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R Ferrari

Publications and source records attributed to R Ferrari.

At least 163 records · Page 9Linked to original sources
PubMed1997

Major differences among the three classes of calcium antagonists.

The safety of calcium antagonists has recently become a controversial issue among cardiologists. Thus, the role of calcium antagonists in the treatment of myocardial infarction and in secondary cardiovascular prevention is under review. As a consequence, the concept that the words 'calcium antagonists' comprise various drug classes has re-emerged. These differ in basic pharmacological properties, tissue selectivity, pharmacokinetics, and final haemodynamic effect. Obviously, such differences alter their therapeutic effect. In this article, the major differences among the three classes of calcium antagonists, phenylalkylamines, dihydropyridines and benzothiazepines, are discussed and reviewed. A comparative analysis of available clinical trials focusing on the usefulness of each drug class is provided for the reader's interest. Some particularly relevant pathological conditions are considered: chronic stable angina pectoris, vasospastic angina, unstable angina pectoris with threatened myocardial infarction, myocardial infarction, and congestive heart failure.

Aniline Compounds↗
PubMed1997

Skeletal muscle function at low work level as a model for daily activities in patients with chronic heart failure.

AIM: Metabolic exercise abnormalities have been reported in chronic heart failure patients. This study sought to evaluate whether these abnormalities affected daily activity. METHODS AND RESULTS: In 16 patients with moderate-to-severe chronic heart failure and in eight controls we measured femoral flow (thermodilution) and metabolism (glucose, lactate, free fatty acids, blood gas values) at rest and during a constant load of 20 W, which may mimic a daily activity. At rest, chronic heart failure patients had a leg flow similar to controls, but showed a higher leg oxygen consumption (4.6 +/- 0.6 vs 2.6 +/- 0.4 ml.min-1; P < 0.05), a higher arteriovenous oxygen difference (7.2 +/- 0.5 vs 5.4 +/- 0.7 ml.dl-1; P < 0.05), and a lower femoral vein pH (7.37 +/- 5.03 vs 7.42 +/- 0.01; P = 0.01). At 20 W, chronic heart failure patients had a leg flow similar to controls, but showed increased lactate release (from resting 11.7 +/- 33 to 142 +/- 125 micrograms.min-1 P < 0.0001 vs controls, from resting 5.7 +/- 15.4 to 50 +/- 149 micrograms.min-1 ns), higher arterial concentration of free fatty acids (781 +/- 69 vs 481 +/- 85 mumol.l-1; P < 0.01), lower femoral vein HCO3 (24.1 +/- 2.6 vs 26.3 +/- 1.7 mmol.l-1; P < 0.05) and base excess (-2.3 +/- 2.3 vs -0.24 +/- 1.7 mmol.l-1; P = 0.01). CONCLUSION: In chronic heart failure patients, the important cellular metabolic alterations already present at rest partially affect daily activities, owing to a further decrease in the efficiency of muscle metabolic processes, and may preclude tolerance of heavier activities. Such alterations appear, at least in part, independent of peripheral haemodynamic responses to exercise.

Activities of Daily Living↗
PubMed1997

Short- and long-term changes in striatal neurons and astroglia after transient forebrain ischemia in rats.

BACKGROUND AND PURPOSE: The striatum is one of the regions most sensitive to transient forebrain ischemia. After 30-minute ischemia, areas of massive neuronal degeneration are clearly detectable a few hours after the insult and attain their maximal extension 24 hours after the insult. However, for most cellular and neurochemical parameters it is not known whether some recovery occurs at later times. We examined certain cell populations in the caudate putamen at different times after transient ischemia. METHODS: Adult male Sprague-Dawley rats were subjected to 30-minute forebrain ischemia (four-vessel occlusion model). Six experimental groups were considered: control animals and ischemic animals killed 4 hours, 1 day, 7 days, 40 days, and 8 months after reperfusion. Three striatal cell populations were examined by means of immunocytochemistry coupled to computer-assisted image analysis: vulnerable medium spiny neurons, resistant aspiny neurons, and reactive astrocytes, labeled for their content of dopamine- and cAMP-regulated phosphoprotein mr32 (DARPP-32), somatostatin and neuropeptide Y, and glial fibrillary acidic protein, respectively. RESULTS: (1) The area containing DARPP-32 immunoreactive neurons was markedly decreased (15% to 20% of control caudate putamen area) at 1 day after reperfusion and partially recovered at the following times (40% to 50% at 7 days and 50% to 60% at 40 days and 8 months after reperfusion). (2) The appearance of reactive astrocytes was precocious (4 hours to 1 day after ischemia) in the medial caudate putamen, the region in which DARPP-32 recovered within 40 days after ischemia, and late (7 to 40 days after ischemia) in the lateral caudate putamen, where no DARPP-32 recovery was detected. (3) Neuropeptide Y/somatostatin-containing neurons resisted the ischemic insult and could be detected in areas devoid of DARPP-32 immunoreactive neurons as long as 8 months after reperfusion. CONCLUSIONS: The present results show a marked recovery of DARPP-32-positive neurons within 40 days after 30-minute forebrain ischemia in the medial, but not the lateral, caudate putamen. Medial caudate putamen also contains a high density of reactive astrocytes on the first day after ischemia, suggesting that astrocytic support has an important role in the spontaneous recovery of ischemic neurons.

