Deoxycorticosterone acetate-salt rats: hypertension and sympathoexcitation driven by increased NaCl levels

Using deoxycorticosterone acetate (DOCA)-salt rats, we tested the hypothesis that increased plasma NaCl concentration supports sympathetic activity and blood pressure (BP) during salt-sensitive hypertension. One day before experimentation, femoral catheters and an electrode for measurement of lumbar sympathetic nerve activity (LSNA) probe were surgically positioned in DOCA-salt and Sham-salt rats. DOCA-salt rats exhibited increased (P<0.05) BP and NaCl concentration (BP, 163+/-8 mm Hg; NaCl, 260.8+/-3.3 mEq/L [DOCA-salt]: BP, 106.3+/-4.2 mm Hg; NaCl, 254.3+/-1.7 mEq/L [Sham-salt]). After V1 vasopressin blockade (Manning compound, 5 microg IV), infusion (0.12 mL/min) of 5% dextrose in water decreased NaCl concentrations, BP (-28+/-7 mm Hg), and LSNA (-39+/-5%) in DOCA-salt but not Sham-salt rats. To explain how such small (approximately 2%) increases in plasma NaCl could underlie the hypertension, we hypothesized that DOCA augments the pressor and sympathoexcitatory actions of NaCl. To address this hypothesis, animals with equally elevated NaCl but no DOCA (Sham-1.7% salt) and animals with increased DOCA but normal NaCl levels (DOCA-water) were prepared and administered the infusion of 5% dextrose in water. BP and LSNA were not altered in DOCA-water rats. In the Sham-1.7% salt rats, BP fell (P<0.05), but not LSNA, and the responses were significantly smaller than that observed in the DOCA-salt animals. Collectively, these data suggest that increased NaCl levels contribute to sympathoexcitation and hypertension in DOCA-salt rats because of amplification of the NaCl signal by DOCA.     

Regulation of vasopressin receptors in deoxycorticosterone acetate-salt hypertension.

Since arginine vasopressin may play a role in mineralocorticoid hypertension, we examined the effects of deoxycorticosterone acetate (DOCA)-salt on vasopressin V1 and V2 receptor binding and their second messengers, inositol phosphate and adenylate cyclase, respectively, in liver and kidney to determine whether altered vasopressin receptor binding is pathogenetic in mineralocorticoid hypertension. The mean arterial blood pressure of mineralocorticoid (DOCA-salt)-treated rats (163 +/- 1 mm Hg) was increased compared with control salt-treated rats (salt) (122 +/- 1 mm Hg) and water-treated rats (120 +/- 1 mm Hg; p less than 0.001). Mineralocorticoid treatment also increased plasma sodium, osmolality, and vasopressin concentration (p less than 0.001). In the hypertensive animals, there was a reduction in hepatic V1 (DOCA-salt, 91 +/- 12; salt, 132 +/- 13; and water, 145 +/- 13 fmol/mg protein; p less than 0.05) and renal V2 receptor binding density (DOCA-salt, 53 +/- 5; salt, 93 +/- 9; and water, 95 +/- 9 fmol/mg protein; p less than 0.01), although receptor affinities remained unaltered. In contrast, the density of renal V1 receptors was increased by mineralocorticoid treatment (DOCA-salt, 24 +/- 2; salt, 16 +/- 2; water, 18 +/- 1 fmol/mg protein; p less than 0.05), although the affinity was unchanged. Downregulation of V2 receptors was associated with a decrease in maximum cyclic adenosine monophosphate levels (DOCA-salt, 19 +/- 4; salt, 49 +/- 6; water, 53 +/- 9 pmol.mg protein-1.10 min-1; p less than 0.05), whereas changes in V1 receptor levels were not associated with changes in maximum inositol phosphate levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

ETA receptor blockade decreases vascular superoxide generation in DOCA-salt hypertension

