Control of blood volume following hypovolemic challenge in vertebrates: Transcapillary versus lymphatic mechanisms.

Anurans have an exceptional capacity for maintaining vascular volume compared with other groups of vertebrates. They can mobilize interstitial fluids via lymphatic return at rates that are ten-fold higher than mammals. This extraordinary capacity is the result of coordination of specialized skeletal muscles and pulmonary ventilation that vary volume and pressure of subcutaneous lymph sacs, thus moving lymph to dorsally located lymph hearts that return lymph to the vascular space. Variation in the capacity to mobilize lymph within anurans varies with the degree of terrestriality, development of skeletal muscles, lung volume and lung compliance, and lymph heart pressure development. This ability enable anurans, which have the highest rates of evaporative water loss among terrestrial vertebrates, to withstand levels of dehydration far exceeding that of other vertebrates, and to successfully occupy virtually all terrestrial environments during their evolution. Maintenance of vascular fluid volume for all vertebrates can be achieved primarily by moving fluid from the interstitial space to the vascular space by transcapillary uptake and mobilization of interstitial (lymphatic) fluid. Transcapillary fluid uptake at the capillary level has been analyzed historically by Krogh and others from a Starling perspective and involves a balance of hydrostatic and oncotic forces. A complete evaluation of blood volume homeostasis also incorporates pressures and compliances of the vascular and interstitial spaces, but has been applied to only a few species. In this review we outline the current understanding of how anurans and other vertebrates maintain blood volume during hypovolemic challenges such as dehydration and hemorrhage which is crucial for maintaining cardiac output.

August Krogh's contribution to the rise of physiology during the first half the 20th century.

August Krogh (1874-1949) was amongst the most influential physiologists in the first part of the 20th century. This was an era when physiology emerged as a quantitative research field and when many of the current physiological disciplines were defined; Krogh can rightfully be viewed as having introduced comparative physiology, epithelial transport and - together with Johannes Lindhard - exercise physiology as independent disciplines. With a unique ability to design and construct equipment, Krogh could address novel questions in both human and animal physiology with unprecedented precision. Krogh would characteristically focus on a given physiological problem over a couple of years, delineate the focal mechanisms, provide a solution to the major problems, and then move onto new academic ground. For each of his major research areas (respiratory gas exchange, capillary function, osmoregulation), he wrote comprehensive books or monographs that remain important resources for scholars today, and he engaged in the writing of physiology textbooks for the Danish high school. Krogh's research appears to have been driven by curiosity to understand how animals (including humans) work, but he did not hesitate to apply his insight to societal and clinical problems throughout his long academic career.

WITHDRAWN: Utilizing comparative models in biomedical research.

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, Volume 255, 2021, 110593, https://doi.org/10.1016/j.cbpb.2021.110593. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

A metabolic hypothesis for the evolution of temperature effects on the arterial PCO2 and pH of vertebrate ectotherms.

Body temperature increases in ectothermic vertebrates characteristically lead to both increases in arterial PCO2  (PaCO2 ) and declines in resting arterial pH (pHa) of about 0.017 pH units per 1°C increase in temperature. This 'alphastat' pH pattern has previously been interpreted as being evolutionarily driven by the maintenance of a constant protonation state on the imidazole moiety of histidine protein residues, hence stabilizing protein structure-function. Analysis of the existing data for interclass responses of ectothermic vertebrates shows different degrees of PaCO2  increases and pH declines with temperature between the classes, with reptiles>amphibians>fish. The PaCO2  at the temperature where maximal aerobic metabolism (V̇O2,max) is achieved is significantly and positively correlated with temperature for all vertebrate classes. For ectotherms, the PaCO2  where V̇O2,max is greatest is also correlated with V̇O2,max, indicating there is an increased driving force for CO2 efflux that is lowest in fish, intermediate in amphibians and highest in reptiles. The pattern of increased PaCO2  and the resultant reduction of pHa in response to increased body temperature would serve to increase CO2 efflux, O2 delivery and blood buffering capacity and maintain ventilatory scope. This represents a new hypothesis for the selective advantage of arterial pH regulation from a systems physiology perspective in addition to the advantages of maintenance of protein structure-function.

