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Effects of Dehydration and Blockade of the Renin-Angiotensin System in the One-humped Camel (Camelus dromedarius)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The one-humped or the dromedarian camel is a pseudo-ruminant mammal, well adapted to the hot and dry climates of the desert. Its ability to withstand torrid heat and extreme desiccation is of paramount importance to its survival. The studies presented in this thesis were designed to investigate and document the effect of dehydration in the presence or absence of angiotensin II (Ang II) AT1 receptor blocker (losartan) on blood constituents, electrolytes, hormones, neurotransmitters as well as liver and kidney enzymes in a subset of dehydrated camels and to compare them with hydrated camels. Additionally, we studied the response of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) and revealed for the first time the cardiac storage form of BNP in the camel heart. Dehydration induced significant increments in packed cell volume (PCV), white blood cells (WBC), gamma glutamyl-transferase (GGT), serum sodium, creatinine and urea levels, and a doubling in plasma cortisol and arginine vasopressin (AVP) levels. At the same time dehydration caused significant decrease in body weights, plasma insulin like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3), and a 50% decrement in ANP and BNP levels. Moreover, dehydration with and without losartan resulted in significant changes in stress hormones and anti-oxidants in plasma, liver and kidney homogenates. Losartan on one hand enhanced the effect of dehydration resulting in significant increases in sodium, creatinine and urea levels. In addition losartan raised the  binding affinity of Ang II AT2 receptors in the small intestine with 8-fold and with 16-fold for liver AT1 receptors, indicating that Ang II AT1 and AT2 receptor binding sites were present in camel's small intestine while only AT1 receptor binding sites were found in the camel liver. One the other hand losartan resulted in significant decrease in body weights impaired the rise in anti-diuretic hormone and reduced aldosterone level. Finally, we showed that the proBNP is the storage form of BNP in the camel heart.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 178
Keyword [en]
Blood, biochemical analysis, catecholamine, colorimetric assay, cortisol, dehydration, dromedary camel, glutathione, hematological analysis, HPLC, insulin- like growth factor-1, losartan, plasma, receptors, radioimmunoassay, serum
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-207574ISBN: 978-91-554-8757-7 (print)OAI: oai:DiVA.org:uu-207574DiVA: diva2:649063
Public defence
2013-10-16, C8:321, Biomedical center, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-09-26 Created: 2013-09-16 Last updated: 2016-10-14
List of papers
1. Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel
Open this publication in new window or tab >>Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel
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2011 (English)In: Journal of Medical Sciences, ISSN 1996-3262, E-ISSN 1996-3270, Vol. 4, no 2, 73-78 p.Article in journal (Refereed) Published
Abstract [en]

Aim: Dromedary camels are extremely well adapted to periods of water deprivation. The physiological mechanisms underlying this adaptation, however, are imperfectly understood. It is likely that the renin-angiotensin system plays an important role although few studies have addressed this possibility in the camel. Accordingly, the effects of long term dehydration alone and with angiotensin II type 1 receptor blocker, losartan, on whole blood and serum constituents were studied in camels.

Methods:Twenty eight male camels 3-4 years old were studied while under shade during summer in the Gulf-region, where the ambient temperature was above 40 degree Celsius. The camels were divided into three groups: a control group(n=6) was allowed free access to feed and water, a dehydration group (n=16) was given food ad-lib during 20days of total water deprivation, and a dehydration plus losartan (losartan) group (n=6) which received losartan 5mg/Kg daily by intravenous injection during 20 days of dehydration.  

Results: The body weight of the losartan group decreased by nearly 39.1% across dehydration whereas the reduction in body weight for the dehydration group was nearly 34.5% compared to controls. There was a significant increase in the packed cell volume (p<0.05) and leucocytes count (p<0.01) in the losartan group compared to controls. However, the mean corpuscular volume was significantly higher (p<0.05) in the dehydration group compared to controls. We observed major, statistically significant increases in serum urea (p<0.01) and creatinine (p<0.05) levels in the dehydration and losartan groups compared to controls. By the end of the period ofwater restriction, serum levels of gamma glutamyl transferase were significantly (p<0.01) lower in the losartan group compared to controls.

Conclusion: The results of our experiment show that dehydration alone or in combination with Angiotensin II receptor blocker has major effects on the biochemical and hematological parameters of the camel blood.

Keyword
Blood, camel, dehydration, losartan, and serum
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-207413 (URN)10.2174/1996327001104020073 (DOI)
Available from: 2013-09-13 Created: 2013-09-13 Last updated: 2017-12-06Bibliographically approved
2. Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
Open this publication in new window or tab >>Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, e37299- p.Article in journal (Refereed) Published
Abstract [en]

Our objectives were to compare the levels of circulating electrolytes, hormones, and renal function during 20 days of dehydration in camels versus the level in non-dehydrated camels and to record the effect of blocking angiotensin II AT1 receptors with losartan during dehydration. Dehydration induced significant increments in serum sodium, creatinine, urea, a substantial fall in body weight, and a doubling in plasma arginine vasopressin (AVP) levels. Plasma aldosterone, however, was unaltered compared with time-matched controls. Losartan significantly enhanced the effect of dehydration to reduce body weight and increase serum levels of creatinine and urea, whilst also impairing the rise in plasma AVP and reducing aldosterone levels. We conclude that dehydration in the camel induces substantial increments in serum sodium, creatinine, urea and AVP levels; that aldosterone levels are altered little by dehydration; that blockade of angiotensin II type 1 receptors enhances the dehydration-induced fall in body weight and increase in serum creatinine and urea levels whilst reducing aldosterone and attenuating the rise in plasma AVP.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-177622 (URN)10.1371/journal.pone.0037299 (DOI)000305343500092 ()
Available from: 2012-07-18 Created: 2012-07-17 Last updated: 2017-12-07Bibliographically approved
3. Changes in insulin-like growth factor-1 and IGF-binding protein-3 in camel plasma during dehydration in the presence and absence of losartan
Open this publication in new window or tab >>Changes in insulin-like growth factor-1 and IGF-binding protein-3 in camel plasma during dehydration in the presence and absence of losartan
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2012 (English)In: Comparative Clinical Pathology, ISSN 1618-5641, E-ISSN 1618-565X, Vol. 21, no 6, 1745-1749 p.Article in journal (Refereed) Published
Abstract [en]