Animals↗
PubMed1997

Angiotensin converting enzyme inhibitor-calcium antagonist combination: an alliance for cardioprotection?

MECHANISMS OF ACTION IN SMOOTH MUSCLE: Calcium antagonists and angiotensin converting enzyme (ACE) inhibitors act synergistically in reducing blood pressure. Calcium antagonists counter an excess of calcium entry through the voltage-operated channels of the vascular smooth muscle. ACE inhibitors reduce the vasoconstrictive properties of local and circulating angiotensin II. In addition, they improve endothelium-dependent vasodilation by increasing the expression of endothelial inositol by a bradykinin-related mechanism. Thus, at the smooth muscle level, calcium antagonists cause dilation by reducing external calcium entry and ACE inhibitors cause dilation by reducing internal calcium cycling and improving nitric oxide production. EFFECTS AT MOLECULAR LEVEL: The two agents have synergistic antagonists exert a potent cardioprotective action; this effect requires prophylactic administration and relies on the ATP-sparing capacity of these drugs. Moreover, prophylactic administration of verapamil but not to other calcium antagonists in patients who have suffered an acute myocardial infarction reduces overall mortality, provided no overt heart failure is present. The molecular effect of ACE inhibitors on the ischaemic heart is less well known but seems to be related to a reduction in noradrenaline release or to an improvement in bradykinin; the effect is thus complementary to that of calcium antagonists. OTHER ACTIONS OF ACE INHIBITORS: There is evidence that ACE inhibitors may have additional cardioprotective properties in being able to improve coronary flow, prevent arrhythmias, reduce the toxicity of oxygen free radicals, improve myocardial energy metabolism and prevent remodelling of the heart. ACE inhibitors can also protect the ischaemic heart by inhibiting bradykinin breakdown and by interfering with the central and peripheral nervous and hormone systems such as the kallikrein-kinin, prostaglandin and sympathetic nervous systems. The administration of ACE inhibitors to patients with acute myocardial infarction failed to reduce mortality. However, prophylactic administration to patients with myocardial infarction and heart failure resulted in a significant reduction in mortality and in hospitalization for cardiac disease. CONCLUSIONS: The combination of verapamil with an ACE inhibitor is promising not only for the treatment of hypertension, but also for ischaemic heart disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Metabolic adaptation during a sequence of no-flow and low-flow ischemia. A possible trigger for hibernation.

BACKGROUND: Myocardial hibernation is an adaptive phenomenon occurring in patients with a history of acute ischemia followed by prolonged hypoperfusion. METHODS AND RESULTS: We investigated, in isolated rabbit heart, whether a brief episode of global ischemia followed by hypoperfusion maintains viability. Four groups were studied; group 1,300 minutes of aerobia; group 2,240 minutes of total ischemia and 60 minutes of reperfusion; group 3, 10 minutes of total ischemia, 230 minutes of hypoperfusion (90% coronary flow reduction), and 60 minutes of reperfusion; and group 4, 240 minutes of hypoperfusion followed by reperfusion. In group 3, viability was maintained. Ten minutes of ischemia caused quiescence, a fall in interstitial pH (from 7.2 +/- 0.01 to 6.1 +/- 0.8), creatine phosphate (CP), and ATP (from 54.5 +/- 5.0 and 25.0 +/- 1.9 to 5.0 +/- 1.1 and 15.3 +/- 2.5 mumol/g dry wt, P < .01). Subsequent hypoperfusion failed to restore contraction and pH but improved CP (from 5.0 +/- 1.1 to 20.1 +/- 3.4, P < .01). Reperfusion restored pH, developed pressure (to 92.3%), and NAD/NADH and caused a washout of lactate and creatine phosphokinase with no alterations of mitochondrial function or oxidative stress. In group 4, hypoperfusion resulted in progressive damage. pH fell to 6.2 +/- 0.7, diastolic pressure increased to 34 +/- 5.6 mm Hg, CP and ATP became depressed, and oxidative stress occurred. Reperfusion partially restored cardiac metabolism and function (47%). CONCLUSIONS: A brief episode of total ischemia without intermittent reperfusion maintains viability despite prolonged hypoperfusion. This could be mediated by metabolic adaptation, preconditioning, or both.

Adaptation, Physiological↗
PubMed1996

Impaired skeletal muscle fatigue resistance in rats with pressure overload-induced left ventricular hypertrophy.

In rats with left ventricular (LV) hypertrophy, we investigated whether abnormalities of skeletal muscle could result in reduced exercise tolerance in the absence of reduced cardiac function. LV pressure overload was induced by partial constriction of the abdominal aorta (AC) with controls subjected to sham operation. Cardiac and skeletal muscle function and blood flow were assessed in vivo 3 and 6 weeks later. AC induced LV hypertrophy of 41% and 37% at 3 and 6 weeks post-operation. In AC rats, cardiac index was 31 +/- 8 and 35 +/- 4 ml/min/100 g at 3 and 6 weeks compared to 38 +/- 4 and 34 +/- 2 ml/min/100 g in controls (N.S.). Fatigue index of the soleus (type-I rich) muscle in AC rats was reduced by 14% (P < 0.05) at both time points, while that of the tibialis anterior (mixed fiber) muscle was unchanged at 3 weeks but reduced by 18% (P < 0.05) at 6 weeks. Function of the extensor digitorum longus (type-IIB rich) muscle was unaltered at both time points. Blood flow at rest was paradoxically increased in muscles which exhibited increased fatigue susceptibility. At 3 weeks, blood flow during fatigue stimulation was reduced by 33% in the soleus muscle; the only muscle to exhibit impaired fatigue resistance at this time point. Blood flow during stimulation remained unaltered in the EDL and TA muscles. Thus, impaired fatigue resistance was observed in skeletal muscle with high oxidative and oxidative glycolytic fiber content during the compensatory phase of LV hypertrophy, prior to overt cardiac dysfunction. A selective impairment of blood flow to these muscles during exercise may play a causal role in exercise intolerance.

Animals↗
PubMed1996

Dichotomy in the post-ischemic metabolic and functional recovery profiles of isolated blood-versus buffer-perfused heart.

There is evidence that buffer- and blood-perfused hearts differ in their postischemic functional recoveries. The present study was designed to: (i) compare ischemia-induced contracture and post-ischemic functional recovery, and (ii) investigate whether the recovery profiles were related to either the release of purines and norepinephrine or high-energy phosphate content. Rat hearts (n = 8/group) were perfused at 37 degrees C with buffer (60 mmHg) or blood (60 mmHg from a support rat), made globally ischemic (15 min) and reperfused (15 min). The onset and severity of ischemic contracture were identical in both models [left ventricular end-diastolic pressure (LVEDP) at the end of 15 min ischemia was 30 +/- 5 and 27 +/- 4 mmHg respectively; P = N.S.]. However, the rate and extent of post-ischemic left ventricular developed pressure (LVDP) differed considerably. Blood-perfused hearts exhibited an initial rapid and complete recovery of LVDP followed by a steady decline to approximately 60% of pre-ischemic values. Buffer-perfused hearts recovered to only 80% after 5 min reperfusion and remained at this level for the duration of reperfusion LVEDP was higher in buffer-perfused than in blood-perfused hearts during the first 5 min of reperfusion; thereafter, LVEDP fell in buffer-perfused hearts to a level than was not significantly different from the observed in blood-perfused hearts. In buffer-perfused hearts, coronary flow recovered to 90% within 5 min and then remained constant; in blood-perfused hearts flow recovered to 100% by 1 min and continued to rise to a maximum by 7 min (201 +/- 15%). This increase appeared to mirror the secondary decline in LVDP. During the first 4 min of reperfusion, in both preparations, venous norepinephrine increased to six- to nine-fold of pre-ischemic values and then fell rapidly to near control levels by 6-9 min. Total purine release was high in early reperfusion in both groups. At the end of 15 min reperfusion, the tissue adenylate pool was similar in both groups. This study demonstrates that the nature of the perfusate used for an isolated rat heart preparation: (i) does not appear to influence the severity of ischemic injury as assessed by ischemic contracture, but (ii) does influence the qualitative and quantitative characteristics of the temporal profile that describes the recovery of systolic and diastolic function during the first 15 min of reperfusion: and (iii) it has no effect upon the changes seen in a number of metabolic indices that are often used for the assessment of injury and protection.

