Deoxycorticosterone Acetate Hypertension Research Articles

Is the Serotonin1b Receptor Involved in Arterial Serotonergic Hypersensitivity in Deoxycorticosterone Acetate-Salt Hypertension?

P27 The 5-HT1B receptor has been recently implicated in mediating arterial contraction to serotonin (5-hydroxytryptamine, 5-HT).The 5-HT1B receptor is unmasked/enabled by depolarizing stimuli. It is possible that 5-HT1B receptors in arteries from hypertensive animals, arteries reported to have a depolarized resting potential in smooth muscle cells, are enabled and participate in the supersensitivity observed to 5-HT in hypertension. To test this hypothesis, we utilized an isolated tissue bath apparatus and examined the response of thoracic aorta from normotensive sham rats [systolic blood pressure (SBP) 123 +2 mmHg] and hypertensive deoxycorticosterone acetate (DOCA)-salt rats [SBP 194 + 10 mmHg]. The 5-HT1B agonist RU24969 and the 5-HT1B/1D receptor agonist sumatriptan (10-9 -10-5 M) caused a maximal contraction [50 % + 12 of phenylephrine (10-5 M) contraction] in tissues from DOCA-salt rats; no contraction was observed in normotensive arteries. The 5-HT1B antagonist SB216641 (30 nM) was unable to block the RU24969-induced contraction as well as the 5-HT (10-9 -10-4 M)-induced contraction in aorta from both DOCA-salt and normotensive rats. Tissues from normotensive rats were incubated with 15mM KCl as a depolarizing stimulus, and then curves were performed to 5-HT, RU24969, and sumatriptan. These studies were performed in the presence of ketanserin (10 nM, 5-HT 2A receptor antagonist) to remove the contribution of the 5-HT2A receptor. The 5-HT-induced contraction was not changed in the presence of the KCl stimulus. High concentrations (10-5 M) of RU24969 did result in a 30% + 9 contraction. However, the presence of a depolarizing stimulus was unable to produce a leftward shift of the response to resemble that of aorta from DOCA-salt rats. These data support the conclusions that 5-HT1B receptors do not contribute significantly to the 5-HT-induced contraction in the rat aorta or to the hypersensitivity to 5-HT observed in DOCA-salt hypertension. In addition, these data support the conclusion that the arterial hypersensitivity to 5-HT in hypertension is not due to membrane depolarization alone.

Ginkgo biloba extract attenuates the development of hypertension in deoxycorticosterone acetate-salt hypertensive rats.

1. We examined the effects of Ginkgo biloba extract (GBE) on the development of hypertension, platelet activation and renal dysfunction in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Both DOCA-salt hypertensive rats and normotensive rats were fed a 2% GBE diet for 20 days. Blood pressure (BP) was measured by two methods, namely by the tail-cuff and telemetry methods. 2. Development of hypertension was attenuated in rats fed a 2% GBE diet. In addition, an increase in heart weight, an indicator of sustained high BP, was inhibited significantly by feeding of the GBE diet. 3. Decreases in 5-hydroxytryptamine content in platelets, a marker of platelet activation in vivo associated with hypertension, were also prevented by feeding of the GBE diet. Ginkgo biloba extract itself did not inhibit ADP- and collagen-induced platelet aggregation examined in vitro. Feeding of the GBE diet tended to inhibit increases in plasma urea nitrogen due to hypertension. 4. The telemetry study demonstrated that BP and heart rate (HR) showed a clear circadian rhythm and the antihypertensive effect of GBE was prominent in the daytime, a resting period for rats. This anti-hypertensive effect of GBE was not detected in normotensive rats. In contrast, the inhibitory effect of GBE on HR was independent of time and was observed in both normotensive and hypertensive rats. 5. These results indicate that GBE has an anti-hypertensive and bradycardiac action, which are time dependent and independent, respectively. Thus, it appears that the chronopharmacological action of GBE may be ascribed not to pharmacokinetic factors, but rather to a circadian susceptibility rhythm to GBE in DOCA-salt hypertensive rats.