Physiological vagility affects population genetic structure and dispersal and enables migratory capacity in vertebrates.

Vagility is defined as the relative capacity for movement. We developed previously a quantitative metric in vertebrates for physiological vagility (PV), the speed at which an animal can move sustainably, incorporating aerobic capacity, body size, body temperature, and transport costs, allowing quantitative tests of whether PV can explain variation in interclass population genetic structure and behaviors involved in dispersal. We found that PV increased with body mass, correlated with maximal dispersal distances, and was inversely related to genetic structure in multiple vertebrate groups. Here we review these relationships and expand our analysis to include additional groups; we also suggest that PV may be utilized to partially explain variation in migratory capacity between groups. We show a positive correlation between PV and maximum migration distance (MMAX) in most groups that reflects many of the relationships observed between PV and dispersal. Flying birds, marine mammals, and large terrestrial mammals display the greatest MMAX and each of these groups has the highest PV among vertebrate groups, while reptiles and small terrestrial mammals had the lowest PV and MMAX. By contrast, marine turtles have exceptional MMAX but do not possess high PV. We suggest that PV is an important mechanism enabling both dispersal and migratory capacity, and affects genetic structure, but that other life history characteristics also need to be considered.

Improved cardiac filling facilitates the postprandial elevation of stroke volume in Python regius.

To accommodate the pronounced metabolic response to digestion, pythons increase heart rate and elevate stroke volume, where the latter has been ascribed to a massive and fast cardiac hypertrophy. However, numerous recent studies show that heart mass rarely increases, even upon ingestion of large meals, and we therefore explored the possibility that a rise in mean circulatory filling pressure (MCFP) serves to elevate venous pressure and cardiac filling during digestion. To this end, we measured blood flows and pressures in anaesthetized Python regius The anaesthetized snakes exhibited the archetypal tachycardia as well as a rise in both venous pressure and MCFP that fully account for the approximate doubling of stroke volume. There was no rise in blood volume and the elevated MCFP must therefore stem from increased vascular tone, possibly by means of increased sympathetic tone on the veins. Furthermore, although both venous pressure and MCFP increased during volume loading, there was no evidence that postprandial hearts were endowed with an additional capacity to elevate stroke volume. In vitro measurements of force development of paced ventricular strips also failed to reveal signs of increased contractility, but the postprandial hearts had higher activities of cytochrome oxidase and pyruvate kinase, which probably serves to sustain the rise in cardiac work during digestion.

A meta-analysis of in vivo vertebrate cardiac performance: implications for cardiovascular support in the evolution of endothermy.

Endothermy in birds and mammals is associated with high body temperatures, and high rates of metabolism that are aerobically supported by elevated rates of cardiovascular O2 transport. The purpose of this meta-analysis was to examine cardiovascular data from ectothermic and endothermic vertebrates, at rest and during exercise, with the goal of identifying key variables that may have contributed to the role of the cardiovascular system in supporting high rates of O2 transport associated with endothermy. Vascular conductance, cardiac power and stroke work were summarized and calculated from a variety of studies at rest and during exercise for five classes of vertebrates where data were available. Conductance and cardiac power were linearly related to cardiac output from rest to exercise and also interspecifically. Exercise cardiac power and stroke work were greater in the endothermic species, owing to increased flow resulting from increased heart rate and increased pressure. Increased relative ventricle mass (RVM) was related to increased stroke volume in both groups. However, the increased RVM of endotherms was related to the increased pressure, as stroke work per gram of ventricle during exercise was equivalent between the groups. Cardiac power was linearly related to aerobic metabolic power, with 158 mW aerobic power output achieved per mW of cardiac power input. This analysis indicates that the greatly increased heart rate and cardiac stroke work leading to increased blood flow rate and blood pressure was necessary to support the metabolic requirements of endothermy.

Baroreflex function in anurans from different environments.