Development and progression of end-organ damage in hypertension have been associated with increased oxidative stress. Superoxide anion accumulation has been reported in deoxycorticosterone acetate (DOCA)-salt hypertension, in which endothelin-1 plays an important role in cardiovascular damage. We hypothesized that blockade of ETA receptors in DOCA-salt rats would decrease oxidative stress. Both systolic blood pressure (SBP, 210+/-9 mm Hg; P<0.05) and vascular superoxide generation in vivo were increased in DOCA-salt (44.9+/-10.3% of ethidium bromide-positive nuclei; P<0.05) versus control uninephrectomized (UniNx) rats (118+/-3 mm Hg; 18.5+/-3%, respectively). In DOCA-salt rats, the ETA antagonist BMS 182874 (40 mg/kg per day PO) lowered SBP (170+/-4 versus UniNx, 120+/-3 mm Hg) and normalized superoxide production (21.7+/-6 versus UniNx, 11.9+/-7%). Vitamin E (200 mg/kg per day PO) decreased superoxide formation in DOCA-salt rats (18.8+/-7%) but did not alter SBP. Oxidative stress in nonstimulated circulating polymorphonuclear cells (PMNs) or in PMNs treated with zymosan, an inducer of superoxide release, was similar in DOCA-salt and UniNx groups. Superoxide formation by PMNs was unaffected by treatment with BMS 182874. Western blot analysis showed increased nitrotyrosine-containing proteins in mesenteric vessels from DOCA-salt compared with UniNX. Treatment with either BMS 182874 or vitamin E abolished the differences in vascular nitrotyrosine-containing proteins between DOCA-salt and UniNX. Maximal relaxation to acetylcholine was decreased in DOCA-salt aortas (75.8+/-4.2% versus UniNx, 95.4+/-1.9%, P<0.05). BMS 182874 treatment increased acetylcholine-induced relaxation in DOCA-salt aortas to 93.5+/-4.5%. These in vivo findings indicate that increased vascular superoxide production is associated with activation of the endothelin system through ETA receptors in DOCA-salt hypertension, in apparently blood pressure-independent fashion.     

Chronic V2 vasopressin receptor stimulation increases basal blood pressure and exacerbates deoxycorticosterone acetate-salt hypertension

The present study was intended to determine whether the long-term V2 receptor-mediated effects of vasopressin on sodium reabsorption in the renal collecting duct is an aggravating factor in salt-sensitive hypertension. Deoxycorticosterone acetate (DOCA)-salt hypertension was induced in uninephrectomized rats that had been chronically pretreated with a V2 agonist (dDAVP; 1-deamino-8D-arginine vasopressin; 0.6 microg/kg.d) or a V2 antagonist (SR121463, 3 mg/kg.d) or were untreated. Plasma osmolality and natremia were not significantly different in the groups. Blood pressure was significantly increased by dDAVP pretreatment (+11 mm Hg; P = 0.006), and this effect was exacerbated after DOCA-salt-induced hypertension (+17 mm Hg; P = 0.042). The dDAVP-treated rats had a lower hematocrit (40 +/- 2% vs. 47 +/- 1% and 45 +/- 2%) and markedly higher albuminuria (91 +/- 9 vs. 17 +/- 8 and 15 +/- 8 mg/d), mortality rate (50% vs. 0% and 0%), and cardiac and renal hypertrophy than the control and SR121463 groups. Histological renal lesions were worsened by V2 agonism and prevented by V2 antagonism. Renal mRNA expression of beta- and gamma-subunits of the epithelial sodium channel was significantly increased by dDAVP treatment (P < 0.05). These findings provide evidence that chronic stimulation of vasopressin V2 receptor raises basal blood pressure in rats and exacerbates the development of DOCA-salt hypertension, organ damage, and mortality. These effects could be due at least in part to the sustained stimulation of sodium reabsorption by epithelial sodium channel in the distal part of the nephron, which promotes sodium retention.     