Influence of enalapril on established pressure-overload cardiac hypertrophy in low and normal renin states in female rats

To determine whether effects of angiotensin converting enzyme (ACE) inhibitors on well-established pressure overload-induced cardiac hypertrophy and coronary remodeling depend upon normal plasma renin levels, the influence of enalapril on ventricular mass and coronary vascular resistance (CVR) was determined in a lowrenin female rat model of chronic pressure overload, (deoxycorticosterone acetate hypertension, DOCA) and compared to its effect in a normal-renin model, (aortic constriction, AC). Six weeks after experiment initiation, plasma renin activity of DOCA-treated rats was reduced to ~12% that of sham-treated and AC-treated groups. Enalapril was then added to the drinking water of half the animals in each group for two additional weeks. Comparing experimental groups to controls, this delayed enalapril treatment had 1) no effect on the elevated arterial pressures, 2) no effect on the elevated coronary resistance and, in the DOCA group, 3) no effect on cardiac hypertrophy. However, this brief enalapril treatment reduced absolute and relative ventricular weights of AC rats. These data suggest that circulating renin is required for the anti-hypertrophic efficacy of late-onset brief treatment with enalapril. Since enalapril-induced reversal of cardiac hypertrophy in AC rats was not accompanied by reversal of coronary remodeling, growth signals other than angiotensin II may be involved in coronary remodeling.

Hoechst Marion Roussel Hypertension Research Clinical Fellowship Award 1999

Hoechst Marion Roussel Hypertension Research Clinical Fellowship Award 1999

Effect of Long-Term Treatment with Enalapril in Streptozotocin Diabetic and DOCA Hypertensive Rats

We studied the effects of long-term treatment with enalapril (5 mg/kg/day orally) on various biochemical and cardiovascular complications in streptozotocin (STZ) diabetic and deoxycorticosterone acetate (DOCA) hypertensive rats. Female Wistar rats made diabetic or hypertensive or both by streptozotocin (STZ; 45 mg/kg) or deoxycorticosterone acetate (DOCA; 10 mg/kg, p.o., daily) or both. Enalapril (5 mg/kg) was administered daily by the oral route for 6 weeks. At the end of 6 weeks, blood samples were taken to analyze glucose, insulin, and lipids. Blood pressure and heart rate were recorded by a noninvasive technique, and cardiac functions were recorded by Neely's working heart preparation. Injection of STZ produced severe glycosuria (>2%), hyperglycemia, hypoinsulinemia, and loss of body weight. It also produced hypercholesterolemia, hypertriglyceridemia, hypertension, bradycardia, and decreased left ventricular developed pressure (LVDP) and increase in angiotensin-converting enzyme (ACE) in left ventricular tissue. DOCA by itself did not produce any change in blood glucose but reduced serum insulin levels in nondiabetic animals. However, in the diabetic group, DOCA reduced blood sugar levels. Treatment with enalapril prevented an increase in the blood pressure and the heart weight. Decrease in the heart rate, reduction in LVDP, and increase in intracardiac activity were observed in diabetic rats; these were also prevented by enalapril treatment. Enalapril had no effect on plasma glucose and did not modify plasma insulin levels in diabetic animals. The effects of STZ and DOCA together were not additive on the investigated parameters, and enalapril was similarly efficient in diabetic and diabetic hypertensive animals.

Cardiac type-1 angiotensin II receptor status in deoxycorticosterone acetate-salt hypertension in rats.

The regulation of angiotensin II (Ang II) receptors and Ang II-induced modulation of intracellular Ca2+ concentration in cardiac cells from hearts of experimentally induced hypertensive deoxycorticosterone acetate (DOCA)-salt and control unilaterally nephrectomized (Uni-Nx) Sprague-Dawley rats was assessed. Ang II receptor density and intracellular Ca2+ concentration measurements were examined in adult ventricular myocytes and fibroblasts by radioligand binding assay and digital imaging using fura 2 methodology, respectively. Four-week DOCA-salt treatment induced hypertension associated with cardiac hypertrophy. Ang II binding studies demonstrated that adult ventricular myocytes and fibroblasts possess mainly the AT1 subtype receptor. Moreover, DOCA-salt hypertension was associated with a 1.8-fold increase in Ang II-specific binding compared with myocytes from Uni-Nx control rats. Intracellular Ca2+ responses induced by increasing Ang II concentrations (10[-12] to 10[-4] mol/L) were significantly enhanced in cardiomyocytes from DOCA-salt rats. The effects of Ang II on intracellular Ca2+ spike frequency were unaltered in cardiomyocytes from DOCA-salt-hypertensive rats. The density of AT1 subtype receptors was not modified in ventricular fibroblasts after DOCA-salt treatment. Ang II increased intracellular Ca2+ concentration similarly in ventricular fibroblasts from normal and hypertensive rats. In conclusion, DOCA-salt hypertension is characterized by an increased AT1 receptor density and intracellular calcium responses in ventricular myocytes, whereas in ventricular fibroblasts the AT1 receptor status is unaltered. These findings report for the first time the cardiac cell-specific implication of Ang II and the intracellular calcium signaling pathway stimulated by the AT1 receptor in cardiac hypertrophy in DOCA-salt-hypertensive rats.

