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2-Mercaptoethylguanidine and nicotinic receptors
DIFFERENTIAL EFFECT OF P - S E L E C T I N BLOCKADE ON THE VASCULAR RESPONSES TO CATHETER INJURY D.B, McNamara, I-L. Chen, A,N. Tenaglia, R.G. Wilkens, A.J. Buda. J. Rice, P.J. K~dowitz and D.L Akers Tutane Medical School, New Odeans, LA USA.
2-MERCAPTOETItYLGUANIDINE AND NICOTINIC RECEPTORS IM. Michailov, 2,1E. Neu, 2,1U. Welscher, 1W. Miiller, 2D. Weiss. IGSF-Inst. Strahlanbiol., Mfinchen; 2Inst. Zool., Univ. Restock; FRG j2-Mercaptoethylguanidine (MEG/AET, 100-400 mg/kg, i.p.) influences reactions of blood pressure (BP, mmHg) to acetylcholine (ACh), bradykinine and 5-HT (Strahlenther 151, 549, 1976; Proc Int Un Physiol Sci 13, 506, 1977). To examine further MEG influences on the cardiovascular system we recorded the BP (a. carotis) in anesthetized male Sprague Dawley rats (pentobarbital-Na: 40 mg/kg, urethane: 0.8 g/kg or chloralose: 50 mg/kg). In untreated animals with a mean BP of 105 ___ 16 nicotine (N: 60-170 #g/kg) induced a reversible presser test reaction (pR) of 12 _ 5 for N: 125/~g/kg (n=27) which persisted after adrenaleetomy (14 _+ 6, n = 10), hypophysectomy (10 _ 4, n=5), and also in spinal rats (mean BP 73.6 +_ 9.6, pR to N: 38 _+ 3, n=5). Higher doses of anesthetics converted the pR to N into a depressor reaction (dR). The cordial origin of an initial dR preeeeding the pR to N was ascertained by N/y9°-injection. Atropine, eserine, hexamethonium, mepyramine, and methysergide had no influence on pR and dR to N, while the ganglion- (guanethidine) and ll-adrenergic(dichlorisoprenaline) blocking agents (10-30 mg/kg) as well as cocaine (5 mg/kg) potentiated the pR or inverted the dR to N. MEG also potentiated the pR (243 ___ 67%, n=15) and inverted the dR to N. This aminothiol blocked the dR to peripheral, but converted the dR to central vagal electro-stimulation into a biphasic dR/pR. N (5-35 mg/kg s.c.) and MEG induced also a biphasic reaction to ACh (1-6 #g/kg). MEG potentiated the pR to DMPP (15-120 #g/kg), AHR-602 (0.1-1 mg/kg), and MCN-A-343 (25-100 /zg/kg). MEG effects appeared in normal and spinal rats. Conclusion: Similar to ganglion-stimulating agents, MEG excites the sympathetic neurons of the peripheral and central adrenergic nervous system by stimulation of nicotinic (and nonnicotinic) cholinoceptors, finally leading to BP reactions via an activation of adrenergic and other receptors of vascular myocytes as well as of endothel. MEG and other isothioureas strongly inhibit Ca++-independent isoform(s) of NO-synthase (Br J Pharmacol 114, 510, 1995): The importance of this inhibitory property for the ganglion-stimulating and radioprotective effects of these substances needs to be clarified.
Balloon catheter injury produces endothelial (ENDO) denudation and intimal hyperplasia (IF/). The neoENDO formed after injury exhibits altered histology and depressed ENDO-dependent relaxation to acetylcholine (ACh) - a btoassay for nitric oxide (NO) formation. As NO has been shown to attenuat~ [eukocyte adhesion, we tested the hypothesis that administration of a monoclona[ antibody (MAb) to the adhesion molecular P-selectin alters the response to catheter injury of the rabbit thoracic aorta. Immediately before and 12 hr after injury the MAb (PB 1.3, Cytel), 2 mg/kg, was given. Other groups rece'nted no injury (control) or injury with no treatment (NOTx). All animats were sacrificed 2 weeks after injury. Both NOTx and MAbtreated animals exhibited increased intimal areas (0.89+0.33 vs. 0.98+0.31 cm2). However, MAb-tmated animals exhibited improved histology as visualized by scanning electron microscopy but not improved AChstimulated rela}cation of vascular rings. These data suggest that early attenuation of leukocyte adhesion positively affects the appearance and metabolism of the neoENDO without affecting the development of [H.
