Blood pressure increases with body size in mammals

In a recent technical comment regarding our analysis of the scaling of blood pressure with body mass in mammals (White and Seymour 2014), Packard (2015) argues that the trends in our graphs do not accurately reflect the relationship between the original variables, and that neither the graphics nor the accompanying statistical analyses provide strong support for the conclusions from the study, namely that larger mammals have higher arterial blood pressures. Here we take the opportunity to respond to these criticisms.     

THE ROLE OF GRAVITY IN THE EVOLUTION OF MAMMALIAN BLOOD PRESSURE

Understanding of the factors involved in determining the level of central arterial blood pressure in mammals has been clouded by inappropriate allometric analyses that fail to account for phylogenetic relationships among species, and require pressure to approach 0 as body size decreases. The present study analyses systolic, mean arterial, and diastolic blood pressure in 47 species of mammal with phylogenetically informed techniques applied to two‐parameter equations. It also sets nonlinear, three‐parameter equations to the data to remove the assumption of the two‐parameter power equation that the smallest animals must have negligible blood pressure. These analyses show that blood pressure increases with body size. Nonlinear analyses show that mean blood pressure increases from 93 mmHg in a 10 g mouse to 156 mmHg in a 4 tonne elephant. The scaling exponent of blood pressure is generally lower than, though not significantly different from, the exponent predicted on the basis of the expected scaling of the vertical distance between the head and the heart. This indicates that compensation for the vertical distance above the heart is not perfect and suggests that the pressure required to perfuse the capillaries at the top of the body may decrease in larger species.     

Four methods for general anaesthesia in the rabbit: a comparative study

The efficacy and safety of pentobarbitone, ketamine/xylazine, fentanyl/fluanisone/diazepam, and halothane/nitrous oxide anaesthesia were compared in 4 groups of six New Zealand White rabbits. Heart and respiratory rates, body temperature, reflexes, blood pressure and blood gases were measured. Pentobarbitone appeared to be unsuitable for anaesthesia in rabbits, as 5 of the 6 rabbits to whom it was administered, required artificial respiration or died. The combinations of ketamine/xylazine and fentanyl-fluanisone/diazepam both produced unpredictable levels of anaesthesia together with a substantial decline in arterial blood pressure and PO2. Despite a severe drop in blood pressure (up to 37.5%), anaesthesia with halothane and nitrous oxide was found to be superior to the other anaesthetic agents.     

Hemodynamic effects of blood loss during a passive response to a stressor in the conscious rabbit

In the conscious rabbit, exposure to an air jet stressor increases arterial pressure, heart rate, and cardiac output. During hemorrhage, air jet exposure extends the blood loss necessary to produce hypotension. It is possible that this enhanced defense of arterial pressure is a general characteristic of stressors. However, some stressors such as oscillation (OSC), although they increase arterial pressure, do not change heart rate or cardiac output. The cardiovascular changes during OSC resemble those seen during freezing behavior. In the present study, our hypothesis was that, unlike air jet, OSC would not affect defense of arterial blood pressure during blood loss. Male New Zealand White rabbits were chronically prepared with arterial and venous catheters and Doppler flow probes. We removed venous blood until mean arterial pressure decreased to 40 mmHg. We repeated the experiment in each rabbit on separate days in the presence and absence (SHAM) of OSC. Compared with SHAM, OSC increased arterial pressure 14 +/- 1 mmHg, central venous pressure 3.3 +/- 0.4 mmHg, and hindquarter blood flow 34 +/- 4% while decreasing mesenteric conductance 32 +/- 3% and not changing heart rate or cardiac output. During normotensive hemorrhage, OSC enhanced hindquarter and renal vasoconstriction. Contrary to our hypothesis, OSC (23.5 +/- 0.6 ml/kg) increased the blood loss necessary to produce hypotension compared with SHAM (16.8 +/- 0.6 ml/kg). In nine rabbits, OSC prevented hypotension even after a blood loss of 27 ml/kg. Thus a stressful stimulus that resulted in cardiovascular changes similar to those seen during freezing behavior enhanced defense of arterial pressure during hemorrhage.     