Effects of the Endothelin ETA-Receptor Antagonist FR139317 on Development of Hypertension and Cardiovascular Hypertrophy in Deoxycorticosterone Acetate-Salt Hypertensive Rats

We investigated the role of endothelin-1 (ET-1) in the development of hypertension and cardiovascular hypertrophy in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Two weeks after the start of DOCA-salt treatment, the rats were divided into two groups and were given FR139317 [(R)2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]-carbonyl]amino-4-methyl-pentanoyl]amino-3-[3-(1-methyl-lH-indolyl)]propionyl]amino-3-(2-pyridyl) propionic acid], a specific ETA-receptor antagonist, or its vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as controls. Vehicle-treated DOCA-salt rats developed marked hypertension after 4 weeks. FR139317 significantly suppressed the increase in systolic blood pressure with values averaging 163±8 mmHg (P<0.05 vs DOCA-salt rats receiving vehicle, 195±9 mmHg). Morphological studies in the rats given the vehicle showed vascular medial hypertrophy, with a significant increase in the wall area and wall-to-lumen ratio. A marked decrease in vascular wall hypertrophy was observed in the FR139317-treated DOCA-salt rats. The cardiac hypertrophy in DOCA-salt hypertensive rats was also significantly reduced by FR139317. Therefore, these results suggest that ET-1 plays an important role in the development of DOCA-salt hypertension presumably by stimulating the ETA receptor. In addition, we found that an ETA-receptor antagonist effectively reduced cardiovascular hypertrophy in the rats, so the cardiovascular hypertrophy noted in DOCA-salt hypertensive rats may be related to ET-1.

Sarcoplasmic reticulum Ca2+ uptake is not decreased in aorta from deoxycorticosterone acetate hypertensive rats: functional assessment with cyclopiazonic acid.

Ca2+ plays a major role in vascular contraction, and a defect in intracellular Ca2+ regulation has been associated with increased vascular reactivity in hypertension. To test the hypothesis that the sarcoplasmic reticulum does not adequately buffer Ca2+ in deoxycorticosterone acetate (DOCA) hypertension, contractile experiments were performed with a specific inhibitor of the sarcoplasmic reticulum Ca2+ ATPase, cyclopiazonic acid (CPA). Contractile force in aortic strips from DOCA and control rats was measured, using standard muscle bath procedures, to evaluate (i) Ca2+ handling, assessing caffeine and serotonin (5HT) induced contractions in Ca(2+)-free buffer and (ii) relaxation rate after 5HT washout. Contractile responses elicited with 5HT (3 x 10(-6) mol/L) and caffeine (20 mmol/L) were greater in DOCA than in control arteries. CPA (1 x 10(-7) to 3 x 10(-5) mol/L) reduced phasic contractions to 5HT and caffeine in DOCA and control aorta, and no differences in the IC50 values were observed. Aortae from DOCA rats contracted when placed in normal buffer, subsequent to treatment with Ca(2+)-free buffer, but control aortae did not. CPA potentiated these responses in DOCA aorta and only caused a modest contraction in control aorta. CPA-induced contraction did not occur in Ca(2+)-free buffer, and it was inhibited by nifedipine (IC50 = 4 x 10(-9) mol/L). The relaxation rate, after 5HT washout (3 x 10(-6) mol/L), was increased in DOCA aorta (2.6 +/- 0.3 min) compared with control (1.7 +/- 0.2 min), and CPA (10(-5) mol/L) increased the relaxation rate in both groups. The results support the hypothesis of defective Ca2+ handling in DOCA hypertension. However, an increased Ca2+ influx, and not a decreased buffering ability of the sarcoplasmic reticulum, contributes to the enhanced vascular reactivity observed in DOCA hypertension.

