Adrenergic effects on force-frequency relationship: a pivotal role for the cardiac intrinsic systems.

AIM: The force-frequency relationship (F-FR) is an important intrinsic regulatory mechanism of cardiac contractility. The involvement of autonomic nervous system in this physiological aspect of cardiac control remains unclear. The aim of the study was to evaluate the role of extrinsic and intrinsic cardiac adrenergic innervations on the heart rate (HR)-related positive inotropic response. METHODS: Twenty-four dogs were anesthetized and acutely instrumented to monitor and record ECG, systemic and left ventricular pressures and derivatives, and to pace the heart at 130, 150, 170, 190 and 210 bpm, in order to construct the F-FR curve. Animals were randomly assigned to four groups (n = 6 each): vehicle (V), ganglion-blocked (G-B), ß-blocked (ß-B) and ganglion-blocked plus ß-blocked (G-B + ß-B). RESULTS: Vehicle treated animals presented the classical F-FR. In the ß-B group F-FR was blunted, but never fully suppressed. The G-B treated animals showed a bell-shape response curve of the induced inotropic effect with the zenith at 170 bpm: the first part of the curve resembling the control one, followed by a rapid decline toward baseline value. The co-administration of G-B and ß-B agents reversed the contractile response to HR rise with a curve resembling the negative F-FR curve observed in the failing heart. CONCLUSION: The F-FR appeared to be constituted by two consecutive mechanisms: first depolarization-rate dependent, and a second catecholamine-dependent. The natural consequence of these observations is that the full expression of F-FR needs an intact adrenergic system.

Pharmacological profile of the novel inotropic agent (E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744).

The novel Na(+)/K(+)-ATPase inhibitor (E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744) was characterized for its inotropic and toxic properties. Inhibition potency on dog kidney Na(+)/K(+)-ATPase was comparable (0.43 microM) to that of digoxin (0.45 microM). PST2744 concentration-dependently increased force of contraction in guinea pig atria and twitch amplitude in isolated guinea pig myocytes; in the latter, aftercontractions developed significantly less than with digoxin. Intravenous infusion of 0.2 mg/kg/min PST2744 in anesthetized guinea pigs exerted an immediate and long-lasting inotropic effect (ED(80) of 1.89 +/- 0.37 mg/kg) without causing lethal arrhythmias up to a cumulative dose of 18 mg/kg. Conversely, an equieffective infusion of digoxin (0.016 mg/kg/min; ED(80) of 0.32 mg/kg) caused lethal arrhythmias at a cumulative dose of 0.81 mg/kg. At a higher rate (0.4 mg/kg/min), PST2744 induced lethal arrhythmias, with a lethal dose/ED(80) ratio significantly greater than digoxin (20.2 +/- 6.3 versus 3.23 +/- 0.55, p < 0.05). Decay of the inotropic effect (t(1/2), min) was significantly faster for PST2744 (6.0 +/- 0.39) than for digoxin (18.3 +/- 4.5, p < 0.05). In anesthetized dogs, PST2744 dose-dependently increased maximum velocity of pressure rise (+dP/dt(max)) in the range 32 to 500 microg/kg i.v. and was safer than digoxin. In conscious dogs with a healed myocardial infarction, PST2744 significantly increased resting values of +dP/dt(max), left ventricular pressure, and SPB, and increased +dP/dt(max) throughout treadmill exercise while reverting the increase in left ventricular end diastolic pressure seen in control animals. Digoxin significantly decreased basal heart rate, while not affecting the hemodynamic response to exercise. Thus, PST2744 represents a new class of Na(+)/K(+)-ATPase inhibitors endowed with inotropic activity comparable with that of digitalis but having greater safety.

Combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) anf erythropoietin (EPO) for the treatment of advanced non-responsive chronic lymphocytic leukemia.

We report the use of a colony-stimulating granulocyte-macrophage factor (GM/CSF) and erythropoietin (EPO) combination as salvage treatment in four heavily-pretreated patients with refractory/ recurrent B-CLL. Induction therapy was subcutaneous GM-CSF 2.5 microg/ kg, and EPO, 150 units/kg both daily for the first 14 d. Maintenance therapy was GM-CSF on days 1, 3 and 5 and Epo on days 2, 4 and 6 at the same doses with weekly recycling. All the patients responded favourably. A significant reduction of lymphocytosis, lymphoadenomegaly, and organomegaly was obtained within one month of therapy. The number of infections and transfusional requirement decreased dramatically. The hemoglobin increased to over 11 g/dl in 3 out of 4 patients. With a median follow-up of 11 months (range 5-13) we observed 4 partial responses (NCI/IWCLL) and only one progression after a 10-month partial response. This combination regimen seems very active, safe and easy to administer. It may represent a promising therapeutical option in heavily pretreated patients. Further clinical and biological studies on a larger cohort of patients are needed to confirm these preliminary data, to clarify the hypothetical interactions between these cytokines and B-CLL cell proliferation pathways, and to establish if this therapy may have an impact on survival.