RECEPTOR RESPONSIVENESS OF RAT MESENTERIC VASCULAR BED IN DIFFERENT STAGES OF NEUROGENESIS, Montagnan L M. Serio, M. A. Potenza. G. Mansi, G. De Salvatore, D. Mitolo-Chieppa.
STRUCTURE-ACTIVITY
OF
N-ARYLOXYALKYLAMINOALKYL-2 -
MEDICINAL CHEMISTRY OF Z 1 0 4 6 .
S. Montanari,P. Cavalleri,F. Santangelo,F. Marchini,F~Poechiari and C. Semeraro. Zambon Group Spa, Via L. Del Duca 10 - Bresso (Milan) Italy
Institute of Pharmacology, Policlinico, 70124 Bad, Italy. Some investigators have studied the ontogenesis of cardiac and vascular adrenergic receptors correlating it with sympathetic neuronal development. In the neonatal rat, the cardiac-simpathetic axis is nonfunctional during the 1st week of postnatal life; over the ensuing 2 to 3 weeks, simpathetic function undergoes major developmental changes. The present study, cari-ied out on rat mesenteric vascular bed, evaluated adrenoceptor responsiveness in comparison with that of other receptors. The experiments were performed on rat groups of different ages: 5-7, 11-14, 16-18, 20-22 days, using 60-day rats as controls. The variation of the perfusion pressure achieved by in bole administration (100 ~tl/30 sec) of receptor agonists, as NE, ACh, 5-HT, ISO, DA was recorded. Dose-response curves were constructed and PD 2 value (-log mg DE5o) calculated. Furthermore, the response to perivascular nervous stimulation (PNS), before and after treatment with TTX, was tested. Results showed that at 5-7 days the response to PNS was TTX-resistant; it was probably evoked by muscolsx stimulation. At 11-14, 16-18, 20-22 days the response to PNS was only partially blocked by TTX and this block increased with age. In the controls the response to PNS was completely blocked by TTX. NE contraction was present since 5-7 days; this group showed statistically significant supersensitivity compared to controls (PDz: 3.46_+0.05 vs 2.83i-0.02; P<0.01). 5-HT contraction, DA and ISO relaxation were also present since 5-7 days. No significant difference in the respective PD2 values of these agouists was observed with age. ACh relaxation, absent at 5-7 days, set out on 9th day, then remaining unchanged. At 5-7 days ACh evoked a contractile response that disappeared after 16th day. In conclusion, these findings suggest that during the 1st week, before the onset of functional irmervation, DA, 5-HT and ISO receptors exist and they function as in adults (60 days). NE receptor shows supersensitivity; ACH receptor is immature (only contractile effect) and the typical response (only relaxant effect) appears from 18th day, when the nervous control is nearly complete. This work was supported by grants from MURST 40% and 60% to DMC.
Dopamine (DA) is involvedin a wide variety of both central and peripheral functions [I,2]. It has been demostratedthat there are two subfamiliesof dopamine receptors called Dl-like and D2.1ike with each group comprising several molecular isoforms [3]. Stimulatiunof these receptors induces renal and peripheral vasodilation diuresis and nalrluresis [4]. However, DA and the eonformatianallyblocked N,N-dipropyl5,6-dihydroxy-2-aminotetralhle(DP-ADTN)does not show a marked specificitysince they also act at O~l-adrenergicreceptor. The aim ofthls work is to obtain more specific dopaminergic agents, by studying the class of compoundsrepresented b'y the general formula. Structure-activity relationship evaluation shows the importance of the consideredmolecularmodifications,particularlythe appropriatesubstitutiunon either nitrogen atom. Moreover, the 5,6-dthydroxy substitution elicits higher potency than the 6,7-dihydroxyrelated compound, As expected, the activity resides mainly in the enantiomerof (S) absoluteconfiguration.From this study, Z1046 e.g. (S)-6-[[6-[[2-(2methoxyphenoxy)ethyl]amino]-5,6,7,8-tetrahydro-1,2-napthtaienedioldihydroehloride emergedas the most promisingcompound. A I(
IHOI HO
All(
OCH~
"(CH~)mN --(CHa) E-
.2HC1
[1] L.I. Goldberg Pharm. Rev, 24 1, 1972. [2] T.L. Sourkes Psychoneuroendocrinology I_, 69, 1975. [3] P.A. Jose R.A. Felder, F.J. Monsma, D.R Sibley and H. M. Mouradima in Cardiovascular and Renal Actions of Dopamine, P. Soares da Silva Eds., 1993, 51-61. [4] R.A. Hahn, J. R. Wardell, H.M., Saran and P.T. Ridley J. Pharrn. Exp. Ther. ~
- -
RELATIONSHIP
AMINOTETRALINE DERIVATIVES AS PERIPHERAL DOPAMINERGIC AGONISTS,
2 4 9
- -
305,1982.
