NO-dependent attenuation of TPA-induced immunoinflammatory skin changes in Balb/c mice by pindolol, heptaminol or ATRA, but not by verapamil.

Recently a mouse skin carcinogenesis study reported that a ß-blocker carvedilol displayed antitumor-properties via antihyperplastic effects. However, the antihyperplastic mechanism is unclear as the ß-blocker is characterized with multiple pleiotropic effects including stimulation of endothelial NO release and verapamil-like calcium channel blocking activity. To investigate the nature and the origin of the antihyperplastic effects, we tested topical pretreatment with pindolol, heptaminol, ATRA or verapamil against Balb/c mouse ear skin hyperplasia that was induced by TPA. We found that pindolol, heptaminol or ATRA, but not verapamil, inhibited the TPA-induced immunoinflammatory skin changes in an NO-dependent manner, which included epidermal hyperplasia, skin edema and fibrosis. Furthermore, we also observed NO-dependent alleviation of the TPA-induced NK cell depletion in the ear tissues by heptaminol pretreatment. Together our results suggest that stimulation of NO generation from constitutive synthases may be primarily responsible for the reported antihyperplastic and NK cell-preserving effects of the ß-blockers, and that similar effects may be observed in other immunity normalizing compounds that also promote endothelial NO synthesis.

Use of heptaminol hydrochloride for catecholamine weaning in septic shock.

We analyze in the current study the impact of heptaminol hydrochloride (Heptamyl) administration in patients with septic shock requiring adrenergic support on the duration of vasopressor infusion and on catecholamine delay weaning. In this prospective study were included 49 nonconsecutive patients with septic shock requiring vasopressor infusion and with stable hemodynamic parameters during more than 24 hours. All these patients were included in a random way to receive or not heptaminol hydrochloride. The primary end point was the effect of heptaminol hydrochloride administration on duration of weaning, defined as cessation of vasopressor support. There were 32 males (65%) and 17 females (35%). The mean age (± standard deviation) was 53.9 ± 22.2 years. Norepinephrine was the most commonly used vasopressor agent (73.4%). The comparison between two groups (with and without heptaminol hydrochloride) showed that two groups had the same epidemiologic, clinical, and biologic findings on intensive care unit admission. In our study, we found that the introduction of Heptamyl was associated with a quick decrease of dose of dopamine and norepinephrine in comparison with the Heptamyl-free group. By comparing the two groups, we found that the delay of catecholamine weaning was significantly faster for the dopamine (P = 0.008) and noradrenalin (P = 0.001) in the Heptamyl group. Finally, the intensive care unit mortality rate and the hospital mortality rate were significantly lower in the Heptamyl group. Our study shows a reduction in norepinephrine and dopamine weaning duration in septic patients enrolled in the heptaminol hydrochloride group.

Hair lightening in an hemodialysis patient treated by heptaminol (heptamyl).

Hair lightening occurred in a patient treated with heptaminol (heptamyl). This patient had chronic renal failure and had been undergoing hemodialysis since 2003. The hair hypopigmentation reversed after stopping the drug. The mechanism of the hair color modification is not understood.

Alteration of the L-type calcium current in guinea-pig single ventricular myocytes by heptaminol hydrochloride.

1. The effects of heptaminol on calcium current amplitude and characteristics were studied in single ventricular myocytes of guinea-pig by use of the whole cell configuration of the patch clamp technique. 2. A concentration-dependent decrease in ICa amplitude was observed. At heptaminol concentration as low as 10(-6) M, this effect was observed in only two cells (n = 6). At 10(-5) M the reduction of ICa was of 30 +/- 15% (n = 11). 3. The current recovery from inactivation at -40 mV holding potential (HP) seemed less sensitive to perfusion with heptaminol (greater than 10(-6) M). However, at -80 mV HP the overshoot of the recovery curve was decreased by heptaminol. 4. Both at -40 mV and -80 mV HP, heptaminol (10(-5) M) significantly increased the steady state inactivation of ICa. 5. As previously proposed by others to explain the effects of membrane active substances, the effects of heptaminol may result from alterations in cell membrane properties and possibly from an increase in intracellular free calcium ion concentration.

