Ä.Ñ.Óãäûæåêîâà, Ë.À.Ìàéìåñêóëîâà, Þ.Ã.Äàâûäîâà ÊÀÍÍÀÁÈÍÎÈÄ HU-210 ÓÂÅËÈ×ÈÂÀÅÒ ÓÑÒÎÉ×ÈÂÎÑÒÜ ÑÅÐÄÖÀ Ê
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68 Ä.Ñ.Óãäûæåêîâà, Ë.À.Ìàéìåñêóëîâà, Þ.Ã.Äàâûäîâà ÊÀÍÍÀÁÈÍÎÈÄ HU-210 ÓÂÅËÈ×ÈÂÀÅÒ ÓÑÒÎÉ×ÈÂÎÑÒÜ ÑÅÐÄÖÀ Ê ÀÐÈÒÌÎÃÅÍÍÎÌÓ ÄÅÉÑÒÂÈÞ ÀÄÐÅÍÀËÈÍÀ È ÀÊÎÍÈÒÈÍÀ Òîìñêèé Ãîñóäàðñòâåííûé Ïåäàãîãè÷åñêèé Óíèâåðñèòåò, ã. Òîìñê, Ðîññèÿ. Îáíàðóæåí àíòèàðèòìè÷åñêèé ýôôåêò ñåëåêòèâíîãî àãîíèñòà êàííàáèíîèäíûõ ðåöåïòîðîâ HU-210 ïðè àäðåíàëîâûõ è àêîíèòèíîâûõ àðèòìèÿõ ó êðûñ. Êëþ÷åâûå ñëîâà: êàííàáèíîèäû, àðèòìèè. It has been found antiarrhythmic effect of selective cannabinoid receptor agonist HU-210 at epinephrine and aconitine induced arrhythmias in rats. Key words: cannabinoids, arrhythmias. Ñîâðåìåííàÿ ôàðìàêîëîãèÿ íå çíàåò ÿñíîãî îòâåòà íà âîïðîñ î òîì, êàêèå ôèçèêî-õèìè÷åñêèå ñâîéñòâà ñîåäèíåíèé ïðåäîïðåäåëÿþò èõ àíòèàðèòìè÷åñêóþ àêòèâíîñòü. Çíàÿ ñòðóêòóðó ìîëåêóëû âíîâü ñèíòåçèðîâàííîãî âåùåñòâà, íåëüçÿ a priori ñêàçàòü, áóäåò ëè ýòî ñîåäèíåíèå îáëàäàòü àíòèàðèòìè÷åñêèìè ñâîéñòâàìè èëè íåò. Ìíîãèå ñîåäèíåíèÿ, ñèíòåçèðîâàííûå ïåðâîíà÷àëüíî ñ öåëüþ ñîçäàòü íîâîå ëåêàðñòâî äëÿ ëå÷åíèÿ îïðåäåëåííûõ çàáîëåâàíèé âåñüìà äàëåêèõ îò ñåðäå÷íî-ñîñóäèñòîé ïàòîëîãèè, íàøëè ñâîå ïðèìåíåíèå â êëèíè÷åñêîé ïðàêòèêå êàê àíòèàðèòìè÷åñêèå ïðåïàðàòû. Ïðèìåðîì ÿâëÿåòñÿ ôåíèòîèí, êîòîðûé ïëàíèðîâàëè ïðèìåíÿòü äëÿ ëå÷åíèÿ ýïèëåïñèè, îäíàêî ýòîò ïðåïàðàò îêàçàëñÿ õîðîøèì àíòèàðèòìèêîì [3]. Ïðîòèâîñóäîðîæíûé ïðåïàðàò ôèíëåïñèí èñïîëüçóþò äëÿ ïðåäóïðåæäåíèÿ æåëóäî÷êîâîé ýêñòðàñèñòîëèè è æåëóäî÷êîâîé òàõèêàðäèè [3]. Äðóãèå ïñèõîôàðìàêîëîãè÷åñêèå ñðåäñòâà, íàïðèìåð, èìèïðàìèí, àçàôåí, òàêæå îáëàäàþò àíòèàðèòìè÷åñêèìè ñâîéñòâàìè, õîòÿ ðåäêî èñïîëüçóþòñÿ â òåðàïèè íàðóøåíèé ñåðäå÷íîãî ðèòìà [3]. Âñå âûøåñêàçàííîå â ïîëíîé ìåðå îòíîñèòñÿ ê àãîíèñòàì êàííàáèíîèäíûõ (ÑÂ) ðåöåïòîðîâ, êîòîðûå ìîãóò îêàçàòüñÿ ïåðñïåêòèâíîé ãðóïïîé ñîåäèíåíèé äëÿ ïîèñêà íîâûõ àíòèàðèòìè÷åñêèõ àãåíòîâ. Êàêèå ó íàñ åñòü îñíîâàíèÿ äëÿ ïîäîáíîãî ïðåäïîëîæåíèÿ? Ýòè ïðåïàðàòû îáëàäàþò êàðäèîâàñêóëÿðíîé àêòèâíîñòüþ [5, 7, 12, 19, 20]. Êàííàáèíîèäû èíãèáèðóþò àêòèâíîñòü àäåíèëàòöèêëàçû â ìåìáðàíàõ êàðäèîìèîöèòîâ [13] è, òåì ñàìûì, ñíèæàþò ñèíòåç öÀÌÔ, êîòîðûé, êàê èçâåñòíî [14], èãðàåò âàæíóþ ðîëü â ãåíåçå àðèòìèé. Àãîíèñòû êàííàáèíîèäíûõ ðåöåïòîðîâ îêàçûâàþò ìîäóëèðóþùåå äåéñòâèå íà ñîñòîÿíèå âåãåòàòèâíîé íåðâíîé ñèñòåìû [5, 