| Sažetak | Uvod: Frenička dugoročna facilitacija (pLTF) predstavlja dugotrajno povećanje respiracijskoga motornog odgovora nakon epizoda akutne intermitentne hipoksije (AIH), ali ne i nakon akutne trajne hipoksije sličnog kumulativnog trajanja. Smatra se oblikom respiracijske plastičnosti ovisne o serotoninu (5-HT). pLTF je dokazan u štakora anesteziranih uretanom. Dosad nije istraživan utjecaj propofolske monoanestezije na pojavu pLTF u modelu AIH u anesteziranog štakora. Hipoteza je da će propofol oslabiti pLTF u odnosu na uretan. U drugom dijelu rada ispitalo se moguće mehanizme djelovanja propofola na pLTF usporedbom učinaka intravenske primjene agonista 5-HT1A receptora 8-OH DPAT-a. Metode: Četrnaest odraslih, muških, vagotomiranih, paraliziranih i mehanički ventiliranih Sprague-Dawley štakora (7 u svakoj skupini) bilo je izloženo hipoksijskim epizodama (FiO2 = 9%) po obrascu 5x3 minute (TH1-TH5), međusobno odvojenih s 3 minute hiperoksije (FiO2=50%). Životinje su bile pod uretanskom (1,2 g/kg intraperitonejski, skupina U) ili propofolskom anestezijom (intravenski bolus 11,9 mg/kg + infuzija 78 mg/kg/h, skupina P). Vršna aktivnost freničkoga živca (PNA), frekvencija izbijanja (f), te parametri ritma disanja (Ti, Te, Ttot) analizirani su i uspoređeni s kontrolnim bazalnim vrijednostima i to tijekom prve hipoksijske epizode (TH1), kao i 15 (T15), 30 (T30) i 60 (T60) minuta iza završetka posljednje hipoksijske epizode. U drugom dijelu eksperimenta (n=10) promjena freničkoga neurograma nakon injiciranja lijeka uspoređivana je s kontrolnim vrijednostima prije davanja 8-OHDPAT. Rezultati: Izokapnija se uspješno održavala tijekom čitavog protokola. U skupini P, PNA se nije značajno promijenila ni u jednoj vremenskoj točki nakon završetka zadnje hipoksijske epizode, tj. pLTF je bio ugašen. Postojalo je značajno povećanje PNA u skupini U u točki T60, a u usporedbi s kontrolom (59,4 ± 6,6%, P<0,001), odnosno zabilježen je pLTF. Tijekom prve hipoksijske epizode, PNA je bila značajno povišena u obje skupine životinja u odnosu na kontrolu (172,0 ± 15,8 % u skupini U, a 106,8 ± 16,9 % u skupini P, P<0,001). Za vrijeme svih hipoksijskih epizoda (TH1–TH5) HVR je bio održan u obje skupine životinja (P<0,001 u usporedbi s bazalnom PNA). Međutim, akutni HVR bio je veći u skupini U u odnosu na skupinu P (P<0,001). AIH nije dovela ni u jednoj vremenskoj točki nakon zadnje hipoksijske epizode (T15, T30, T60) do značajnih promjena f, kao ni parametara vezanih za ritam disanja (Ti, Te, Ttot) u obje ispitivane skupine. U drugom dijelu eksperimenta davanje 8-OH DPAT nije dovelo do povećanja PNA u 40% ispitanih životinja u skupini P. Zaključak: Potvrđena je hipoteza da veličina pLTF ovisi u korištenom anestetiku. pLTF je jasno dokazan u životinja anesteziranih uretanom 60 minuta iza zadnje hipoksijske epizode, te se očitovao značajnim porastom amplitude, ali ne i frekvencije. Nasuprot ovome, pLTF je bio ugašen u štakora anesteziranih propofolom. Mogući mehanizmi su kombinirani učinci propofola na sinaptičku plastičnost, interakcija s 5-HT receptorima u kontroli disanja (nekonzistentno povećanje PNA nakon iv primjene 8-OHDPAT-a), kao i neizravni učinci putem kvantitativnih ili kvalitativnih promjena HVR. Ti rezultati mogli bi imati kliničku važnost u onih bolesnika koji su ovisni o fenomenu respiracijske plastičnosti, a to su oni s opstrukcijskom sleep apnejom, te zatajenjem disanja nakon ozljeda leđne moždine ili u sklopu raznih neurodegenerativnih bolesti, posebice kad se podvrgavaju propofolskoj sedaciji i anesteziji. |