Relationship between mercury concentration in blood, cognitive performance, and blood pressure, in an elderly urban population

Concentration of mercury (Hg) in whole blood in an elderly urban population with a mean age of 87 years was studied in relation to cognitive function, arterial blood pressure (arterial BP), age, gender, body mass index (BMI) and smoking habits. This population-based study consisted of 106 subjects both males and females. Clinical assessment of the subjects included medical and social history, physical and neurologic examination and assessment of cognitive functions with Mini-Mental State Examination (MMSE). Information on use of all potentially anti-hypertensive drugs was collected. Whole blood from 106 subjects were collected and analysed for mercury by Cold Vapour Atomic Absorption Spectrometry (Milton Ray ASS-CV) with Seronorm Trace Element as matrix matched quality control. Males and females did not differ in blood-mercury (B-Hg) concentrations or in any of the other studied variables. B-Hg concentrations did not differ between smokers and non-smokers. Females were treated more often than males with antihypertensive drugs. There was no relation found between B-Hg concentration and cognitive function, arterial BP, age, gender or BMI. In conclusion, no relations were found between B-Hg concentrations and the studied variables.     

Postnatal development of arterial pressure: influence of the intrauterine environment

A substantial number of epidemiological studies have shown that small size at birth is associated with an increased risk of developing hypertension and metabolic dysfunction later in life; however these associations have not been found in all studies. In animals, several models have been used to investigate the effects of perturbations to the fetal environment on later arterial pressure, with differing effects on size at birth and arterial pressure. Ovine models include maternal dietary manipulations, antenatal glucocorticoid exposure, and restriction of placental size and function. In our laboratory, we have induced late gestational placental insufficiency and growth restriction in sheep by umbilico-placental embolisation; during the early postnatal period the growth restricted lambs remained small and were hypotensive relative to controls. More recent long-term studies indicate that these growth restricted animals were able to catch up in body weight within the first postnatal year; however, their arterial pressure remained lower than that of controls throughout the first 2 postnatal years (deltaMAP, -4.2 +/- 1.4 mmHg). This relative hypotension may be due to altered vascular or cardiac development resulting from increased vascular resistance or nutrient restriction during fetal life. As late gestational placental insufficiency led to a persistent reduction in arterial pressure from birth to adulthood, our findings do not support the hypothesis that restricted fetal growth per se leads to hypertension after birth. It is likely that the effects of a prenatal compromise on postnatal arterial pressure will vary depending on the nature of the associated developmental perturbations and their gestational timing.     

Defense reaction alters the response to blood loss in the conscious rabbit

The interaction of sensory stressors with the cardiovascular response to blood loss has not been studied. The cardiovascular response to a stressor (i.e., the defense reaction) includes increased skeletal muscle blood flow and perhaps a reduction in arterial baroreflex function. Arterial pressure maintenance during blood loss requires baroreflex-mediated skeletal muscle vasoconstriction. Therefore, we hypothesized that the defense reaction would limit arterial pressure maintenance during blood loss. Male, New Zealand White rabbits were chronically prepared with arterial and venous catheters and Doppler flow probes. We removed venous blood in conscious rabbits until mean arterial pressure decreased to <40 mmHg. We repeated the experiment with (air) and without (sham) simultaneous exposure to an air jet stressor. Air resulted in a defense reaction (e.g., mean arterial pressure = 94 +/- 1 and 67 +/- 1 mmHg for air and sham, respectively). Contrary to our hypothesis, air increased the blood loss necessary to produce hypotension (19.3 +/- 0.2 vs. 16.9 +/- 0.2 ml/kg for sham). Air did not reduce skeletal muscle vasoconstriction during normotensive hemorrhage. However, air did enhance renal vasoconstriction (97 +/- 3 and 59 +/- 3% of baseline for sham and air, respectively) during the normotensive phase. Thus the defense reaction did not limit but rather extended defense of arterial pressure during hemorrhage.     

Body height and blood pressure regulation in humans during anti-orthostatic tilting

The hypothesis was tested that the cardiovascular changes during an upper body anti-orthostatic maneuver in humans are more pronounced in tall than in short individuals, because of the larger intravascular hydrostatic pressure gradients. In 34 males and 41 females [20-30 yr, body height (BH) = 147-206 cm], inter-individual multiple linear regression analyses adjusted for gender and body weight were conducted between changes in cardiovascular variables versus BH during tilting of the upper body from vertical to horizontal while keeping the legs horizontal. In all the subjects, tilting induced increases in stroke volume and arterial pulse pressure and a decrease in heart rate, which each correlated significantly with BH. In males (n = 51, BH = 163-206 cm), 24-h ambulatory mean arterial pressure increased significantly with BH (P = 0.004, r = 0.40, α = 0.15 mmHg/cm) so that systolic/diastolic blood pressure increased by 2/2 mmHg per 15 cm increase in BH. There was no significant correlation between mean arterial pressure and BH in females (n = 53, BH = 147-193 cm). In conclusion, a larger BH induces larger cardiovascular changes during anti-orthostatic tilting, and in males 24-h ambulatory mean arterial pressure increases with BH. The lack of a mean arterial pressure to BH correlation in females is probably because of their lower BH and greater variability in blood pressure.     

