Role of the antiglucocorticoid RU 486 in the prevention of steroid-induced hypertension.

In the present study, we determined the effect of RU 486 on two experimental models of hypertension in the rat, deoxycorticosterone acetate (DOCA)-salt in nephrectomized rats and spontaneously hypertensive rats. Uni-nephrectomized saline-drinking male Sprague-Dawley rats were divided into three groups and each animal was given either 0.2 ml olive oil (control), 1 mg DOCA, or 1 mg DOCA + 10 mg RU 486 dissolved in 0.2 ml olive oil every third day for a period of three weeks. Within a week of steroid administration, there was a significant increase in the systolic blood pressure (SBP) in the DOCA-salt (157 +/- 3.8 mmHg) and DOCA + RU 486 (155 +/- 2.1 mmHg) treated rats over the control (116 +/- 2.6 mmHg) rats, which remained elevated throughout the experimental period. There was significant increase in the water intake and urine output in DOCA or DOCA + RU 486 treated rats as compared to the control untreated rats. In the experiment involving the spontaneously hypertensive rats, the rats were divided into three groups and each animal given 0.2 ml olive oil (control), 1 mg RU 486, or 5 mg RU 486 dissolved in 0.2 ml olive oil for six weeks. Instead of the expected decrease in the blood pressure, RU 486 significantly elevated blood pressure during the six weeks of drug administration. Water intake, urine output, and weights remained comparable in both groups. We conclude that RU 486 has no effect on the DOCA-salt model of hypertension but, surprisingly, elevates hypertension in the spontaneously hypertensive rats.     

Enhancement of the hypertensinogenic action of 19-hydroxyandrostenedione by aromatase inhibitor, delta 1-testololactone

To evaluate the enhancing effects of 1,2-dehydrotestololactone (delta 1-testololactone) on the hypertensinogenic action of 19-hydroxyandrostenedione (19-OH-A-dione), 1 mg 19-OH-A-dione, 10 mg delta 1-testololactone, or a combination of 1 mg 19-OH-A-dione and 10 mg delta 1-testololactone was injected into intact rats drinking water once a week for 4 weeks. The blood pressure of control rats and rats given 19-OH-A-dione, delta 1-testololactone, and a combination of 19-OH-A-dione and delta 1-testololactone in the fourth week was 130 +/- 2 (SE), 140 +/- 2, 128 +/- 6, and 152 +/- 5 mmHg, respectively. The blood pressure of rats given 19-OH-A-dione and a combination of 19-OH-A-dione and delta 1-testololactone was significantly higher than that of control rats. In addition, the blood pressure of rats given a combination of 19-OH-A-dione and delta 1-testololactone was significantly higher than that of rats given 19-OH-A-dione alone. As delta 1-testololactone itself did not show any hypertensinogenic action, it is considered to enhance the hypertensinogenic action of 19-OH-A-dione. Although plasma 19-OH-A-dione concentrations of control rats and rats given delta 1-testololactone were lower than the sensitivity of RIA, those of rats given 19-OH-A-dione and a combination of 19-OH-A-dione and delta 1-testololactone were 116 +/- 3 and 222 +/- 37 pg/ml, respectively. Plasma 19-OH-A-dione concentrations of rats given a combination of 19-OH-A-dione and delta 1-testololactone were significantly higher than those of rats given 19-OH-A-dione alone. Therefore, delta 1-testololactone is considered to enhance the action of 19-OH-A-dione by increasing plasma concentrations of 19-OH-A-dione. As delta 1-testololactone is an aromatase inhibitor, the inhibition of the conversion of circulating 19-OH-A-dione to estrogens in peripheral tissues might be the cause of the elevation of plasma 19-OH-A-dione concentrations. These results indicate that aromatose inhibitors enhance the hypertensinogenic action of 19-OH-A-dione by decreasing the degradation of 19-OH-A-dione.     

