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ExperimentalPhysiologyPhysiological Society Symposium - Vagal Control: From Axolotl to Man

The crocodilian heart; more controlled than we thought?Michael Axelsson *

Department of Zoolog y, Goteborg University, PO Box 463, SE-40530 Goteborg, Sweden

CONTENTS PAGEIntroduction 785The subpulmonary conus 786The foramen of Panizza 787The aortic anastomosis 788Future directions 788References 788

ExperimentalPhysiology (2001) 86.6,785-789.

IntroductionThere are large differences in the morphology of thevertebrate heart; from the fish heart with its single atrium andsingle ventricle to the crocodilian, bird and mammalian heartswith two fully separated atria and ventricles (van Mierop &Kutsche, 1985). It is only in crocodilians, birds and mammalswhere the heart has a complete interventricular septum, thata full intracardiac separation of blood pressure and flow inthe systemic and pulmonary circulations can occur. Inbirds and mammals the left ventricle gives rise to the aortasupplying the body with oxygenated blood and thepulmonary arteries arise from the right ventricle carryingdeoxygenated blood to the lungs. In these two animalgroups no intra- or extra-cardiac mixing of blood (shunting)is possible, and no shunting of blood between the pulmonaryand systemic circulations occurs in healthy adults. Thecrocodilians are unique in comparison to other reptiles andalso to birds and mammals. In comparison to other reptiles(snakes, lizards and turtles) the crocodilian heart is uniquein that the ventricle is fully divided into a left and a rightventricle whereas the non-crocodilian reptile heart is sub-divided into three intraventricular compartments that areinterconnected (no morphological subdivision of theventricle) allowing intracardiac mixing of oxygenated anddeoxygenated blood. The crocodilian heart is also uniquecompared to the bird and mammalian heart in that shuntingof blood away from the pulmonary circulation is still possibleas the right ventricle gives rise not only to the pulmonary

arteries but also to the left aorta (Fig. 1). This allowsdeoxygenated blood from the right ventricle to bypass thelungs and to be recirculated into the systemic circulation(pulmonary-to-systemic shunt). Apart from the extra leftaorta from the right ventricle, three other morphologicalfeatures of the crocodilian cardiovascular system have beenthe focus of discussion over recent years. (1) The foramen ofPanizza; an opening between the right and left aorta situatedin the common wall of the left and right aorta (Fig. 1A).(2) The subpulmonary conus situated in the pulmonary out-flow tract of the right ventricle (Fig. 1B). (3) The aorticanastomosis that connects the two aortic arches just posteriorto the heart (Fig. 1C; van Mierop & Kutsche, 1985). Thesubpulmonary conus contains connective tissue nodulesprotruding into the outflow tract that acts as an extra andunique valve mechanism (Fig. 1B). These three areas havereceived much attention from comparative physiologistsinterested in the function of the crocodiliadreptile circulation,and the evolution of the cardiovascular system and itsregulation. There is increasing evidence for a close regulationof the three unique structures in the crocodilian cardio-vascular system and their importance for the normal functionof the crocodilian circulation. This short overview will give asummary of the latest findings.Due to the anatomical arrangement of the heart and majorvessels, the mean blood pressure in the right and left aortasare equal and usually higher than the pulmonary pressure(Axelsson et al. 1989; Jones & Shelton, 1993). For a

Presented at the Oxford Meeting of the Physiological Society in March 2001.Publication of The Physiological Society * Email: [email protected]

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786 M. Axelsson Exp. Physiol. 86.6pulmonary-to-systemic shunt to develop the pressure in theright ventricle must exceed the pressure in the left aorta.Numerous mechanisms for the initiation and maintenanceof the pulmonary-to-systemic shunt have been described:(I ) increasing the end-diastolic volume of the right ventricle(Starling effect; Franklin & Axelsson, 1994; (2) increasing thepulmonary circuit resistance thus increasing right intra-ventricular pressure (White, 1969; Jones & Shelton, 1993);(3) decreasing the systemic vascular resistance (Jones &Shelton, 1993).The subpulmonary conusThe physiological significance of the subpulmonary conus inthe right ventricle of the crocodilian heart has been debatedfor many years (for discussion see Jones, 1995, 1996;Axelsson& Franklin, 1997). It is electrically separated fromthe rest of the right ventricle and contains connective tissuenodules that have been called cog-teeth (Grigg, 1989;Fig. 1). These nodules project from the subpulmonary conus