Action of heptaminol hydrochloride on contractile properties in frog isolated twitch muscle fibre.

1. Heptaminol stopped or delayed the progressive decline in tension which characterizes the phenomenon of fatigue in frog isolated twitch muscle fibre. 2. Heptaminol had no action on the sodium, potassium and calcium voltage-dependent ionic conductances. 3. The hypothesis of an action via an internal alkalinization was tested by comparison with the action of NH4Cl. Both substances increased the tension. 4. The action of heptaminol was suppressed in sodium-free (TRIS) solution or in the presence of amiloride while the action of NH4Cl was always observed. 5. These results could be explained by a stimulation of the Na/H antiport by heptaminol.

Local modulation of intracellular calcium levels near a single-cell wound in human endothelial monolayers.

An endothelial cell monolayer with a single mechanically lysed cell was used as a model to examine the extent, kinetics, and nature of local calcium mobilization in the neighborhood of a wound. Individual endothelial cells from confluent monolayers were mechanically lysed with a minutien needle coupled to a micromanipulator while producing no observable mechanical trauma to the neighboring cells. Changes in calcium levels in individual cells surrounding the wound site were monitored by epifluorescence microphotometry with the calcium-sensitive fluorophore indo-1. Individual cells adjacent to the wound site showed a substantial increase in their intracellular calcium levels, almost as high as the calcium levels attained by ionophore controls. The magnitude of intracellular calcium mobilization in confluent monolayers decreased with distance from the wound site, and those cells located at a radius greater than seven cells from the wound site showed no change in their calcium levels. Thus, lysis of a single cell resulted in calcium mobilization in approximately 200 neighboring cells. The time necessary for intracellular calcium to reach maximum levels also increased with distance from the wound site. Calcium mobilization was partly intracellular and was inhibited by disrupting cell-cell coupling or by increasing gap junction resistance by heptanol. This mobilization was greatly attenuated in subconfluent endothelial monolayers, and it was not observed in fibroblasts or smooth muscle cells; furthermore, the effect was defective in monolayers intentionally contaminated with smooth muscle cells. This study examines the extent and possible mechanisms of local endothelial activation near a microscopic endothelial wound.

Effects of heptaminol AMP amidate on T cell populations of peripheral blood lymphocytes and splenocytes in mice.

Heptaminol AMP amidate (HAA), a nucleotide derivative increased the percentage of T cell surface phenotypes on peripheral blood lymphocytes (PBL) of mice primed with sheep red blood cells. The T cell surface phenotypes Thy1.2, Lyt1, L3T4 and Lyt2 increased on the PBL of HAA administered mice to 136, 145, 144 and 153%, respectively over those on the PBL of control mice.

[Heptaminol chlorhydrate: new data]. / Le chlorhydrate d'heptaminol: nouvelles données.

Heptaminol hydrochloride is widely used for the treatment for orthostatic hypotension. It continues to elicit controversy as to its mode of action since Loubatières (1951) described its powerful inotropic action on an ischaemic preparation. Twenty five years later it has been suggested that this drug exerts its action by interfering with the release and uptake of catecholamines (Grobecker and Grobecker, 1976). The aim of this review was to report new experimental approaches and new data relative to the mode of action of heptaminol hydrochloride. In the rat, heptaminol hydrochloride prevented orthostatic hypotension, and increased the noradrenaline plasma concentration. In bovine chromaffin cells maintained in primary cultures, it was found to be a competitive inhibitor of noradrenaline uptake. This inhibition may partially account for its antihypotensive effect. The cardiotonic effect was studied using 31 P nuclear magnetic resonance spectroscopy and left ventricular pressure measurement in rat isolated hearts. The results suggest that the inotropic effect during moderate ischemia could be related to a restoration of internal pH possibly mediated by a stimulation of the Na+/H+ exchange. The satellite cells of adult skeletal muscles are myogenic cells involved in muscle regeneration. In culture, they differentiate into myotubes and thus mimic some aspects of the in vivo myogenic process. Heptaminol hydrochloride, which did not significantly alter the cloning efficiency or proliferation, increased the capacity of satellite cells to differentiate into myotubes.