Infusion of atrial natriuretic hormone in DOCA/salt and spontaneously hypertensive rats

The effects of a 6-day infusion of atrial natriuretic hormone (ANH) on blood pressure and urinary sodium excretion were determined in conscious DOCA/salt and spontaneously hypertensive rats. The DOCA/salt rats were randomly divided into two groups after 4 weeks and either infused by osmotic minipump with 32.5 pmol/h of ANH in 0.1% gelatin vehicle or sham operated with emplacement of a blind cannula. Thirteen-week-old spontaneously hypertensive rats were studied in a similar fashion. The baseline systolic blood pressure prior to the infusion was 176 +/- 7 mmHg (x +/- SEM) in the ANH group and 169 +/- 5 mmHg in the sham group of DOCA/salt animals. The ANH infusion in the DOCA/salt animals dropped their blood pressure to 160 +/- 10 mmHg (p less than 0.01) compared to that in the sham controls which continued to rise to 200 +/- 7 mmHg. The blood pressure response to ANH infusion in the spontaneously hypertensive rats was slightly greater, with a blood pressure of 192 +/- 5 mmHg in the sham group and 132 +/- 3 mmHg in the ANH-infused animals. ANH infusion produces a qualitatively similar blood pressure response in the DOCA/salt rat as well as the other hypertensive models. This response is relatively less on a quantitative basis than that observed in the spontaneously hypertensive rats and is not related to changes in sodium balance or volume contraction.     

Interaction between nitric oxide and mineralocorticoids in the long-term control of blood pressure

We analyzed the effects of a possible interaction between nitric oxide deficiency and mineralocorticoids on the long-term control of blood pressure and renal and endocrine variables. Six groups of uninephrectomized male Wistar rats were used: control animals and rats that received (1) N(G)-nitro-L-arginine methyl ester (L-NAME) subpressor (0.5 mg/100 mL drinking fluid), (2) L-NAME pressor (35 mg/100 mL drinking fluid), (3) deoxycorticosterone acetate (DOCA; 12. 5 mg/wk per rat), (4) DOCA plus L-NAME subpressor, or (5) L-NAME pressor plus DOCA. For all groups, the drinking fluid was tap water or 1% NaCl solution. We measured the time course of tail systolic blood pressure (SBP) and body weight for 3 weeks in all rats. At the end of the experimental period, we measured mean arterial pressure (direct recording) and endocrine and renal variables. Tail SBP rose significantly in the DOCA plus L-NAME subpressor-treated group but remained at normotensive levels in the DOCA-treated group. The addition of L-NAME to the subpressor dose accelerated the blood pressure increase in DOCA-salt hypertensive rats. The simultaneous administration of DOCA and L-NAME increased blood pressure and mortality rates in rats that drank water or saline compared with the rats treated with L-NAME alone. The subpressor dose of L-NAME did not increase blood pressure in saline-drinking rats. We conclude that impaired NO synthesis results in increased sensitivity to the pressor effect of mineralocorticoids in the presence or absence of an increased saline intake. Hence, nitric oxide contributes to the adaptative response to mineralocorticoid excess, perhaps through the facilitation of natriuresis and, thus, control of blood pressure.     

Mineralocorticoid treatment upregulates the hypothalamic vasopressinergic system of spontaneously hypertensive rats

Mineralocorticoid effects in the brain include the control of cardiovascular functions, induction of salt appetite, interaction with the vasoactive neuropeptides arginine vasopressin (AVP) and angiotensin II and development or aggravation of hypertension. In this regard, mineralocorticoids may play a pathogenic role in rats with a genetic form of hypertension (spontaneously hypertensive rats, SHR). Our objective was to compare the response of the hypothalamic vasopressinergic system to mineralocorticoid administration in SHR and control Wistar-Kyoto (WKY) rats. Sixteen-week-old male SHR showing a systolic blood pressure of 190 +/- 5 mm Hg and normotensive WKY rats (130 +/- 5 mm Hg) were treated subcutaneously with oil vehicle or a single 10-mg dose of deoxycorticosterone acetate (DOCA). After 2 h, rats were sacrificed and brains prepared for immunocytochemistry of Fos and vasopressin V1a receptor (V1aR) and for non-isotopic in situ hybridization of AVP mRNA. In the basal state, SHR demonstrated a higher number of AVP mRNA- and V1aR-immunopositive cells in the magnocellular division of the paraventricular hypothalamic nucleus (PVN) than WKY rats. After DOCA injection, SHR responded with a significant increase in both parameters with respect to vehicle-injected SHR. In WKY rats, DOCA was without effect on AVP mRNA although it increased the number of V1aR-positive cells. Changes in the number of Fos-positive nuclei were measured in the PVN, median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT), a circumventricular region showing anatomical connections with the PVN. In vehicle-injected rats, the PVN of SHR showed a higher number of Fos-positive nuclei than in WKY rats, whereas after DOCA treatment, a significant increment occurred in the OVLT but not in the PVN or MnPO of the SHR group only. These data suggest that the enhanced response of the vasopressinergic system to mineralocorticoids may contribute to the abnormal blood pressure of SHR.     