Anurans from terrestrial environments have an enhanced ability to maintain mean arterial blood pressure (P(m)) through lymph mobilization in response to desiccation or hemorrhage compared with semiaquatic or aquatic species. Because short term blood pressure homeostasis is regulated by arterial baroreceptors, we compared baroreflex function in three species of anurans that span a range of environments, dehydration tolerance and an ability to maintain P(m) with dehydration and hemorrhage. The cardiac limb of the baroreflex loop was studied using pharmacological manipulation of P(m) with phenylephrine and sodium nitroprusside (20­200 µg kg(− 1)), and the resulting changes in heart rate (f(H)) were quantitatively analyzed using a four-parameter sigmoidal logistic function. Resting P(m) in the aquatic species, Xenopus laevis, was 3.6 ± 0.3 kPa and was significantly less (P < 0.005) than for the semiaquatic species, Lithobates catesbeianus (4.1 ± 0.2 kPa), or the terrestrial species, Rhinella marina (4.7 ± 0.2 kPa). The maximal baroreflex gain was not different among the three species and ranged from 12.1 to 14.3 beats min( −1) kPa( −1) and occurred at P(m )ranging from 3.0 to 3.8 kPa, which were slightly below the resting P(m) for each species. Mean arterial blood pressures at rest in the three species were near the saturation point of the baroreflex curve which provides the animals with a greater fH response range to hypotensive, rather than hypertensive, changes in P(m). This is consistent with the hypothesis that arterial baroreceptors are key sensory components that allow anurans to maintain P(m) possibly by mobilization of lymphatic return in response to hypotension.

Reprint of "Baroreflex function in anurans from different environments".

Anurans from terrestrial environments have an enhanced ability to maintain mean arterial blood pressure (Pm) through lymph mobilization in response to desiccation or hemorrhage compared with semiaquatic or aquatic species. Because short term blood pressure homeostasis is regulated by arterial baroreceptors, we compared baroreflex function in three species of anurans that span a range of environments, dehydration tolerance and an ability to maintain Pm with dehydration and hemorrhage. The cardiac limb of the baroreflex loop was studied using pharmacological manipulation of Pm with phenylephrine and sodium nitroprusside (20-200µgkg(-1)), and the resulting changes in heart rate (fH) were quantitatively analyzed using a four-parameter sigmoidal logistic function. Resting Pm in the aquatic species, Xenopus laevis, was 3.6±0.3kPa and was significantly less (P<0.005) than for the semiaquatic species, Lithobates catesbeianus (4.1±0.2kPa), or the terrestrial species, Rhinella marina (4.7±0.2kPa). The maximal baroreflex gain was not different among the three species and ranged from 12.1 to 14.3beatsmin(-1)kPa(-1) and occurred at Pm ranging from 3.0 to 3.8kPa, which were slightly below the resting Pm for each species. Mean arterial blood pressures at rest in the three species were near the saturation point of the baroreflex curve which provides the animals with a greater fH response range to hypotensive, rather than hypertensive, changes in Pm. This is consistent with the hypothesis that arterial baroreceptors are key sensory components that allow anurans to maintain Pm possibly by mobilization of lymphatic return in response to hypotension.

Net cardiac shunts in anuran amphibians: physiology or physics?

Amphibians have a single ventricle and common conus arteriosus that produces an equal pressure to the parallel pulmocutaneous and systemic vascular circuits. The distribution of blood flows between the pulmocutaneous (Qpul) and systemic (Qsys) circuits (net cardiac shunt) varies with a number of environmental conditions and behaviours; although autonomic regulation of pulmonary vascular resistance conductance has been emphasized, little attention has been paid to the possible contribution of the passive physical characteristics of the two circuits to pressure changes associated with variation in cardiac output. In this study, we re-analysed three recent studies that recorded net cardiac shunts in the cane toad (Rhinella marina) under a variety of conditions and treatments. In all three studies, Qpul and Qsys were linearly related to cardiac output (Qtot), but the slope was threefold higher for Qpul compared with Qsys as predicted by relative conductance increases associated with increases in pressure from perfused preparations where autonomic regulation and humoral control were eliminated. Our analysis indicates that the net cardiac shunt in the cane toad is predicted primarily by the physical, rather than physiological, characteristics of the parallel pulmonary and systemic vascular circuits.

