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Calcium channel blockers modulate gluco-corticoid receptors under hypovolemic shock
CALCIUM CHANNEL BLOCKERS MODULATE GLUCOCORTICOID RECEPTORS UNDER HYPOVOLEMIC SHOCK Lyudmlla M. Kozhevnikova, Yurlj V. Arkhipsnko, Pjotr P. Gollkov 6 Nina Yu. Nlkolssva. Instltuts of General Psthology and Psthophyslology, N.V.Skllfosovsky Institute of Emsrgency Msdlcins, Moscow, Russia. The effects of calcium channel blockers on the functioning of cytosolic glucocorticoid receptors (GR) in hemorrhagic shock have been studied. The function of GR was studied in rat liver cytosol using radioligand methods with labelled steroid ligands possessing high spaciftc activities. The densities of types I and II GR as well as association and dissociation rate constants for ligand-receptor complexes were determined by Scatchard analysis. Blood corlicosterone levels were measured with the help of radioimmunoassay kits. It was found that compound A-l from the substituted pyrrole group (3 mg/kg) and nifedipin (Nf, 0.03 mglkg) activated the shock-induced function of type II GR, whereas verapamil (VP, 0.25 mglkg) inhibited it. A-i and Nf restored the biosynthetic activity of the liver under shock. Irrespective of the concentrations used (lo’*-I@’ M), these drugs did not influence the binding of the labelled ligand to type II receptors but produced pronounced dose-dependent effect on the function of type Ill receptors. Thus, Nf increased manyfold in the density of these receptors in rat liver cytosol, while Vp decreased
it.
Both
Nf
concentrations
effect. Compound
and
Vp
decreased
in the blood which
elevated testifies
EFFECTS OF PERiNOOPRlL ON CARDIOMYOPATHY IN t32-ADRENERt3lC RECWTOR OVEREXPRESSING MICE: IYFONTANCE OF GENDER Mwk T. Kmwwszyn, XkolyRno M Anthony M. Dart, Xlao.~un DLL Baker Mdlal Rwrrch Institute, Malbourm, Au&alla. CardiaC owr+n-aukn of BZ-Sdremrgk rewpbm @?AR) In mka by 200 fokl resub in e fibrcdc camfhy, wntrkuler remcdefling. heart hilure and pmmslum d&h. Thb model Is stile for study&g the mechsnkms of aotkn and efksoy of arrrent thsrqMc drugs. We postubfed thel pedndoprif. en Angii C~ Enzyme (ACE) .Mibii, would bs bsrwlkhl in tlw p2AR ovar~i mica. METHODS: 46 p2AR lransgank mke warn studkd for 9 months, starUng at 6 mm of age. 20 WAR mke (12 mab 6 lemab) rewlwd peri&pdl in binking water, at a dose ofO.3- 0.4mgIkg/day and another28 animals (13 each of male and femak?) swwd as conI&. Animsls wara inspected daily and their water tmbnent (6mth) and at 9, i2 and 15 moifhi &ags.besd anlmafs were examined b determine oause of death, tibia1 length and weight of vital organs. Heart8 were kept far histological exsminstlon. RESULTS: All groups ahowed progmaaiva mdvction In fraclknal shortening (FS). but at 12 months ths FS wss better preserved in untreated females vs. malea (28 *3 vs. 16 Kf!% pa.05). The bansfit of psrindopril wss hiihly genderdependent. Males did not havs a survival bsneiit. w impmvemsnt in FS. Treated females had slgnl6oanlly batter ruwival and a raducsd haart weight at the end of the sluby. (Mb). &though tJwre was no sign’ficant knprovement in FS vs. ccnlml females (30.4 k2.1 vs. 27.6 *3%).
cortiwsterone
to their antistressory
A-l had no effect on the hormone
concentration
in the blood but increased the protein content in rat liver cytosol. The drugs under study affected differently the parameters of arterial pressure under shock, viz., Nf and A-l maintained AP at the subnormal level, while Vp enhanced hypotension and thus aggravated the post-hemorrhagic period. The ability of Vp to inhibit the function of GR which results in the inhibition of the glucocofticoid-dependent synthesis of the angiotensin-convertingenzyme in vascular endothelium cells is one of the reasons fat lowered AP.