Decreased density of vascular receptors for atrial natriuretic peptide in DOCA-salt hypertensive rats

We have previously found that vascular receptors for atrial natriuretic peptide (ANP) in the rat are down-regulated by volume expansion. For this reason vascular ANP receptor density and affinity were examined in a model of volume-expanded hypertension, the deoxycorticosterone acetate (DOCA)-salt hypertensive rat. The density of mesenteric vascular ANP binding sites was decreased in DOCA-salt hypertensive rats from a control value in uninephrectomized rats of 203 +/- 25 fmol/mg protein to 60 +/- 13 fmol/mg protein (p less than 0.01). The sensitivity of norepinephrine-precontracted aorta to ANP was significantly reduced in DOCA-salt hypertensive rats (p less than 0.001). DOCA-salt hypertensive rats infused intravenously for 4 days with ANP, 100 to 300 ng/hr, did not experience a lowering of blood pressure, in contrast to the significant reduction in blood pressure seen in two-kidney, one clip Goldblatt hypertensive rats similarly infused. In the latter there was no natriuretic response to ANP, while in the DOCA-salt hypertensive rats natriuresis occurred without lowering of blood pressure. In the DOCA-salt hypertensive rats plasma ANP concentration was increased to 68 +/- 8 fmol/ml from 10 +/- 1 fmol/ml in uninephrectomized rats. In conclusion, raised ANP concentration in plasma of volume-expanded hypertensive rats (DOCA-salt hypertension) may result in decreased density of ANP vascular receptors. These results suggest that a decrement in the number of ANP receptors may be a cause of decreased sensitivity of vascular responses to ANP in vitro and resistance to the blood pressure-lowering action of ANP in vivo.     

Centrally induced vasopressor responses to ouabain in DOCA-salt hypertensive rats

To investigate the effect of inhibition of cerebral Na+, K+-ATPase on cardiovascular regulation ouabain was injected into the lateral ventricle or the posterior hypothalamus in either conscious or urethane anaesthetised, deoxycorticosterone-salt hypertensive (DOCA) and sham operated (sham) rats. Ouabain injected intracerebroventricularly produced dose dependent vasopressor responses and tachycardia in the conscious rat; the magnitude of the pressor response was consistently larger in DOCA than in sham rats. In anaesthetised rats the pressor responses were accompanied by corresponding increases in abdominal sympathetic nerve activity. Thus the magnitude of the pressor responses, tachycardia, and the increases in nerve activity was again significantly greater in DOCA than in sham rats. Intrahypothalamic injections of ouabain produced pressor responses that were accompanied by consistent increases in both heart rate and abdominal sympathetic nerve activity in anaesthetised rats. In contrast to the intracerebroventricular injections the percentage increases from baseline blood pressure were significantly greater in sham than in DOCA rats at 5 min after injection. These results indicate that the centrally induced vasopressor response to ouabain, via the periventricular or bulbospinal system or both, is increased in DOCA-salt hypertensive rats whereas the pressor mechanism via the posterior hypothalamus is suppressed in DOCA rats.     

Development of hypertension in animals with reduced total peripheral resistance.