10, 20], ðîëü êîòîðîé â àðèòìîãåíåçå õîðîøî èçâåñòíà. Ñîïîñòàâëåíèå ýòèõ ôàêòîâ ïîçâîëèëî íàì ïðåäïîëîæèòü, ÷òî êàííàáèíîèäû, ïî-âèäèìîìó, ìîãóò îêàçûâàòü àíòèàðèòìè÷åñêèé ýôôåêò íà ìîäåëè àäðåíàëîâûõ àðèòìèé, êîòîðûå îáóñëîâëåíû èçáûòî÷íûì ñèíòåçîì öÀÌÔ â ðåçóëüòàòå àêòèâàöèè β-àäðåíîðåöåïòîðîâ, ñîïðÿæåííûõ ñ àäåíèëàòöèêëàçîé. Öåëü ðàáîòû: èçó÷èòü àíòèàðèòìè÷åñêèé ýôôåêò ñåëåêòèâíîãî àãîíèñòà êàííàáèíîèäíûõ ðåöåïòîðîâ HU-210. ÌÀÒÅÐÈÀËÛ È ÌÅÒÎÄÛ Îïûòû ïðîâîäèëè íà êðûñàõ-ñàìöàõ ëèíèè Âèñòàð ìàññîé 150–200 ã. Ó êðûñ ìîäåëèðîâàëè àðèòìèè ïóò¸ì âíóòðèâåííîé èíúåêöèè àäðåíàëèíà â äîçå 120 ìêã/êã èëè àêîíèòèíà â äîçå 50 ìêã/êã. Êðûñ íàðêîòèçèðîâàëè ýòèëîâûì ýôèðîì.  òå÷åíèå 5 ìèí ïîñëå èíúåêöèè àäðåíàëèíà ðåãèñòðèðîâàëè ÝÊà â ïåðâîì ãðóäíîì îòâåäåíèè ñ ïîìîùüþ óñèëèòåëÿ áèîïîòåíöèàëîâ (ÓÁÔ4-03, Ðîññèÿ) è êîìïüþòåðà IBM 486 ñ èñïîëüçîâàíèåì îðèãèíàëüíîãî ïàêåòà ïðèêëàäíûõ ïðîãðàìì. Ïðè àíàëèçå ÝÊà ïðèíèìàëè âî âíèìàíèå ÷àñòîòó âîçíèêíîâåíèÿ åäèíè÷íûõ è ìíîæåñòâåííûõ æåëóäî÷êîâûõ ýêñòðàñèñòîë (ÆÝ), æåëóäî÷êîâîé òàõèêàðäèè (ÆÒ), ôèáðèëëÿöèè æåëóäî÷êîâ (ÔÆ). Çà åäèíè÷íûå ÆÝ ïðèíèìàëè ýêñòðàñèñòîëû â êîëè÷åñòâå îò 6 äî 16 çà 5 ìèí ðåãèñòðàöèè ÝÊÃ. Ýêñòðàñèñòîëû â êîëè÷åñòâå áîëåå 16 çà 5 ìèí ïðèíèìàëè çà ìíîæåñòâåííûå.  êà÷åñòâå êðèòåðèÿ àðèòìîãåííîãî äåéñòâèÿ àêîíèòèíà ïðèíèìàëè èíòåðâàë âðåìåíè îò ìîìåíòà èíúåêöèè àêîíèòèíà äî ìîìåíòà ïîÿâëåíèÿ ÆÒ. Äëÿ èíòðàöåðåáðîâåíòðèêóëÿðíîãî (ICV) ââåäåíèÿ êàííàáèíîèäîâ èñïîëüçîâàëè êðûñ ìàññîé 250–300 ã. Çà 5–7 äíåé äî èíäóêöèè àðèòìèé â áîêîâîé æåëóäî÷åê ìîçãà êðûñ èìïëàíòèðîâàëè êàíþëþ, êîòîðóþ ôèêñèðîâàëè íà ïîâåðõíîñòè ÷åðåïà ñ ïîìîùüþ ñòîìàòîëîãè÷åñêîãî öåìåíò-ôîñôàòà. Îïåðàöèÿ âûïîëíÿëàñü ïîä áàðáàìèëîâûì íàðêîçîì (50 ìã/êã âíóòðèáðþøèííî) ïðè ïîìîùè ñòåðåîòàêñè÷åñêîãî àïïàðàòà ÑÝÆ-5 (ÍÏÎ «Êîíñòðóêòîð», Óêðàèíà). Ïðè ýòîì èñïîëüçîâàëè ñëåäóþùèå êîîðäèíàòû: ÀÐ – +1.5 ìì, L – +2.0 ìì, V – –3.5 ìì îòíîñèòåëüíî áðåãìû [17]. Ñåëåêòèâíûé àãîíèñò êàííàáèíîèäíûõ (ÑÂ1 è ÑÂ2) ðåöåïòîðîâ HU-210 [16] áûë ñèíòåçèðîâàí ïðîô. R.Mechoulam (Èåðóñàëèìñêèé Óíèâåðñèòåò, Èçðàèëü). HU-210 ââîäèëè âíóòðèâåííî â äîçå 50 è 250 ìêã/êã ïîñëå ðàñòâîðåíèÿ â ñìåñè Cremophore EL: ýòàíîë: âîäà (1:1:18) çà 30 ìèí äî èíúåêöèè àäðåíàëèíà èëè àêîíèòèíà. Äëÿ ICV ââåäåíèÿ HU-210 ðàñòâîðÿëè â DMSO è ââîäèëè â äîçå 0,5 ìêã èëè 5 ìêã íà êðûñó â 10 ìêë DMSO. Äëÿ òîãî, ÷òîáû îöåíèòü ðåöåïòîðíóþ ñïåöèôè÷íîñòü