Tempol lowers blood pressure and sympathetic nerve activity but not vascular O2- in DOCA-salt rats

This study tested the hypothesis that depressor responses caused by tempol are not associated with reductions in vascular O2- levels in urethane-anesthetized deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We compared the effects of intravenous (IV) administration of tempol, apocynin, superoxide dismutase-polyethylene glycol (PEG-SOD), and SOD on mean arterial blood pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA). In DOCA-salt rats, tempol (30 to 300 micromol/kg) dose-dependently decreased RSNA, MAP, and HR. Tempol (300 micromol/kg) decreased MAP from 140+/-5 to 83+/-4 mm Hg (P<0.05). HR decreased from 435+/-15 to 390+/-12 bpm (P<0.05). RSNA was reduced by 54%+/-6% from baseline. However, in the same rats, tempol did not reduce dihydroethidium-induced fluorescent signals in the aorta and vena cava. Apocynin (200 micromol/kg) did not lower MAP (142+/-5 mm Hg versus 140+/-6 mm Hg) or HR (428+/-15 bpm versus 420+/-13 bpm) and apocynin did not potentiate depressor responses caused by tempol. PEG-SOD (10 000 U/kg, bolus or 5000 U/kg bolus followed by a 30-minutes infusion of 500 U/kg/min) or SOD (25 000 U/kg, bolus or 10 000 U/kg bolus followed by a 30-minutes infusion of 1000 U/kg per minute) did not alter MAP or HR. It is concluded that depressor responses and decreases in HR and RSNA caused by acute tempol treatment are caused by direct sympathetic nerve activity inhibition that is not accompanied by SOD-mimetic action in the aorta or vena cava.     

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)     

Paraventricular nucleus lesions attenuate the development of hypertension in DOCA/salt-treated rats

To determine whether paraventricular nucleus (PVN) can play a role in the hypertension in DOCA/salt-treated rats, DOCA/salt hypertension was produced in PVN lesions and sham-operated rats. In lesioned rats, the development of hypertension was significantly attenuated (day 7: 132 +/- 3 v 157 +/- 5 mm Hg, P less than 0.01; day 14: 132 +/- 3 v 157 +/- 5 mm Hg, P less than 0.01; day 21: 189 +/- 2 v 224 +2- 6 mm Hg, P less than 0.01). Lesions lowered systolic blood pressure in even control rats. Mean blood pressure (mBP) from awake free moving rats was also significantly lower in lesioned DOCA/salt-treated rats than those of sham-operated DOCA/salt-treated rats (155 +/- 14 mm Hg v 193 +/- 13, P less than 0.01), while mBP was not different between lesioned and sham-operated control rats. The reduction of mBP by hexamethonium injections was significantly larger in sham-operated DOCA/salt-treated rats than those of lesioned DOCA/salt rats. (-53 +/- 3% v -45 +/- 2, P less than 0.05). Plasma norepinephrine and epinephrine were significantly elevated in DOCA/salt-treated rats, however, PVN lesions inhibited significantly those elevations. 1-Deaminopenicillamine, 4-valine, 8-D-arginine Vasopressin (dPVDAVP) injections did not affect BP and heart rate in all rats. Body weight, water intake, urine volume, urine Na, K, and vasopressin excretion, and urine osmorality were not altered by lesions. These findings suggest that PVN contributes to development of hypertension in DOCA/salt-treated rats with sympathetic nervous activations.     

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.     

Arterial 5-hydroxytryptamine transporter function is impaired in deoxycorticosterone acetate and Nomega-nitro-L-arginine but not spontaneously hypertensive rats