Role of angiotensin II in cerebrovascular and renal damage in deoxycorticosterone acetate-salt hypertensive rats

To study the effects of blockade of the renin-angiotensin system on the development of hypertension and end-organ damage in hyporeninaemic deoxycorticosterone acetate (DOCA)-salt hypertensive rats, using an angiotensin II (Ang II) receptor antagonist (TCV-116) or an angiotensin converting enzyme (ACE) inhibitor (enalapril). DOCA-salt hypertensive rats were produced by uninephrectomy, implantation with DOCA pellets and 1% NaCl loading. TCV-116 (0.1 or 1 mg/kg) or enalapril (10 mg/kg) was given orally once a day from 3 to 6 weeks after the operation. Body weight, blood pressure, plasma renin and creatinine, urinary protein and blood urea nitrogen were measured. After 3 weeks' treatment, oedema and omega 3-subtype benzodiazepine receptor binding in the brain were measured. Three weeks after the operation the blood pressure in the DOCA-salt hypertensive rats was approximately 200 mmHg, and the plasma renin concentration was lower than in sham-operated rats. However, after a further 3 weeks the renin concentration was slightly above the normal level, and this increase was accompanied by a decrease in body weight and increases in blood urea nitrogen, plasma creatinine, urinary protein and omega 3-subtype benzodiazepine receptor binding in the cerebral cortex, and by brain oedema. Treatment with TCV-116 or enalapril prevented renal damage and decrease in body weight with little effect on blood pressure. Enalapril prevented brain oedema and the increase in benzodiazepine binding in the brain cortex, and 1 mg/kg TCV-116 prevented them markedly. Although the hypertension in DOCA-salt hypertensive rats is independent of the renin-angiotensin system, the degree of cerebral and renal damage is associated with the activity of the renin-angiotensin system and has little relationship with the blood pressure level.

Digoxin amplifies the effects of deoxycorticosterone acetate (DOCA) in intact water-drinking rats

An increase in digitalis-like substances has been reported in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We hypothesized that the role of saline and unilateral nephrectomy in DOCA hypertension may be due to stimulation of endogenous digitalis-like substances. We investigated the effects of digoxin and DOCA alone and in combination in intact rats drinking water. Forty male Sprague-Dawley rats were used (body weight 223-298 g). Neither digoxin (40 micrograms/kg per day, by gavage, for 35 days, n = 10) nor DOCA (30 mg/kg twice a week, subcutaneously, for 5 weeks, n = 10) caused a consistent increase in blood pressure in intact rats drinking water. In contrast, combined digoxin and DOCA administration (n = 10) increased systolic blood pressure from day 18 of treatment onwards, to a maximum at day 34 compared with sham-treated rats (n = 10). There were no consistent changes in water intake, urine volume, urinary sodium or potassium excretion, or plasma sodium or potassium concentration with digoxin treatment. DOCA increased water intake and urine volume, and caused an initial decrease in urinary sodium excretion, but no change in urinary potassium excretion or plasma sodium concentration. Plasma potassium excretion was lower in DOCA- than sham-treated rats. Combined digoxin and DOCA administration in intact rats drinking water increased blood pressure significantly compared with either drug alone, raising the possibility that the mechanism by which nephrectomy and salt loading contribute to DOCA hypertension in the rat might be through stimulation of endogenous digitalis-like substances.

Integrated cardiovascular function in the conscious streptozotocin-diabetic deoxycorticosterone-acetate-hypertensive rats.

Blood pressure, heart rate, and left ventricular function were measured in conscious diabetic Sprague-Dawley rats subjected to 5 weeks of deoxycorticosterone acetate (DOCA) treatment which was started 1 week following intravenous injection of streptozotocin (STZ) (60 mg/kg) to induce diabetes mellitus. It was found that chronic administration of DOCA in nondiabetic animals caused an increase in blood pressure and functional parameters of left ventricle, and a decrease in heart rate and plasma insulin levels. Normotensive diabetic rats exhibited hyperglycemia, hypoinsulinemia, and a lower body weight as compared with control animals but did not show significant abnormalities in cardiovascular function. DOCA-hypertensive STZ-diabetic rats had similar hyperglycemia, milder hypoinsulinemia, and a significantly lower rate of left ventricular relaxation and systolic blood pressure compared with the nondiabetic DOCA-hypertensive animals. It is concluded that the addition of DOCA hypertension to intact 6-week STZ-diabetic Sprague-Dawley rats results in the occurrence of cardiac dysfunction.