îáíàðóæåííûõ ýôôåêòîâ èñïîëüçîâàëè ñåëåêòèâíûé àíòàãîíèñò êàííàáèíîèäíûõ ðåöåïòîðîâ CB1-òèïà SR141716A [18], ëþáåçíî ïðåäîñòàâëåííûé äð. M.Mosse (Sanofi Recherch, ÂÅÑÒÍÈÊ ÀÐÈÒÌÎËÎÃÈÈ, ¹ 19, 2000 69 Òàáëèöà 1. Ôðàíöèÿ). Ýòîò àíòàãîíèñò CB1-ðåöåïòîðîâ ââîäèëè âíóòðèâåííî â Âëèÿíèå âíóòðèâåííîãî ââåäåíèÿ HU-210 íà ÷àñòîòó âîçíèêíîâåíèÿ äîçå 3 ìã/êã çà 30 ìèí äî èíúåêöèè àäðåíàëîâûõ àðèòìèé HU-210. SR141716A ðàñòâîðÿëè òàêБез Ж А n ЕЖ Э n М ЖА ЖТ ЖФ æå, êàê è HU-210. Ïðè âûáîðå äîç ëè- Г руп п ы ж и вотн ы х n (%) (%) n (%) n (%) n (%) ãàíäîâ CB-ðåöåïòîðîâ è ñïîñîáîâ К он троль 15 0 1 (7%) 14 (93%) 8 (53%) 7 (47%) ðàñòâîðåíèÿ ýòèõ ïðåïàðàòîâ ìû H U - 210 0.05 мг/кг 1* * 14 4* (29%) 1 (7%) 9 (64%) 0* * ðóêîâîäñòâîâàëèñü äàííûìè ëèòå(7%) ðàòóðû [15,16,18]. Äëÿ áëîêàäû ïå- H U - 210 (0.25 мг/кг ) 2 2* 13 6* * (46%) 5* * * (38%) 0* * (15%) (15%) ðèôåðè÷åñêèõ âåãåòàòèâíûõ ãàíã2 ëèåâ èñïîëüçîâàëè ïðåäâàðèòåëü- Г ексаметон и й + 14 6* * (43%) 6* * (43%) 3 (21%) 1# (7%) (14%) íîå äâóêðàòíîå âíóòðèâåííîå ââå- H U - 210 (0.05 мг/кг ) äåíèå ãåêñàìåòîíèÿ â äîçå 10 ìã/êã, Ïðèìå÷àíèå. n – êîëè÷åñòâî æèâîòíûõ. * – p<0.05; # – p<0.025 ** – p<0.01; *** – 2 ïåðâûé ðàç çà 10 ìèí äî HU-210 è p<0.001 – äîñòîâåðíîå ðàçëè÷èå ïî îòíîøåíèþ ê êîíòðîëþ (êðèòåðèé χ ). ÆÀ – âòîðîé ðàç çà 10 ìèí äî èíúåêöèè æåëóäî÷êîâûå àðèòìèè; ÅÆÝ – åäèíè÷íûå æåëóäî÷êîâûå ýêñòðàñèñòîëû; ÌÆÝ – ìíîæåñòâåííûå æåëóäî÷êîâûå ýêñòðàñèñòîëû; àäðåíàëèíà. ÆÒ – æåëóäî÷êîâàÿ òàõèêàðäèÿ; ÆÔ – æåëóäî÷êîâàÿ ôèáðèëëÿöèÿ. Êîíòðîëåì ñëóæèëè èíòàêòíûå æèâîòíûå, êîòîðûì ïåðåä èíúåêöèåé àäðåíàëèíà èëè òîíèé, êîòîðûé âûçûâàåò êðàòêîâðåìåííóþ «õèìè÷åñàêîíèòèíà âíóòðèâåííî èëè ICV ââîäèëè ñîîòâåòñòâó- êóþ äåíåðâàöèþ» ñåðäöà, íå îêàçûâàë ýôôåêòà íà àíþùèé ðàñòâîðèòåëü. Ðåçóëüòàòû îáðàáàòûâàëè ñòàòèñ- òèàðèòìè÷åñêèå ñâîéñòâà ýòîãî êàííàáèíîèäà. Âìåñòå òè÷åñêè ñ èñïîëüçîâàíèåì t-êðèòåðèÿ Ñòüþäåíòà è êðè- ñ òåì, âîçìîæíîñòü ó÷àñòèÿ öåíòðàëüíûõ ÑÂ-ðåöåïòîðîâ â ôîðìèðîâàíèè HU-210-èíäóöèðîâàííîé òîëåðàíòåðèÿ χ2. òíîñòè ñåðäöà ê àðèòìîãåííîìó äåéñòâèþ êàòåõîëàìèÐÅÇÓËÜÒÀÒÛ ÈÑÑËÅÄÎÂÀÍÈß íîâ ïðåäñòàâëÿëàñü íàì âïîëíå âåðîÿòíîé, ïîñêîëüêó Êàê ïîêàçàíî â òàáë. 1, àäðåíàëèí âûçûâàåò êàííàáèíîèäû ëåãêî ïðîíèêàþò ÷åðåç ãåìàòî-ýíöåôàæåëóäî÷êîâûå àðèòìèè ó âñåõ æèâîòíûõ. Ó 47% îñî- ëè÷åñêèé áàðüåð [7, 12]. Èññëåäîâàòü ó÷àñòèå âåãåòàáåé ðåãèñòðèðóåòñÿ ÆÔ, à ó 53% êðûñ îòìå÷àåòñÿ òèâíûõ öåíòðîâ ãîëîâíîãî ìîçãà â ðåàëèçàöèè àíòèàðèòÆÒ. Ó áîëüøèíñòâà æèâîòíûõ ýòè àðèòìèè íîñèëè ìè÷åñêîãî äåéñòâèÿ HU-210 ìîæíî ïðè ïîìîùè ICV îáðàòèìûé õàðàêòåð è çàâåðøàëèñü âîññòàíîâëåíè- èíôóçèè ýòîãî ïðåïàðàòà. åì íîðìàëüíîãî ñèíóñîâîãî ðèòìà. Èíúåêöèÿ HUÊàê ïîêàçàíî íà ðèñ. 1, ýòîò êàííàáèíîèä íå îêàçû210 â äîçå 50 ìêã/êã âûçûâàëà ñíèæåíèå ÷àñòîòû ñåð- âàë äîñòîâåðíîãî ýôôåêòà íà ÷àñòîòó âîçíèêíîâåíèÿ àääå÷íûõ ñîêðàùåíèé (×ÑÑ) ñ 377±1,3 óä/ìèí (n=20) ðåíàëîâûõ àðèòìèé, åñëè åãî ââîäèëè â áîêîâîé æåëóäîâ êîíòðîëå äî 221±1,2 óä/ìèí íà 30 ìèíóòå ïîñëå ÷åê ìîçãà â äîçå 0,5 ìêã è 5,0 ìêã íà êðûñó. Âåñ ãîëîâíîãî ââåäåíèå êàííàáèíîèäà (n=10; ð<0,001). Îòðèöàòåëü- ìîçãà êðûñû íå ïðåâûøàåò äâóõ ãðàììîâ [1], ïîýòîìó â íûé õðîíîòðîïíûé ýôôåêò HU-210 íîñèë äîçîçàâè- ïåðåñ÷åòå íà îäèí êèëîãðàìì ìàññû òåëà ICV-äîçà 5,0 ñèìûé õàðàêòåð. Ïîñëå ââåäåíèÿ HU-210 â äîçå ìêã íà êðûñó ñîîòâåòñòâóåò 2500 ìêã/êã, ÷òî â 50 ðàç áîëü250 ìêã/êã ×ÑÑ ñîñòàâëÿëà 185±1,5 (n=10, ð<0,001 øå èñïîëüçîâàííîé íàìè äîçû (50 ìêã/êã) äëÿ âíóòðèâåíïî îòíîøåíèþ ê êîíòðîëþ). Èçâåñòíî, ÷òî àêòèâà- íîãî ââåäåíèÿ. Ñëåäîâàòåëüíî, åñòü îñíîâàíèÿ óòâåðæöèÿ ÑÂ-ðåöåïòîðîâ, ëîêàëèçîâàííûõ â ãîëîâíîì äàòü, ÷òî àíòèàðèòìè÷åñêèé ýôôåêò HU-210 íå ñâÿçàí ñ ìîçãå, âûçûâàåò ñíèæåíèå àêòèâíîñòè ñèìïàòè÷åñ- àêòèâàöèåé öåíòðàëüíûõ Ñ ðåöåïòîðîâ. êîãî çâåíà âåãåòàòèâíîé íåðâíîé ñèñòåìû è ïîâûøåíèå òîíóñà n.vagus [5, 20]. Âåðîÿòíî, íàáëþäàåìàÿ íàìè áðàäèêàðäèÿ ñâÿçàíà ñ àêòèâàöèåé öåíòðàëüíûõ % DM SO êîíòðîëь êàíàáèíîèäíûõ ðåöåïòîðîâ. Êàê âèäíî èç òàáë. 1, 80 HU-210 ïðåäâàðèòåëüíîå ââåäåíèå êàííàáèíîèäà ñïîñîáñòâî(0.5 ìêã) âàëî ñíèæåíèþ ÷àñòîòû âîçíèêíîâåíèÿ çëîêà÷åñòâåí60 HU-210 íûõ àðèòìèé (ÆÒ è ÆÔ), à ó ÷åòûðåõ êðûñ æåëóäî÷(5 ìêã) êîâûå íàðóøåíèÿ ñåðäå÷íîãî ðèòìà âîâñå íå âîçíè40 êàëè. Åùå áîëåå âûðàæåííûé àíòèàðèòìè÷åñêèé ýôôåêò HU-210 îêàçàë â äîçå 250 ìêã/êã. Ãàíãëèîáëîêàòîð ãåêñàìåòîíèé íå óñòðàíÿë àíòèàðèòìè÷åñêèé ýô20 ôåêò HU-210.  îòäåëüíîé ñåðèè ýêñïåðèìåíòîâ (äàííûå íå ïðåäñòàâëåíû â òàáëèöå) íàìè áûëî ïîêàçà0 íî, ÷òî ñàì ïî ñåáå ãåêñàìåòîíèé íå îêàçûâàåò äîñòîБåз æåëóäî÷îâûõ Мíîæåñòâåííûå Жåëóäî÷êîâàÿ àðèòìèé æåëóäî÷êîâûå òàõèêàðäèÿ âåðíîãî ýôôåêòà íà ÷àñòîòó âîçíèêíîâåíèÿ àäðåíàýêñòðàñèñòîëû ëîâûõ àðèòìèé. Ñîïîñòàâëåíèå ýòèõ äàííûõ ïîçâîëèëî íàì Ðèñ. 1. Âëèÿíèå èíòðàöåðåáðîâåíòðèêóëÿðíîãî ïðåäïîëîæèòü, ÷òî àíòèàðèòìè÷åñêèé ýôôåêò HU- ââåäåíèÿ HU-210 íà ÷àñòîòó âîçíèêíîâåíèÿ 210 íå ñâÿçàí ñ èçìåíåíèåì ñîñòîÿíèÿ âåãåòàòèâíîé àäðåíàëîâûõ àðèòìèé. % - ïðîöåíò æèâîòíûõ ñ íåðâíîé ñèñòåìû, ïîñêîëüêó ãàíãëèîáëîêàòîð ãåêñàìå- íàðóøåíèÿìè èëè áåç íàðóøåíèé ñåðäå÷íîãî ðèòìà. ÂÅÑÒÍÈÊ ÀÐÈÒÌÎËÎÃÈÈ, ¹ 19, 2000 70 % Èçâåñòíî, ÷òî êàííàáèíîèäû ñïîñîáíû èíãèáèðîâàòü àäåíèëàòöèêëàçó (ÀÖ) êàðäèîìèîöè- 80 êîíòðîëь òîâ [13], ïîýòîìó ìû ïðåäïîëîæèëè, ÷òî àíòèàðèòSR141716 ìè÷åñêèé ýôôåêò HU-210 â óñëîâèÿõ ñòèìóëÿöèè 60 * β-àäðåíîðåöåïòîðîâ àäðåíàëèíîì ìîã áûòü ñëåäSR141 + HU-210 ñòâèåì ÑÂ-ðåöåïòîð-îïîñðåäîâàííîãî óãíåòåíèÿ 40 àêòèâíîñòè ÀÖ, êàòàëèçèðóþùåãî ñèíòåç ýíäîãåííîãî àðèòìîãåííîãî ôàêòîðà – öÀÌÔ [14]. Ïîñëå* 20 äíèé àêòèâèðóåò Ñà2+-êàíàëû L-òèïà è óñèëèâàåò ìîáèëèçàöèþ Ñà2+ èç ñàðêîïëàçìàòè÷åñêîãî ðåòè0 êóëóìà, âûçûâàÿ òåì ñàìûì óâåëè÷åíèå êîíöåíòБåз æåëóäî÷îâûõ Мíîæåñòâåííûå Жåëóäî÷êîâàÿ 2+ ðàöèè Ñà â ìèîïëàçìå, ÷òî â êîíå÷íîì èòîãå ñïîàðèòìèé æåëóäî÷êîâûå òàõèêàðäèÿ ýêñòðàñèñòîëû ñîáñòâóåò âîçíèêíîâåíèþ ýëåêòðè÷åñêîé íåñòàáèëüíîñòè ñåðäöà è ïîÿâëåíèþ àðèòìèé [8, 14].  Ðèñ. 2. Âëèÿíèå âíóòðèâåííîãî ââåäåíèÿ SR141716 (3 ìã/êã) ýòîì ñëó÷àå, HU-210 äîëæåí áûë çàùèùàòü ñåðä- íà ÷àñòîòó âîçíèêíîâåíèÿ àäðåíàëîâûõ àðèòìèé. % öå òîëüêî îò òîêñè÷åñêîãî äåéñòâèÿ àäðåíàëèíà, ïðîöåíò æèâîòíûõ ñ íàðóøåíèÿìè èëè áåç íàðóøåíèé íî íèêàê íå âëèÿòü íà ðåçèñòåíòíîñòü ñåðäöà ê äåé- ñåðäå÷íîãî ðèòìà. ñòâèþ èíûõ àðèòìîãåííûõ ôàêòîðîâ. Ïðîâåðèòü íàøå ïðåäïîëîæåíèå ìû ðåøèëè íà ìîäåëè àêîíèòè- íûé áëîêàòîð ÑÂ1-ðåöåïòîðîâ SR141716A. Îêàçàëîñü, íîâûõ àðèòìèé.  îñíîâå àðèòìîãåííîãî äåéñòâèÿ àêî- ÷òî ýòîò ïðåïàðàò â äîçå 3 ìã/êã íèêàê íå âëèÿë íà õàíèòèíà ëåæèò åãî ñïîñîáíîñòü çàìåäëÿòü èíàêòèâàöèþ ðàêòåð àäðåíàëîâûõ àðèòìèé (ðèñ. 2). Áîëåå òîãî, ýòîò áûñòðûõ Na+-êàíàëîâ, ÷òî âåäåò ê ïåðåãðóçêå êàðäèî- ïðåïàðàò íèêàê íå âëèÿë íà àíòèàðèòìè÷åñêîå äåéñòâèå ìèîöèòîâ èîíàìè Na+, êîòîðûé îáìåíèâàåòñÿ íà âíå- HU-210 (ðèñ. 2). Ñëåäîâàòåëüíî, àíòèàðèòìè÷åñêèé êëåòî÷íûé Ñà2+, ïî ìåõàíèçìó Na+/Ca2+ îáìåíà [2].  ýôôåêò HU-210 íå ñâÿçàí ñ àêòèâàöèåé ÑÂ1-ðåöåïòîðîâ, êîíå÷íîì èòîãå, âîçíèêàåò Ca2+-ïåðåãðóçêà êàðäèîìèî- ïî-âèäèìîìó, îí ÿâëÿåòñÿ ðåçóëüòàòîì ñòèìóëÿöèè ÑÂ2öèòîâ, ÷òî âåäåò ê ýëåêòðè÷åñêîé íåñòàáèëüíîñòü ñåðä- ðåöåïòîðîâ. Îäíàêî ýòîò âîïðîñ åùå ïðåäñòîèò âûÿñíèòü â ïîñëåäóþùèõ èññëåäîâàíèÿõ. Ðåöåïòîðíàÿ ïðèöà è âîçíèêíîâåíèþ àðèòìèé [2, 8]. Íàìè áûëî óñòàíîâëåíî, ÷òî HU-210 (50 ìêã/êã) ðîäà àíòèàðèòìè÷åñêîãî äåéñòâèÿ HU-210 ó íàñ íå âûñïîñîáñòâóåò ïîâûøåíèþ òîëåðàíòíîñòè ñåðäöà ê àðèò- çûâàåò ñîìíåíèÿ, ïîñêîëüêó ýòîò êàííàáèíîèä àêòèâåí ìîãåííîìó äåéñòâèþ àêîíèòèíà.  