摘要:

Summary—It has been reported that dipyridamole and some benzodiazepines potentiate the responses to adenosine in peripheral organs and in particular in the guinea pig isolated atria or trachea by inhibition of adenosine uptake and/or metabolism. In this study, we have examined the sensitization of guinea pig isolated trachea to relaxant responses to adenosine produced by dipyridamole, diazepam and 3 compounds chemically unrelated to benzodiazepines but which display selective agonistic activity towards the central (zolpidem and zopiclone) or peripheral (alpidem) type benzodiazpine receptors. In preparations under spontaneous tone and in the absence of adenosine, dipyridamole (10−5M) and diazepam (10−5–10−4M), alpidem (3 times 10−6M‐10−5M) and zopiclone (10−6–10−4M) induced a relaxation of the airway smooth muscle. In addition, diazepam (10−4M) attenuated the phasic response to histamine (10−5M). Dipyridamole (10−5M) and diazepam (10−4M) respectively produced a 56.2 and 32.4‐fold potentiation of adenosine relaxant effects. Alpidem (10−6–10−5M), zolpidem (10−6–10−4M) and zopiclone (10−6–10−4M) were without any significant effect on the adenosine concentration—response curves. Moreover, alpidem, zolpidem, and zopiclone did not modify the 2‐chloroadenosine dose‐response curves nor the diazepam induced sensitization of adenosine‐induced relaxation. In conclusion, adenosine sensitization of the guinea pig isolated trachea caused by diazepam might involve a peripherla benzodiazpine receptor subtype coupled to a nucleoside transporter system which is different from those recogni

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1991.tb00696.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary—The role of pertussis toxin‐sensitive guanine nucleotide regulatory proteins (G‐proteins) in the signal transduction process(es) involved in postjunctional vascular α1‐adrenoceptor‐mediated vasoconstriction produced by the full agonist, cirazoline, and the partial agonist, (‐)‐dobutamine, have been investigated in the cardiovascular system of the pithed rat. Pertussis toxin pretreatment (50 μg/kg, iv, 3 days prior to experimentation) only slightly inhibited the pressor response of cirazoline, and the degree of inhibition produced by pertussis toxin was roughly equivalent to the inhibition produced by the calcium channel antagonist, nifedipine (1 mg/kg, ia). In contrast, pertussis toxin pretreatment produced marked inhibition of the α1‐adrenoceptor‐mediated pressor response to the partial agonist, (‐)‐dobutamine, and this large degree of inhibition was qualitatively and quantitatively similar to the degree of inhibition produced by nifedipine. The differential pattern of inhibition of full and partial α1‐adrenoceptor agonists by pertussis toxin suggests that the vasoconstrictor response of an α1‐adrenoceptor partial agonist, which is more dependent upon the translocation of extracellular calcium than a full agonist, as evidenced by its sensitivity to inhibition by nifedipine, involves a pertussis toxin‐sensitive G‐protein that couples the α1‐adrenoceptor to the calcium channel. Furthermore, for α1‐adrenoceptor‐mediated vasoconstriction by full agonists with high intrinsic efficacy, which involves both intracellular and extracellular pools of calcium, and particularly the former, pertussis toxin only inhibits that component of the α1‐adrenoceptor response which is dependent upon the translocation of extracellular calcium, accounting for the limited degree of inhibition of the response to cirazoline by pertussis toxin and by nifedipine. By inference, the other component of the α1‐adrenoceptor‐mediated pressor response to a full agonist, which is dependent upon the mobilization of intracellular stores of calcium through a process believed to involve the activation of phospholipase C, likely utilizes a pertussis toxin insensitive G‐protein that is distinct from that which we propose couples the α1‐adrenoceptor to the calcium channel. We conclude, therefore, that the α1‐adrenoceptor in the vasculature of the pithed rat may be coupled to 2 distinct G‐proteins, only one of which is sensitive to inhibition by pertussis toxin and links the α1‐adrenoceptor to the membrane calcium channel, and w