Effects of dietary magnesium on blood pressure and vascular lesions in hypertensive rats

The present study examines the effects of dietary magnesium on the development of hypertension and hypertensive vascular lesions in deoxycorticosterone acetate and salt induced (DOCA-salt) and 2 kidney one clip (2K1C) hypertensive as well as normotensive control rats. Animals received a regular (0.12% Mg), high (0.4% Mg) or low (0.03% Mg) magnesium diet for 6 wks. Dietary magnesium did not alter the growth or blood pressure in control, DOCA-salt and 2K1C rats even though the plasma magnesium concentration was significantly altered by the diets (ANOVA, p < 0.05 in control, DOCA-salt and 2K1C, respectively). Dietary magnesium did not alter the urinary potassium excretion, plasma sodium, potassium, total calcium concentration and plasma renin activity in any group, while the high magnesium diet significantly increased the urinary sodium excretion in DOCA-salt (p < 0.05) but not in control and 2K1C rats when compared with the regular magnesium diet. In histological studies, dietary magnesium did not alter the percentage media area of intramyocardial arteries, or glomerular and renal arterial and arteriolar lesions in DOCA-salt and 2K1C rats. This study suggests that moderate alterations of dietary magnesium do not modify blood pressure in normotensive control, DOCA-salt and 2K1C hypertensive rats, nor do they modify vascular disease in these 2 hypertensive models.

Indomethacin attenuates exercise-induced proteinuria in hypertensive miniature swine.

Exercise-induced proteinuria may be increased in hypertensives. The mechanisms underlying the increased proteinuria are not known, and it has not been determined whether animal models of hypertension exhibit a similar response. We investigated whether indomethacin (Indo) altered exercise-induced proteinuria in normal and hypertensive deoxycorticosterone acetate (DOCA) Yucatan miniature swine (YMS). Five normal and four DOCA YMS underwent 30 min of treadmill exercise at 80% of maximal heart rate. Cumulative (exercise + recovery) albumin excretion in the DOCA YMS was 25-fold (P < 0.01) greater than observed in the normal YMS. Indo had no effect on resting or exercise-induced proteinuria in the normal YMS. However, Indo decreased the slightly elevated proteinuria at rest, and normalized the exaggerated exercise-induced proteinuria in the DOCA YMS. The antiproteinuric effect of Indo in the DOCA YMS was not associated with altered exercise, recovery blood pressure, or glomerular filtration rate. Thus hypertensive DOCA YMS exhibit an exaggerated exercise-induced proteinuria. It is suggested that eicosanoids are involved in this abnormal renal proteinuric response to exercise.

Failure of Verapamil and Diltiazem to Attenuate the Pressor Response to Hypothalamic Stimulation: A Possible Mechanism

The effects of verapamil or diltiazem on pressor responses to posterior hypothalamic stimulation, injected noradrenaline or tyramine were studied in urethane-anaesthetized normotensive, deoxycorticosterone acetate (DOCA), renal and spontaneously hypertensive rats at the early and established phases of hypertension. Pressor responses to the pressor stimuli were significantly enhanced in the early and established phases of hypertension when compared with the normotensives. While the magnitude of pressor responses in the established phase of renal or spontaneously hypertensive rats was significantly higher (P less than 0.05) than the corresponding value in the early phase, in contrast, the pressor response in the early phase of DOCA hypertension was significantly higher than that of the established phase. Verapamil or diltiazem significantly (P less than 0.005) inhibited pressor responses to injected noradrenaline or tyramine in all groups of rats but not that to hypothalamic stimulation, irrespective of the stage of hypertension. When the probable mechanism of the hypothalamic pressor response's resistance to the calcium antagonists was studied in-vitro, ATP significantly (P less than 0.005) inhibited the relaxant effect of the calcium antagonists in the rat aortic strips. Our data indicate that verapamil or diltiazem is ineffective in inhibiting the pressor response to posterior hypothalamic stimulation. The probable mechanism of the resistance and the clinical implication of the findings are discussed.