Cardiac and renal endothelin-1 binding sites in streptozotocin-induced diabetic rats.

UNLABELLED: The aim of this work was to study cardiac and renal endothelin binding sites during the progression of diabetes. Male Crl:CD (BR) rats were made diabetic by injection of streptozotocin (STZ, 45 mg kg-1 i.v.). Only rats with a glycaemia of 500 mg per 100 ml or higher, were used. The hearts were taken at 2, 4 or 6 weeks and kidneys at 2 and 6 weeks, after diabetes induction, for binding studies. In the heart, the number of Et-1 binding sites was significantly increased 2 weeks after STZ-induction of diabetes (449 +/- 13 vs. 345 +/- 18 fmol (mg protein) -1, in controls; p < 0.05) without modification of KD value (104 +/- 5 vs 101 +/- 7 pM). Comparable results were obtained 4 and 6 weeks after STZ-induction. In the kidney both the parameters were unchanged at all the times tested. IN CONCLUSION: a specific increase in cardiac Et-1 binding sites, without change in affinity of the peptide, was found 2, 4 and 6 weeks after diabetes induction; while renal Et-1 binding sites were not modified.

Endothelins induce prostacyclin release in both vascular and non-vascular tissue.

The effects of an i.v. administration of endothelin-1, -2 and -3 (0.25-3 nmol kg-1) or their corresponding proendothelins (1-20 nmol kg-1) on blood pressure and 6 keto-prostaglandin F1 alpha (6 keto-PGF1 alpha) release in the anaesthetized ganglion-blocked rat were evaluated. The same peptides were tested for their ability to release 6 keto-PGF1 alpha from the rat vas deferens in vitro. Endothelins and proendothelins showed a transient hypotensive effect followed by a potent, long lasting vasopressor response. Blood pressure increase induced by endothelins was found to be dose-dependently correlated with 6 keto-PGF1 alpha plasma level increases. On the other hand proendothelins produced similar pressor responses, but their effect on 6 keto-PGF1 alpha plasma levels was much less intense at equipressor doses. The effects of endothelins on arterial pressure and 6 keto-PGF1 alpha release were phosphoramidon-insensitive, while the activities of proendothelins were reduced by phosphoramidon (10 mg kg-1 i.v.). Both endothelins (5-15 nmol/l) and proendothelins (100-300 nmol/l) were able to increase to a similar extent 6 keto-PGF1 alpha levels in the rat vas deferens incubation buffer. The releasing activity of endothelins was not modified by the pretreatment with phosphoramidon (50 mumol/l). This pretreatment strongly inhibited proendothelin-1 and -2 effects, but not that of proendothelin-3.

Decreased density of endothelin binding sites in adrenal glands but not in aorta, of long term infarcted rats.

Endothelins (Et-s) are biologically active peptides which play a physiological and pathological role in the cardiovascular regulation. The aim of our study was to verify, in a model of experimental long term myocardial ischemia (15 weeks) in rats, whether there was a modification in the ET binding sites of aorta and adrenal glands. Additionally, Ang II binding sites in adrenal glands were studied. The principal finding of the present study was the down-regulation of ET binding sites in adrenal glands of chronic infarcted rats, whereas no modification of binding parameters for Et-1, in thoracic aorta, nor for Ang II, in adrenal glands, were found.

Comparison of the cardiovascular and neural activity of endothelin-1, -2, -3 and respective proendothelins: effects of phosphoramidon and thiorphan.

