Deoxycorticosterone Acetate Animals Research Articles

Early-stage heart failure with preserved ejection fraction in the pig: a cardiovascular magnetic resonance study.

BackgroundThe hypertensive deoxy-corticosterone acetate (DOCA)-salt-treated pig (hereafter, DOCA pig) was recently introduced as large animal model for early-stage heart failure with preserved ejection fraction (HFpEF). The aim of the present study was to evaluate cardiovascular magnetic resonance (CMR) of DOCA pigs and weight-matched control pigs to characterize ventricular, atrial and myocardial structure and function of this phenotype model.MethodsFive anesthetized DOCA and seven control pigs underwent 3 T CMR at rest and during dobutamine stress. Left ventricular/atrial (LV/LA) function and myocardial mass (LVMM), strains and torsion were evaluated from (tagged) cine imaging. 4D phase-contrast measurements were used to assess blood flow and peak velocities, including transmitral early-diastolic (E) and myocardial tissue (E’) velocities and coronary sinus blood flow. Myocardial perfusion reserve was estimated from stress-to-rest time-averaged coronary sinus flow. Global native myocardial T1 times were derived from prototype modified Look-Locker inversion-recovery (MOLLI) short-axis T1 maps. After in-vivo measurements, transmural biopsies were collected for stereological evaluation including the volume fractions of interstitium (VV(int/LV)) and collagen (VV(coll/LV)). Rest, stress, and stress-to-rest differences of cardiac and myocardial parameters in DOCA and control animals were compared by t-test.ResultsIn DOCA pigs LVMM (p < 0.001) and LV wall-thickness (end-systole/end-diastole, p = 0.003/p = 0.007) were elevated. During stress, increase of LV ejection-fraction and decrease of end-systolic volume accounted for normal contractility reserves in DOCA and control pigs. Rest-to-stress differences of cardiac index (p = 0.040) and end-diastolic volume (p = 0.042) were documented. Maximal (p = 0.042) and minimal (p = 0.012) LA volumes in DOCA pigs were elevated at rest; total LA ejection-fraction decreased during stress (p = 0.006). E’ was lower in DOCA pigs, corresponding to higher E/E’ at rest (p = 0.013) and stress (p = 0.026). Myocardial perfusion reserve was reduced in DOCA pigs (p = 0.031). T1-times and VV(int/LV) did not differ between groups, whereas VV(coll/LV) levels were higher in DOCA pigs (p = 0.044).ConclusionsLA enlargement, E’ and E/E’ were the markers that showed the most pronounced differences between DOCA and control pigs at rest. Inadequate increase of myocardial perfusion reserve during stress might represent a metrics for early-stage HFpEF. Myocardial T1 mapping could not detect elevated levels of myocardial collagen in this model.Trial registrationThe study was approved by the local Bioethics Committee of Vienna, Austria (BMWF-66.010/0091-II/3b/2013).

Norepinephrine transporter protein is downregulated in left ventricle from chronically hypertensive rats, but is unchanged during hypertension development

Hypertension is associated with a reduction in reuptake of norepinephrine (NE) in the heart. NE transporter (NET) is responsible for reuptake of NE. A reduction in NET would be associated with an increase in post-synaptic effects of NE (e.g., elevated heart rate, contractility, and cardiac output). It was hypothesized that hypertension would be associated a reduction in cardiac NET protein, and that the reduction in NET would parallel the rise in blood pressure during hypertension development. Uninephrectomized, male rats, implanted with deoxycorticosterone acetate (DOCA) and were fed a 1% salt diet. At all time points analyzed, systolic blood pressures were significantly elevated in DOCA animals (p<0.05) showing progressive increase with time (4 week: Normotensive 120.0 + 3.81 mmHg vs. DOCA: 195.7 + 8.76 mmHg, p<0.05). Animals were euthanized at three days (n=10), one-week (n=12), and four-weeks (n=8) after initiation of DOCA treatment. Isolated heart chambers were analyzed with western blotting. At four-weeks, NET protein (80 kD) was significantly lower in the hypertensive left ventricle (p<0.05). However, there was no change in NET protein (p>0.05) at three days or one week despite significantly greater blood pressure in DOCA animals. The hypothesis was not supported, as changes in NET do not parallel blood pressure increases during hypertension development. Nevertheless, reduced NET protein in chronic hypertension may be the underlying cause of functionally reduced cardiac reuptake of NE, which contributes to hypertension. P01HL70687.