Relationship of body size and body mass to blood pressure: sex-specific and developmental influences.

The relationship of body mass and body fat distribution to blood pressure has been recognized for many years. This relationship has formed the basis for much additional research, including the impact of growth and developmental factors on blood pressure levels. Blood pressure in children is related to somatic growth and is tied to increases in height, skeletal maturation, and sexual maturation. Sexual and ethnic differences in blood pressure levels are already apparent during childhood and may also be related to the process of growth and sexual maturity. Body size exerts a profound influence on a variety of physiological functions, including blood pressure and the onset of sexual maturity. In general, studies have reported a strong linear relationship between height and blood pressure and between body mass and blood pressure such that tracking correlations from childhood to adulthood for both blood pressure and body mass index are significant for most sex and ethnic groups. Studies evaluating the effects of hormone replacement therapy on post-menopausal women have thus far generated results suggesting that the age-related rise of blood pressure is not due directly to hormonal changes associated with menopause. The interrelated effects of growth, maturation, body weight, and body fat are influenced by both genetic and environmental factors. Environmental influences may modify relationships established much earlier, perhaps as early as prenatally, during infancy, or during early childhood. Directions for future research and implications resulting from the complex relationship between body weight and blood pressure are discussed.     

Restoration of T cell depression and suppression of blood pressure in spontaneously hypertensive rats (SHR) by thymus grafts or thymus extracts

Spontaneously hypertensive rats (SHR) that develop hypertension and arterial lesions resembling human periarteritis nodosa were found to possess a selective depression of T cell functions with an appearance of natural thymocytotoxic autoantibody (NTA). The relationship between T cell depression and hypertension in these animals was investigated. The immune responsiveness of T cell-depressed SHR was completely recovered by histocompatible thymus grafts and was partially restored by histoincompatible allogeneic or xenogeneic thymus grafts or by injection of thymus extracts. Transplantation of compatible thymus tissues into neonatal SHR produced long-lasting recovery of immune functions. When complete immunologic restoration was achieved, significant suppression of high blood pressure was obtained. The SHR that showed high blood pressure were always accompanied with high NTA titers and arterial lesions. Thymus grafts or thymus extracts significantly decreased the titers of NTA. The development and dissemination of arterial lesions, which may cause increased blood flow resistance, were completely prevented by compatible thymus grafts into neonatal SHR. These results suggest that thymus grafts and thymus extracts may suppress the development of hypertension by preventing or curing the periarteritis nodosa in SHR.     

The carotid bodies of spontaneously hypertensive rats (SHR): a functional and morphologic study

The parameters of the acid-base-state of the arterial blood were measured in spontaneously hypertensive rats of the Okamoto-strain (SHR) and in normotensive Wistar rats (NWR) of a random-bred strain. The animals were anaesthetized with chloralose-urethane and breathed normal air under sea-level conditions. Structure and size of their carotid bodies were studied by light-microscopic methods. When compared with the NWR, the SHR showed a respiratory alkalosis and enlarged carotid bodies. In the SHR, never in the NWR, the lumen of the branches of the glomic arteries was narrowed by pad-like structures. The data suggest that systemic hypertension leads to morphologically and functionally detectable alterations of both carotid body structure and function. The interdependence of arterial chemoreceptor activity, sodium household, and the adjustment of systemic arterial blood pressure is briefly discussed.     

Regression of cardiac hypertrophy with drug treatment in spontaneously hypertensive rats

Left ventricular hypertrophy is an important complication of essential hypertension. Some antihypertensive drugs have been shown to allow regression of cardiac hypertrophy, both in spontaneously hypertensive rats and in hypertensive patients. Recent results show that the agents which interfere with the functions of the sympathetic nervous system, converting enzyme inhibitors and calcium antagonists are effective in reducing arterial blood pressure and regression of left ventricular hypertrophy. The use of vasodilators and diuretics may under certain circumstances, however, even exacerbate cardiac hypertrophy. Regression of left ventricular hypertrophy in hypertension does not appear to depend solely on reduction of arterial blood pressure. Other factors seem to modulate the myocardial response to antihypertensive treatment. Included among these mechanisms are neural, humoral, haemodynamic and biochemical factors. The available experimental data further suggest that some functional derangements and biochemical changes associated with hypertrophy may be reversed by antihypertensive treatment. There is, however, insufficient experience with human subjects to determine whether a reduction in left ventricular mass is associated with lower incidences of heart failure or mortality than may be achieved by adequate blood pressure control alone.     