We reported upregulation of the 5-hydroxytryptamine (HT) transporter (5-HTT) protein in peripheral arteries from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We hypothesized that upregulated 5-HTT may be generally elevated in hypertensive models and, as a consequence, a higher basal concentration of 5-HT, the 5-HT metabolite 5-hydroxyindoleacetic acid, and an increased 5-HT uptake would occur in peripheral arteries of hypertensive rats compared with normotensive rats. We examined 3 hypertension models: DOCA-salt rats, Nomega-nitro-L-arginine (LNNA) rats, and spontaneously hypertensive rats (SHRs) in our study (systolic blood pressure [mm Hg]: DOCA (D)=197+/-6, SHAM(D)=112+/-4, LNNA (L)=228+/-9, SHAM(L)=128+/-2, SHR=172+/-7, and Wistar-Kyoto [WKY]= 121+/-3). High-pressure liquid chromatography measurements showed lower basal 5-HT concentrations in aorta from DOCA-salt and LNNA rats compared with their SHAM rats but not in SHR compared with WKY. In all of the 5-HT-uptake studies, we used arteries isolated from rats treated with the monoamine oxidase-A inhibitor pargyline to minimize 5-HT metabolism. Exogenous 5-HT was taken up by aorta, and this was inhibited by the 5-HTT inhibitor fluoxetine (1 micromol/L) or fluvoxamine (1 micromol/L). Total 5-HT uptake and 5-HTT-dependent active 5-HT uptake were decreased in aorta from DOCA-salt and LNNA rats compared with SHAM rats, but this was not observed in SHRs compared with WKYs. Western analysis revealed similar expression of 5-HTT in aorta from WKYs and SHRs as opposed to an upregulated 5-HTT in aorta from DOCA-salt and LNNA-hypertensive rats. Our study suggested that an altered serotonergic system by impaired 5-HTT function might play a role in blood pressure regulation in DOCA-salt and LNNA-hypertensive rats.     

Repeated administration of vasopressin but not epinephrine maintains coronary perfusion pressure after early and late administration during prolonged cardiopulmonary resuscitation in pigs

BACKGROUND: It is unknown whether repeated dosages of vasopressin or epinephrine given early or late during basic life support cardiopulmonary resuscitation (CPR) may be able to increase coronary perfusion pressure above a threshold between 20 and 30 mm Hg that renders defibrillation successful. METHODS AND RESULTS: After 4 minutes of cardiac arrest, followed by 3 minutes of basic life support CPR, 12 animals were randomly assigned to receive, every 5 minutes, either vasopressin (early vasopressin: 0.4, 0.4, and 0.8 U/kg, respectively; n=6) or epinephrine (early epinephrine: 45, 45, and 200 microg/kg, respectively; n=6). Another 12 animals were randomly allocated after 4 minutes of cardiac arrest, followed by 8 minutes of basic life support CPR, to receive, every 5 minutes, either vasopressin (late vasopressin: 0.4 and 0.8 U/kg, respectively; n=6), or epinephrine (late epinephrine: 45 and 200 microg/kg, respectively; n=6). Defibrillation was attempted after 22 minutes of cardiac arrest. Mean+/-SEM coronary perfusion pressure was significantly higher 90 seconds after early vasopressin compared with early epinephrine (50+/-4 versus 34+/-3 mm Hg, P<0.02; 42+/-5 versus 15+/-3 mm Hg, P<0.0008; and 37+/-5 versus 11+/-3 mm Hg, P<0. 002, respectively). Mean+/-SEM coronary perfusion pressure was significantly higher 90 seconds after late vasopressin compared with late epinephrine (40+/-3 versus 22+/-4 mm Hg, P<0.004, and 32+/-4 versus 15+/-4 mm Hg, P<0.01, respectively). All vasopressin animals survived 60 minutes, whereas no epinephrine pig had return of spontaneous circulation (P<0.05). CONCLUSIONS: Repeated administration of vasopressin but only the first epinephrine dose given early and late during basic life support CPR maintained coronary perfusion pressure above the threshold that is needed for successful defibrillation.     

Vasopressin response in collecting ducts of rats resistant to mineralocorticoid hypertension.