| Sažetak (engleski) | Background: Phrenic long term facilitation (pLTF) is sustained augmentation of respiratory motor output elicited by acute intermittent hypoxia (AIH), but not acute sustained hypoxia of similar cumulative duration. It is considered as a serotonin (5-HT)-dependent form of the respiratory plasticity. The pLTF was demonstrated in urethane-anesthetized rats. So far, the influence of propofol anesthesia on pLTF in the model of AIH has not been studied in rats. We hypothesized that pLTF would be abolished during propofol- compared with urethane anesthesia. In the second part of the study, the possible mechanism of propofol action was tested with intravenous administration of specific 5-HT1A receptor agonist 8-hydroxy-2-di- npropylamino-tetralin (8-OH-DPAT). Methods: Fourteen adult, male, anesthetized, vagotomized, paralyzed, and mechanically ventilated Sprague–Dawley rats (seven per group), were exposed to the AIH, i.e. five (TH1- TH5), 3-min hypoxic episodes (FiO2=9%), separated by 3 minutes of hyperoxia (FiO2=50%). The animals were urethane-anesthetized (1.2 g/kg i.p., group U) or propofol-anesthetized (iv bolus 11.9 mg/kg + infusion 78 mg/kg/h, group P). Peak phrenic nerve activity (PNA), burst frequency (f), and breathing rhythm parameters (Ti, Te, Ttot) were analyzed during the first hypoxia (TH1), as well as at 15 (T15), 30 (T30), and 60 min (T60) after the final hypoxic episode, and compared to the baseline values.protocol. Regarding the second part of the study (n=10), PNA was analyzed during 60 minutes after administration of 8-OHDPAT and compared to the baseline values immediately before the administration of 8-OHDPAT. Results: Isocapnia was successfully maintained throughout the protocol. In propofol- anesthetized rats no significant changes of PNA were recorded after the last hypoxic episode, i.e. no pLTF was induced. There was a significant increase of PNA (59.4 ± 6.6%, P<0,001) in urethane-anesthetized group at T60, i.e. pLTF was observed. During the first hypoxic episode, PNA was significantly increased in both urethane- and propofol-anesthetized rats (172.3 ± 15.8% in the group U vs 106.8 ± 16.9 % in the group P, P<0.001). HVR in either group of animals was preserved during all five (TH1–TH5) hypoxic episodes (P<0.001 compared with baseline phrenic nerve activity). Also, the acute HVR was greater in urethane-anesthetized compared with propofol-anesthetized animals (P<0.001). AIH did not elicit significant changes in f, Ti, Te, and Ttot in either group at T15, T30, and T60. During the second part of the study, intravenous administration of 8-OHDPAT failed to increase PNA in 40 per cent of the propofol-anesthetized animals. Conclusions: We confirmed the hypothesis that the magnitude of pLTF was influenced by the specific anesthetic used. The pLTF was observed in urethane-anesthetized rats 60 min after the last hypoxia and was expressed mainly as amplitude, and not frequency pLTF. On the contrary, pLTF was abolished in the propofol-anesthetized rats. We might speculate about combined effects of propofol on synaptic plasticity, interaction with 5-HT receptors in the control of breathing (inconsistent increase of PNA after intravenous 8-OHDPAT), as well as about indirect effects through quantitative or qualitative alterations in HVR. These findings could have clinical implications, especially in patients dependent on respiratory plasticity, i.e. patients suffering from obstructive sleep apnea and respiratory insufficiency either following spinal cord injury or during neurodegenerative diseases and undergoing propofol anesthesia. |