The object of the present study was to determine whether deoxycorticosterone acetate (DOCA)-salt hypertension can be produced in rats in the presence of low total peripheral resistance (TPR) induced by long-term administration of minoxidil, a vasodilator. The rats were divided into four groups: sham-control, DOCA-salt, minoxidil, and DOCA-salt with minoxidil. The rats in both DOCA groups had DOCA pellets implanted subcutaneously and were given saline to drink. The rats in both minoxidil groups were given minoxidil (3 mg/day) in the drinking water throughout the experiment. Final measurements, including mean arterial blood pressure, cardiac index, and renal blood flow were made after 4-6 weeks. Flow measurements were made using radioactive microspheres. Cardiac index (ml.min-1.100 g-1) in sham-control rats averaged 18 +/- 2 and was higher in the other groups: 23 +/- 4 (DOCA-salt), 25 +/- 2 (minoxidil), and 30 +/- 2 (DOCA-salt plus minoxidil). Mean arterial pressure (mm Hg) was increased in both DOCA-salt rats (160 +/- 8) and DOCA-salt plus minoxidil rats (153 +/- 5) as compared with sham-control (116 +/- 2) and minoxidil (113 +/- 3) rats. There was no significant difference in TPR between the sham-control and DOCA-salt rats, but TPR in minoxidil and DOCA-salt plus minoxidil rats was 30% and 28% lower than that in untreated sham-control and DOCA-salt hypertensive rats, respectively. In contrast, renal vascular resistance was significantly increased in both DOCA-salt groups as compared with non-DOCA-salt groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive Actions of Isoprenoids

Specific features of antihypertensive action of two new isoprenoid compounds, i.e. 5-nicotinooxymethyl - δ- tocopherylnicotinate (NNT) and decaprenoic ethylester (EDP) were studied in rats. NNT and EDP were very similar to each other in their pharmacological features as far as we studied.

Both NNT and EDP did not affect blood pressure in normotensive animals but significantly reduced blood pressure in SHR and DOCA/salt hypertensive animals in the acute studies with single dosing of 1 to 10 mg/kg (p.o.). Their antihypertensive action was mild but long-lasting and cumulated by the repeated administration.

The chronic administration of NNT and EDP at oral doses of 0.2 and 2 mg/kg once a day completely suppressed the development of hypertension in rats unilaterally nephrectomized and treated with DOCA/salt and in SHR which were unilaterally ureter-ligated to accerelate the progress of their genetic hypertension.

The mechanism of their antihypertensive action remain s to be solved.     

Sequential changes in urinary catecholamine in the transition from benign to malignant hypertension in rats

The sequential changes in 24-hour urinary norepinephrine (NE) and epinephrine (E) excretion levels were measured in spontaneously hypertensive rats (SHR) that received deoxycorticosterone acetate (DOCA) and 1% NaCl drinking water. These were compared with those from control SHR and similarly treated Wistar-Kyoto rats (WKY). Blood pressure, NE and E increased progressively in DOCA-SHR group, and NE (2392 +/- 94 vs. 998 +/- 49 ng/day) and E (250 +/- 21 vs. 116 +/- 6 ng/day) exceeded twice that of the control SHR group in the sixth week of DOCA treatment. In WKY rats, NE (1372 +/- 48 vs. 968 +/- 37 ng/day) and E (147 +/- 9 vs. 121 +/- 7 ng/day) levels were significantly higher in rats given DOCA than those in control group in the sixth week of the treatment, but were not so remarkably high as in DOCA-SHR group. A histological examination of DOCA-SHR kidneys revealed fibrinoid necrosis in the vascular walls. These data suggest that sympathoadrenal activity plays an important role in the development of malignant hypertension in DOCA-SHR group.     

