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F Conci

Publications and source records attributed to F Conci.

At least 19 recordsLinked to original sources
PubMed1996

Affinity of angiotensin I-converting enzyme (ACE) inhibitors for N- and C-binding sites of human ACE is different in heart, lung, arteries, and veins.

Angiotensin-converting enzyme (ACE) has two enzymatically active domains: a C-domain in the carboxy terminal region and an N-domain in the amino terminal region. We based the pharmacologic characterization of these sites on the rat testis-lung model. In testis, only a truncate form of ACE is present (C-site), whereas both N- and C-sites are present in lung. In this model, captopril was shown to be N-selective and delaprilat to be C-selective. Ro 31-8472, a cilazapril derivative, and enalaprilat proved to be not site selective. We used these drugs to evaluate the affinity of C and N sites in various human tissues involved in the cardiovascular actions of ACE and used [125I]Ro31-8472 as ligand. The number and affinity of ACE binding sites were 17,680 +/- 2,345 fmol/mg protein (Kd = 0.32 +/- 0.04 nM) in lung, 560 +/- 65 (Kd = 0.36 +/- 0.05 nM) in heart, 237 +/- 51 (Kd = 0.37 +/- 0.06 nM) in coronary artery, 236 +/- 63 (Kd = 0.14 +/- 0.05 nM) in saphenous vein, and 603 +/- 121 (Kd = 0.50 +/- 0.06 nM) in mammary artery. The affinity (pKi) of captopril for the N sites ranged from 9.40 +/- 0.14 (lung) to 8.41 +/- 0.10 (coronary artery). The affinity for the C-site by delaprilat ranged from 9.97 +/- 0.15 (coronary artery) to 9.10 +/- 0.14 (mammary artery). Therefore, the affinity of C- and N-sites of ACE for ACE inhibitor (ACEI) drugs is different according to the organ involved. Because ACE is a glycosylated enzyme and glycosylation is organ dependent, we suggest that organ-specific glycosylation affects the binding characteristics of ACE inhibitors to N- or C-site of human tissular ACE.

Adult↗
PubMed1995

Pharmacologic data reveal the heterogeneity of angiotensin-converting enzyme according to its source (lung versus heart).

Angiotensin-converting enzyme (ACE) has 2 different active sites: a C-site (in the carboxy terminal region) and an N-site (in the amino terminal part). Some ACE inhibitors have a relatively greater affinity for the C-sites, whereas others bind to the 2 sites with equal affinity. The different ontogenesis of lung and heart endothelial cells can be related to binding differences to the C- and N-sites. We labeled Ro31-8472, a clizapril derivative, which has the same affinity for the 2 ACE sites. Binding of 125I-Ro31-8472 to human left ventricle and lung plasma membranes was saturable, inhibited by ethylene diaminetetraacetic acid and displayed affinities of 360 +/- 41 pM in heart and 320 +/- 51 pM in lung. For captopril the Hill slope was 0.57 +/- 0.03 for heart and 0.48 +/- 0.05 for lung; for delaprilat, a nonsulfhydryl analogue of captopril, the slope was 0.43 +/- 0.05 for heart and 0.55 +/- 0.05 for lung. These drugs were characterized by biphasic competition isotherms. The Hill slope of enalaprilat was 1.01 +/- 0.06 for heart and 0.93 +/- 0.06 for lung, and Ro31-8472 had a slope of 0.97 +/- 0.04 for heart and 0.93 +/- 0.03 for lung. The affinity of ACE inhibitors with Hill slope different from unity varied according to the source of ACE; in fact, delaprilat had greater affinity for the high-affinity sites of heart than lung (pKi, 9.89 and 9.47, respectively), whereas captopril had greater affinity for the high-affinity sites of lung than heart (9.40 and 8.85, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Angiotensin converting enzyme binding sites in human heart and lung: comparison with rat tissues.

1. Angiotensin converting enzyme (ACE), a dipeptidyl carboxypeptidase which catalyzes the final activation step in the formation of angiotensin II, was identified by radioligand studies in rat heart and lung. In this work we identified ACE binding sites in human left ventricle and lung by radioligand binding using the ACE inhibitor [3H]-ramiprilat in all tissues tested was saturable, temperature and zinc-dependent, and inhibited by EDTA. In human left ventricle homogenate we found a density of binding sites of 121 +/- 15 fmol mg-1 protein (n = 4) with an affinity (Kd) of 850 +/- 55 pM, whereas in rat left ventricle the same values were 23 +/- 4 fmol mg-1 protein and 315 +/- 30 pM, (n = 4), respectively. 3. [3H]-ramiprilat binding to rat (n = 4) and human lung (n = 4) showed a binding site density of 2132 +/- 155 and 1085 +/- 51 fmol mg-1 protein respectively with an affinity of 639 +/- 54 and 325 +/- 22 pM. The lung:heart ratio of ACE binding site density was about 9:1 in man and 100:1 in rat. 4. The binding affinities of 13 ACE inhibitors were evaluated on human heart and lung: the drugs tested showed a wide range of affinities for the ACE binding sites in both tissues, and the affinity for lung was significantly greater than for heart for most of the drugs. 5. The greater potency of some ACE inhibitors in displacing [3H]-ramiprilat in human lung compared with the heart indicates differences between ACE binding sites in these tissues and suggests the possibility of a selective organ-targeted therapeutic approach.