Arterial Blood Pressure and Modernization in Brazil

The relationship between individual modernization and elevated arterial blood pressure was examined in a study in urban Brazil. We hypothesized that elevated blood pressure would result from the discrepancy between an individual's style of life and his or her economic resources; specifically, we suggested that when modern life-style acquisition exceeded economic resources, a circumstance referred to as "life-style stress," blood pressure would be elevated. This factor was related to diastolic, but not systolic, blood pressure, independently of a variety of biologic, dietary, and sociocultural confounding factors. The perceived change associated with life events also predicted diastolic, but not systolic, blood pressure. Other predictors of diastolic blood pressure were calcium intake, fat intake, race, age, and the body mass index. We argue that sociocultural risk factors emerge in the modernization process as a result of social structural imbalances generated by economic development and represent independent risk factors for elevated arterial blood pressure.     

Strength training reduces arterial blood pressure but not sympathetic neural activity in young normotensive subjects.

The effects of resistance training on arterial blood pressure and muscle sympathetic nerve activity (MSNA) at rest have not been established. Although endurance training is commonly recommended to lower arterial blood pressure, it is not known whether similar adaptations occur with resistance training. Therefore, we tested the hypothesis that whole body resistance training reduces arterial blood pressure at rest, with concomitant reductions in MSNA. Twelve young [21 +/- 0.3 (SE) yr] subjects underwent a program of whole body resistance training 3 days/wk for 8 wk. Resting arterial blood pressure (n = 12; automated sphygmomanometer) and MSNA (n = 8; peroneal nerve microneurography) were measured during a 5-min period of supine rest before and after exercise training. Thirteen additional young (21 +/- 0.8 yr) subjects served as controls. Resistance training significantly increased one-repetition maximum values in all trained muscle groups (P < 0.001), and it significantly decreased systolic (130 +/- 3 to 121 +/- 2 mmHg; P = 0.01), diastolic (69 +/- 3 to 61 +/- 2 mmHg; P = 0.04), and mean (89 +/- 2 to 81 +/- 2 mmHg; P = 0.01) arterial blood pressures at rest. Resistance training did not affect MSNA or heart rate. Arterial blood pressures and MSNA were unchanged, but heart rate increased after 8 wk of relative inactivity for subjects in the control group (61 +/- 2 to 67 +/- 3 beats/min; P = 0.01). These results indicate that whole body resistance exercise training might decrease the risk for development of cardiovascular disease by lowering arterial blood pressure but that reductions of pressure are not coupled to resistance exercise-induced decreases of sympathetic tone.     

Relative latency of responses of chemoreceptor afferents from aortic and carotid bodies

Discharges from aortic and carotid body chemoreceptor afferents were simultaneously recorded in 18 anesthetized cats to test the hypothesis that aortic chemoreceptors, because of their proximity to the heart, respond to changes in arterial blood gases before carotid chemoreceptors. We found that carotid chemoreceptor responses to the onset of hypoxia and hypercapnia, and to the intravenously administered excitatory drugs (cyanide, nicotine, and doxapram), preceded those of aortic chemoreceptors. Postulating that this unexpected result was due to differences in microcirculation and mass transport, we also investigated their relative speed of responses to changes in arterial blood pressure. The aortic chemoreceptors responded to decreases in arterial blood pressure before the carotid chemoreceptors, supporting the idea that the aortic body has microcirculatory impediments not generally present in the carotid body. These findings strengthened the concept that carotid bodies are more suited for monitoring blood gas changes due to respiration, whereas aortic bodies are for monitoring circulation.     

Sodium and potassium in essential hypertension.

A study was carried out of arterial pressure and body content of electrolytes in 91 patients with essential hypertension and 121 normal controls. Exchangeable sodium was found to be positively correlated with arterial pressure in the patients, the correlation being closest in older patients; values of exchangeable sodium were subnormal in young patients; and plasma, exchangeable, and total body potassium correlated inversely with arterial pressure in the patients, the correlations being closest in young patients. Three hypotheses were proposed to explain the mechanisms relating electrolytes and arterial pressure in essential hypertension--namely, a cell-salt hypothesis, a dietary salt hypothesis, and a kidney-salt hypothesis. It was concluded that two mechanisms probably operate in essential hypertension. In the early stages of the disease blood pressure is raised by an abnormal process related more closely to potassium than to sodium. A renal lesion develops later, possibly as a consequence of the hypertension. This lesion is characterised by resetting of pressure natriuresis and is manifest by an abnormal relation between body sodium and arterial pressure and by susceptibility to increased dietary sodium intake.     

Periodic hemodynamics in skeletal muscle during local arterial pressure reduction.