Chronic angiotensin-(1–7) prevents cardiac fibrosis in DOCA-salt model of hypertension

Cardiac remodeling is a hallmark hypertension-induced pathophysiology. In the current study, the role of the angiotensin-(1-7) fragment in modulating cardiac remodeling was examined. Sprague-Dawley rats underwent uninephrectomy surgery and were implanted with a deoxycorticosterone acetate (DOCA) pellet. DOCA animals had their drinking water replaced with 0.9% saline solution. A subgroup of DOCA-salt animals was implanted with osmotic minipumps, which delivered angiotensin-(1-7) chronically (100 ng.kg(-1).min(-1)). Control animals underwent sham surgery and were maintained on normal drinking water. Blood pressure was measured weekly with the use of the tail-cuff method, and after 4 wk of treatment, blood pressure responses to graded doses of angiotensin II were determined by direct carotid artery cannulation. Ventricle size was measured, and cross sections of the heart ventricles were paraffin embedded and stained using Masson's Trichrome to measure interstitial and perivascular collagen deposition and myocyte diameter. DOCA-salt treatment caused significant increases in blood pressure, cardiac hypertrophy, and myocardial and perivascular fibrosis. Angiotensin-(1-7) infusion prevented the collagen deposition effects without any effect on blood pressure or cardiac hypertrophy. These results indicate that angiotensin-(1-7) selectively prevents cardiac fibrosis independent of blood pressure or cardiac hypertrophy in the DOCA-salt model of hypertension.

Acute Renal Function in Chronically Sympathectomized Deoxycorticosterone Acetate-Treated Miniature Swine

We recently validated a swine model in which chronic treatment with 6-hydroxydopamine (6-OHDA) produced an effective sympathectomy. These sympathectomized swine demonstrated a significantly attenuated hypertensive response when treated with deoxycorticosterone acetate (DOCA). Because renal nerve activity is elevated and important in controlling renal function and blood pressure in the DOCA swine model, we wanted to study the effect of chronic sympathectomy on acute renal hemodynamics and tubular function. Kidney function was assessed in 14 DOCA-treated miniature swine, 8 of which were sympathectomized by chronic treatment with 6-OHDA, while 6 served as controls. Effective renal sympathectomy in this model has been previously confirmed by a significant reduction (97%) of norepinephrine in renal cortical tissue. When anesthetized, mean arterial pressure and renal blood flow were similar between the two groups. Glomerular filtration rate was lower by 43%, urine flow rate by 71%, sodium excretion by 66%, and potassium excretion by 48% in the 6-OHDA DOCA animals. All of these parameters were significantly different from the intact DOCA controls. These results indicate that anesthetized, chronically sympathectomized swine exhibit decreased renal excretory function. The changes in renal function may have been due to the development of a tubular or glomerular supersensitivity to circulating antinatriuretic factors, since the 6-OHDA group had a 28% greater pressor response to the alpha-agonist phenylephrine and a significantly greater fall in mean arterial pressure in response to alpha-blockade with prazosin when compared with the controls. These changes in renal function may also explain why the 6-OHDA animals demonstrated a slight increase in mean arterial pressure in response to DOCA. Because acute renal denervation in DOCA-treated swine produces a diuresis and natriuresis, this study affirms that there may be important functional differences in acutely versus chronically denervated kidneys for which the implications under normal physiologic conditions are unknown.