Physiological vagility and its relationship to dispersal and neutral genetic heterogeneity in vertebrates.

Vagility is the inherent power of movement by individuals. Vagility and the available duration of movement determine the dispersal distance individuals can move to interbreed, which affects the fine-scale genetic structure of vertebrate populations. Vagility and variation in population genetic structure are normally explained by geographic variation and not by the inherent power of movement by individuals. We present a new, quantitative definition for physiological vagility that incorporates aerobic capacity, body size, body temperature and the metabolic cost of transport, variables that are independent of the physical environment. Physiological vagility is the speed at which an animal can move sustainably based on these parameters. This meta-analysis tests whether this definition of physiological vagility correlates with empirical data for maximal dispersal distances and measured microsatellite genetic differentiation with distance {[F(ST)/[1-F(ST))]/ln distance} for amphibians, reptiles, birds and mammals utilizing three locomotor modes (running, flying, swimming). Maximal dispersal distance and physiological vagility increased with body mass for amphibians, reptiles and mammals utilizing terrestrial movement. The relative slopes of these relationships indicate that larger individuals require longer movement durations to achieve maximal dispersal distances. Both physiological vagility and maximal dispersal distance were independent of body mass for flying vertebrates. Genetic differentiation with distance was greatest for terrestrial locomotion, with amphibians showing the greatest mean and variance in differentiation. Flying birds, flying mammals and swimming marine mammals showed the least differentiation. Mean physiological vagility of different groups (class and locomotor mode) accounted for 98% of the mean variation in genetic differentiation with distance in each group. Genetic differentiation with distance was not related to body mass. The physiological capacity for movement (physiological vagility) quantitatively predicts genetic isolation by distance in the vertebrates examined.

Visualising lymph movement in anuran amphibians with computed tomography.

Lymph flux rates in anuran amphibians are high relative to those of other vertebrates owing to 'leaky' capillaries and a high interstitial compliance. Lymph movement is accomplished primarily by specialised lymph muscles and lung ventilation that move lymph through highly compartmentalised lymph sacs to the dorsally located lymph hearts, which are responsible for pumping lymph into the circulatory system; however, it is unclear how lymph reaches the lymph hearts. We used computed tomography (CT) to visualise an iodinated contrast agent, injected into various lymph sacs, through the lymph system in cane toads (Rhinella marina). We observed vertical movement of contrast agent from lymph sacs as predicted, but the precise pathways were sometimes unexpected. These visual results confirm predictions regarding lymph movement, but also provide some novel findings regarding the pathways for lymph movement and establish CT as a useful technique for visualising lymph movement in amphibians.

Control of Breathing in Ectothermic Vertebrates.

The ectothermic vertebrates are a diverse group that includes the Fishes (Agnatha, Chondrichthyes, and Osteichthyes), and the stem Tetrapods (Amphibians and Reptiles). From an evolutionary perspective, it is within this group that we see the origin of air-breathing and the transition from the use of water to air as a respiratory medium. This is accompanied by a switch from gills to lungs as the major respiratory organ and from oxygen to carbon dioxide as the primary respiratory stimulant. This transition first required the evolution of bimodal breathing (gas exchange with both water and air), the differential regulation of O2 and CO2 at multiple sites, periodic or intermittent ventilation, and unsteady states with wide oscillations in arterial blood gases. It also required changes in respiratory pump muscles (from buccopharyngeal muscles innervated by cranial nerves to axial muscles innervated by spinal nerves). The question of the extent to which common mechanisms of respiratory control accompany this progression is an intriguing one. While the ventilatory control systems seen in all extant vertebrates have been derived from common ancestors, the trends seen in respiratory control in the living members of each vertebrate class reflect both shared-derived features (ancestral traits) as well as unique specializations. In this overview article, we provide a comprehensive survey of the diversity that is seen in the afferent inputs (chemo and mechanoreceptor), the central respiratory rhythm generators, and the efferent outputs (drive to the respiratory pumps and valves) in this group. © 2022 American Physiological Society. Compr Physiol 12: 1-120, 2022.