Effect of tuamine, heptaminol and two analogues on uptake and release of catecholamines in cultured chromaffin cells.

The effects of tuamine (1-methylhexylamine), a sympathomimetic compound with hypertensive properties, heptaminol (6-amino-2-methyl-2-heptanol), an aliphatic amine with pressor properties, and two structural analogues of tuamine on high-affinity Na(+)-dependent noradrenaline uptake and on nicotine-evoked release were examined in bovine chromaffin cells maintained in primary culture for 3 to 6 days. Tuamine was found to be a potent competitive inhibitor of noradrenaline uptake with an effect similar to that of cocaine. Its inhibition constant (Ki) was 1.1 +/- 0.1 microM while Ki values of heptaminol, of 1-methylamino-5-pentanol oxalate and of 5-amino-2-methylhexanol oxalate, which were also found to be competitive inhibitors of noradrenaline uptake, were 60 +/- 2 microM, 260 +/- 28 microM and 48 +/- 76 microM, respectively. Tuamine, hepataminol and 5-amino-2-methyl-2-hexanol were also shown to be inhibitors of nicotine-induced release of catecholamines, with IC50 values of 26 +/- 2 microM, 650 +/- 11 microM and 500 +/- 10 microM, respectively. Tuamine and hepataminol did not inhibit noradrenaline release evoked by 59 mM K+, suggesting that it acts at a step prior to calcium entry. The pharmacological properties of heptaminol as an anti-hypotension agent may partially account for its inhibitory effect on catecholamine uptake and release.

[Heptaminol hydrochloride as an epithelium transporter]. / Heptaminol-chlorohydrate agit sur un épithélium transporteur.

Electrophysiological and transport effects induced by heptaminol hydrochloride were studied in frog epithelium. This tissue, which can easily be maintained in vitro, is a valuable model for studying sodium active transport with hormone-dependent characteristics that reproduce mammalian nephron behavior (notably in areas with tight gap junctions). The two following techniques were used: the Ussing short-circuit current method and the swept-frequency impedance measurement method. Our findings indicate the following. (i) Heptaminol hydrochloride significantly increases the short-circuit current and transepithelial polarization. (ii) This effect develops progressively as the molecule is introduced on the serous side (3Na+/2K+ active countertransport sites). Time to maximum development is approximately 20 min and the electrophysiological effect lasts from 60 to 90 min. (iii) The mean equivalent cationic current rise is larger in sulfate-Ringer (+23 +/- 4.6 microA, p less than 0.01) than in chloride-Ringer (+14 +/- 4.9 microA, p less than 0.05). The increase in short-circuit current is approximately 0.9 muequiv. cm-2 h-1 in sulfate-Ringer. (iv) The increase in mean polarization is greater in chloride (+21 +/- 6.2 mV, p less than 0.02) than in sulfate (+6 +/- 1.5 mV, p less than 0.01) following a diphasic effect on potential. (v) Changes in apical impedance Z are small (-454 +/- 323 omega, nonsignificant) compared with transepithelial resistance in sulfate (-1065 +/- 359 omega, p less than 0.05). (vi) Changes in membrane capacitance reflect changes in the membrane surface. However, no significant capacitance changes are produced in sulfate and chloride solution by heptaminol hydrochloride (-0.04 +/- 0.11 microF and 0.05 +/- 0.11 microF, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Moving average improves the signal-to-noise ratio of kinetic studies in magnetic resonance spectroscopy.

Moving average can be used to improve the signal-to-noise ratio of NMR kinetic studies. The method was tested on simulated spectra with time-dependent intensities or peak positions. It was then applied to a series of in vivo spectra, showing the pharmacological effect of heptaminol on the intracellular pH of perfused hearts.

Comparisons of heptaminol AMP amidate and dibutyryl cyclic AMP on murine splenocytes proliferation.