In previous studies we found that vasopressin stimulation of both cyclic AMP (cAMP) formation in cortical collecting tubules (CCT) and sodium reabsorption in isolated perfused kidneys was markedly exaggerated in rats with mineralocorticoid hypertension. In the present study, we tested the response (cAMP accumulation) of cortical and outer medullary collecting tubules (OMCT) to vasopressin in two rat models that are resistant to deoxycorticosterone acetate (DOCA)-induced hypertension, the Wistar-Furth strain and NaCl-deficient rats. The blood pressure of normal outbred Wistar rats rose to hypertensive levels (systolic pressure more than 165 mm Hg) during a 5-week treatment with DOCA (10 mg/week) and 1% saline to drink. Significant hypertrophy of the heart and kidneys was also observed. Vasopressin (10(-8) M)-induced cAMP formation was enhanced 3.4-fold in the CCT (OMCT unchanged) of hypertensive rats compared with normotensive controls. Significant hypertrophy (as indexed by tubule diameter) of the CCT but not the OMCT was also observed in DOCA-salt hypertensive rats. Restriction of dietary NaCl (0.13% in chow, tap water to drink) completely prevented DOCA-induced hypertension, organ and CCT hypertrophy, and enhancement of vasopressin-stimulated cAMP formation in the CCT. In Wistar-Furth rats, DOCA-salt treatment did not alter blood pressure or cause significant organ hypertrophy. However, DOCA-salt treatment enhanced vasopressin-stimulated cAMP formation by 4.1-fold in CCT of Wistar-Furth rats, with significant tubular hypertrophy in the CCT but not the OMCT. We conclude that DOCA-induced hypertension and changes in CCT function are dependent on excess dietary NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metformin attenuates salt-induced hypertension in spontaneously hypertensive rats.

Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes mellitus, lowers blood pressure in humans and experimental animals. We recently demonstrated that short-term administration of metformin may lower blood pressure by reducing sympathetic neural outflow. The present studies were initiated to determine whether long-term administration of metformin blunts salt-induced hypertension, a condition characterized by elevated sympathetic activity. Male spontaneously hypertensive rats, in which radiotelemeters had been implanted for continuous monitoring of heart rate and blood pressure, were randomly assigned to groups that received vehicle (drinking water) or metformin (500 mg/kg per day) and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not affect blood pressure in the animals that ate the normal-salt diet (vehicle, 130+/-3 mm Hg; metformin, 133+/-5 mm Hg; mean+/-SEM), drug treatment blunted the rise in pressure caused by a high-salt diet (vehicle, 153+/-4 mm Hg; metformin, 140+/-5 mm Hg; P<0.001). In agreement, during direct pressure recordings in anesthetized rats, the animals that ate the high-salt diet had higher pressures (136+/-13 mm Hg) than those in the control (98+/-5 mm Hg, P<0.01), metformin (100+/-7 mm Hg, P<0.01), and metformin/high-salt groups (92+/-3 mm Hg, P<0.01). Finally, metformin lowered heart rate in rats that ate the normal- and high-salt diets (310+/-3 and 305+/-4 bpm) compared with rats that ate normal- and high-salt diets given vehicle (332+/-3 and 324+/-2 bpm, P<0.01). These data indicate that the chronic depressor actions of metformin are enhanced in animals with hypertension exacerbated by a high-salt diet.     

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.     

Effects of pergolide on blood pressure and tissue injury in DOCA-salt hypertension

The present study was designed to evaluate the possible antioxidant effect of pergolide, a DA-2 receptor agonist, in deoxycorticosterone acetate (DOCA)-salt hypertension and its role in endogenous endothelin-1 (ET- 1) production and organ hypertrophy. Male Sprague-Dawley rats were uninephrectomized (UNx) or uninephrectomized, and received subcutaneous implants of DOCA and drank 1% sodium chloride (DOCA). DOCA rats were treated daily for 3 weeks with pergolide (1 mg/kg, i.p.) or vitamin C (1 mg/rat, orally). DOCA-salt treatment increased systolic blood pressure (SBP) in UNx rats by 45 +/- 2 mmHg from 117 +/- 5 to 162 +/- 10 mmHg (p < 0.05), an effect blunted by pergolide and vitamin C. Superoxide generation was not increased in DOCA rats; however, both pergolide and vitamin C significantly reduced superoxide generation by 49 +/- 7% and 52 +/- 13%, respectively (p < 0.05). Plasma ET-1 levels increased twofold in UNx rats but was reduced to 42 +/- 7% (p < 0.05) in DOCA compared to UNx rats. Pergolide and vitamin C reduced plasma ET-1 levels further by 43 +/-10% (p < 0.05) and 46 +/- 8% (p < 0.05), respectively. Pergolide increased urinary Na+ excretion but did not alter urinary protein excretion or the left ventricular and aortic hypertrophy in DOCA rats. These data suggest that the reduction of SBP by pergolide in DOCA-salt hypertension may be attributed to its natriuretic ability, not its ability to reduce superoxide generation or ET- 1 production.     