êîíòðîëüíîé ãðóï- óæå â äîçå 50 ìêã/êã, ÷òî íà ïîðÿäîê íèæå ìèíèìàëüïå âðåìÿ îò ìîìåíòà èíúåêöèè àêîíèòèíà äî ìîìåíòà íîé àíòèàðèòìè÷åñêîé äîçû òàêèõ ïðåïàðàòîâ êàê ïðîâîçíèêíîâåíèÿ íåîáðàòèìîé ÆÒ èëè ÆÔ ñîñòàâëÿåò ïðàíîëîë, ëèäîêàèí è âåðàïàìèë [6, 9]. Âìåñòå ñ òåì, 116,2±7,9 ñåê (n=15). Ïîñëå ïðåäâàðèòåëüíîé èíúåêöèè ãîâîðèòü î ïåðñïåêòèâàõ øèðîêîãî ïðèìåíåíèè êàíêàííàáèíîèäà (50 ìêã/êã) ýòîò ïðîìåæóòîê âðåìåíè íàáèíîèäîâ â êëèíè÷åñêîé ïðàêòèêå êàê àíòèàðèòóâåëè÷èâàåòñÿ äî 278,3±22,8 ñåê (n=14, P<0,001 ïî îò- ìèêîâ ïîêà íå ïðèõîäèòñÿ, ïîñêîëüêó èìåþòñÿ ñîíîøåíèþ ê êîíòðîëþ). Ñëåäîâàòåëüíî, àíòèàðèòìè÷åñ- îáùåíèÿ î ñïîñîáíîñòè ìàðèõóàíû (äåéñòâóþùèì êèé ýôôåêò HU-210 íå ìîæåò áûòü ñâÿçàí òîëüêî ñî íà÷àëîì êîòîðîé ÿâëÿþòñÿ êàííàáèíîèäû) ïðîâîñíèæåíèåì àêòèâíîñòè ÀÖ.  îñíîâå àðèòìîãåííîãî öèðîâàòü âîçíèêíîâåíèå æåëóäî÷êîâûõ ýêñòðàñèñäåéñòâèÿ àêîíèòèíà è àäðåíàëèíà ëåæèò ñïîñîáíîñòü òîë ó çäîðîâûõ äîáðîâîëüöåâ [11] è ñíèæàòü òîëåýòèõ ïðåïàðàòîâ óâåëè÷èâàòü Ñà2+-ïåðåãðóçêó êàðäèî- ðàíòíîñòü ê ôèçè÷åñêèì íàãðóçêàì ó ïàöèåíòîâ, ìèîöèòîâ [2,8,14], ïîýòîìó ïðåäñòàâëÿåòñÿ óìåñòíûì ñòðàäàþùèõ ñòåíîêàðäèåé [4]. ïðåäïîëîæèòü, ÷òî â îñíîâå àíòèàðèòìè÷åñêîãî äåéÂÛÂÎÄÛ ñòâèÿ HU-210 ëåæèò ñïîñîáíîñòü ýòîãî ïðåïàðàòà èíãèáèðîâàòü Ñà2+-ïåðåãðóçêó êàðäèîìèîöèòîâ. Ìåõàíèçì 1. Ñåëåêòèâíûé àãîíèñò êàííàáèíîèäíûõ ðåöåïòîðîâ HU-210 îáëàäàåò âûñîêîé àíòèàðèòìè÷åñêîé ïîäîáíîãî ýôôåêòà HU-210 ïðåäñòîèò âûÿñíèòü. Âàæíûì àñïåêòîì â èññëåäîâàíèè àíòèàðèòìè÷åñ- àêòèâíîñòüþ íà ìîäåëÿõ àäðåíàëîâûõ è àêîíèòèíîêîãî äåéñòâèÿ ëþáîãî ôàðìàêîëîãè÷åñêîãî àãåíòà ëå- âûõ àðèòìèé. æèò èçó÷åíèå ðåöåïòîðíîé ïðèðîäû âûÿâëåííîãî ýô- 2. Àíòèàðèòìè÷åñêîå äåéñòâèå HU-210 íå ñâÿçàíî ñ ôåêòà. Ñ ýòîé öåëüþ íàìè áûë èñïîëüçîâàí ñåëåêòèâ- àêòèâàöèåé ÑÂ1-ðåöåïòîðîâ. ËÈÒÅÐÀÒÓÐÀ 1. Áëèíêîâ Ñ.Ì., Ãëåçåð È.È. Ìîçã ÷åëîâåêà â öèôðàõ è òàáëèöàõ. Ë.: Ìåäèöèíà, 1964. 471 ñ. 2. Ëàçäèíñêèé Ì., Ðåíî Äæ.Ô. Äåéñòâèå êàðäèîòîêñèíîâ íà èîííûå êàíàëû ìåìáðàíû. Ôèçèîëîãèÿ è ïàòîôèçèîëîãèÿ ñåðäöà. Ïîä ðåä. Í.Ñïåðåëàêèñà. – Ì.: Ìåäèöèíà, 1990. – Ñ. 593–617. 3. Ìàçóð Í.À., Àáäàëëà À. Ôàðìàêîòåðàïèÿ àðèòìèé. – Ì.: Îâåðëåé, 1995. – 224 ñ. 4. Aronow W.S., Cassidy J. Effect of marihuana and placebo-marihuana smoking on angina pectoris. N.Engl.J.Med. 1974; 291 (2): 65–67. 