Endojen adenozin’in santral solunum kontrol mekanizmalarına etkisi

Çalışmamızda Na-pentobarbital (25 mg/kg i.v) ile anesteziye edilen intakt (Periferik kimoreseptörleri sağlam) ve periferik kimoreseptörleri denerve tavşanlar kullanıldı. Her iki grup tavşanda sol lateral ventrikül içine adenozin geri-alım inhibitörü olan dipyridamole (0.05-0.1 mg) yan ventrikül içine intraserebroventriküler (ICV) uygulanarak, endojen adenozinin'in santral solunum kontrol mekanizmalarına ve hipoksiye karşı oluşan solunumsal cevaba etkisi incelendi. İntakt ve kimodenerve grup tavşanlara, ICV dipyridamole uygulanması öncesinde ve sonrasında, gerek hava (normoksi) gerek¬se hipoksik gaz karışımı (% 8 O2 - % 92 N2) solutulmasında soluk hacmi (VT), solunum frekansı (f/dk.) ve sistemik arteriyel basınç (SAB) poligrafta kaydedildi. Vrve f/dk. değerlerinden solunum dakika hacmi (VE) hesaplandı. İntakt grup tavşanlara hipoksik gaz karışımı solutulması f/dk., V-r, VE ve SAB'da anlamlı artışlar oluşturdu (p < 0.01, p < 0.05, p < 0.05, p < 0.001). ICV dipyridamole verilmesi ise, VT ve VE'de anlamlı artışlar meydana getirirken (p < 0.05, p < 0.05), f/dk.'da anlamsız bir azalma oluşturdu. SAB'da ise anlamlı bir azalma gözlendi (p < 0.05). Periferik kimodenerve tavşanlara hipoksik gaz karışımı solutulmasında f/dk., VT, VE ve SAB'da anlamlı azalmalar gözlendi (p < 0.01, p < 0.001, p < 0.001, p < 0.001). ICV dipyridamole ise VT, VE veSAB'ı anlamlı olarak azaltırken (p < 0.01, p < 0.05, p < 0.001), f/dk.'da anlamsız bir artış oluşturdu. Dipyridamole ile birlikte hipoksi uygulanmasında benzer bulgular elde edildi. Sonuç olarak bulgularımız, beyinde dipyridamole ile oluşturulan endojen adenozin'in, ventilasyona olan santral etkilerinin, hipoksinin direkt merkezsel etkilerine benzer şekilde, inhibitor nitelikte olduğunu göstermektedir.

Effect of endogenous adenosine on central respiratory control mechanisms

In this study the effect of endogen adenosine on central respiratory control mechanisms and hypoxic ventilatory responses was investigated. For this purpose dipyridamole, an adenosine reuptake inhibitor was injected into left lateral cerebral ventricle (ICV) of anesthetized (Na-pentobarbital 25 mg/kg i.v) peripheral chemoreceptors intact and chemodenervated rabbits. Systemic arterial blood pressure (BP), tidal volume (VT) and respiratory frequency (f/min) were recorded while the animals were breathing air or hypoxic gas mixture (8 % O2 - 92 % N2) before and after dipyridamole (0.05-0.1 mg ICV) administration, f/min, VT ,VE and BP increased significantly during hypoxic gas mixture breathing before dipyridamole administration in intact rabbits (p < 0.0'1, p < 0.05, p < 0.05, p < 0.001). When dipyridamole was administered (ICV) during air breathing VT and VE increased significantly (p < 0.05, p < 0.05) while no significant decreases was observed in f/min. BP decreased significantly (p < 0.05). On the breathing of hypoxic gas mixture before dipyridamole administration of chemodenervated rabbits, the decreases in f/min,VT ,VE and BP were founded significantly (p < 0.01, p < 0.001, p < 0.001, p < 0.001). ICV administration of dipyridamole during 'Rormoxia caused significant decreases in VT, VE and BP (p < 0.01, p < 0.05 p < 0.001) while no significant change was observed in f/min. Comparable findings were obtained when dipyridamole was administered during hypoxic gas mixture breathing. The results of this study show that augmentation of endogenous adenosine in brain with dipyridamole produces a direct inhibitory effect on central respiratory control mechanisms similar to that of hypoxia.

___

  • 1. Vizek M, Pickett CK, Weil JV. Biphasic ventilatory response of adult cats to sustained hypoxia has central origin. J Appl Physiol 1987; 63: 1658-1664.
  • 2. Şahin G, Terzioğlu M. The influence of chronic hypoxia on erytrocytic 2.3 diphospho glycerate and the sensivity of peripheral chemoreceptors of rabbits. Cerrahpaşa Med Rev 1985; 4: 46-56.
  • 3. Maxova M, Vizek M. Biphasic ventilatory response to hypoxia in unanesthetized rats. Physiol Res 2001 ; 50:91-96.
  • 4. Maxova H, Vizek M. Ventilatory response to sustained hypoxia in carotid body denervated rats. Physiol Res 2001; 50: 327-331.
  • 5. Long WO, Ggiestbrecht GG,Anthonisen NR. Ventilatory response to moderate hypoxia in awake chemode-nervated cats. J Appl Physiol 1993; 74: 805-810.
  • 6. Richter DW, Schmit-Garcon P, Pierrefishe O, and et al. Neurotransmitters and neuromodulators controlling the hypoxic respiratory response in anesthetized cat. J Physiol 1999; 514: 567-578.
  • 7. Winn HR, Rubio R, Berne RM. Brain adenosine concentrationduring hypoxia in rats. Am J Physiol 1981; 241:235-242.
  • 8. Gourine AV, Llaudet E, Thomas T, and et al. Adenosine release in nucleus tractus solitarii does not appear to mediate hypoxia induced respiratory depression in rats. J Physiol 2002; 544: 161-170.
  • 9. Wu JD. A possible role for gamma amino butyric acid in the homeostatic control of brain metabolism under conditions of hypoxia. Exp Brain Res 1967; 4:81-84.
  • 10. Melton JE, Neubauer JA, Edelman NH. Gaba antagonism reverses hypoxic respiratory depression in the cat. J Appl Physiol 1990; 69: 1296-1301.
  • 11. Yelmen NK. Anestezi verilmiş tavşanlara intraserebroventriküler GABA verilmesinin hipoksik solunum cevabına etkisi. Solunum 2003; 5: 73-80.
  • 12. Tatsumi K, Pickett CK, Weil JW. Effect of haloperidol and domperidone on ventilatory roll off during sustained hypoxia in cats. J Appl Physiol 1992; 72: 1945-1952.
  • 13. Guner İ, Yelmen N, Şahin G, ve ark. The effect of intracerebroventriculardopamine administration on the respiratory response to hypoxia. Tohoku J Exp Med 2002; 196: 219-230.
  • 14. Wenging L, Lobchuk D, Anthonjshen NR. Ventilatory response to CO2 and hypoxia after sustained hypoxia in awake cats. J Appl Physiol 1994; 76: 2262-2266.
  • 15. Krnjevic K. Early effects of hypoxia on brain cell function. Croat Med J 1999; 40: 375-380.
  • 16. Elridge FL, Milhorn DE, Waldrop TG, and et al. Mechanism of respiratory effects of methylxanthines. Respir Physiol 1983; 53: 239-261.
  • 17. Phillis JW, Kostopoulus GK, LimacherJJ. Depression of cortico-spinal cells by various purines and pyrimidines. Can J Physiol Pharmacol 1974; 52: 1226-1229.
  • 18. Elridge FL, Milhor DE, Kiley JP. Respiratory effect of a long-acting analog of adenosine. Brain Res 1984; 301:273-280.
  • 19. Cunha RA. Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors (Review). Neurochem lnt2001;38: 107-125.
  • 20. Engelstein ED, Lerman BB, Somers VK, and et al. Role of arterial chemoreceptors in mediating the effects of endogenous adenosine on sympathetic nerve activity. Circulation 1994; 90: 2919-2926.
  • 21. Oruç T, Terzioğlu M, Şahin G, ve ark. Response of the central respiratory control mechanism to hyperoxia and hypoxia. Bull Europ Physiopath Resp 1982; 18:439-447.
  • 22. Oruc T. The activation of the central and peripheral respiratory control mechanism in hyperoxia and hypoxia. Bull Europ Physiopath Resp Suppl 1982; 18:113.
  • 23. Terzioğlu M, Yiğit G, Oruç T. Fizyoloji ders kitabı. Cilt II (Genişletilmiş 2. baskı), İstanbul Üniversitesi Cerrahpaşa Tıp Fakültesi Yayınları. İstanbul, 1993.
  • 24. Klabunde RE. Dipyridamole inhibition of adenosine metabolism in human blood. EurJ Pharmacol 1983; 93:21-26.
  • 25. Sollevi A, Stergren J, Fagrell B, and et al. Teophylline antagonizes cardio-vascular responses to dipyridamole in man without affecting increases in plasma adenosine. Acta Physiol Scand 1984; 121:165-171.
  • 26. Runold M, Lagercrantz H, Fredholm BB. Ventilatory effect of an adenosine analogue in unanesthetized rabbits during devolopment. J Apll Physiol 1986; 61: 255-259.
  • 27. Brundege JM, Dunwiddio TV. Role of adenosine as a modulator of synaptic activity in the central nervous system. Advances in Pharmacol 1997; 39: 353-391.
  • 28. Herlenius E, Lagercrantz H. Adenosinergic modulation of the respiratory neurons in the neonatal rat brainstem in vitro. J Physiol 1999; 518: 159-172.
  • 29. Kang MJ, Park MS, Shin IC, and et al. Modification of cardiovascular response of posterior hipotalamic adenosine A2 receptor stimulation by adenylate cyclase, guanilate cyclase and by K(ATP) channel blockade in anesthetized rats. Neurosci Lett 2003; 344:57-61.
  • 30. Lee HH, Koh HC, Chae SL, and et al. Modification of cardiovascular responses to adenosine Al receptor stimulation in the posterior hypothalamus of anaesthetized ratss by cAMP and by GABA (B) receptor blockade. J Auton Pharmacol 2001; 21: 249-254.
  • 31. Lo WC, Jan CR, Wu SN, and et al. Cardiovascular effectsof nitric oxide and adenosine in the nucleus tractus solitarii of rats. Hypertension 1998; 32:1034-1038.
  • 32. Beckenbosh A, De Gioede J. Effects of brain hypoxia on ventilation Eur Respir J 1988; 1: 184-190.
  • 33. Herlenius E, Lagercrantz H, Yamamoto Y. Adenosine modulates inspiratory neurons and the respiratory pattern in the brainstem of neonatal rats. Pediatric Researc 1997; 42: 46-53.