2-MERCAPTOETItYLGUANIDINE AND NICOTINIC RECEPTORS IM. Michailov, 2,1E. Neu, 2,1U. Welscher, 1W. Miiller, 2D. Weiss. IGSF-Inst. Strahlanbiol., Mfinchen; 2Inst. Zool., Univ. Restock; FRG j2-Mercaptoethylguanidine (MEG/AET, 100-400 mg/kg, i.p.) influences reactions of blood pressure (BP, mmHg) to acetylcholine (ACh), bradykinine and 5-HT (Strahlenther 151, 549, 1976; Proc Int Un Physiol Sci 13, 506, 1977). To examine further MEG influences on the cardiovascular system we recorded the BP (a. carotis) in anesthetized male Sprague Dawley rats (pentobarbital-Na: 40 mg/kg, urethane: 0.8 g/kg or chloralose: 50 mg/kg). In untreated animals with a mean BP of 105 ___ 16 nicotine (N: 60-170 #g/kg) induced a reversible presser test reaction (pR) of 12 _ 5 for N: 125/~g/kg (n=27) which persisted after adrenaleetomy (14 _+ 6, n = 10), hypophysectomy (10 _ 4, n=5), and also in spinal rats (mean BP 73.6 +_ 9.6, pR to N: 38 _+ 3, n=5). Higher doses of anesthetics converted the pR to N into a depressor reaction (dR). The cordial origin of an initial dR preeeeding the pR to N was ascertained by N/y9°-injection. Atropine, eserine, hexamethonium, mepyramine, and methysergide had no influence on pR and dR to N, while the ganglion- (guanethidine) and ll-adrenergic(dichlorisoprenaline) blocking agents (10-30 mg/kg) as well as cocaine (5 mg/kg) potentiated the pR or inverted the dR to N. MEG also potentiated the pR (243 ___ 67%, n=15) and inverted the dR to N. This aminothiol blocked the dR to peripheral, but converted the dR to central vagal electro-stimulation into a biphasic dR/pR. N (5-35 mg/kg s.c.) and MEG induced also a biphasic reaction to ACh (1-6 #g/kg). MEG potentiated the pR to DMPP (15-120 #g/kg), AHR-602 (0.1-1 mg/kg), and MCN-A-343 (25-100 /zg/kg). MEG effects appeared in normal and spinal rats. Conclusion: Similar to ganglion-stimulating agents, MEG excites the sympathetic neurons of the peripheral and central adrenergic nervous system by stimulation of nicotinic (and nonnicotinic) cholinoceptors, finally leading to BP reactions via an activation of adrenergic and other receptors of vascular myocytes as well as of endothel. MEG and other isothioureas strongly inhibit Ca++-independent isoform(s) of NO-synthase (Br J Pharmacol 114, 510, 1995): The importance of this inhibitory property for the ganglion-stimulating and radioprotective effects of these substances needs to be clarified.
Balloon catheter injury produces endothelial (ENDO) denudation and intimal hyperplasia (IF/). The neoENDO formed after injury exhibits altered histology and depressed ENDO-dependent relaxation to acetylcholine (ACh) - a btoassay for nitric oxide (NO) formation. As NO has been shown to attenuat~ [eukocyte adhesion, we tested the hypothesis that administration of a monoclona[ antibody (MAb) to the adhesion molecular P-selectin alters the response to catheter injury of the rabbit thoracic aorta. Immediately before and 12 hr after injury the MAb (PB 1.3, Cytel), 2 mg/kg, was given. Other groups rece'nted no injury (control) or injury with no treatment (NOTx). All animats were sacrificed 2 weeks after injury. Both NOTx and MAbtreated animals exhibited increased intimal areas (0.89+0.33 vs. 0.98+0.31 cm2). However, MAb-tmated animals exhibited improved histology as visualized by scanning electron microscopy but not improved AChstimulated rela}cation of vascular rings. These data suggest that early attenuation of leukocyte adhesion positively affects the appearance and metabolism of the neoENDO without affecting the development of [H.
RECEPTOR RESPONSIVENESS OF RAT MESENTERIC VASCULAR BED IN DIFFERENT STAGES OF NEUROGENESIS, Montagnan L M. Serio, M. A. Potenza. G. Mansi, G. De Salvatore, D. Mitolo-Chieppa.
