Abstract:The effect of feeding frequency and associated meal size on the renin-angiotensin-aldosterone system (RAAS) in seven horses was examined. A daily maintenance ration of hay-grain pellets was provided either as a multiple feeding regimen (MF), in which the ration was divided into six equal portions fed at 4-h intervals, or as a single large feeding (SF) given from 9 A.M. until 11 A.M. Plasma renin activity (PRA), aldosterone (PAC), cortisol (PCC), protein concentration (TP), packed cell volume (PCV), and serum s… Show more
“…Our results are consistent with previous investigations in dogs , horses (Clarke et al 1978(Clarke et al , 1988, and humans (Cugini et al 1981(Cugini et al , 1985, which underlines the similarity of body fluid homeostasis in mammals. A cosine model with a fixed 24-h period was found to fit the periodic variations of RA, BP, urinary aldosterone, and potassium excretion well, as suggested by the quality of the model diagnostics.…”
Section: Components Of the Renin Cascade Blood Pressure And Urinarysupporting
confidence: 94%
“…Studies have been performed under (i) sodium restriction (Cugini et al 1981(Cugini et al , 1985, (ii) episodic vs. continuous feeding (Blair-West and Brook 1969;Clarke et al 1978Clarke et al , 1988, and (iii) fasting conditions (Cugini et al 1987). In contrast, the impact of timed feeding on the chronobiology of the renin cascade remains controversial.…”
Section: Components Of the Renin Cascade Blood Pressure And Urinarymentioning
Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides in spontaneous cases of canine CHF. If such a link could be established, profiling of these biomarkers could support determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes.
“…Our results are consistent with previous investigations in dogs , horses (Clarke et al 1978(Clarke et al , 1988, and humans (Cugini et al 1981(Cugini et al , 1985, which underlines the similarity of body fluid homeostasis in mammals. A cosine model with a fixed 24-h period was found to fit the periodic variations of RA, BP, urinary aldosterone, and potassium excretion well, as suggested by the quality of the model diagnostics.…”
Section: Components Of the Renin Cascade Blood Pressure And Urinarysupporting
confidence: 94%
“…Studies have been performed under (i) sodium restriction (Cugini et al 1981(Cugini et al , 1985, (ii) episodic vs. continuous feeding (Blair-West and Brook 1969;Clarke et al 1978Clarke et al , 1988, and (iii) fasting conditions (Cugini et al 1987). In contrast, the impact of timed feeding on the chronobiology of the renin cascade remains controversial.…”
Section: Components Of the Renin Cascade Blood Pressure And Urinarymentioning
Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24 h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides in spontaneous cases of canine CHF. If such a link could be established, profiling of these biomarkers could support determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes.
“…However, a transient increase in PCV and plasma protein concentration lasting < 3 hours after ingestion of large amounts of grain has been observed in other studies. [17][18][19][35][36][37] There may be 2 reasons why postprandial dehydration was not observed in the present study. First, blood samples were only collected 5.5 and 11.5 hours after a large amount of grain was offered, whereas in other studies, [17][18][19][35][36][37] a postprandial increase in PCV and plasma protein concentration lasted < 3 hours.…”
Section: Discussionmentioning
confidence: 86%
“…In horses, experimental administration of 1 or 2 meals/d that are 1-hour in duration induces a state of transient dehydration with activation of the renin-angiotensin-aldosterone system. [16][17][18][19] On the basis of those findings, it was proposed that feeding a few large meals could cause postprandial dehydration of colonic contents and lead to impaction of the large colon, which could initiate other forms of colic such as large colon displacement and volvulus. 3 However, this theory was determined by use of artificial feeding regimens that are not used for domestic horses.…”
Changes observed in the colonic contents and feces may be explained by the large amounts of hydrolyzable carbohydrates provided by grain. Access to large amounts of grain may increase the risk of tympany and displacement of the large intestine.
“…To study the ability of mice to adapt to a high K + diet, TK −/− and TK +/+ mice were equilibrated for a few days on the standard diet (0.8% K + ) and then switched to a "high" K + (2% K + ) diet (Institut National de la Recherche Agronomique, Jouy en Josas, France). To maximize feedingdependent influences on plasma K + level (39), TK −/− and TK +/+ mice were supplied with their daily ration, which they were allowed to eat over a 4-h period (between 10:00 AM and 2:00 PM). For convenience, the 12:12 light/dark cycle was inverted.…”
Tissue kallikrein (TK) is a serine protease synthetized in renal tubular cells located upstream from the collecting duct where renal potassium balance is regulated. Because secretion of TK is promoted by K
+
intake, we hypothesized that this enzyme might regulate plasma K
+
concentration ([K
+
]). We showed in wild-type mice that renal K
+
and TK excretion increase in parallel after a single meal, representing an acute K
+
load, whereas aldosterone secretion is not modified. Using aldosterone synthase-deficient mice, we confirmed that the control of TK secretion is aldosterone-independent. Mice with
TK
gene disruption (
TK
−/−
) were used to assess the impact of the enzyme on plasma [K
+
]. A single large feeding did not lead to any significant change in plasma [K
+
] in
TK
+/+
, whereas
TK
−/−
mice became hyperkalemic. We next examined the impact of
TK
disruption on K
+
transport in isolated cortical collecting ducts (CCDs) microperfused in vitro. We found that CCDs isolated from
TK
−/−
mice exhibit net transepithelial K
+
absorption because of abnormal activation of the colonic H
+
,K
+
-ATPase in the intercalated cells. Finally, in CCDs isolated from
TK
−/−
mice and microperfused in vitro, the addition of TK to the perfusate but not to the peritubular bath caused a 70% inhibition of H
+
,K
+
-ATPase activity. In conclusion, we have identified the serine protease TK as a unique kalliuretic factor that protects against hyperkalemia after a dietary K
+
load.
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