wall into the pulmonary outflow tract just proximal to thepulmonary leaflet-like valves. Evidence for a role of thesubpulmonary conus in initiating and regulating pulmonary-to-systemic shunts in crocodilians comes from pressurerecordings from the right ventricle and pulmonary arteryboth in anaesthetised (Jones & Shelton, 1993) andunanaesthetised animals (Axelsson et al. 1996). In both thealligator (Alligator mississippiensis) and saltwater crocodile(Crocodylusporosus) a biphasic pressure development in theright ventricle has been found (Grigg & Johansen, 1987;Jones& Shelton, 1993; Axelsson et al. 1996). The secondarypressure peak in the right ventricle is only possible if there isan increase in resistance in the pulmonary outflow tract, andthis cannot be attributed to the normal leaflet-like valves buthas to be a function of the subpulmonary conus with theextra cog-teeth valves. It is interesting that the same type ofpressure pattern is seen in the left ventricle and aorta ofhumans diagnosed with left ventricular hypertrophiccardiomyopathy (Murgo et al. 1980). The most accepted

Figure 1Schematic representation of the crocodilian heart, outflow tract and major arteries; arrows indicateblood flow pattern during non-shunting conditions. Blood is ejected from the left ventricle (LV) into theright aorta (RAo), right subclavian artery (RS) and the common carotid artery (CCA). The rightventricle (RV) ejects blood into the common pulmonary trunk that divides into the left and rightpulmonary artery (LPA and RPA). During a pulmonary-to-systemic shunt, blood is also ejected fromthe right ventricle into the left aorta (LAO) hat continues to the gut as the coeliac artery. The right andleft aortas communicate through the foramen of Panizza located a t the base of the aortas just outsidethe bicuspid semilunar valves ( A ) and posterior to the heart via the aortic anastomosis ( B ) . The cog-teeth valves are found in the subpulmonary conus just proximal to the bicuspid semilunar valves (C).



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Exp.Pliysiol. 86.6 Control o the crocodilian heart 787explanation for the ventricular-aortic pressure gradients inthese patients is a mechanical obstruction to left ventricularoutflow. In humans this is a pathological situation, but incrocodilians it is an effect of the cog-teeth valves in the rightventricular wall and represents a unique possibility forregulating the resistance of the pulmonary outflow tract.Further support for this was found in a study using anintracardiac angioscope to look at the various valves in thebeating heart of the Cuban crocodile (Cvocodylusrhomhfer). It was shown that the individual tissue nodules(cog-teeth valves) fitted snugly together and, during systole,reduced the diameter of the pulmonary outflow tract(Axelsson et al. 1996). This could explain the increase in theresistance in the subpulmonary conus and the developmentof the secondary pressure peak in the right ventricle. In amore recent study it was shown that the subpulmonaryconus is also regulated by p-adrenoceptors in such a waythat when the p-adrenergic tone on the heart is low the cog-teeth valves close more during systole thereby increasing theresistance between the right ventricle and the pulmonarycircuit, initiating a pulmonary-to-systemic shunt. When thep-adrenergic tone on the heart is high the cog-teeth valvesstay fully open and the crocodilian circulation works in thesame way as aviadmammalian hearts without any shuntingof blood between the pulmonary and systemic circuits(Fig. 2 4 Franklin & Axelsson, 2000). This fits with theresults from long term recordings of flow in unanaesthetisedanimals where during stress or exercise no shunts can beobserved, while at rest the pulmonary-to-systemic shunts areoperational up to 85% of the time (Jones, 1996). Of the threemechanisms listed above that can initiate and maintain apulmonary-to-systemic shunt, the subpulmonary conusfulfils the criteria for mechanisms 1 and 2. By increasing thepulmonary circuit resistance the shunt is initiated(mechanism 2), when a shunt is initiated more blood returnsto the right side of the heart leading to the Starling effectthat in itself can initiate/maintain a shunt (mechanism 1).The subpulinonary conus is obviously an important site forthe control of pulmonary blood flow in crocodilians, but arethe functions of the foramen of Panizza and the aorticanastomosis linked to that of the subpulmonaryconus andthe capacity of the crocodilian heart to shunt blood awayfrom the pulmonary circulation or do they have otherfunctions?The foramen of PanizzaThe foramen of Panizza was first described by the Italiananatomist B. Panizza in 1833 (Panizza, 1833). It is found deepwithin the pockets formed by the aortic valves and has beendescribed as an insignificant aperture in the common wall ofthe right and left aortic arch. In an angioscopic study of thebeating heart of the Cuban crocodile (Crocodylus rhombfer)it was shown that at physiological pressures the foramen ofPanizza is a substantial opening (around 3WO% of thediameter of the right aorta) between the two aortic arches(Fig. 1.4; Axelsson et al. 1996). The mean blood pressure inthe two aortic arches is equal, but the phasic pressures andblood flow profiles are more complicated. Under non-shunting conditions there is a multiphasic profile of pressure