Animals↗
PubMed1996

Aorta and skeletal muscle NO synthase expression in experimental heart failure.

Nitric oxide (NO), the free radical that accounts for the biological activity of endothelium-derived relaxing factor, is synthesized from L-arginine by NO synthase (NOS). There is evidence that NO availability is reduced in the peripheral vasculature of patients with congestive heart failure (CHF). The aim of this study was to investigate the expression of NOS in the descending aorta and in the skeletal muscles of rats subjected to heart failure. The alkaloid, monocrotaline, was used to induce pulmonary hypertension and cardiac failure in rats. The expression of both the constitutive (ecNOS) and the inducible (iNOS) isoforms of the enzyme was assessed by Western blot analysis. In CHF animals, the ecNOS location in the aorta is altered: the endothelial protein expression is substantially reduced (from 0.083 +/- 0.012 to 0.003 +/- 0.004 OD/microgram total proteins, P < 0.001) whereas the expression of ecNOS in the smooth muscle is increased (from 0.024 +/- 0.004 to 0.059 +/- 0.009 OD/ microgram total proteins, P < 0.01). The total aortic ecNOS is diminished in CHF respect to control animals (0.062 +/- 0.009 v 0.107 +/- 0.013 OD/microgram total proteins, P < 0.01). On the contrary, no difference in ecNOS protein expression was observed in the extensor digitorum longus and soleus muscles. Furthermore, iNOS was not detected in any of the tissues considered. In conclusion, experimental CHF causes a re-setting of the ecNOS protein expression in the descending aorta but not in skeletal muscles. The reduced abundance of ecNOS in the aortic endothelium is consistent with the impairment of the vasodilating function reported in patients with CHF.

Animals↗
PubMed1996

Skeletal muscle metabolism in experimental heart failure.

We studied peripheral skeletal muscle metabolism in monocrotaline-treated rats. Two distinct groups emerged: a percentage of the animals developed ventricular hypertrophy, with no signs of heart failure (compensated group), whilst others, besides ventricular hypertrophy, developed the syndrome of congestive heart failure (CFH group). Oxidative metabolism and redox cellular state were expressed in terms of creatine phosphate, purine (ATP, ADP and AMP) and pyridine (NAD and NADH) nucleotides tissue content. Skeletal muscles with different metabolism were studied: (a) Soleus (oxidative), (b) extensor digitorium longus (glycolytic) and tibialis anterior (oxidative and glycolytic). The results showed that in CFH animals a decreased high-energy phosphates content occurs in the soleus and extensor digitorum longus, but not in the tibialis anterior. In the soleus. ATP declined from 20.31 +/- 2.5 of control group to 9.55 +/- 0.61 mumol/g dry wt. while in the extensor digitorum longus ATP declined from 30.92 +/- 2.68 to 22.7 +/- 1.54 mumol/g dry wt. In both these muscles, a shift of NAD/NADH couple towards oxidation was also observed (from 26.58 +/- 3.34 to 6.95 +/- 0.97 and from 18.88 +/- 3.43 to 10.57 +/- 1.61, respectively). These alterations were more evident in the aerobic soleus muscle. On the contrary, no major changes occurred in skeletal muscle metabolism of compensated animals. The results show that: (1) a decrease in muscle high-energy phosphates occurs in CFH; (2) this is accompanied by a decrease of NAD/NADH couple suggesting an impairment in oxygen utilization or availability.

Adenosine Diphosphate↗
PubMed1996

Is stunning an important component of preconditioning?