A reevaluation of the mineralocorticoid and hypertensinogenic potential of 19-hydroxyandrostenedione

Experiments were done to evaluate whether 19-hydroxyandrostenedione (19-OH-A) is a steroid which produces hypertension and amplifies the mineralocorticoid effects of aldosterone. No intrinsic mineralocorticoid or adosterone-amplifying effect was found in several bioassays using adrenalectomized rats at doses of 100 micrograms 19-OH-A and/or 0.1 microgram aldosterone or in assays in which urine electrolytes were measured daily during a 14-day continuous infusion of 100 micrograms/day 19-OH-A. In two different experiments, the twice weekly administration of 0.1-1 mg 19-OH-A in oil to intact rats' drinking water failed to produce a change in blood pressure after 6 weeks. When one kidney was removed from these rats and 0.9% saline was substituted for drinking water, the blood pressures of rats receiving 1 mg twice weekly of 19-OH-A became significantly elevated in only one of the two experiments. At the end of 10 weeks, the average 19-OH-A pressure (139 mmHg) was significantly (P less than 0.01) greater than average control pressure (114 mmHg), but significantly (P less than 0.01) less than the mean average pressure of rats receiving 5 mg deoxycorticosterone acetate (DOCA) (161 mmHg). In another experiment uninephrectomized rats received 0.5 mg 19-OH-A or 1 mg DOCA 3 times a week. After 5 weeks the pressure of those receiving 19-OH-A was 149 mmHg, significantly greater (P less than 0.01) than controls (123 mmHg), but significantly less (P less than 0.01) than that of those rats receiving DOCA (189 mmHg). Our data failed to confirm the aldosterone amplifying effect of 19-OH-A. We did obtain a small elevation of arterial pressure in unilaterally nephrectomized rats receiving saline to drink. The differences between our results and those reported for this compound are not readily apparent, but may be related to genetic differences within the Sprague-Dawley strain used in both studies and/or to diet.     

Structural changes vary along individual arterioles in deoxycorticosterone acetate hypertensive rats

The variability of structural changes along individual arterioles in deoxycorticosterone acetate (DOCA) hypertensive rats was measured by coefficients of variation of: (a) serial lumen diameters along microfil casts of individual mesenteric arterioles; and (b) wall and lumen indices in serial histological cross-sections along individual renal arterioles. The mean lumen diameter of third-order mesenteric arterioles decreased with increasing duration of hypertension. There was increased variability of lumen diameter along lengths of DOCA arterioles, the coefficient of variation at 10 weeks DOCA treatment being 20.2 +/- 0.6% compared to 9.2 +/- 0.2% in controls (P less than 0.001). Medial area to internal elastic lamina (IEL) radius ratio of renal arterioles was increased in DOCA rats compared with control rats (P less than 0.025) and its variability along individual arterioles expressed as the coefficient of variation was 31.70 +/- 3.87% in DOCA rats compared with 15.29 +/- 1.72% in controls (P less than 0.005). The observed increase in variability of lumen diameter and medial area along short lengths of individual arterioles in DOCA hypertensive rats indicates that hypertensive structural changes are probably not directly related to local blood pressure. We suggest that irregular functional vasoconstriction in hypertensive rats could account for this distribution of structural changes.     

Effects of captopril on vascular noradrenergic transmission during the development of two-kidney, one clip Goldblatt hypertension in rats

Vascular noradrenergic transmission and the effect of captopril on this transmission were examined in the blood perfused rat mesenteric vasculature in situ during the development of two-kidney, one clip Goldblatt hypertension. Three groups of rats including sham operated, 6-8 day hypertensive and 4-6 week hypertensive were studied. Mean blood pressures during anaesthesia were 90.0 +/- 2.0, 119.7 +/- 4.7 and 131.8 +/- 6.8 mmHg in the three groups, respectively. Mesenteric vasoconstrictor responses to norepinephrine were significantly potentiated in both of the hypertensive groups relative to the sham group. Mesenteric vasoconstrictor responses to nerve stimulation were similar in the sham and 6-8 day hypertensive groups. However, responses to nerve stimulation were significantly potentiated in the 4-6 week hypertensive group relative to the sham group. Captopril (1 mg/kg, i.v.) lowered mean blood pressure in all groups, equalizing blood pressure in the 6-8 day hypertensive and sham groups. However, the blood pressure in the 4-6 week hypertensive rats remained significantly elevated after 1 mg/kg captopril. An additional dose of captopril did not lower blood pressure further in this group. Mesenteric vasoconstrictor responses to nerve stimulation and norepinephrine in the three groups were minimally affected by captopril, with significant differences between control and captopril-treated responses occurring randomly at a point or two in a dose-response or frequency-response curve for a given group. The differences in vascular responsiveness to nerve stimulation and norepinephrine between the hypertensive and sham groups continued to be evident after captopril.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of oral magnesium supplementation on blood pressure, platelet aggregation and calcium handling in deoxycorticosterone acetate induced hypertension in rats