The time-dependent features of red blood cell flow were evaluated with laser-Doppler flowmetry (LDF) in the left gastrocnemius muscle of 31 anesthetized New Zealand White rabbits during stepwise arterial occlusion. During the control period with a median femoral pressure of 72 mmHg, 29 animals showed minor irregular fluctuations in LDF blood flow, and only two animals displayed periodic variations of blood flow. Lowering femoral arterial pressure induced maximal periodic blood flow variations at a median pressure of 35 mmHg in all animals with a median frequency of 1.5 cycles/min (termed "slow-wave flow motion"). The median amplitude was 48% of the corresponding average flow. These slow waves disappeared at a median femoral pressure of 20 mmHg. The median LDF flow value was 4.00 arbitrary units (AU) at control pressure and 2.05 AU at maximum slow-wave flow motion. When slow-wave flow motion was seen at several pressure levels, their frequency was identical, which supports the local pacemaker concept. This study promotes a novel concept for the role and physiological significance of periodic hemodynamics in that it is a condition not characteristic for normal control situations but is activated below a specific local arterial blood pressure and flow threshold, which is known to be the lower end of autoregulation in the microcirculation of rabbit skeletal muscle. This also suggests that slow-wave flow motion is primarily under local control mechanisms.     

Suprarenal aortic flow reduction versus angiotensin I infusion in fetal sheep

In the unanaesthetized fetal sheep, long-term suprarenal aortic blood flow reduction will cause upper body arterial blood pressure to increase. To see if the response to this procedure was entirely due to the concomitant increase in plasma renin activity, we gave an angiotensin I infusion of several days to 7 fetal sheep and compared their responses to those of 4 fetal sheep undergoing partial occlusion of the aorta above the renal arteries. Both protocols caused upper body arterial blood pressure to increase to comparable levels. Angiotensin I infusion had no effect upon venous blood pressure while suprarenal aortic blood flow reduction caused a significant increase in venous blood pressure as early as 1 day after blood flow reduction. Haematocrits were unchanged in the fetuses with flow restriction but increased in the infused fetuses. We conclude that long-term angiotensin I infusion in the fetus does not mimic the entire complex of responses to suprarenal aortic blood flow reduction.     

Cardiorespiratory effects of diazepam-ketamine, xylazine-ketamine and thiopentone anesthesia in male Wistar rats--a comparative analysis

Several anesthetics are known to cause respiratory and cardiovascular depression in humans and animals; but, these diverse effects have not been extensively investigated in laboratory rodents. The objective of this study is to choose a suitable anesthetic combination for use in surgical models eg. coronary artery ligation in rats. Male Wistar rats were anesthetized with three different drugs viz. diazepam-ketamine (DK) (2.5 mg/Kg, intraperitoneally (i.p); 50 mg/Kg, i.p), xylazine-ketamine (XK) (5 mg/Kg i.p; 50 mg/Kg i.p) and thiopentone (T) (40 mg/Kg i.p) and the respiratory and cardiovascular functions were assessed after coronary artery ligation. Heart rate (HR), mean arterial pressure (MAP), partial pressure of carbon dioxide (PaCO2), partial pressure of oxygen (PaO2), oxygen saturation percentage (O2 sat (%)), arterial blood pH and rectal body temperature were studied in detail. During the anesthetic regime, HR was lower till 60 min in XK and T ligated group (333 +/- 6; 304 +/- 8 beats/min) and it was near normalcy in the case of DK ligated group (394 +/- 6 beats/min). Significant respiratory depression was particularly reflected in the T ligated group with an increase in PaCO2 at 30 min (40.32 +/- 2.64 mmHg), which decreased to 38.2 +/- 2.23 mmHg at 60 min. Throughout the investigation, DK showed the least overall effects compared to XK and T on respiratory functions. Thus, DK could be considered to be a suitable anesthetic for use in a surgical model such as coronary artery ligation in albino rats.     

Some observatoons on the carotid bodies of the New Zealand strain of genetically hypertensive rats

We report preliminary studies of the carotid bodies in the New Zealand strain of hypertensive rats. Female animals have a higher blood pressure than males of the same colony, but in both sexes mean arterial pressure is elevated significantly when compared to normal animals. The carotid bodies are enlarged in both the hypertensive and normotensive animals and there is no correlation between carotid body size and arterial pressure. The only structural abnormality detected in the hypertensive carotid bodies was a gross thickening of the intimal layer of the arterioles. The content of dopamine in the organs was similar in normotensives and hypertensives but the noradrenaline levels were some 50% lower in the hypotensives. These results are discussed and compared with data available for SHR animals.