Remodelling of the heart in DOCA-salt hypertensive rats by propranolol and by an alpha-2 agonist, rilmenidine

The effects of rilmenidine [(N-dicyclopropylmethyl) amino-2-oxazoline; S 3341], an alpha 2 agonist, on the hypertensive rat heart have been compared with those of propranolol, using a model of deoxycorticosterone acetate (DOCA)-salt hypertension. One week after nephrectomy and initial treatment with DOCA-salt, which was continued for an additional 7 weeks, the two drugs were added to the rats drinking water at a concentration of 10 mg/kg per day for rilmenidine and 15 mg/kg per day for propranolol. Both drugs had a slight and similarly significant antihypertensive effect at their respective concentrations [systolic blood pressure in controls, 141 +/- 15 mmHg (n = 20); after DOCA-salt, 209 +/- 22 mmHg (n = 24); after propranolol, 182 +/- 19 mmHg (n = 20, P less than 0.01); after rilmenidine, 192 +/- 15 mmHg (n = 19, P less than 0.05)]. They also lowered the systolic blood pressure x frequency product (P less than 0.001). Propranolol, but not rilmenidine, significantly reduced the left ventricular weight: body weight ratio [in controls, 2.00 +/- 0.2 mg/g; after DOCA-salt, 3.04 +/- 0.5 mg/g; after propranolol, 2.67 +/- 0.4 mg/g (P less than 0.05); after rilmenidine, 3.13 +/- 0.6 mg/g (P = NS)]. However, both propranolol and rilmenidine reduced left ventricular weight [in controls, 676 +/- 57 mg; after DOCA-salt, 827 +/- 114 mg; after propranolol, 732 +/- 108 mg (P less than 0.01); after rilmenidine, 760 +/- 100 mg (P less than 0.05)].(ABSTRACT TRUNCATED AT 250 WORDS)     

Extrarenal Na+ balance, volume, and blood pressure homeostasis in intact and ovariectomized deoxycorticosterone-acetate salt rats

Water-free Na+ storage may buffer extracellular volume and mean arterial pressure (MAP) in spite of Na+ retention. We studied the relationship among internal Na+, K+, water balance, and MAP in Sprague-Dawley rats, with or without deoxycorticosterone-acetate (DOCA) salt, with or without ovariectomy (OVX). The rats were fed a low-salt (0.1% NaCl) or high-salt (8% NaCl) diet for 5 weeks. DOCA salt increased MAP (161+/-14 versus 123+/-4 mm Hg; P<0.05), and DOCA-OVX salt increased MAP further (181+/-22 mm Hg; P<0.05). DOCA salt increased the total body Na+ by &40% to 45%; however, water-free Na+ retention by osmotically inactive Na+ storage and by osmotically neutral Na+/K+ exchange allowed the rats to maintain the extracellular volume close to normal. DOCA-OVX salt rats showed similar Na+ retention. However, their osmotically inactive Na+ storage capacity was greatly reduced and only partially compensated by neutral Na+/K+ exchange, resulting in greater volume retention despite similar Na+ retention. For every 1% wet weight total body water gain, MAP increased by 2.3+/-0.2 mm Hg in DOCA salt rats and 2.5+/-0.3 mm Hg in DOCA-OVX salt rats. Because water-free Na+ retention buffered total body water content by 8% to 11% wet weight, we conclude that this internal Na+ escape buffered MAP. Extrarenal Na+ and volume balance seem to play an important role in long-term volume and MAP control.     