OBJECTIVE: To study the effect of oral magnesium supplementation on blood pressure, platelet aggregation and platelet calcium handling in deoxycorticosterone acetate (DOCA)-induced hypertension in rats. DESIGN AND METHODS: Rats were divided into four groups of 20 each. Drug treatments were given for a 6-week period. Control rats were vehicle treated. In the second group, DOCA, 15 mg/kg, was injected subcutaneously twice weekly with 1% NaCl used instead of drinking water. The third group was given magnesium oxide (MgO), 1 g/kg daily, orally by gavage. The fourth group was given MgO along with DOCA and 1% NaCl. Blood pressure and heart rate were measured weekly. Platelet aggregation, intracellular calcium, calcium uptake and calcium efflux studies were performed at the end of sixth week. Serum magnesium concentration, plasma levels of reactive nitrogen intermediates (RNI) and citrulline were also measured RESULTS: There was a significant rise in blood pressure in the DOCA-treated rats. Magnesium prevented the gradual rise in blood pressure when given along with DOCA, but had no effect in normotensive rats. Heart rate did not show any significant change. Platelet aggregation was significantly reduced in all the treatment groups compared to the control group. DOCA treatment produced a significant increase in the intracellular calcium concentration as well as the calcium uptake compared to the control group. Magnesium supplementation inhibited the increased intracellular calcium concentration and calcium uptake in DOCA-treated rats. RNI and citrulline levels were elevated in all the treatment groups. Serum magnesium levels were significantly higher in the magnesium-treated and DOCA plus magnesium-treated rats. CONCLUSIONS: Magnesium supplementation prevents blood pressure elevation in DOCA hypertensive rats. These effects are associated with inhibition of platelet calcium uptake and decreased intracellular free calcium concentration.     

Effects of omapatrilat on blood pressure and renal injury in L-NAME and L-NAME plus DOCA-treated rats

BACKGROUND: This study investigates the effects of chronic administration of omapatrilat (OMA) on blood pressure (BP), renal injury, and other variables in N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension and in the low-renin model produced by the simultaneous administration of L-NAME and deoxycorticosterone acetate (DOCA). METHODS: The control, DOCA, L-NAME, L-NAME + DOCA, L-NAME + OMA, and L-NAME + DOCA + OMA groups were used. Tail systolic BP was measured twice a week. After 4 weeks of treatment, mean arterial pressure (MAP), and metabolic, morphologic, and renal variables were measured. RESULTS: The final values of MAP were 109 +/- 5.1 mm Hg for the control group, 113 +/- 3.0 mm Hg for DOCA, 175 +/- 3.7 mm Hg for L-NAME, 193 +/- 3.8 mm Hg for L-NAME + DOCA, 117 +/- 3.9 mm Hg for L-NAME + OMA, and 158 +/- 3.0 mm Hg for L-NAME + DOCA + OMA. The rats treated with L-NAME showed mild and scarce renal lesions, which were prevented by OMA treatment and the L-NAME + DOCA group showed proteinuria and hyaline arteriopathy, which were markedly attenuated in the L-NAME + DOCA + OMA group. Plasma urea and creatinine were significantly increased in the L-NAME + DOCA group, whereas these variables were not significantly greater in the L-NAME + DOCA + OMA group versus controls. The L-NAME + DOCA group showed relative renal and cardiac hypertrophy that was not observed in the L-NAME + DOCA + OMA group. CONCLUSIONS: The simultaneous blockade of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) completely prevents L-NAME hypertension. Our results also show that OMA attenuates the increased BP and the renal injury in L-NAME hypertensive rats treated with DOCA. Assuming that this is a low-renin model of hypertension, the protective effect of OMA may be due to an increase in vasodilator peptides produced by both ACE and NEP inhibition.     