5. Cavero I., Solomon T., Buckley J.P., Jandhyla B.S. Studies on the bradycardia induced by (-)-∆9-trans-tetrahydrocannabinol in anesthetized dogs. Eur. J. Pharmacol. 1973; 22 (3): 263–269. 6. Cambell C.A.,Parratt J.R. The effect of beta-adrenore- ÂÅÑÒÍÈÊ ÀÐÈÒÌÎËÎÃÈÈ, ¹ 19, 2000 71 ceptor blocking agents, with differing ancillary properties, on the arrhythmias resulting from acute coronary artery ligation in anaesthetised rats. Brit. J. Pharmacol. 1983; 79: 939–946. 7. Dewy W.L. Cannabinoid Pharmacology. Pharmacol. Rev. 1986; 38 (1): 151–178. 8. Eisner D.A. The role of intracellular Ca ions in the the therapeutic and toxic effects of cardiac glycosides and catecholamines. J. Cardiovasc. Pharmacol. 1986; 8 (Suppl 3): S2–S9. 9. Harumi K., Tsutsumi T., Sato T., Sekiya S. Classification of antiarrhythmic drugs based on ventricular fibrillation threshold. Am. J. Cardiol. 1989; 64: 10J–14J. 10. Hosko M.J., Schmeling W.T., Hardman H.F. Delta-9tetrahydrocannabinol: site of action for autonomic effects. In: The Cannabinoids: Chemical, Pharmacological and Therapeutic Aspects. Agurell S., Dewey W.L., Willette R.E. eds. New York: Academic Press, 1984; pp. 635–648. 11. Johnson S., Domino E.F. Some cardiovascular effects of marihuana smoking in normal volunteers. Clin. Pharmacol. Ther. 1971: 12 (5): 762–768. 12. Jones R.T. Cardiovascular effects of cannabinoids. In: Marihuana ’84, Harvey D.J. ed. Oxford: IRL Press. 1984; pp. 325–334. 13. Li D.M.F., Ng C.K.M. Effects of ∆1- and ∆6-tetrahydrocannabinol on the adenylate cyclase activity in ventricular tissue of the rat heart. Clin. Exp. Pharmacol. Physiol. 1984; 11 (1): 81–85 14. Lubbe W.F., Podzuweit T., Opie L.H. Potential arrhythmogenic role of cyclic adenosine monophsphate (AMP) and cytosolic calcium overload: Implications for prophilactic effects of beta-blockers in myocardial infarction and proarrhythmic effects of phosphodiesterase inhibitors. J Am. Coll. Cardiol. 1992; 19 (7): 1622–1633 15. Mansbach R.S., Rovertti C.C., Winston E.N., Lowe J.A.III Effects of the cannabinoid CB1 receptor antagonist SR141716A on the behavior of pigeons and rats. Psychopharmacology 1996; 124: 315–322 16. Mechoulam R., Feigenbaum J.J.,Lander N. et al. Enantiomeric cannabinoids: Stereospecificity of psychotropic activity. Experientia 1988; 44: 762–764 17. Pellegrino L.J., Pellegrino A.S., Cushman A.J. A Stereotaxic Atlas of the Rat Brain.