced increase in arterial pressure and heart rate and blood pressure changes induced by increased neck tissue pressure by means of a neck chamber. The heart rate response to phenylephrine (evaluated by the regression of the R-R interval versus the systolic blood pressure) was depressed both in borderline and established hypertensives as compared with controls. Similarly, the heart rate and the pressor response to increased neck tissue pressure were depressed in both groups of hypertensives. In borderline, but not in established hypertensives, neostigmine administration improved consistently the pressor baroreflex response to increased neck tissue pressure and the heart rate reflex response to both the employed stimuli. These findings indicate that a reduced parasympathetic activity is one of the components involved in the altered baroreflex sensitivity in borderline hypertensives.

Effects of oral salt loading on beta-adrenergic receptor responsiveness in normal and hypertensive subjects.

The effect of oral salt loading (400 mmol per day of NaCl for 7 days) on cardiac and pancreatic beta-receptor responsiveness has been evaluated in 12 patients with established essential hypertension and in seven age-matched control subjects. Cardiac beta-receptor responsiveness was evaluated by assessing the dose of isoprenaline which increased a stable heart rate by 25% (chronotropic dose 25%, CD 25%). Pancreatic beta-receptor responsiveness was measured by the incremental areas of insulin secretion induced by iv infusion of increasing amounts of isoprenaline. Before salt load, CD 25% was significantly higher in hypertensives compared with controls (7.84 +/- 1.34 micrograms vs 3.9 +/- 0.48 micrograms, P less than 0.05) while there was no difference in the isoprenaline-induced insulin secretion between the two groups of subjects. After salt loading, CD 25% was significantly reduced in hypertensive patients but was not modified in normal subjects. Therefore, the difference in CD 25% was no longer detectable between the two groups (5.5 +/- 1.42 micrograms vs 3.2 +/- 0.48 micrograms in normal subjects and in hypertensives, respectively, NS). Furthermore, salt loading failed to induce any change in isoprenaline-induced insulin secretion in either groups. These results support the existence of a relationship between sodium intake and adrenergic beta-receptor responsiveness in human hypertension.

Role of aging on electrical, mechanical, and coronary modification induced by ouabain and epinine in isolated rat heart.

OBJECTIVE: The contractile response to digitalis and beta adrenoceptor agonists is lower in the senescent than in the adult myocardium, while the development of ventricular arrhythmias is increased. The aim of this study was to examine the effects of aging on cardiac response to digitalis and an adrenergic agonist used clinically. METHODS: The electrical and mechanical responses were tested in isolated and perfused hearts from 3-24 month old rats receiving 15 min infusion of digitalis drug (ouabain, 6 x 10(-5) M) alone, and after 5 min of beta adrenoceptor agonist drug (epinine, 1.5 x 10(-7) M). RESULTS: Ouabain action was associated with a rise in left ventricular end diastolic pressure (p < 0.01) which increased progressively with aging, and with an elevation of left ventricular developed pressure (p < 0.01) which decreased progressively with aging. Epinine induced a reduction of left ventricular end diastolic pressure (p < 0.01) and a rise in left ventricular developed pressure (p < 0.01) but both effects decreased progressively with aging. Ouabain reduced coronary flow and this decrease was more pronounced with aging (p < 0.01), while epinine caused an increase (p < 0.01) that diminished in older hearts. Ouabain given after epinine resulted in a greater increase in left ventricular end diastolic pressure than epinine (p < 0.01) but lower than that caused by ouabain alone (p < 0.01), a greater increase in left ventricular developed pressure than epinine and ouabain (p < 0.01), and a smaller reduction of coronary flow rate than ouabain alone (p < 0.01). All these effects, however, diminished progressively with aging. Arrhythmia scores were higher during ouabain than in control (p < 0.01) and in epinine treated hearts (p < 0.01); pretreatment with epinine did not modify arrhythmia score during ouabain administration. The number and severity of arrhythmias, however, increased with aging in all groups. CONCLUSIONS: Aging has a negative effect on both the positive inotropic and the arrhythmogenic effects of ouabain and epinine, although these phenomena are more pronounced during ouabain administration. However, when the two drugs are given simultaneously, epinine does not modify the arrhythmogenic effect of ouabain but reduces some of its deleterious haemodynamic effects.