ENDOTHELIAL DYSFUNCTION IS PREVENTED BY IACIDIPINE TREATMENT IN SALT-LOADED STROKE-PRONE HYPERTENSIVE RATS Peter Krenek, Salvatore Salomone, Jan Kyselovic, Maurice Wibo, Nicole Morel & Thbophile Godfraind. Laboratoire de Pharmacologic, Universitb Catholique Louvain, Brussels, Belgium
de
Endothelium-dependent vasorelaxation (VR) is defective in hypertensive rats, especially in conduit arteries. In the strokeprone spontaneously hypertensive rat (SHRSP), impaired endothelium-dependent VR appears to contribute to the pathogenesis of stroke independently of blood pressure. As treatment with the calcium channel blocker lacidipine protects from stroke and cardiovascular remodeling in this model, we investigated the effect of this treatment on endotheliumdependent VR in the aorta. SHRSP were exposed to a saltrich diet (1% NaCl in drinking water) with or without lacidipine (1 mg.kg-l.day-1) for 8 weeks. High-sodium diet (i) increased systolic blood pressure, aottic weight and wall thickness and plasma renin activity ; (ii) markedly reduced nitric oxide (NO)-mediated endothelium-dependent VR to acetylcholine and the sensitivity to the relaxing effect of S-nitroso-Nacetylpenicillamine, a NO donor; (iii) induced an elevation of preproendothelin-1 (preproET-1) mRNA levels in aortic wall, whithout affecting endothelial NO synthase (eNOS) mRNA levels. Lacidipine treatment prevented the salt-dependent functional and structural alterations of the aorta, including the overexpression of the preproET-1 gene, and increased eNOS mRNA levels in aortic wall. In conclusion, lacidipine protects SHRSP against the impairment of endothelium-dependent VR evoked by a salt-rich diet and this effect may contribute to its beneficial effect against end-organ damage and stroke.
CONCLUSIONS: Over-expresebn of WAR at a very high lsvel leads to a wdiiyopalhy with a high mwtality. The severity df Ihis phenotype is gender dependent. Similarly, the benafil of an ACE inhibitor is only obsarved in females.
MODULATION OF CARDIAC IP, RECEPTORS BY IMMOBILIZATION STRESS Olga Krizanova, Lubomira Lencesova,Karol Ondrias & Richard Kvetnansky. Inst Molec Physiol Genet, SAS, Bratislava, SK This work was focused on characterization of the gene expression of type 1 and 2 IP, receptors in the rat cardiac atria and ventricles and to study their possible modulation by single immobilization stress. We detected the gene expression of IP, receptor of type 1 and 2 in both, cardiac atria and ventricles. Although in ventricles a clear signal of mRNA of type 1 and 2 IP, receptors was detected only by seminested RT-PCR, in atria the gene expression this receptor occurs in much higher abundance. Using competitive RT-PCR we quantify the mRNA amount of both types of IP, receptor in left and right atrium. Single immobilization stress for two hours significantly elevates mRNA levels for both types of these receptors. Since adrenalectomy and/or hypophysectomy completely abolished increase in IP, receptor’s mRNA levels after the immobilization, we assume the involvement of glucocorticoids in this process. Physiological relevance of our results remains to be elucidated. Nevertheless, we proposed that immobilization stress might indirectly modulate excitation-contraction coupling through IP, receptors. (Supported by grant VEGA 2/715&f)
A61
it.
Both
Nf
concentrations
effect. Compound
and
Vp
decreased
in the blood which
elevated testifies
EFFECTS OF PERiNOOPRlL ON CARDIOMYOPATHY IN t32-ADRENERt3lC RECWTOR OVEREXPRESSING MICE: IYFONTANCE OF GENDER Mwk T. Kmwwszyn, XkolyRno M Anthony M. Dart, Xlao.~un DLL Baker Mdlal Rwrrch Institute, Malbourm, Au&alla. CardiaC owr+n-aukn of BZ-Sdremrgk rewpbm @?AR) In mka by 200 fokl resub in e fibrcdc camfhy, wntrkuler remcdefling. heart hilure and pmmslum d&h. Thb model Is stile for study&g the mechsnkms of aotkn and efksoy of arrrent thsrqMc drugs. We postubfed thel pedndoprif. en Angii C~ Enzyme (ACE) .Mibii, would bs bsrwlkhl in tlw p2AR ovar~i mica. METHODS: 46 p2AR lransgank mke warn studkd for 9 months, starUng at 6 mm of age. 20 WAR mke (12 mab 6 lemab) rewlwd peri&pdl in binking water, at a dose ofO.3- 0.4mgIkg/day and another28 animals (13 each of male and femak?) swwd as conI&. Animsls wara inspected daily and their water tmbnent (6mth) and at 9, i2 and 15 moifhi &ags.besd anlmafs were examined b determine oause of death, tibia1 length and weight of vital organs. Heart8 were kept far histological exsminstlon. RESULTS: All groups ahowed progmaaiva mdvction In fraclknal shortening (FS). but at 12 months ths FS wss better preserved in untreated females vs. malea (28 *3 vs. 16 Kf!% pa.05). The bansfit of psrindopril wss hiihly genderdependent. Males did not havs a survival bsneiit. w impmvemsnt in FS. Treated females had slgnl6oanlly batter ruwival and a raducsd haart weight at the end of the sluby. (Mb). &though tJwre was no sign’ficant knprovement in FS vs. ccnlml females (30.4 k2.1 vs. 27.6 *3%).