Hepataminol AMP amidate (HAA), a nucleotide derivative possessing immunopotentiating activities, inhibited the mitogen-induced proliferation of murine splenocytes in vitro at the higher concentrations. Concanavalin A-induced mitogenic response was inhibited to 65 and 15% of the control value by HAA at the concentrations of 10(-4) and 10(-3) M, respectively. HAA also inhibited phytohemagglutinin P and lipopolysaccharide-induced responses at the same concentrations. The pattern of inhibition of mitogen-induced responses by HAA at higher concentrations was found to be almost similar to that of dibutyryl cyclic AMP (DbcAMP). Both HAA and DbcAMP also inhibited the blastogenesis of spleen cells in one way mixed lymphocyte reaction.

Effects of heptaminol AMP amidate (HAA) on cyclic AMP level and mitogen-induced proliferation of murine spleen cells.

Heptaminol AMP amidate (HAA), a nucleotide derivative, was found to elevate the intracellular cyclic AMP (cAMP) level of cultured mice spleen cells in a time- and dose-dependent manner. Theophylline and imidazole, when added to the spleen cell culture simultaneously with HAA, respectively caused a further rise and a fall of the cAMP level increased by HAA alone. When comparatively higher doses of the T cell mitogen concanavalin A (Con A) were used in the culture, Con A-induced cell proliferation was mildly inhibited in the culture of spleen cells pooled from HAA administered mice in comparison to the culture of spleen cells pooled from saline treated mice. On the other hand, when another T cell mitogen phytohemagglutinin P (PHA) was used in different concentrations in the culture, there was a trend of enhanced cell proliferation in the culture of spleen cells pooled from HAA administered mice in comparison to the responses in the culture of spleen cells pooled from saline treated mice. The present results supported the previous findings that HAA-mediated immunopotentiation was closely related with a cAMP level elevating property of HAA, and the compound also enhanced the function of helper T cells.

Decrease in internal H+ and positive inotropic effect of heptaminol hydrochloride: a 31P n.m.r. spectroscopy study in rat isolated heart.

1. The cardiotonic effect of heptaminol hydrochloride (Hept-a-myl, Delalande) was studied using 31P-nuclear magnetic resonance (n.m.r.) spectroscopy and left ventricular pressure (LVP) measurements in rat isolated hearts. The possibility of this effect being mediated by an intracellular realkalinisation was tested. 2. Isolated hearts were perfused at 10 ml min-1 by the Langendorff method with Krebs-Henseleit solution at 37 degrees C and stimulated at 5 Hz. Mechanical activity was measured as variations of left ventricular pressure (LVP). 31P-n.m.r. spectra were recorded every 2 min. Changes in cardiac adenosine triphosphate (ATP), phosphocreatine (PCr) and inorganic phosphate (Pi) were followed and intracellular pH (pHi) was estimated from the chemical shift of Pi. 3. The effects of heptaminol were tested in different conditions: normoxia, moderate ischaemia, severe ischaemia, and moderate ischaemia in the presence of amiloride or guanidinium chloride as inhibitors of the Na-H exchange. 4. In normoxia, heptaminol induced a cyclic increase of systolic LVP, associated with an increase in Pi. No significant effect on pHi was observed. In changing from normoxia to moderate ischaemia, PCr and systolic LVP decreased; a mild intracellular acidification (pHi 6.96) was obtained. Heptaminol induced a restoration of pHi and increased LVP. In severe ischaemia, the realkalinization effect and the restoration of LVP induced by heptaminol were no longer observed. During moderate ischaemia, Na-H exchange inhibitors decreased pHi and LVP. Heptaminol applied in the presence of these inhibitors was unable to restore pHi and LVP. In severe ischaemia, the realkalinization effect and the restoration of LVP induced by heptaminol were no longer observed. During moderate ischaemia, Na-H exchange inhibitors decreased pHi and LVP. Heptaminol applied in the presence of these inhibitors was unable to restore pHi and LVP. 5. These results suggest that the positive inotropic effect of heptaminol during moderate ischaemia could be related to a restoration of internal pH, possibly mediated by a stimulation of the Na-H exchange.