The pathogenesis of DOCA-salt hypertension

Deoxycorticosterone acetate (DOCA) is an agent commonly used to induce hypertension in experimental animals. This form of hypertension is dependent on altered regulation of central pressor mechanisms including the brain renin-angiotensin system. Additionally, there are characteristic changes involving the cardiovascular system and baroreflex responses. This review will discuss aspects of the pathogenesis of DOCA hypertension and the effect of various antihypertensive agents on the development of this form of hypertension.

Angiotensin II receptor antagonists. From discovery to antihypertensive drugs.

Some simple N-benzylimidazoles, originally described by Takeda Chemical Industries (Osaka, Japan), were characterized to be very weak but selective nonpeptide angiotensin II (Ang II) receptor antagonists with a competitive mode of action. Chemical modifications of these led to EXP6155 and EXP6803, which showed approximately 10- and 100-fold higher affinity, respectively, but were orally ineffective. Oral activity was obtained for the biphenyl carboxylic acid derivatives EXP7711 and especially EXP9654. A further advance in the design of nonpeptide Ang II receptor antagonists was provided by DuP 753, an analogue of EXP7711 in which the carboxylic acid function is replaced by its tetrazol-5-yl equivalent. DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bi phe nyl-4- yl)methyl]imidazole, potassium salt) displaces radiolabeled Ang II from its specific binding sites in various tissues, affording IC50 values of approximately 20 nM. DuP 753 competitively antagonizes Ang II-induced responses in various in vitro and in vivo preparations but does not influence those to KCl, norepinephrine, vasopressin, and others, nor does it affect converting enzyme and renin. In high renin animal models of elevated arterial blood pressure, intravenous and oral administrations of DuP 753 produce a sustained decrease in pressure without influencing heart rate. Marked antihypertensive effects are observed in spontaneously hypertensive rats, but no efficacy is noticed in deoxycorticosterone acetate hypertensive animals. DuP 753 showed no agonistic properties in any of the above test systems and has been chosen to undergo clinical trials for the treatment of hypertension. In rats, the 5-carboxylic acid (EXP3174) represents a major metabolite of DuP 753.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoregulatory capacity in renal and mesenteric vasculatures of mineralocorticoid hypertensive dogs

Experiments were performed in seven conscious dogs to quantitate the renal and mesenteric autoregulatory capacity in deoxycorticosterone acetate (DOCA)-salt hypertensive dogs. Each dog was chronically instrumented for the measurement of aortic blood pressure and blood flows through the superior mesenteric and left renal arteries (Doppler measurements); a right nephrectomy was also performed. To induce hypertension, animals were administered 5 mg/kg DOCA each day and given 1% saline as a drinking solution. After arterial pressure had increased by 25% (8-14 days of DOCA), a large-bore catheter was positioned retrograde in the left common carotid artery for subsequent connection to a gravity reservoir system for acute control of arterial pressure. Autoregulatory capacity was evaluated by controlling arterial pressure via the gravity reservoir at hypertensive and then normotensive values for 15-min periods. In neurally intact animals the renal, but not the mesenteric, circulation displayed autoregulatory capacity; the closed-loop gain of renal flow control averaged 0.92 +/- 0.06. Inhibition of autonomic ganglionic transmission (hexamethonium) increased the gain of flow regulation in the mesenteric circulation, but mesenteric autoregulation was not manifest. Ganglionic blockade, inhibition of prostaglandin formation, or blockade of histamine or adenosine receptors did not significantly influence renal autoregulatory capacity. These data demonstrate that the kidney has a high capacity to autoregulate in DOCA hypertension and suggest that autoregulatory-mediated renal vasoconstriction contributes to the increased total peripheral resistance.

Association of DOCA hypertension with induction of atherosclerosis in rats with short-term diabetes mellitus

We investigated the effect of deoxycorticosterone acetate (DOCA)-induced hypertension on plasma lipid and cholesterol levels and the development of vascular atherosclerotic changes in male Wistar rats injected with streptozotocin (STZ) or saline (CON). Rats given STZ alone demonstrated a mild hyperlipidemia and hypercholesterolemia without any change in blood pressure. One week of DOCA administration was without effect on blood pressure in CON and STZ groups, but at 3 and 6 wk caused a significant and similar elevation in both groups. This DOCA-induced elevation in blood pressure appeared to be associated with the increase in plasma lipid and cholesterol levels seen in both CON and STZ groups at 3 and 6 wk, although the elevation in lipid and cholesterol levels was significantly more pronounced in the STZ rats. Both CON and STZ groups injected with DOCA developed significant pathological changes in all vessels under investigation. However, the degree of atherosclerosis appeared, from a semiquantitative analysis, to be worse in the thoracic aortas and renal arteries of the STZ group. Neither normotensive group developed any atherosclerosis. It is concluded that hypertension is associated with atherosclerosis in normal rats and rats with short-term STZ-induced diabetes mellitus, although the higher plasma lipid and cholesterol levels of the latter group may potentiate the degree of vascular damage.