Autoregulation of the glomerular filtration rate and the single-nephron glomerular filtration rate despite inhibition of tubuloglomerular feedback in rats chronically volume-expanded by deoxycorticosterone acetate

Tubuloglomerular feedback (TGF) function and autoregulation (renal blood flow RBF; glomerular filtration rate, GFR; single-nephron glomerular filtration rate, SNGFR) were examined in rats chronically treated with deoxycorticosterone acetate (DOCA) and given isotonic saline to drink. DOCA treatment depressed arterial plasma renin activity, expanded plasma volume by 25% and increased arterial blood pressure. Autoregulation of RBF and GFR was maintained in the DOCA animals above 90 mm Hg and 110 mm Hg respectively, whereby both GFR and RBF were lower than in controls. Micropuncture experiments demonstrated the absence of TGF in the DOCA animals. There was no difference between SNGFR values measured in the distal and proximal tubules, nor was there a significant response of SNGFR when loops of Henle were perfused with Ringer's solution at 20 nl/min. Loop perfusion in control rats with tubular fluid collected in DOCA rats elicited a normal TGF response, showing that TGF inhibition in the DOCA animals is due to changes in the function of the juxtaglomerular apparatus. In contrast to control rats, proximal SNGFR was perfectly autoregulated. These results suggest that TGF is not primarily responsible for autoregulation and that the vasodilatation normally resulting from acute TGF interruption is therefore compensated by some other mechanism such that RBF and GFR are lower than in controls.

Effects of aortic constriction and renal denervation in DOCA-hypertensive swine.

The autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR) was examined in normal and deoxycorticosterone acetate (DOCA)-hypertensive Yucatan miniature swine (YMS). Aortic constriction (AC) was used to vary renal perfusion pressure (RPP) from 158 to 90 mmHg for DOCA-YMS and 124 to 50 mmHg for normals. DOCA animals had calculated RBF autoregulatory indexes demonstrating less effective autoregulation compared with controls. Over the pressure range of RBF autoregulation, control animals also autoregulated their GFR, whereas most DOCA animals did not. When renal function in DOCA-YMS was evaluated at the normotensive RPP of 115 mmHg, GFR, urine volume, and sodium excretion were decreased by approximately 60, 70, and 80%, respectively. In DOCA-YMS, after the normalization of RPP to 115 mmHg, renal denervation significantly increased RBF. In DOCA animals the relative decrease in sodium and water excretion in relation to decreased RPP was not altered by renal denervation. In this hypertensive model the excretion of water and sodium are closely linked to RPP. At a normotensive RPP the sodium retention in the DOCA animals may be even further exaggerated by their inability to autoregulate GFR.

Effects of deoxycorticosterone on arterial wall properties in two-kidney rats.

The contribution of deoxycorticosterone acetate (DOCA) and salt to arterial pressure and hypertension-related arterial wall changes was assessed in Wistar rats. One group of two-kidney DOCA-treated animals was given a high salt diet and another group a low salt diet. After 16 weeks of treatment, the animals on low salt intake did not exhibit a significant increase in arterial pressure compared with untreated controls, while pressure was significantly elevated in the high-salt group. Values for the latter group were not as high as values in one-kidney, high salt DOCA-treated animals. Segments of the carotid and tail arteries were used for mechanical and chemical studies. Data obtained using arteries from the low salt two-kidney DOCA group were not significantly different from those of untreated controls. A number of significant differences were found in the two high salt groups compared with the low salt group and untreated controls; these included cardiac hypertrophy, increased passive arterial stiffness, decreased connective tissue concentration and increased maximum force development in response to high potassium plus norepinephrine activation. Larger changes were found in one-kidney compared to two-kidney DOCA animals. Thus DOCA administration to two-kidney rats on high salt intake produces moderate arterial hypertension and hypertension-related arterial wall changes. On the other hand DOCA administration to two-kidney rats on low salt intake does not produce an increase in arterial pressure nor altered arterial wall properties. These results suggest that DOCA in the absence of salt excess does not elevate arterial pressure or produce arterial wall changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of phenoxybenzamine, metoprolol, captopril, and meclofenamate on cardiovascular function in deoxycorticosterone acetate hypertensive Yucatan miniature swine.

Eight adult Yucatan miniature swine were implanted with deoxycorticosterone acetate (DOCA) impregnated silicone strips (100 mg X kg-1). After 16 weeks of DOCA treatment mean arterial pressure (MAP) increased to 183 +/- 4 mmHg (1 mmHg = 133.322 Pa). In four normal animals arterial pressure was 126 +/- 8 mmHg. The increase in MAP in the DOCA animals was due to an elevated total peripheral resistance (TPR) with cardiac output remaining normal. In tests with conscious animals, phenoxybenzamine (1 mg X kg-1) significantly decreased arterial pressure via a selective decrease in TPR. Neither meclofenamate, metoprolol, nor captopril affected MAP in these DOCA hypertensive animals. Dose--response curves to exogenous norepinephrine and angiotensin II revealed that the DOCA animals had an increased pressor sensitivity to both of these agents. These data suggest that in the DOCA hypertensive Yucatan swine an increase in alpha adrenergic activity and (or) an increase in smooth muscle responsiveness to circulating catecholamines is responsible for the increase in blood pressure as a result of an increase in total peripheral resistance.