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 less than 0.001) increased only in the DOCA group. The urinary Na/K ratio was significantly (p less than 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 less than 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.(ABSTRACT TRUNCATED AT 400 WORDS)     

The Mechanism of the Antihypertensive Action of Progesterone: Hemodynamic Studies in Rats with Partial Nephrectomy Salt Hypertension

In order to assess the mechanism of the antihypertensive action of progesterone, its effect on blood pressure, plasma volume, extracellular fluid volume, cardiac output and total peripheral resistance was studied in salt loaded 2/3 nephrectomized rats (one kidney and both poles of the remaining one removed) and in salt loaded rats in which in addition to nephrectomy adrenalectomy was also performed. Administration of progesterone (15 mg/kg, s.c., 3 times a week) during the six week course of salt loading significantly (P > 0.01) lowered blood pressure in both nephrectomized and nephrectomized, adrenalectomized rats. When compared to normal, untreated rats both plasma and extracellular fluid volume were found to be elevated in all nephrectomized salt loaded rats. However, no effect of progesterone on body fluid volumes was noted in either nephrectomized or nephrectomized, adrenalectomized rats. Progesterone lowered blood pressure and total peripheral resistance and had no effect on cardiac output in partially nephrectomized, salt loaded rats. The results indicate that: 1. in partially nephrectomized, salt loaded rats progesterone exhibits its antihypertensive action in the absence of mineralocorticoids, 2. in this hypertensive model progesterone does not     

Studies on the pressor mechanism of 19-hydroxyandrostenedione

In the present study, the pressor activity of 19-hydroxyandrostenedione (19-OH-AD) (which is a kind of androgen) and the presence or absence of the possibility of its role as an amplifier of mineralocorticoid were investigated. 34 Wistar rats of 8 weeks of age were used as the experimental subjects. The rats were divided into 3 groups, the control group (n = 12), 19-OH-AD group (n = 12) and DOCA group (n = 10). The control group was given 0.2 ml of sesame oil, the 19-OH-AD group was given 10 mg of 19-OH-AD dissolved in 0.2 ml of sesame oil, and the DOCA group was given 10 mg of DOCA dissolved in 0.2 ml of sesame oil. This was subcutaneously administered three times a week for 4 weeks, and body weight and blood pressure were observed. At the termination of the experiment, blood was sampled by decapitation, and the serum sodium concentration, erythrocyte sodium content, plasma renin activity (PRA), plasma atrial natriuretic hormone (alpha-rANP), and contents of DOC, corticosterone and aldosterone in adrenal gland were determined. The following results were obtained. The blood pressure at the termination of the experiment was higher than that at the initiation of the experiment by 9.9 +/- 1.9 (S.E.), 31.3 +/- 1.7, and 46.2 +/- 2.0 mmHg in the control, 19-OH-AD and DOCA groups, respectively, where significant elevations were observed in both the 19-OH-AD and DOCA groups as compared with the control group. As to the serum sodium concentration, only the DOCA group showed a significant elevation (p less than 0.001) as compared with the other two groups. However, the erythrocyte sodium contents of both the 19-OH-AD and DOCA groups increased significantly as compared with the control group. Moreover, the increase of the DOCA group was significantly higher (p less than 0.001) than that of the 19-OH-AD, and a significant positive correlation between the elevation of blood pressure and the erythrocyte sodium content was observed (p less than 0.001). As to the PRA value, only the DOCA group showed a significant lowering as compared with the other two groups, whereas alpha-rANP value of the DOCA group showed a significant elevation as compared with the other two groups. As to the contents of steroid hormones in the adrenal gland, all of the steroid hormones were significantly lower in the DOCA group, while those of the 19-OH-AD group were unchanged as were those of the control group.(ABSTRACT TRUNCATED AT 400 WORDS)     