STRUCTURE-ACTIVITY
OF
N-ARYLOXYALKYLAMINOALKYL-2 -
MEDICINAL CHEMISTRY OF Z 1 0 4 6 .
S. Montanari,P. Cavalleri,F. Santangelo,F. Marchini,F~Poechiari and C. Semeraro. Zambon Group Spa, Via L. Del Duca 10 - Bresso (Milan) Italy
Institute of Pharmacology, Policlinico, 70124 Bad, Italy. Some investigators have studied the ontogenesis of cardiac and vascular adrenergic receptors correlating it with sympathetic neuronal development. In the neonatal rat, the cardiac-simpathetic axis is nonfunctional during the 1st week of postnatal life; over the ensuing 2 to 3 weeks, simpathetic function undergoes major developmental changes. The present study, cari-ied out on rat mesenteric vascular bed, evaluated adrenoceptor responsiveness in comparison with that of other receptors. The experiments were performed on rat groups of different ages: 5-7, 11-14, 16-18, 20-22 days, using 60-day rats as controls. The variation of the perfusion pressure achieved by in bole administration (100 ~tl/30 sec) of receptor agonists, as NE, ACh, 5-HT, ISO, DA was recorded. Dose-response curves were constructed and PD 2 value (-log mg DE5o) calculated. Furthermore, the response to perivascular nervous stimulation (PNS), before and after treatment with TTX, was tested. Results showed that at 5-7 days the response to PNS was TTX-resistant; it was probably evoked by muscolsx stimulation. At 11-14, 16-18, 20-22 days the response to PNS was only partially blocked by TTX and this block increased with age. In the controls the response to PNS was completely blocked by TTX. NE contraction was present since 5-7 days; this group showed statistically significant supersensitivity compared to controls (PDz: 3.46_+0.05 vs 2.83i-0.02; P<0.01). 5-HT contraction, DA and ISO relaxation were also present since 5-7 days. No significant difference in the respective PD2 values of these agouists was observed with age. ACh relaxation, absent at 5-7 days, set out on 9th day, then remaining unchanged. At 5-7 days ACh evoked a contractile response that disappeared after 16th day. In conclusion, these findings suggest that during the 1st week, before the onset of functional irmervation, DA, 5-HT and ISO receptors exist and they function as in adults (60 days). NE receptor shows supersensitivity; ACH receptor is immature (only contractile effect) and the typical response (only relaxant effect) appears from 18th day, when the nervous control is nearly complete. This work was supported by grants from MURST 40% and 60% to DMC.
Dopamine (DA) is involvedin a wide variety of both central and peripheral functions [I,2]. It has been demostratedthat there are two subfamiliesof dopamine receptors called Dl-like and D2.1ike with each group comprising several molecular isoforms [3]. Stimulatiunof these receptors induces renal and peripheral vasodilation diuresis and nalrluresis [4]. However, DA and the eonformatianallyblocked N,N-dipropyl5,6-dihydroxy-2-aminotetralhle(DP-ADTN)does not show a marked specificitysince they also act at O~l-adrenergicreceptor. The aim ofthls work is to obtain more specific dopaminergic agents, by studying the class of compoundsrepresented b'y the general formula. Structure-activity relationship evaluation shows the importance of the consideredmolecularmodifications,particularlythe appropriatesubstitutiunon either nitrogen atom. Moreover, the 5,6-dthydroxy substitution elicits higher potency than the 6,7-dihydroxyrelated compound, As expected, the activity resides mainly in the enantiomerof (S) absoluteconfiguration.From this study, Z1046 e.g. (S)-6-[[6-[[2-(2methoxyphenoxy)ethyl]amino]-5,6,7,8-tetrahydro-1,2-napthtaienedioldihydroehloride emergedas the most promisingcompound. A I(
IHOI HO
All(
OCH~
"(CH~)mN --(CHa) E-
.2HC1
[1] L.I. Goldberg Pharm. Rev, 24 1, 1972. [2] T.L. Sourkes Psychoneuroendocrinology I_, 69, 1975. [3] P.A. Jose R.A. Felder, F.J. Monsma, D.R Sibley and H. M. Mouradima in Cardiovascular and Renal Actions of Dopamine, P. Soares da Silva Eds., 1993, 51-61. [4] R.A. Hahn, J. R. Wardell, H.M., Saran and P.T. Ridley J. Pharrn. Exp. Ther. ~
- -
RELATIONSHIP
AMINOTETRALINE DERIVATIVES AS PERIPHERAL DOPAMINERGIC AGONISTS,
2 4 9
- -
305,1982.