A Comparative Study of C19 Steroid-Induced Hypertension and Deoxycorticosterone Acetate (DOCA)-Salt Hypertension

In order to evaluate the hypertensinogenic action of 19-hydroxyandrostenedione (19-OH-AD), which has been reported to be an amplifier of mineralocorticoid, the changes in several humoral factors were observed in 19-OH-AD treated rats as compared to those in DOCA hypertensive rats.Twenty-five male Wistar rats were castrated at 11 weeks of age, and the experiments were begun at 12 weeks of age. The rats were divided into 3 groups. The control group (n = 8) was given an s.c. injection of 0.2 ml of sesame oil. The 19-OH-AD group (n = 10) was injected s.c. with 10 mg of 19-OH-AD dissolved in 0.2 ml of sesame oil, and the DOCA group (n = 8) was injected s.c. with 10 mg of DOCA dissolved in 0.2 ml of sesame oil three time weekly. The urine was collected for a period of 24 hours, and the urine volume, and urinary excretions of electrolytes, prostaglandin E2 (PGE2), kinin and catecholamine were measured before and after the start of the experiment. The systolic blood pressure (S.B.P.) was measured by the tail-cuff method.The S.B.P. values before and at 9 weeks after the start of the experiments were 136.7 ± 3.8 and 156.0 ± 2.6 mmHg in the 19-OH-AD group, and 140.6 ± 5.6 and 179.3 ± 5.5 mmHg in the DOCA group, respectively. Body weight, which was elevated in both groups, was higher in the 19-OH-AD group than in the DOCA group. Water intake and urine volume were significantly (p<0.001) increased only in the DOCA group. The urinary Na/K ratio was significantly (p<0.001) elevated in the DOCA group as compared to that in the other two groups. However, there was no significant difference in urinary Na/K ratio between the control and 19-OH-AD groups. The urinary PGE2 and kinin excretions were significantly (p<0.01) increased in the DOCA group but did not change appreciably in the 19-OH-AD group. The urinary catecholamine excretion was significantly increased in the DOCA group. However, there were no differences in the catecholamine excretion between the control and 19-OH-AD groups.These experimental results suggest that the mechanism of the hypertensinogenic action of 19-OH-AD differs from that of mineralocorticoid dependent hypertension, such as DOCA hypertension, since the urinary Na/K ratio, and the urinary excretions of PGE2, kinin and catecholamine did not change appreciably during the elevation of blood pressure induced by the 19-OH-AD administration.

Increased urinary clearance of lysine vasopressin in the deoxycorticosterone acetate-hypertensive pig.

We have previously reported an increased urinary excretion of vasopressin without a rise in circulating levels of this hormone in the deoxycorticosterone acetate (DOCA)-hypertensive pig (DH). The present study was designed to characterize the renal handling of vasopressin in DH that might account for this paradox. DOCA hypertension was produced in seven domestic female pigs by means of subcutaneous implants of Silastic rubber impregnated with DOCA. Thirty days after DOCA implantation, urinary clearances of inulin, para-aminohippurate (PAH), and vasopressin were measured in the conscious animals during infusion of a 5% dextrose solution, first without and then with lysine vasopressin. Subsequent to this study, four of the pigs were placed on a low-sodium (10 meq/kg food) diet for 4 wk. At the end of this period, the clearances were again evaluated. We observed an increased urinary vasopressin clearance (CLVP) in the DH associated with an increased urinary flow but without significant changes in the clearances of inulin or PAH. Dietary sodium restrictions reversed the hypertension and the increased urinary flow and returned the CLVP to normotensive levels. These results indicate that the increased urinary excretion of vasopressin in DH is because of an increased urinary clearance of this hormone. This increased urinary CLVP is the consequence of the high urine flow in these pigs.