1. In the anaesthetized, ganglion-blocked rat, intravenous boluses of endothelin-1, endothelin-2 and endothelin-3 induced a transient hypotensive effect followed by a potent long lasting pressor response (ED50 mmHg: 0.72 +/- 0.05, 1.8 +/- 0.2 and 2.7 +/- 0.3 nmol kg-1, respectively). The maximal effect for the three peptides was of a similar order of magnitude (delta MAP: 84 to 89 mmHg). Neither of these effects was influenced by phosphoramidon or thiorphan (10 mg kg-1, i.v.). 2. Intravenously administered big-endothelin-1 and -2 induced a transient (1-2 min) hypotension followed by a potent long lasting (> 25 min) vasopressor effect (ED50 mmHg: 1.8 +/- 0.2 and 6.7 +/- 0.4 nmol kg-1, respectively), with a similar maximal activity (delta MAP: 85 +/- 4 and 81 +/- 2.4 mmHg, respectively). The onset of the big-endothelin-1 vasopressor effect was more rapid (5-6 min) than that of big-endothelin-2 (10-13 min). Big-endothelin-3 was found to induce only a potent, long lasting (> 35 min) hypertension, with a maximal effect of 75 +/- 4.6 mmHg at 10 nmol kg-1 and an ED50 mmHg of 6.5 +/- 0.4 nmol kg-1. The onset of this effect was much slower (20-25 min) than that of the other proendothelins. Pressor responses induced by big-endothelin-1, -2 and -3 (3, 15 and 10 nmol kg-1, respectively) were markedly reduced (60, 80 and 100%) in the presence of phosphoramidon (10 mg kg-1, i.v.). Thiorphan (10 mg kg-1, i.v.) did not inhibit the effects of big-endothelin-1, -2 and -3. 3. In the electrically stimulated rat vas deferens, endothelin-I and -2 were found to be equipotent enhancers of the twitch response (EC100%: 4.0 +/- 0.4 nm and 7.9 +/- 4.8 nm, respectively), both about 3-4 fold as active as endothelin-3 (EC100%: 19 +/- 2.5 nM). Endothelin-1 and -3 showed a comparable maximalstimulatory effect (Emax: 296 +/- 30 and 262 +/- 24%) while endothelin-2 was less active (Emax: 194 +/- 30%).4. Big-endothelin-l and -2 were potent enhancers of the twitch response too (EC 100,%: 10.0 +/- 2.6 nM and 21.6 +/- 3.2 nM, respectively), with a comparable maximal stimulatory effect (Emax: 254 +/- 22 and 264 +/-24%). Big-endothelin-3 was found to be less potent (EC,100%: 275 +/- 21 nM), but retained a marked potentiating effect (Emax: 200 +/- 38%). Phosphoramidon, but not thiorphan, concentration-dependently(10 and 100 microM) reduced big-endothelin-1 (58 and 86% respectively) and big-endothelin-2 (21 and 56%)-mediated responses. Conversely, the big-endothelin-3 effect was reduced by phosphoramidon only at 100 microM (-70%), while thiorphan acts concentration-dependently (31 and 71% at 10 and 100 microM respectively); thus, in the rat vas deferens, big-endothelin-I and -2 were as potent as their corresponding endothelins, while big-endothelin-3 was about 20 times less potent than endothelin-3.5. The increasing effect of endothelin-2 (194 +/- 30% over baseline) was significantly enhanced by either 10 microM phosphoramidon (277 +/- 42%) or thiorphan (318 +/- 15%). The endothelin-I and endothelin-3-mediated twitch enhancement was not affected by the two protease inhibitors (10 microM).6. These results suggest that in vivo big-endothelin-1, -2 and -3, are processed through a similar phosphoramid on-sensitive enzymatic pathway although with different apparent affinity. This enzymatic process is probably attributable to a neutral endoprotease, distinct from neutral-endopeptidase 24.11(NEP). On the other hand, a NEP-like enzymatic activity may be involved, in the rat vas deferens, in the activation of big-endothelin-3 to endothelin-3 and in the metabolism of endothelin-2, but not of endothelin-I or endothelin-3.

Alcohol use among migrant laborers in western New York.

A survey of alcohol use among 217 Black and Haitian migrant agricultural workers was conducted in 13 camps in three counties of upstate New York. The orienting hypothesis stated that older, unattached men account for much of the drinking on migrant camps and that older, unattached men have experienced a variety of personal troubles as a result of their drinking. The results of the survey were found to support the initial hypothesis. In camps composed primarily of family groups, social control mechanisms were found to be more highly developed than in camps composed primarily of unattached, isolated men. It was also found that this difference in degree of social control was reflected in differences of drinking behavior. It is suggested that the mechanization of agriculture has become a self-reinforcing process that results in a proportional increase in the use of the homeless and troubled as a source of low-cost agricultural labor.