Adult↗
PubMed1991

Effects of diazepam on nociception in rats.

Acute i.p. injection of diazepam (1 mg/kg) resulted in a moderate increase in the tail-flick latency in rats. Tolerance to this diazepam effect developed after 10 days of diazepam treatment (1 mg kg-1 day-1). The benzodiazepine antagonist Ro 15-3505 only partially reversed the effect of diazepam on nociception. Naloxone (5 mg/kg i.p.) failed to affect the effect of diazepam on nociception, while the kappa antagonist MR 2266 fully antagonized the diazepam-induced increase of the tail-flick latency. Diazepam injected intracerebroventricularly (1, 5, 20 micrograms/rat) did not alter basal nociceptive threshold, however, diazepam injected intrathecally (20 micrograms/rat) prolonged the tail-flick latency. Furthermore, intracerebroventricular injection of muscimol partially antagonized the i.p. diazepam-induced increase of the tail-flick latency. These results suggest that benzodiazepine receptor sites are partially involved in the effect of diazepam on nociception and indicate that an indirect kappa-opioid-receptor-mediated mechanism may be involved. The anatomical site of diazepam action on tail-flick latency seems to be at the spinal level. Descending axons to the spinal cord from brain areas reached by intracerebroventricular injection of muscimol seem to modulate the effect of diazepam effect on nociception.

Animals↗
PubMed1989

Changes in spinal reflex excitability in brain-dead humans.

The excitability of proprio- and exteroceptive spinal reflexes was monitored electrophysiologically and clinically during the occurrence of brain death (BD) in 8 patients. After a period of total reflex unresponsiveness, the soleus H reflex attained a steady-state excitability level in 2-6 h. The recovery cycle of this response regained its normal shape at 10-20 h. The threshold of the cutaneous reflex evoked in the biceps femoris by electrical stimulation of the sural nerve had become normal in 4-13 h, although the response displayed an abnormal multi-component pattern. Digital responses to mechanical stimulation of the foot sole were evident after 6-8 h. Knee and ankle jerks were never evoked during the time of monitoring. The time-courses of the changes in excitability were not directly correlated with the fall in the blood pressure which may occur during BD. It is concluded that the human spinal cord reacts to BD with a spinal shock, characterized by sequential recovery of reflex transmission. The overall timing of this process appears to be much shorter than that previously described for the spinal shock following traumatic transection of the cord, but the latter was never studied in the earliest phases.

Adult↗
PubMed1987

Zopiclone potentiates the antinociceptive effect of morphine in rats.

The antinociceptive effect of morphine, as determined by the tail-flick test, was dose-dependently increased by the intraperitoneal injection of zopiclone. The benzodiazepine antagonists Ro 15-1788 (flumazepil) and Ro 15-3505, when intraperitoneally injected, significantly antagonized the effect of intraperitoneal injection of zopiclone on morphine antinociception. Intrathecal injection of zopiclone potentiated morphine antinociception, while the intracerebroventricular injection of zopiclone failed to enhance morphine antinociception and the intracerebroventricular injection of flumazepil to antagonize the intraperitoneal-zopiclone-induced increase in morphine antinociception. These results suggest that benzodiazepine sites are specifically involved in the potentiating effect of zopiclone on morphine antinociception. The anatomical locations of the receptors involved seem to be at the spinal level.

Animals↗
PubMed1986

Viscero-somatic and viscero-visceral reflexes in brain death.

Little is known about spinal visceral reflexes in brain-dead man, although they have been described in experimental animals. In 1983, 25 brain-dead individuals were observed during donor nephrectomy. It was confirmed that some of these donors, without higher centre modulation and not under significant pharmacological influence, had viscero-somatic motor reflexes and viscero-visceral cardiovascular reflexes.

Adolescent↗
PubMed1979

[Circulatory disorders and acupuncture].

The present study was designed to examine whether acupuncture is useful in the treatment of some disorders of the vascular system as the thromboangiitis obliterans of the extremities, the Raynaud's disease and in the therapy of ulcers by venous stasis. From the data presented it appears that acupuncture is effective in releasing the arterial spasm and especially in increasing the circulation in collateral vessels. In order to prove the efficiency of acupuncture in the above disorders, the response to acupuncture was compared with that obtained by a pharmacological treatment with lumbar paravertebral block.

Acupuncture Therapy↗
PubMed1976

[Acupuncture analgesia in experimental animals].

Main experimental works on acupuncture analgesia (A.A.) have been examinated and a technique to perform A.A. in rabbits has been described. Furthermore an anatomic study of acupuncture loci used has been given. It is suggested that several mechanisms are involved in A.A., not only limited to stimuli on the posterior horns, but extending to higher levels.

Acupuncture Therapy↗