In the present study, the effect of 20 days of dehydration in the presence or absence of losartan (angiotensin II AT1 receptor antagonist) on insulin-like growth factor-1(IGF-1) and insulin-like growth factor-binding protein-3(IGFBP-3) in plasma of the one-humped camel was studied. Eighteen male camels, 3-4 years of age, were divided into three equal groups: control, dehydrated, and dehydrated-losartan-treated groups. The control camels were given food and water ad libitum. The two dehydrated groups underwent 20 days of water deprivation but were given food ad libitum. The dehydrated-losartan-treated camels were given losartan injection (Merck, USA), intravenously at a dose of 5 mg/kg body weight daily for 20 days. Our results demonstrated a progressive decrease in the circulating levels of IGF-1 and IGFBP-3 in the dehydrated and dehydrated-losartan-treated animals across dehydration compared to their basal levels and time-matched control. On day 5 of dehydration, the IGF-1 level in the losartan-treated group showed a decrease of 60 % and the dehydrated group showed 45 % decrease from their baseline levels and time-matched control. On day 10 the decrease in the losartan-treated animals reached 74 % and for the dehydrated was 62 %. On day 20 the decrease in the losartan-treated was 89 % and for the dehydrated reached 80 % from their baseline levels and time-matched control. Dehydration in the presence or absence of losartan caused a decrease in the circulating level of IGFBP-3. The decrement reached 26 % on day 10 and 20 for the treated camels, while the decrease for the dehydrated was 22 % on day 10 of dehydration and reached 29 % on day 20 compared to their baseline levels and time-matched control. In conclusion, dehydration alone, or in presence of Angiotensin II AT1 receptor blocker caused significant decrease in the circulating levels of IGF-1 and IGFBP-3 compared to their basal values and to time-matched controls. Losartan enhanced the effect of dehydration mainly in the early phase of dehydration for both parameters; albeit, no significant differences between the two dehydrated groups was observed. Finally, these findings suggest an essential role of IGF-1and IGFBP-3 in the dehydration state of these dromedarian camels.

Keyword
Camel, Dehydration, IGF-1, IGFBP-3, Losartan
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-193751 (URN)10.1007/s00580-012-1562-y (DOI)
Available from: 2013-02-06 Created: 2013-02-06 Last updated: 2017-12-06Bibliographically approved
4. ANP and BNP Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
Open this publication in new window or tab >>ANP and BNP Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, e57806- p.Article in journal (Refereed) Published
Abstract [en]

The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6), dehydrated camels (n = 6) and dehydrated losartan-treated camels (n = 6) which were dehydrated and received the angiotensin II (Ang II) AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-200116 (URN)10.1371/journal.pone.0057806 (DOI)000316849200019 ()
Available from: 2013-05-21 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
5. Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel
Open this publication in new window or tab >>Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel
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2013 (English)In: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 9, 232- p.Article in journal (Refereed) Published
Abstract [en]

Our objectives were to document and compare plasma levels of Catecholamines, Cortisol,Glutathione and Malondialdehyde in camels after long term dehydration (20 days) in the presenceor absence of angiotensin II AT1 receptor blocker (Losartan) versus levels in non-dehydratedcamels; and to record the effects on glutathione and malondialdehyde activity in liver and kidneyhomogenate in the one-humped camel. Eighteen male camels were used in this study, sixcontrols, six dehydrated and treated with losartan (5mg/kg daily) and six were dehydrated withouttreatment. Our results revealed significant decrease (P<0.05) in plasma epinephrine level in bothtreated and dehydrated camels; while, Plasma norepinephrine showed significant increase in bothdehydrated groups (P< 0.01). Levels of plasma dopamine were also significantly increased (P<0.01) in both dehydrated groups compared to control camels.Plasma levels of cortisol increased significantly across dehydration with or without losartanadministration (P<0.01) compared with time-matched levels in control camels. Losartan had nosignificant modulating effect on the cortisol response to dehydration.Plasma, liver and kidney homogenates revealed significant increase (P<0.05) in glutathione levelsin both dehydrated groups compared to control.Plasma, liver and kidney homogenates for malondialdehyde levels in both treated and dehydratedcamels also showed significant increase (P<0.05 & P<0.01) compared to controls.In conclusion, our study demonstrates that the effect of dehydration with or without losartaninduced oxidative stress in these camels, leading to significant changes in plasma catecholaminesand cortisol levels, together with significant increments in glutathione and malondialdehydeactivities in plasma, liver and kidney homogenate to counter act the damaging effect of the freeradicals in the dehydrated camels.

Keyword
Camel, Catecholamine, Cortisol, dehydration, Glutathione and Malondialdehyde
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-207417 (URN)10.1186/1746-6148-9-232 (DOI)000329620900001 ()
Available from: 2013-09-13 Created: 2013-09-13 Last updated: 2017-12-06Bibliographically approved

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