Effect of furosemide on plasma concentration and beta-blockade by propranolol.

Although propranolol and furosemide are used together for hypertension, the effects of furosemide on plasma levels and beta-blocking action of propranolol are not known. Ten healthy subjects received propranolol 40 mg orally; the mean plasma propranolol levels in 60, 90, 180, and 300 min were 85 +/- 16, 90 +/- 7, 82 +/- 8, and 58 +/- 8 ng/ml. Propranolol was then given together with furosemide (25 mg orally) and the propranolol blood level was measured. Mean propranolol plasma levels were 106 +/- 11 ng/ml at 60 min, 120 +/- 12 ng/ml at 90 min (p less than 0.01), 102 +/- 8 ng/ml at 180 min (p less than 0.05), and 78 +/- 8 ng/ml at 300 min (p less than 0.01). Six additional subjects were given an infusion of 1 microgram/min isoproterenol increased by 0.5 microgram/min every 2 min until the heart rate rose by 25% after oral administration of furosemide 25 mg. This procedure was repeated after propranolol (40 mg orally) and propranolol with furosemide (25 mg orally). The amount of isoproterenol which raised the heart rate by 25% was 2.6 +/- 0.3 micrograms after furosemide alone and 17.7 +/- 2 micrograms after propranolol (p less than 0.01). After propranolol with furosemide the dose of isoproterenol required to elevate heart rate by 25% was 109 +/- 15 micrograms (p less than 0.001).

Effects of melatonin in isolated rat papillary muscle.

Melatonin (N-acetyl-5-methoxytryptamine), the principal hormone of the vertebral pineal gland, elicits several neurobiological effects. However, the effects of melatonin on cardiac muscle are still unknown. The first goal of the study was to investigate the role of melatonin on myocardial contractility in isolated rat papillary muscle using dose-response curves to melatonin, to isoproterenol and calcium either in the presence or in the absence of melatonin (0.3 nM). Response curves to isoproterenol were additionally performed in the presence of melatonin plus the specific receptor antagonist N-acetyltryptamine (10 microM); the adenylate-cyclase stimulator forskolin (10 microM) was also used. Melatonin has no direct inotropic effect in isolated rat papillary muscle but counteracts isoproterenol but not [Ca2+] effects. In fact, the EC50 for isoproterenol was significantly higher in the presence than in the absence of melatonin (p < 0.001). This anti-adrenergic action occurs through an interaction to a specific cardiac receptor. Forskolin-stimulated adenylate cyclase induced an increase of contractile force (+118 +/- 25%) which was reduced in the presence of melatonin (+26 +/- 10%; p < 0.01). In conclusion, we found that melatonin possess anti-adrenergic effect in isolated rat papillary muscle. This phenomenon was abolished in the presence of its receptor antagonist N-acetyl-tryptamine demonstrating that melatonin operates through a specific cardiac receptor. The reduction of contractility increase, induced by forskolin-stimulated adenylate cyclase, shows that melatonin may act through a reduction of cyclic AMP accumulation.

The role of blood pressure in cognitive impairment in an elderly population. Osservatorio Geriatrico Campano Group.

OBJECTIVE: The aim of this study was to investigate the cross-sectional relationship between arterial blood pressure and cognitive impairment in a group of elderly subjects, controlling for such confounding variables as age, education, depression, drug use and antihypertensive treatment. DESIGN AND SETTING: A cross-sectional survey in Campania, a region in southern Italy. SUBJECTS AND METHODS: A random sample of 1339 elderly subjects aged 65-95 years (mean 73.9 +/- 6.2 years) selected from the electoral rolls was interviewed by trained physicians. Sociodemographic characteristics, results of Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), blood pressure and whether antihypertensive treatment was being administered were recorded. When subjects with neurological diseases and those under psychotropic therapy were excluded from the analyses, the population numbered 1106. RESULTS: The MMSE score was less than 24 for 27.9% of the subjects and the mean GDS score was 10.8 +/- 6.3. The mean systolic blood pressure (SBP) was 145.3 +/- 19.0 mmHg and the mean diastolic blood pressure (DBP) was 82.0 +/- 9.2 mmHg. Logistic regression analysis showed that female sex, age, GDS score and DBP but not SBP were predictive of cognitive impairment. Educational level and antihypertensive treatment, on the contrary, play a protective role. DBP was associated with cognitive impairment in subjects aged 75 years (odds ratio 1.62, 95% confidence interval 1.16-2.25) and over (odds ratio 5.16, 95% confidence interval 1.50-17.71) but not in those aged 65-74 years. CONCLUSION: DBP but not SBP is predictive of cognitive impairment in subjects aged 75 years and over without neurological disorders independently from sex, age, education, GDS and antihypertensive treatment