Effects of heptaminol AMP amidate on suppressor and helper function of murine T cells.

Heptaminol AMP amidate (HAA), a newly developed nucleotide derivative, was found to restore the immunosuppression in mice due to the induction of suppressor T (Ts) cells by concanavalin A (Con A) (50 micrograms/body). HAA also inhibited Con A-mediated in vitro induction of Ts cells. On the contrary, the administration of HAA in mice primed with keyhole lympet hemocyanin (KLH) (30 micrograms/body) caused an enhanced induction of antigen specific helper T (Th) cells. Effects of HAA on Ts and Th cells were found to be dependent on their level of induction. The administration of HAA also increased the spleen cell number and augmented the plaque forming cell response to some extent in cyclophosphamide treated mice. The present results suggested that HAA-mediated immunopotentiation was possible by a combined suppressive effect on Ts cells and enhancing effect on Th cells.

[The effects of heptaminol chlorhydrate on neuromuscular transmission]. / Effets du chlorhydrate d'heptaminol sur la transmission neuromusculaire.

6-Amino-2-methyl-2-heptanol chlorhydrate, heptaminol chlorhydrate, blocks the response to indirect stimulation of the mouse diaphragm in vitro. This effect is due to a dose-dependent pre- and post-synaptic block of neuromuscular transmission starting at 1 mM heptaminol (HEPT). The complete block of neuromuscular transmission occurs at 10 mM. At 2 mM, the decrease in quantal size is more significant in the presence of d-tubocurarine than when the extracellular calcium is lowered. At this concentration, heptaminol also prolongs the depolarization time of the motor end plate potential. Slightly higher concentrations of heptaminol produce a decrease in quantal content. This latter effect is associated with an increase in synaptic delay.

Effect of heptaminol AMP amidate, a new nucleotide derivative, on in vitro humoral immunity.

Heptaminol AMP amidate (HAA), a newly developed derivative of 5'-AMP, was found to potentiate the in vitro primary humoral immune response against T cell-dependent antigen, sheep red blood cells, when HAA was present in the early phase of spleen cell culture. Such a potentiating effect was not found against T cell-independent antigens such as lipopolysaccharide (LPS), trinitrophenylated (TNP)-LPS and TNP-Ficoll. The pattern of HAA-mediated immunopotentiation was similar to that of dibutyryl cyclic AMP. When HAA was added to the culture simultaneously with theophylline and imidazole, the immunopotentiating effect of HAA was further augmented and suppressed, respectively. The present results suggested that HAA-mediated immunopotentiation might be in some way related to the intracellular level of cyclic nucleotides in the early phase of culture.

Immunopotentiating activity of a nucleotide derivative, heptaminol AMP amidate (HAA) in mice and spontaneously hypertensive rats (SHR).

The immunopotentiating activity of heptaminol AMP amidate (HAA), a new derivative of 5'-AMP, was examined in experimental animals. Anti-SRBC PFC activity and antibody titer values augmented for both of single and 4 days consecutive administrations in ICR male mice. The dose of 10 mg/kg was found to cause the maximum enhancement. In spontaneously hypertensive rats, with a state of immunosuppression, 10 days consecutive administrations of HAA at the dose of 10 mg/kg was found to increase significantly the anti-SRBC PFC and antibody titer values. From these results, it is tempting to suggest that HAA may possess an immunopotentiating activity.

[Experiences with drug therapy in association with ischaemic vascular disease of the fundus oculi (author's transl)]. / Erfahrungen mit medikamentöser Therapie bei Durchblutungsstörungen des Augenhintergrundes.

The action of Thilocombin was tested on various eye conditions classified in groups. Common to all six groups was the presence of ischaemic vascular disease with reduciton of central visual acuity. The results of long term treatment with Thilocombin were significant: in almost 60% of cases a lasting improvement of function could be achieved. In the remainder of cases worsening of the loss of vision could usually be arrested.