Chronic endopeptidase inhibition in DOCA-salt hypertension: mechanism of cardiovascular protection

These studies examined the interactions of neutral endopeptidase (NEP), endothelin-1 (ET-1), and nitric oxide (NO) in deoxycorticosterone acetate (DOCA)-induced hypertension. Male Sprague-Dawley rats (n = 35) were uninephrectomized (UNx) or uninephrectomized and treated with DOCA (25 mg pellet implanted subcutaneously). Candoxatril (30 mg/kg day(-1)), a NEP inhibitor, was given orally for 3 weeks in UNx or DOCA rats. Sham nephrectomized rats (SHAM) served as controls. Except SHAM, all other groups received 1% NaCl in drinking water ad libitum. Measurements were taken of systolic blood pressure (SBP), left ventricle (LV), and aortic weight (AW), plasma ET-1, and urinary excretion of nitrite and Na+. Whole body vascular hypertrophy and morphometric analysis of histological sections of the heart were also determined. In DOCA rats, SBP increased from 113 +/- 5 to 170 +/- 5 mmHg without significant changes in body weight (BW). Candoxatril reduced the increase in SBP to 135 +/- 9 mmHg (P < 0.05), abolished the increased LV wall thickness (P < 0.05), and increased the reduced LV lumen diameter (P < 0.05) in DOCA-salt rats. Candoxatril also reduced plasma ET-1 by 88 +/- 9% and 89 +/- 17% (P < 0.05) in UNx and DOCA rats, respectively, and elicited increases in urinary excretion of nitrite. These effects were accompanied by a marked increase in urinary excretion of Na+ (U(Na)V) (P < 0.05) and a blunting of the proteinuria (32 +/- 5%; P < 0.05) in DOCA rats. We conclude that endopeptidase inhibition in DOCA-salt hypertension reduced the increase in blood pressure and the attendant tissue hypertrophy and renal injury. These effects suggest a correlation between endopeptidase-related reduction in ET-1 production and protection in DOCA-salt hypertension.     

Coronary vascular function and morphology in hydralazine treated DOCA salt rats

The purpose of these studies was to evaluate structural and functional changes in a model of hypertension-induced cardiac hypertrophy in which vasodilator therapy prevented the increase in blood pressure. Uninephrectomized weanling (125 g) Sprague-Dawley rats received a Silastic implant containing deoxycorticosterone acetate (DOCA, 150 mg/kg) subcutaneously and were given drinking water containing sodium chloride and potassium chloride. Vasodilator antihypertensive treatment (hydralazine; HYD) was started immediately after DOCA implantation. The rise in blood pressure was prevented in DOCA + HYD (124 +/- 5.4 mm Hg, +/- S.E.M.) compared to DOCA (213 +/- 7.5 mm Hg), and blood pressure was not different from control (CON; 118 +/- 5.5 mm Hg). Hydralazine lowered blood pressure in CON + HYD (102 + 3.9 mm Hg) but this decrease was not significant (P greater than 0.05). Hydralazine treatment prevented hypertension in DOCA + HYD but did not prevent development of cardiac hypertrophy (heart weight/body weight of DOCA + HYD 3.99 +/- 0.1 vs. DOCA 4.15 +/- 0.1; CON, 3.23 +/- 0.2 and CON + HYD 3.27 +/- 0.1). Coronary flow reserve measured by adenosine vasodilatation in a modified Langendorff isolated perfused rat heart model, was decreased in hearts from DOCA rats (41% increase in flow above baseline) compared to controls (CON, 132%; CON + HYD 139%), and was significantly improved in DOCA + HYD (98%). Morphometric evaluation of perfusion-fixed coronary arteries demonstrated a significant increase in the slope of the regression line comparing the square root of medial area vs. outer diameter in DOCA (0.619) compared to CON (0.501) and CON + HYD (0.491). Blood vessels from DOCA + HYD were not different from control (0.503). These studies suggest that significant alterations in coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although coronary deficits do remain after antihypertensive therapy.