and flow in the left aortic arch, which is due to the fact thatduring systole the medial cusp of the right aorta covers theforamen completely while in diastole when the valves areclosed the foramen is uncovered and there is a connectionbetween the two arches (Axelsson et al. 1989; Shelton &Jones, 1991; Malvin et al. 1995). This is further complicatedby the fact that there is another connection between the twoaortic arches further down in the abdomen called the aorticanastomosis (Fig. 1). During non-shunting conditions there isa small net blood flow from the right aorta into the left via theforamen of Panizza (Axelsson et al. 1989; Shelton & Jones,1991). In a few studies it was noted that the pressure profile ofthe right and left aorta was superimposable during the entire

Adr, 0.2 ml M

A A A1Adr, 10-7M Adr, M VIP, lo-*M0

i2" 70 -

1 minAdr 10-6M L-NAME 1 e 4 MI

Figure 2A , the effects of a bolus injections of adrenaline onthe pulmonary outflow resistance (Rp,,,)is shown.Recordings are taken from a double perfusedcrocodile heart. Adrenaline decreases the pulmonaryoutflow tract resistance leading to anavianlmammalian type of circulation with nopulmonary-to-systemic shunting of blood. B, theeffects of adrenaline and vasoactive intestinalpolypeptide (VIP) on the foramen of Panizza. Notethat VIP relaxes the adrenaline pre-contractedpreparations. C, the effects of adrenaline and thenitric oxide inhibitor L-NAME on the isolatedanastomosis ring preparations. Note the antagonisticaction of adrenaline and nitric oxide as indicated bythe oscillating tone in the preparation after additionof adrenaline.



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788 M. Axelsson Exp. Physiol. 86.6cardiac cycle, indicating that the foramen of Panizza wasopen during the entire cardiac cycle (White, 1956,1969; Grigg& Johanssen, 1987). Grigg& Johansen (1987) suggested thesevariable pressure and flow patterns seen in the left aorta, evenin the same animals at different times, could be a consequenceof a change in diameter of the foramen of Panizza. This maybe important during pulmonary-to-systemicshunts when lessblood is ejected from the left ventricle; they also suggestedthat during shunting a reversed foramen flow could occurwith blood flowing from the left into the right aorta.Morphologically the left aortic valves do not reach theforamen of Panizza as is the case with the medial cusp of theright aortic valves, and therefore there is no obstruction toflow from the left to the right aorta during any part of thecardiac cycle (Axelsson et al. 1996). The variable foramenhypothesis was debated for many years but more recently twostudies have presented evidence in favour of this hypotheis. Inthe study by Karila and coworkers it was shown that theforamen of Panizza and the surrounding tissue containedsmooth muscle cells and a number of potential neuro-transmitters were also identified including adrenaline andvasoactive intestinal polypeptide (VIP) (Karila et af. 1995). Ina more recent study by Axelsson& Franklin (2001) the effectsof the identified substances were tested and it was shown thatadrenaline produced a reduction in the diameter of theforamen of Panizza while VIP caused a relaxation of theadrenaline-induced contraction of the preparations (Fig. 2B).This is the first evidence in support of the variable foramenhypothesis proposed by Grigg& Johansen (1987).The aortic anastomosisThe last of the three unique structures in the crocodiliancardiovascular system to be discussed in this short overviewis the aortic anastomosis, a short muscular connectionbetween the right and left aorta just posterior to the heart(Fig. 1C). In contrast to the view of Webb (1979), Shelton&Jones(l991) pointed out that the aortic anastomosis is asubstantial connection between the two aortas and that itmight be of importance for the control of circulatoryfunction in crocodilians. In the non-shunting condition,blood flow in the aortic anastomosis is from the right to theleft aorta, and from there to the gastrointestinal canal sinceafter the anastomosis the left aorta becomes the coeliacartery (Fig. I) . Direct measurements of blood flow in theanastomosis have shown that it varies spontaneously overtime indicating a possible regulatory function for theanastomosis (Axelsson et af. 1997). In an immuno-histological study by Karila and coworkers (Karila et al.1995) a number of potential regulatory substances wereidentified and it was shown that both Substance P (SP) andNeuropeptide Y (NPY) increase the flow through theanastomosis. In a recent study by Axelsson and coworkers itwas shown that adrenaline and nitric oxide had profoundeffects on the isolated anastomosis (Fig. 2C;Axelsson et al.2001). Adrenaline induced contraction of the anastomosisbut this effect was counteracted by the release of nitric oxideresulting in a cyclic variation in the wall tension duringexposure to adrenaline; a basal nitric oxide-induced tone onthe anastomosis was also found. The aortic anastomosis