We tested the hypothesis that stunning following a brief period of ischaemia is a component of cardioprotection afforded by preconditioning in an in vitro model of global normothermic ischaemia. Isolated Langendorff-perfused rat hearts, after 120-150 min of aerobic perfusion, were divided into four groups. Groups 1 and 2 constituted the aerobic and ischaemic controls. The other hearts were preconditioned by two 2-min ischaemia/reperfusion cycles. Two ischaemic preconditioning protocols were used, the only difference being prolongation of the reperfusion cycle from 5 (group 3) to 20 min (group 4) before the onset of severe ischaemic insult. Mechanical function, energetic metabolism and the rate of enzyme release were followed throughout. In group 3, myocardial function remained significantly downregulated before the onset of severe ischaemia. This resulted in cardiac protection as evidenced by enhanced recovery of systolic pressure (37.7 +/- 3.6 v 61.9 +/- 5.7 mmHg for groups 2 and 3, respectively; P < 0.02), reduced rise in diastolic pressure (55.8 +/- 5.9 v 34.3 +/- 5.2 mmHg; P < 0.02), reduced creatine kinase (CK) release (957.3 +/- 175.7 v 541.5 +/- 85.9 mU/min/gww; P < 0.05) and higher contents of high-energy phosphate at the end of ischaemia [3.6 +/- 0.3 v 25.3 +/- 2.9 mumol/gdw for creatine phosphate (CP), P < 0.001] as well as after reperfusion (16.8 +/- 2.4 v 31.4 +/- 1.8 for CP, P < 0.01, and 3.9 +/- 0.5 v 6.2 +/- 0.8 mumol/gdw for ATP, P < 0.05). When severe ischaemia was started only after complete recovery of mechanical function (group 4), no protection was observed. Our data suggest that a decrease in mechanical function or stunning occurring after the short period of ischaemia causes ATP sparing and constitutes an additional mechanism of preconditioning cardioprotection in vitro.

Animals↗
PubMed1996

Metabolic and functional consequences of successive no-flow and sustained low-flow ischaemia; a 31P MRS study in rat hearts.

Recently, a model of acute hibernation, based on successive no-flow and low-flow ischaemia in the isolated rabbit heart has been described. In the present study this model was used in isolated rat hearts. 31P NMR was used to follow the time course of intracellular pH (pHi) and high-energy phosphates; mechanical activity of the heart was assessed simultaneously. Control hearts were subjected to 180 min of low-flow ischaemia and 60 min of reperfusion (group A). In the acute hibernation group, low-flow was preceded by 5 min of no-flow ischaemia (group B). In group A contracture developed during low-flow. The time to onset of contracture was 51 min (range: 28 to 123 min). In group B, contracture did not occur during low-flow ischaemia (P < 0.01): recovery of left ventricular developed pressure and end-diastolic pressure was significantly better during the first 15 min of reperfusion (P < 0.05). In group A pHi decreased from 7.06 +/- 0.04 to 6.64 +/- 0.14 during the first 30 min of low-flow. After contracture developed in this group two pHi values were measured amounting to 6.33 +/- 0.15 and 6.86 +/- 0.05 at the end of low-flow. At the end of reperfusion pHi was 6.29 +/- 0.05 and 7.09 +/- 0.06. In group B, pHi decreased from 7.08 +/- 0.03 to 6.55 +/- 0.03 during no-flow ischaemia. During low-flow ischaemia, pHi increased to 6.73 +/- 0.05 and remained constant. During reperfusion pHi recovered to 7.06 +/- 0.03. In group A and B phosphocreatine (PCr) levels at the end of low-flow ischaemia amounted to 13 +/- 8% and 26 +/- 6% of pre-ischaemic levels, respectively. During reperfusion, PCr recovery was better in group B: 67 +/- 12% v 23 +/- 11% (P < 0.05). In group A and B, ATP levels at the end of low-flow ischaemia were 5 +/- 10% and 19 +/- 9%, respectively. The rate of ATP depletion during low-flow ischaemia was initially similar in both groups, but between 45 and 90 min ATP depletion still continued in group A, while this had leveled off in group B (P < 0.01). During reperfusion no significant changes in ATP were observed. We propose that increased glucose transport and glycolytic flux are able to maintain ionic homeostasis and diastolic function when low-flow ischaemia is preceded by a short period of no-flow ischaemia.

Animals↗