cortiwsterone
to their antistressory
A-l had no effect on the hormone
concentration
in the blood but increased the protein content in rat liver cytosol. The drugs under study affected differently the parameters of arterial pressure under shock, viz., Nf and A-l maintained AP at the subnormal level, while Vp enhanced hypotension and thus aggravated the post-hemorrhagic period. The ability of Vp to inhibit the function of GR which results in the inhibition of the glucocofticoid-dependent synthesis of the angiotensin-convertingenzyme in vascular endothelium cells is one of the reasons fat lowered AP.
ENDOTHELIAL DYSFUNCTION IS PREVENTED BY IACIDIPINE TREATMENT IN SALT-LOADED STROKE-PRONE HYPERTENSIVE RATS Peter Krenek, Salvatore Salomone, Jan Kyselovic, Maurice Wibo, Nicole Morel & Thbophile Godfraind. Laboratoire de Pharmacologic, Universitb Catholique Louvain, Brussels, Belgium
de
Endothelium-dependent vasorelaxation (VR) is defective in hypertensive rats, especially in conduit arteries. In the strokeprone spontaneously hypertensive rat (SHRSP), impaired endothelium-dependent VR appears to contribute to the pathogenesis of stroke independently of blood pressure. As treatment with the calcium channel blocker lacidipine protects from stroke and cardiovascular remodeling in this model, we investigated the effect of this treatment on endotheliumdependent VR in the aorta. SHRSP were exposed to a saltrich diet (1% NaCl in drinking water) with or without lacidipine (1 mg.kg-l.day-1) for 8 weeks. High-sodium diet (i) increased systolic blood pressure, aottic weight and wall thickness and plasma renin activity ; (ii) markedly reduced nitric oxide (NO)-mediated endothelium-dependent VR to acetylcholine and the sensitivity to the relaxing effect of S-nitroso-Nacetylpenicillamine, a NO donor; (iii) induced an elevation of preproendothelin-1 (preproET-1) mRNA levels in aortic wall, whithout affecting endothelial NO synthase (eNOS) mRNA levels. Lacidipine treatment prevented the salt-dependent functional and structural alterations of the aorta, including the overexpression of the preproET-1 gene, and increased eNOS mRNA levels in aortic wall. In conclusion, lacidipine protects SHRSP against the impairment of endothelium-dependent VR evoked by a salt-rich diet and this effect may contribute to its beneficial effect against end-organ damage and stroke.
CONCLUSIONS: Over-expresebn of WAR at a very high lsvel leads to a wdiiyopalhy with a high mwtality. The severity df Ihis phenotype is gender dependent. Similarly, the benafil of an ACE inhibitor is only obsarved in females.
MODULATION OF CARDIAC IP, RECEPTORS BY IMMOBILIZATION STRESS Olga Krizanova, Lubomira Lencesova,Karol Ondrias & Richard Kvetnansky. Inst Molec Physiol Genet, SAS, Bratislava, SK This work was focused on characterization of the gene expression of type 1 and 2 IP, receptors in the rat cardiac atria and ventricles and to study their possible modulation by single immobilization stress. We detected the gene expression of IP, receptor of type 1 and 2 in both, cardiac atria and ventricles. Although in ventricles a clear signal of mRNA of type 1 and 2 IP, receptors was detected only by seminested RT-PCR, in atria the gene expression this receptor occurs in much higher abundance. Using competitive RT-PCR we quantify the mRNA amount of both types of IP, receptor in left and right atrium. Single immobilization stress for two hours significantly elevates mRNA levels for both types of these receptors. Since adrenalectomy and/or hypophysectomy completely abolished increase in IP, receptor’s mRNA levels after the immobilization, we assume the involvement of glucocorticoids in this process. Physiological relevance of our results remains to be elucidated. Nevertheless, we proposed that immobilization stress might indirectly modulate excitation-contraction coupling through IP, receptors. (Supported by grant VEGA 2/715&f)
A61