with its unusually thick media and adventitia resembles asphincter similar to the sphincters found in amphibians aridlungfish (Saint Aubain & Wingstrand, 1976; Fishman et al.1985). The significance of this muscular connection is stillunclear but experimentally it has been shown that if theanastomosis is closed, a pulmonary-to-systemic shuntdevelops (Axelsson et al. 1997). When the blood flowthrough the anastomosis ceases or is reduced the small netblood flow into the left aorta via the foramen of Panizza isnot enough to supply the gastrointestinal canal andtherefore the pressure in the left aorta falls below the level ofthe right intraventricular pressure and this initiates apulmonary-to-systemic shunt (mechanism 3 above).Another function of the aortic anastomosis might be toprevent back-flow of blood into the right aorta duringperiods of shunting, to maintain pressure in the left aorticarch for a reversed foramen flow (Axelsson & Franklin,1997).Future directionsThe functional significance of the actively regulatedintracardiac cog-teeth valves, the foramen of Panizza with itsvariable diameter, and the thick sphincter-like aorticanastomosis is still unclear but together with otherspecialisations, such as a modified haemoglobin (Bauer &Jelkman, 1977; Grigg& Gruca, 1979; Bauer et af. 1981) thesethree structures may increase the capacity for prolongeddiving in resting crocodilians. It is clear from the publisheddata that the answers to the final questions about thefunction of this unique circulatory system are not to be foundin the laboratory environment but in the field, and thatstudies should be carried out in a multidisciplinary way sincethere might not be a single answer.

AXELSSON, . & FRANKLIN,. E. (1997). From anatomy toangioscopy: 164 years of crocodilian cardiovascular research,recent advances and speculations. Comparative Biochemistry andPhysiology A 118, 51-62.AXELSSON, . & FRANKLIN,. E. (2001). The calibre of theforamen of Panizza in Crocodylus porosus is variable and underadrenergic control. Journal o Comparative Physiology B 171,AXELSSON,., FRANKLIN,., FRITSCHE,., GRIGG, .& NILSSON,S. (1997). The sub -pulmonary conu s and the arterial anastomosisas important sites of cardiovascular regulation in the crocodileCrocodylus porosus. Journal o Experimental Biology 200,807-8 14.AXELSSON,., FRANKLIN,. E., LOFMAN, . O., NILSSON, . &GRIGG,G. C. (1996). Dynamic anatomical study of cardiacshunting in crocodiles using high resolution an gioscopy. Journal o jExperimental Biology 199, 359-365.AXELSSON,., HOLM, . & NILSSON,. (1989). Flow dynamics ofthe crocodile heart. American Journal o Physiology 256,AXELSSON, ., OLSSON,C., GIBBINS,., HOLMGREN,. &

FRANKLIN,. E. (2001). Nitric oxide, a potent vasodilator of theaortic anastomosis in the estuarine crocodile, Crocodylus porosus.General and Comparative Endocrinology 122, 198-204.

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