Mads Damkjær

Pharmacological activation of KCa3.1/KCa2.3 channels produces endothelial hyperpolarization and lowers blood pressure in conscious dogs.

BACKGROUND AND PURPOSE In rodents, the endothelial KCa channels, KCa3.1 and KCa2.3, have been shown to play a crucial role in initiating endothelium‐derived hyperpolarizing factor (EDHF) vasodilator responses. However, it is not known to what extent these channels are involved in blood pressure regulation in large mammals, which would also allow us to address safety issues. We therefore characterized canine endothelial KCa3.1 and KCa2.3 functions and evaluated the effect of the KCa3.1/KCa2.3 activator SKA‐31 on blood pressure and heart rate in dogs.

Renin secretion and total body sodium: Pathways of integrative control

1. Herein, we review mechanisms of sodium balance operating at constant mean arterial blood pressure (MABP); that is, under conditions where MABP does not provide the primary signal to the kidney.

Renal cortical and medullary blood flow responses to altered NO availability in humans

The objective of this study was to quantify regional renal blood flow in humans. In nine young volunteers on a controlled diet, the lower abdomen was CT-scanned, and regional renal blood flow was determined by positron emission tomography (PET) scanning using H(2)(15)O as tracer. Measurements were performed at baseline, during constant intravenous infusion of nitric oxide (NO) donor glyceryl nitrate and after intravenous injection of NO synthase inhibitor N(ω)-monomethyl-L-arginine (L-NMMA). Using the CT image, the kidney pole areas were delineated as volumes of interest (VOI). In the data analysis, tissue layers with a thickness of one voxel were eliminated stepwise from the external surface of the VOI (voxel peeling), and the blood flow subsequently was determined in each new, reduced VOI. Blood flow in the shrinking VOIs decreased as the number of cycles of voxel peeling increased. After 4-5 cycles, blood flow was not reduced further by additional voxel peeling. This volume-insensitive flow was measured to be 2.30 ± 0.17 ml·g tissue(-1)·min(-1) during the control period; it increased during infusion of glyceryl nitrate to 2.97 ± 0.18 ml·g tissue(-1)·min(-1) (P < 0.05) and decreased after L-NMMA injection to 1.57 ± 0.17 ml·g tissue(-1)·min(-1) (P < 0.05). Cortical blood flow was 4.67 ± 0.31 ml·g tissue(-1)·min(-1) during control, unchanged by glyceryl nitrate, and decreased after L-NMMA [3.48 ± 0.23 ml·(g·min)(-1), P < 0.05]. PET/CT scanning allows identification of a renal medullary region in which the measured blood flow is 1) low, 2) independent of reduction in the VOI, and 3) reactive to changes in systemic NO supply. The technique seems to provide indices of renal medullary blood flow in humans.

The thick left ventricular wall of the giraffe heart normalises wall tension, but limits stroke volume and cardiac output

ABSTRACT Giraffes – the tallest extant animals on Earth – are renowned for their high central arterial blood pressure, which is necessary to secure brain perfusion. Arterial pressure may exceed 300 mmHg and has historically been attributed to an exceptionally large heart. Recently, this has been refuted by several studies demonstrating that the mass of giraffe heart is similar to that of other mammals when expressed relative to body mass. It thus remains unexplained how the normal-sized giraffe heart generates such massive arterial pressures. We hypothesized that giraffe hearts have a small intraventricular cavity and a relatively thick ventricular wall, allowing for generation of high arterial pressures at normal left ventricular wall tension. In nine anaesthetized giraffes (495±38 kg), we determined in vivo ventricular dimensions using echocardiography along with intraventricular and aortic pressures to calculate left ventricular wall stress. Cardiac output was also determined by inert gas rebreathing to provide an additional and independent estimate of stroke volume. Echocardiography and inert gas-rebreathing yielded similar cardiac outputs of 16.1±2.5 and 16.4±1.4 l min−1, respectively. End-diastolic and end-systolic volumes were 521±61 ml and 228±42 ml, respectively, yielding an ejection fraction of 56±4% and a stroke volume of 0.59 ml kg−1. Left ventricular circumferential wall stress was 7.83±1.76 kPa. We conclude that, relative to body mass, a small left ventricular cavity and a low stroke volume characterizes the giraffe heart. The adaptations result in typical mammalian left ventricular wall tensions, but produce a lowered cardiac output. Summary: A left ventricular cavity and low stroke volume characterise the giraffe heart, resulting in typical mammalian left ventricular wall tensions but lowered cardiac output.

Renal cortical and medullary blood flow during modest saline loading in humans.

Renal medullary blood flow (RMBF) is considered an important element of sodium homeostasis, but the experimental evidence is incongruent. Studies in anaesthetized animals generally support the concept in contrast to measurements in conscious animals. We hypothesized that saline‐induced natriuresis is associated with changes in RMBF in humans.

The giraffe kidney tolerates high arterial blood pressure by high renal interstitial pressure and low glomerular filtration rate

The tallest animal on earth, the giraffe (Giraffa camelopardalis) is endowed with a mean arterial blood pressure (MAP) twice that of other mammals. The kidneys reside at heart level and show no sign of hypertension‐related damage. We hypothesized that a species‐specific evolutionary adaption in the giraffe kidney allows normal for size renal haemodynamics and glomerular filtration rate (GFR) despite a MAP double that of other mammals.

Does mean arterial blood pressure scale with body mass in mammals?: Effects of measurement of blood pressure

For at least the last 30 years, it has been discussed whether mean arterial blood pressure (MAP) is independent of body mass or whether it increases in accordance with the vertical height between the heart and the brain. The debate has centred on the most appropriate mathematical models for analysing allometric scaling and phylogenetic relationships; there has been previously little focus on evaluating the validity of underlying physiological data. Currently, the 2 most comprehensive scaling analyses are based on data from 47 species of mammals, based on 114 references. We reviewed all available references to determine under which physiological conditions MAP had been recorded. In 44 (38.6%) of the cited references, MAP was measured in anaesthetized animals. Data from conscious animals were reported in 59 (51.8%) of references; of these, 3 (2.6%) were radiotelemetric studies. In 5 species, data were reported from both anaesthetized and conscious animals, and the mean difference in the MAP between these settings was 20 ± 29 mm Hg. From a literature search, we identified MAP measurements performed by radiotelemetry in 11 of the 47 species included in the meta‐analyses. A Bland‐Altman analysis showed a bias of 1 mm Hg with 95% confidence interval (from −35 to 36 mm Hg); that is, the limits of agreement between radiotelemetric studies and studies in restrained animals were double the supposed difference in the MAP between the mouse and elephant. In conclusion, the existing literature does not provide evidence for either a positive or neutral scaling of arterial pressure to body mass across taxa.

ACCURACY OF NONINVASIVE ANESTHETIC MONITORING IN THE ANESTHETIZED GIRAFFE (GIRAFFA CAMELOPARDALIS)

Abstract This study evaluated the accuracy of pulse oximetry, capnography, and oscillometric blood pressure during general anesthesia in giraffes (Giraffa camelopardalis). Thirty-two giraffes anesthetized for physiologic experiments were instrumented with a pulse oximeter transmittance probe positioned on the tongue and a capnograph sampling line placed at the oral end of the endotracheal tube. A human size 10 blood pressure cuff was placed around the base of the tail, and an indwelling arterial catheter in the auricular artery continuously measured blood pressure. Giraffes were intermittently ventilated using a Hudson demand valve throughout the procedures. Arterial blood for blood gas analysis was collected at multiple time points. Relationships between oxygen saturation as determined by pulse oximetry and arterial oxygen saturation, between arterial carbon dioxide partial pressure and end-tidal carbon dioxide, and between oscillometric pressure and invasive arterial blood pressure were assessed, and the accuracy of pulse oximetry, capnography, and oscillometric blood pressure monitoring evaluated using Bland-Altman analysis. All three noninvasive methods provided relatively poor estimates of the reference values. Receiver operating characteristic curve fitting was used to determine cut-off values for hypoxia, hypocapnia, hypercapnia, and hypotension for dichotomous decision-making. Applying these cut-off values, there was reasonable sensitivity for detection of hypocapnia, hypercapnia, and hypotension, but not for hypoxemia. Noninvasive anesthetic monitoring should be interpreted with caution in giraffes and, ideally, invasive monitoring should be employed.

Non-traditional Models: The Giraffe Kidney from a Comparative and Evolutionary Biology Perspective

Giraffes are the tallest living animals and endowed with the highest arterial blood pressure of any animal on Earth. Here we present novel data on kidney function in this extraordinary animal obtained over the course of two major expeditions in 2010 and 2012. As expected, the anaesthetised giraffes had very high mean arterial blood pressure ranging between 150 and 300 mmHg. However, despite the high filtration pressure, the rate of glomerular filtration (GFR) was only 0.7 ± 0.2 ml/min/kg, which is approximately 40 % below similar-sized mammals. The renal blood flow of 3.1 l/min accounts for approximately 20 % of cardiac output, and the calculated filtration fraction (GFR/ERPF) was approximately 0.3, and hence within typical mammalian values. The normal kidney function of the giraffes appears due to very high interstitial pressures within the kidney, a feature that is possible due to the very thick and strong capsule surrounding the kidney in combination with a vascular valve at the entrance of the renal vein into the abdominal cava. These relatively simple structural modifications normalize the Starling forces driving filtration over the Bowman capsula.

Carotid stimulation studies support a prominent role for the sympathetic nervous system

109:2003-2014, 2010. J Appl Physiol Romer A. Gonzalez-Villalobos, Ruy R. Campos and Marcelo V. Negrao Peter Bie, Michael L. Mathai, Megan N. Murphy, Qi Fu, Steven D. Crowley, Szelenyi, Erica A. Wehrwein, Allen W. Cowley, Jr., Di Zhao, Geoffrey A. Head, Cohn, Andreas Rohrwasser, Valdir A. Braga, Peng Li, John W. Osborn, Zoltan A. P. Fontes, Nisha Charkoudian, David S. Goldstein, Carlos E. Negrao, Jay N. Hiroyuki Kobori, Niels Juel Christensen, Claude Julien, Thiago S. Moreira, Marco Activation of the intrarenal renin-angiotensin system activation of the sympathetic nervous system vs. contributor to systemic hypertension: Chronic Comments on Point:Counterpoint: The dominant