Effects of prostaglandin inhibition on renal function in deoxycorticosterone-acetate hypertensive Yucatan miniature swine

This study evaluated the effect of prostaglandin (PG) on renal function in normal and deoxycorticosterone-acetate (DOCA) hypertensive Yucatan miniature swine. Eight animals were implanted with DOCA impregnated silicone strips. MAP increased in the conscious DOCA animals from a normal pressure of 110–115 mmHg, to 148 ± 4 mmHg.After 3–4 weeks, the DOCA hypertensive and eight normal (sham or non-implanted) animals were anesthetized with sodium pentobarbital which reduced MAP in the DOCA pigs to normotensive levels. Under anesthesia, PG inhibition (indomethacin or meclofenamate, 2 mg/kg i.v.) increased MAP only in the normal group (P < .05). PG inhibition caused a significant reduction in renal blood flow in both groups, but only decreased glomerular filtration rate in the DOCA animals (P < .05). Radioactive microsphere distribution to the outer cortex of the normal animals was significantly decreased with PG inhibition, (P < .05). No consistant changes in electrolyte excretion or urine flow rate was seen in either group following PG inhibition. These data indicate that PG may influence renal hemodynamics in both normal and DOCA hypertensive Yucatan miniature swine. The finding that PG inhibition selectively decreases GFR in the DOCA animals suggests a possible protective role of these hormones in this hypertensive animal model.

Renal function in two-kidney deoxycorticosterone acetate-hypertensive Yucatan miniature swine.

AbstractTo determine renal function in two-kidney deoxycorticosterone acetate (DOCA)-treated Yucatan miniature swine, eight animals were implanted with DOCA-treated silicone strips. After 3–4 weeks, mean arterial pressure (MAP) increased by approximately 32% to 148 ± 4 mm Hg. Eight sham-implanted control swine were also studied. Pentobarbital anesthesia decreased MAP in DOCA animals to 116 ± 6 mm Hg, a value similar to that seen in the anesthetized controls (112 ± 4 mm Hg). Renal blood flow and glomerular filtration rates were significantly higher in control as compared to DOCA animals (P < 0.05). Radioactive microsphere distribution to the outer cortex was also significantly decreased and inner cortical blood flow was significantly higher in the DOCA-treated animals (P < 0.05). Urine flow rates were similar between the two groups, whereas sodium excretion was lower and potassium excretion was higher in the DOCA-treated animals. These data indicate that DOCA-hypertensive Yucatan miniature swine appear to ...

Proximal and distal tubular function in salt-deprived and in salt-loaded deoxycorticosterone acetate-escaped rats.

Proximal and distal tubular function was compared with urinary excretion in rats after chronic administration of salt and deoxycorticosterone acetate (DOCA) or during salt deprivation. DOCA rats excreted significantly more sodium than did salt-deprived rats. Measurements of tubular fluid to plasma (TF/P) inulin ratios and concentrations of sodium and potassium in quantitative, timed collections, related to measured tubular length, allowed calculation of absolute reabsorption of fluid and ions in the different nephron segments. Proximal transport was not reduced in DOCA-treated rats compared with salt-deprived animals; in distal tubule the former group reabsorbed more sodium and secreted less potassium than the latter. Calculation of sodium transport in loop of Henle as the difference in flow between the end of the proximal convolution and the beginnings of the distal tubule indicated no inhibition of reabsorption in DOCA animals. Comparison of end-distal tubular flow with simultaneous urinary excretion suggested that sodium load was not the determining factor of enhanced natriuresis in DOCA-treated animals. The data are interpreted as indicating that DOCA-escape in the rat is associated with specific alteration of sodium transport in the collecting duct system.