- Plenum Press, New York, London: 1979. 18. Rinaldi-Cramona M., Barth F.,Heaulme M. et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor FEBS Lett. 1994; 350: 240–244 19. Varga K., Lake K.D., Huangfu D., Guyenet P.G., Kunos G. Mechanism of the hypotensive action of anandamide in anesthetized rats. Hypertension, 1996; 28: 682–686 20. Volmer R.R., Cavero I., Ertel R.J., Solomon T.A., Burckley J.P. Role of central autonomic nervous system in the hypotension and bradycardia induced by (-)-∆9-trans-tetrahydrocannabinol. J.Pharm. Pharmac. 1974; 26(3): 186–192. ÊÀÍÍÀÁÈÍÎÈÄ HU-210 ÓÂÅËÈ×ÈÂÀÅÒ ÓÑÒÎÉ×ÈÂÎÑÒÜ ÑÅÐÄÖÀ Ê ÀÐÈÒÌÎÃÅÍÍÎÌÓ ÄÅÉÑÒÂÈÞ ÀÄÐÅÍÀËÈÍÀ È ÀÊÎÍÈÒÈÍÀ Ä.Ñ.Óãäûæåêîâà, Ë.À.Ìàéìåñêóëîâà, Þ.Ã.Äàâûäîâà Îáíàðóæåíî, ÷òî ñåëåêòèâíûé àãîíèñò ÑÂ1 è ÑÂ2 êàííàáèíîèäíûõ ðåöåïòîðîâ HU-210 (0,05 è 0,25 ìã/êã âíóòðèâåííî) îêàçûâàåò âûðàæåííûé àíòèàðèòìè÷åñêèé ýôôåêò ó êðûñ ïðè àäðåíàëîâûõ èëè àêîíèòèíîâûõ àðèòìèÿõ. Îäíàêî ýòîò ïðåïàðàò íå âëèÿë íà õàðàêòåð àäðåíàëîâûõ àðèòìèé ïðè èíòðàöåðåáðîâåíòðèêóëÿðíîì ââåäåíèè. Ïðåäâàðèòåëüíîå ââåäåíèå ãàíëèîáëîêàòîðà ãåêñàìåòîíèÿ (10 ìã/êã) èëè ñåëåêòèâíîãî àíòàãîíèñòà ÑÂ1-ðåöåïòîðîâ SR141716 (3 ìã/êã) íå óñòðàíÿëî àíòèàðèòìè÷åñêèé ýôôåêò HU-210. Äåëàþò âûâîä, ÷òî àíòèàðèòìè÷åñêèé ýôôåêò HU-210 íå çàâèñèò îò àêòèâàöèè ÑÂ1-ðåöåïòîðîâ è íå îïîñðåäîâàí ÷åðåç âåãåòàòèâíóþ íåðâíóþ ñèñòåìó. CANNABINOID HU-210 INCREASES HEART TOLERANCE TO ARRHYTHMOGENIC ACTION OF EPINEPHRINE AND ACONITINE D.S.Ugdyzhekova, L.A.Maymeskulova, Yu.G.Davydova It has been found that a selective agonist of CB1 and CB2 cannabinoid receptors, HU-210 (0.05 and 0,25 mg/kg intravenously) had a strong antiarrhythmic effect at epinephrine and aconitine induced arrhythmias in rats. However, this compound did not affect on the incidence of epinephrine induced arrhythmias at intracerebroventricular administration. The pretreatment with ganglion blocker hexamethonium (10 mg/kg) or selective CB1 cannabinoid receptor antagonist, SR141716 (3 mg/kg) did not abolish antiarrhythmic effect of HU-210. It has been conclused that antiarrhythmic effect of HU-210 did not depend on CB1 receptor activation and did not mediated by autonomic nervous system. ÂÅÑÒÍÈÊ ÀÐÈÒÌÎËÎÃÈÈ, ¹ 19, 2000