Congestive heart failure in elderly patients: controlled study of delapril versus captopril.

In this controlled trial, 30 elderly patients with congestive heart failure, New York Heart Association (NYHA) classes II and III, were randomly assigned to treatment with captopril 25 mg three times daily or delapril 15 mg twice daily. At the end of an 8-week treatment period, clinical symptoms of heart failure were significantly relieved by both drugs, with a consistent and statistically significant improvement in patients' quality of life evaluated using a symptoms/activity scale (p < 0.001). None of the patients was judged NYHA class III at the end of the trial and 40% were assigned to class I (p < 0.01). There was a relevant, but not statistically significant, increase in exercise duration in both treatment groups (10% captopril group, 14% delapril group), but the number of patients discontinuing the exercise test for dyspnea was 50% less in the delapril group. Neither drug had evident effects on echocardiographic left ventricular parameters. Two patients treated with captopril and 3 with delapril complained of mild-to-moderate adverse reactions. The safety of both drugs was confirmed by laboratory tests.

Use of the epinephrine test in diagnosis of coronary artery disease.

Two-dimensional echocardiographic (2-D echo) and electrocardiographic (ECG) monitoring was performed in 53 patients with anginal chest pain during infusion of physiologic doses of epinephrine. Technically adequate 2-D echo studies were recorded in 45 patients. Of these 45 patients, 35 had significant coronary artery disease. Twenty-two patients showed ECG changes during the test (ECG sensitivity 63%), 13 of whom also showed wall motion abnormalities (2-D echo sensitivity 48.5%). Combined ECG and 2-D echo criteria of a positive test yielded a sensitivity of 74%. None of the 10 patients without coronary artery disease had electrical or mechanical abnormalities during the test (specificity 100%). Thus, the epinephrine test during simultaneous 2-D echo and ECG monitoring is a valid alternative to echocardiographic exercise stress testing. Furthermore, the adequate images obtained during the infusion allow better investigation of relation between wall motion abnormalities and ECG changes during myocardial ischemia.

Effect of beta-adrenoceptor blockade on dipyridamole-induced myocardial asynergies in coronary artery disease.

Twenty-one patients with angiographic evidence of significant coronary artery disease, and positive dipyridamole echocardiographic test results at basal condition and after 7 days of placebo treatment were prospectively studied to see whether beta blockade modifies the effects of dipyridamole echocardiographic testing on regional myocardial contractility. Patients were randomized to propranolol (120 mg/day) or placebo treatment in 3 divided doses for 7 days, after which each patient crossed over to the alternate regimen. Dipyridamole-echocardiographic testing was repeated at the end of each treatment. Propranolol abolished new mechanical signs of transient dipyridamole-induced ischemia (new wall motion abnormalities or an increase in degree of basal asynergies, or both) in 13 of 21 patients. The remaining 8 patients had positive results on dipyridamole echocardiographic testing after the propranolol treatment period. At basal conditions both heart rate and rate-pressure product were significantly reduced with propranolol; there was also a significant decrease in these parameters at peak dipyridamole infusion. At peak dipyridamole infusion heart rate and rate-pressure product were significantly lower in patients with negative than in those with positive echocardiographic test results after propranolol. Our data show that administration of beta blockade significantly reduces the development of transient dipyridamole-induced myocardial asynergies, the earliest markers of acute myocardial ischemia, detected with 2-dimensional echocardiography.