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1991.tb00697.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary—The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03–3.0 mg/kg, iv) produced a dose‐dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose‐dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the β1adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the β2adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both β1and β2adrenoceptors at antihypertensive doses, with modest selectivity being observed for the β1adrenoceptor subtype. Carvedilol produced significant inhibition of the α1adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the α2adrenoceptor mediated pressor response to B‐HT 933, suggesting that carvedilol is also an α1adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY‐K‐8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previousin vitrostudies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the α1adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective β adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of β and α1adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of β1, β2, and α1adrenoceptors, and also of calcium channels in vascular smooth muscle. The β1adrenoceptor blocking properties of carvedilol appear to account for the lack of reflex tachycardia that occurs in response to baroreceptor activation, and the arterial vasodilation appears to result largely from selective α1adrenoceptor blockade, with little or no contribution being derived

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1991.tb00698.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary—Bismuth encephalopathies appeared in the mid‐seventies in France and concerned about 1000 people and led to a fatal outcome in 70 cases. Responsibility of Bi was clearly confirmed by the disappearance of the intoxication after prescription of drugs containing Bi had been more tightly regulated. Since the implication of a substance increasing the intestinal absorption of Bi has been suspected, we studied the concentrations of Bi in the tissues of rats who had been treated with bismuth nitrate basic 400 mg/kg per d for one month with and without an intake of a chelating agent added to the drinking water at a concentration of 10 mmol/1. The chelating agents tested were ethylenediaminetetraacetic acid (EDTA), nitriloacetic acid (NTA) and tripolyphosphate (TPP), cysteine and diethyldithiocarbamate (DEDTC). Cysteine and DEDTC gave the highest increase of Bi in tissues but with a wide dispersion of levels. However, even in the rats with the highest levels of Bi, there were no behavioral problems. EDTA induced an increase of Bi in kidney, brain and bone and NTA in kidney but there was no obvious sign of toxicity. We did not succeed in reproducing in rats the Bi toxicity observed in patients some years

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1991.tb00699.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary—Ponsinomycin is a new macrolide antibiotic. Its effect on DHE pharmacokinetics was investigated in this study. Twelve young healthy volunteers received a single 9 mg oral dose of DHE before and on the 8th day of treatment (800 mg twice daily) with ponsinomycin. DHE was assayed in plasma by RIA. Because of low plasma levels, only peak concentrations could be accurately compared for a ponsinomycin effect. We observed a 3–40‐fold increase in maximum DHE plasma levels in the majority of cases and a much more important effect on one occasion, when DHE was administered in the presence of ponsinomycin. These data are consistent with an increase of DHE bioavailability in the presence of ponsinomycin, probably related to a reduction of its first‐pass elimination. This pharmacokinetic interaction is likely to have clinical consequences and administration of ponsinomycin should be avoided in patients treated orally w

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1991.tb00700.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary—Heterogeneous diffusion of some antibiotics into fibrin rich infectious processes is one explanation of the difficulty to cure infections such as endocarditis. Ceftriaxone is a β lactam antibiotic, potentially useful due to a broad spectrum of activity and its long elimination half‐life. We investigated by means of autoradiography the diffusion of labelled ceftriaxone into large infected cardiac vegetations obtained in a rabbit model of endocarditis. Ten d after infection 250 μCi14C ceftriaxone was injected over 30 min. Thirty min after the end of infusion (T30) vegetation/blood radioactivity ratio was 0.58 ± 0.4 (n= 3). At T200, radioactivity decreased approximatively 3‐fold, in blood and in vegetations simultaneously. Autoradiography showed that at T30, ceftriaxone was 20–30 times more concentrated at the periphery of vegetation than in the core. Autoradiography obtained at T200 showed a progressive diffusion toward the core. The diffusion gradient may explain the fact that high local concentrations are necessary to sterilize vegetations. The pattern of diffusion of antibiotics in fibrin is an important pharmacokinetic parameter for predictingin vi

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1991.tb00701.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary—Probing the regional distribution and affinity of receptors in the brain,in vivo, in human and non human primates has become possible with the use of selective ligands labelled with positron emitting radionuclides and positron emission tomography (PET). After describing the techniques used in positron emission tomography to characterize a ligand receptor binding and discussing the choice of the label and the limitations and complexities of thein vivoapproach, the results obtained in the PET studies of various neurotransmission systems: dopaminergic, opiate, benzodiazepine, serotonin and cholinergic systems are reviewe

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1991.tb00702.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY