Journal of Comparative Physiology B

, Volume 188, Issue 4, pp 657–669 | Cite as

Chronic captopril treatment reveals the role of ANG II in cardiovascular function of embryonic American alligators (Alligator mississippiensis)

  • Casey A. Mueller
  • John Eme
  • Kevin B. Tate
  • Dane A. CrossleyII
Original Paper


Angiotensin II (ANG II) is a powerful vasoconstrictor of the renin–angiotensin system (RAS) that plays an important role in cardiovascular regulation in adult and developing vertebrates. Knowledge of ANG II’s contribution to developmental cardiovascular function comes from studies in fetal mammals and embryonic chickens. This is the first study to examine the role of ANG II in cardiovascular control in an embryonic reptile, the American alligator (Alligator mississippiensis). Using chronic low (~ 5-mg kg embryo−1), or high doses (~ 450-mg kg embryo−1) of captopril, an angiotensin-converting enzyme (ACE) inhibitor, we disrupted the RAS and examined the influence of ANG II in cardiovascular function at 90% of embryonic development. Compared to embryos injected with saline, mean arterial pressure (MAP) was significantly reduced by 41 and 72% under low- and high-dose captopril treatments, respectively, a greater decrease in MAP than observed in other developing vertebrates following ACE inhibition. Acute exogenous ANG II injection produced a stronger hypertensive response in low-dose captopril-treated embryos compared to saline injection embryos. However, ACE inhibition with the low dose of captopril did not change adrenergic tone, and the ANG II response did not include an α-adrenergic component. Despite decreased MAP that caused a left shifted baroreflex curve for low-dose captopril embryos, ANG II did not influence baroreflex sensitivity. This study demonstrates that ANG II contributes to cardiovascular function in a developing reptile, and that the RAS contributes to arterial blood pressure maintenance during development across multiple vertebrate groups.


Angiotensin-converting enzyme inhibitor Baroreflex Blood pressure Heart rate Reptile 



The study was supported by the National Science Foundation (Career award IBN IOS-0845741 to DAC).


  1. Altimiras J, Franklin CE, Axelsson M (1998) Relationships between blood pressure and heart rate in the saltwater crocodile Crocodylus porosus. J Exp Biol 201(15):2235–2242PubMedGoogle Scholar
  2. Berger PJ, Evans BK, Smith DG (1980) Localization of baroreceptors and gain of the baroreceptor-heart rate reflex in the lizard Trachydosaurus Rugosus. J Exp Biol 86(1):197–209Google Scholar
  3. Bottari SP, de Gasparo M, Steckelings UM, Levens NR (1993) Angiotensin II receptor subtypes: characterization, signalling mechanisms, and possible physiological implications. Front Neuroendocrin 14(2):123–171CrossRefGoogle Scholar
  4. Brooks VL, Reid IA (1986) Interaction between angiotensin II and the baroreceptor reflex in the control of adrenocorticotropic hormone secretion and heart rate in conscious dogs. Circ Res 58(6):816–828CrossRefPubMedGoogle Scholar
  5. Brown SR, Stevens GA, Todt MJ (1983) Systemic and renal effects of angiotensin II in the freshwater turtle Pseudemys scripta elegans. Am J Physiol Reg Int Comp Physiol 245(6):R837–R842CrossRefGoogle Scholar
  6. Crossley DA II, Burggren WW, Altimiras J (2003a) Cardiovascular regulation during hypoxia in embryos of the domestic chicken Gallus gallus. Am J Physiol Regul Integr Comp Physiol 284(1):R219-226CrossRefGoogle Scholar
  7. Crossley DA II, Hicks JW, Altimiras J (2003b) Ontogeny of baroreflex control in the American alligator Alligator mississippiensis. J Exp Biol 206(16):2895–2902CrossRefPubMedGoogle Scholar
  8. Crossley DA II, Hicks JW, Altimiras J (2003c) Ontogeny of baroreflex control in the American alligator Alligator mississippiensis. J Exp Biol 206:2895–2902CrossRefPubMedGoogle Scholar
  9. Crossley DA II, Altimiras J (2005) Cardiovascular development in embryos of the American alligator Alligator mississippiensis: effects of chronic and acute hypoxia. J Exp Biol 208(Pt 1):31–39CrossRefPubMedGoogle Scholar
  10. Crossley DA II, Burggren WW (2009) Development of cardiac form and function in ectothermic sauropsids. J Morphol 270(11):1400–1412CrossRefPubMedGoogle Scholar
  11. Crossley D II, Jonker S, Hicks J, Thornburg K (2010) Maturation of the angiotensin II cardiovascular response in the embryonic White Leghorn chicken (Gallus gallus). J Comp Physiol B 180(7):1057–1065CrossRefPubMedPubMedCentralGoogle Scholar
  12. Crossley DA II, Altimiras J (2012) Effect of selection for commercially productive traits on the plasticity of cardiovascular regulation in chicken breeds during embryonic development. Poult Sci 91(10):2628–2636CrossRefPubMedGoogle Scholar
  13. Daïkha-Dahmane F, Levy-Beff E, Jugie M, Lenclen R (2006) Foetal kidney maldevelopment in maternal use of angiotensin II type I receptor antagonists. Pediatr Nephrol 21(5):729–732CrossRefPubMedGoogle Scholar
  14. Deeming DC, Ferguson MWJ (1989) Effects of incubation temperature on growth and development of embryos of Alligator mississippiensis. J Comp Physiol B 159:183–193CrossRefGoogle Scholar
  15. Dendorfer A, Thornagel A, Raasch W, Grisk O, Tempel K, Dominiak P (2002) Angiotensin II induces catecholamine release by direct ganglionic excitation. Hypertension 40(3):348–354CrossRefPubMedGoogle Scholar
  16. Düsing R, Kayser G, Wagner S, Scherf H, Glänzer K, Predel H-G, Kramer HJ (1987) Baroreflex setting and sensitivity in normal subjects: effects of pharmacologic inhibition of the angiotensin I converting enzyme. Am J Cardiol 59(10):D50–D54CrossRefGoogle Scholar
  17. Eme J, Altimiras J, Hicks JW, Crossley DA II (2011a) Hypoxic alligator embryos: chronic hypoxia, catecholamine levels and autonomic responses of in ovo alligators. Comp Biochem Physiol A 160(3):412–420CrossRefGoogle Scholar
  18. Eme J, Crossley DA, Hicks JW (2011b) Role of the left aortic arch and blood flows in embryonic American alligator (Alligator mississippiensis). J Comp Physiol B 181(3):391–401CrossRefPubMedGoogle Scholar
  19. Eme J, Hicks JW, Crossley DA II (2011c) Chronic hypoxic incubation blunts a cardiovascular reflex loop in embryonic American alligator (Alligator mississippiensis). J Comp Physiol B 181(7):981–990CrossRefPubMedGoogle Scholar
  20. Eme J, Rhen T, Tate K, Gruchalla K, Kohl Z, Slay C, Crossley DA II (2013) Plasticity of cardiovascular function in snapping turtle embryos (Chelydra serpentina): chronic hypoxia alters autonomic regulation and gene expression. Am J Physiol Reg Int Comp Physiol 304:R966–R979CrossRefGoogle Scholar
  21. Esteves CA, Burckhardt PL, Breno MC (2012) Presence of functional angiotensin II receptor and angiotensin converting enzyme in the aorta of the snake Bothrops jararaca. Life Sci 91(19–20):944–950CrossRefPubMedGoogle Scholar
  22. Farrell DM, Wei C-C, Tallaj J, Ardell JL, Armour JA, Hageman GR, Bradley WE, Dell’Italia LJ (2001) Angiotensin II modulates catecholamine release into interstitial fluid of canine myocardium in vivo. Am J Physiol Heart Circ Physiol 281(2):H813–H822CrossRefPubMedGoogle Scholar
  23. Ferguson MWJ (1985) Reproductive biology and embryology of the crocodilians. In: Gans C, Billet F, Maderson P (eds) Biology of the reptilia, vol 14. Wiley, New York, pp 329–491Google Scholar
  24. Friberg P, Sundelin B, Bohman S-O, Bobik A, Nilsson H, Wickman A, Gustafsson H, Petersen J et al (1994) Renin–angiotensin system in neonatal rats: induction of a renal abnormality in response to ACE inhibition or angiotensin II antagonism. Kidney Int 45(2):485–492CrossRefPubMedGoogle Scholar
  25. Garner MG, Phippard AF, Fletcher PJ, Maclean JM, Duggin GG, Horvath JS, Tiller DJ (1987) Effect of angiotensin II on baroreceptor reflex control of heart rate in conscious baboons. Hypertension 10(6):628–634CrossRefPubMedGoogle Scholar
  26. Guo GB, Abboud FM (1984) Angiotensin II attenuates baroreflex control of heart rate and sympathetic activity. Am J Physiol Heart Circ Physiol 246(1):H80–H89CrossRefGoogle Scholar
  27. Harrison-Bernard LM (2009) The renal renin–angiotensin system. Adv Physiol Educ 33(4):270–274CrossRefPubMedGoogle Scholar
  28. Hatton R, Clough D, Faulkner K, Conway J (1981) Angiotensin-converting enzyme inhibitor resets baroreceptor reflexes in conscious dogs. Hypertension 3(6):676–681CrossRefPubMedGoogle Scholar
  29. JÓ§hren O, Dendorfer A, Dominiak P (2004) Cardiovascular and renal function of angiotensin II type-2 receptors. Cardiovasc Res 62(3):460–467CrossRefGoogle Scholar
  30. Lee WB, Lumbers ER (1981) Angiotensin and the cardiac baroreflex response to phenylephrine. Clin Exp Pharmacol P 8(2):109–117CrossRefGoogle Scholar
  31. Lumbers ER, Kingsford NM, Menzies RI, Stevens AD (1992) Acute effects of captopril, an angiotensin-converting enzyme inhibitor, on the pregnant ewe and fetus. Am J Physiol Reg Int Comp Physiol 262(5):R754–R760CrossRefGoogle Scholar
  32. Martinovic J, Benachi A, Laurent N, Daïkha-Dahmane F, Gubler MC (2001) Fetal toxic effects and angiotensin-II-receptor antagonists. Lancet 358(9277):241–242CrossRefPubMedGoogle Scholar
  33. Matsumura Y, Hasser EM, Bishop VS (1989) Central effect of angiotensin II on baroreflex regulation in conscious rabbits. Am J Physiol Reg Int Comp Physiol 256(3):R694–R700CrossRefGoogle Scholar
  34. Mueller CA, Crossley DA II, Burggren WW (2014) The actions of the renin–angiotensin system on cardiovascular and renal development in embryonic chickens (Gallus gallus domesticus). Comp Biochem Physiol A 178:37–45CrossRefGoogle Scholar
  35. Mueller CA, Burggren WW, Crossley DA II (2013) Angiotensin II and baroreflex control of heart rate in embryonic chickens (Gallus gallus domesticus). Am J Physiol Reg Int Comp Physiol 305:R855–R863CrossRefGoogle Scholar
  36. Nishimura H, Nakamura Y, Sumner RP, Khosla MC (1982) Vasopressor and depressor actions of angiotensin in the anesthetized fowl. Am J Physiol Heart Circ Physiol 242(3):H314–H324CrossRefGoogle Scholar
  37. Reid I (1996) Angiotensin II and baroreflex control of heart rate. Physiology 11(6):270–274CrossRefGoogle Scholar
  38. Robillard JE, Nakamura KT (1988) Neurohormonal regulation of renal function during development. Am J Physiol Renal Physiol 254(6):F771–F779CrossRefGoogle Scholar
  39. Robillard JE, Weismann DN, Gomez RA, Ayres NA, Lawton WJ, VanOrden DE (1983) Renal and adrenal responses to converting-enzyme inhibition in fetal and newborn life. Am J Physiol Reg Int Comp Physiol 244(2):R249–R256CrossRefGoogle Scholar
  40. Segar JL, Merrill DC, Robillard JE (1994) Role of endogenous ANG II on resetting arterial baroreflex during development. Am J Physiol Heart Circ Physiol 266(1):H52–H59CrossRefGoogle Scholar
  41. Siegel SR, Fisher DA (1980) Ontogeny of the renin–angiotensin–aldosterone system in the fetal and newborn lamb. Pediatr Res 14(2):99–102CrossRefPubMedGoogle Scholar
  42. Silldorff EP, Stephens GA (1992) Effects of converting enzyme inhibition and α receptor blockade on the angiotension pressor response in the American alligator. Gen Comp Endocrinol 87(1):134–140CrossRefPubMedGoogle Scholar
  43. Tate KB, Eme J, Swart J, Conlon JM, Crossley DA II (2012) Effects of dehydration on cardiovascular development in the embryonic American alligator (Alligator mississipiensis). Comp Biochem Physiol A 162:252–258CrossRefGoogle Scholar
  44. Tate KB, Rhen T, Eme J, Kohl ZF, Crossley J, Elsey RM, Crossley DA (2016) Periods of cardiovascular susceptibility to hypoxia in embryonic American alligators (Alligator mississippiensis). Am J Physiol Reg Int Comp Physiol 310(11):R1267–R1278CrossRefGoogle Scholar
  45. Tufro-McReddie A, Romano LM, Harris JM, Ferder L, Gomez RA (1995) Angiotensin II regulates nephrogenesis and renal vascular development. Am J Physiol Renal Physiol 269(1):F110–F115CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Casey A. Mueller
    • 1
  • John Eme
    • 1
  • Kevin B. Tate
    • 2
  • Dane A. CrossleyII
    • 3
  1. 1.Department of Biological SciencesCalifornia State University San MarcosSan MarcosUSA
  2. 2.Department of BiologyTruman State UniversityKirksvilleUSA
  3. 3.Developmental Integrative Biology, Department of Biological SciencesUniversity of North TexasDentonUSA

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