Placental insufficiency leads to development of hypertension in growth-restricted offspring

Low birth weight is a suggested risk factor for the development of hypertension. The purpose of the present study was to determine whether a model of intrauterine growth restriction produced in response to placental insufficiency in the pregnant rat was associated with marked elevations in blood pressure. Reduced uterine perfusion initiated in late gestation resulted in low-birth-weight offspring (5.8+/-0.1 versus 6.6+/-0.2 g, P<0.05, growth-restricted versus control, respectively). Mean arterial pressure, as measured in conscious, chronically instrumented rats, was significantly elevated as early as 4 weeks of age (113+/-3 versus 98+/-2 mm Hg, P<0.05) and was associated with significant decreases in body weight (66+/-2 versus 81+/-3 g, P<0.05) in growth-restricted (n=15) versus control (n=15) rats. Marked elevations in arterial pressure at 8 weeks of age (male: 133+/-3 versus 121+/-6 mm Hg, P<0.05; female: 137+/-4 versus 112+/-6 mm Hg, P<0.01) were associated with sex-specific decreases in body weight (male: 251+/-6 versus 275+/-10 g, P<0.05; female: 163+/-6 versus 180+/-6 g) in male growth-restricted (n=12) versus male control (n=9) rats and in female growth-restricted (n=8) versus female control (n=7) rats. At 12 weeks of age, hypertensive (144+/-4 versus 131+/-3 mm Hg, P<0.05) male growth-restricted offspring (n=10) had no alterations in glomerular filtration rate (2.3+/-0.3 versus 2.2+/-0.2 mL/min) compared with control (n=10) offspring; even when adjusted for kidney weight (1.7+/-0.3 versus 1.5+/-0.3 mL x min(-1) x g(-1) kidney), despite marked decreases in body weight (305+/-9 versus 343+/-10 g, P<0.05). These data suggest that placental insufficiency induced by reduced uterine perfusion in the pregnant rat results in low-birth-weight offspring predisposed to development of hypertension.     

Cerebral blood flow autoregulation and edema formation during pregnancy in anesthetized rats

Eclampsia is considered a form of hypertensive encephalopathy in which an acute elevation in blood pressure causes autoregulatory breakthrough, blood-brain barrier disruption, and edema formation. We hypothesized that pregnancy predisposes the brain to eclampsia by lowering the pressure of autoregulatory breakthrough and enhancing cerebral edema formation. Because NO production is increased in pregnancy, we also investigated the role of NO in modulating autoregulation. Cerebral blood flow autoregulation was determined by phenylephrine infusion and laser Doppler flowmetry. Four groups were studied: untreated nonpregnant (n=7) and late-pregnant (days 19 to 21; n=8) Sprague-Dawley rats and nonpregnant (n=8) and late-pregnant (n=8) animals treated with an NO synthase inhibitor (N(G)-nitro-l-arginine methyl ester; 0.5 to 0.7 g/L). Brain water content and blood-brain barrier permeability to sodium fluorescein were determined after breakthrough. Pregnancy caused no change in autoregulation or the pressure of breakthrough. However, treatment with the NO synthase inhibitor significantly increased the pressure of autoregulatory breakthrough (nonpregnant: 183.6+/-3.0 mm Hg versus 212.0+/-2.8 mm Hg, P<0.05; late-pregnant: 180.8+/-3.2 mm Hg versus 209.3+/-4.7 mm Hg, P<0.05). After autoregulatory breakthrough, only late-pregnant animals showed a significant increase in cerebral edema formation, which was attenuated by NO synthase inhibition. There was no difference in blood-brain barrier permeability between nonpregnant and late-pregnant animals in response to acute hypertension, suggesting that pregnancy may predispose the brain to eclampsia by increasing cerebral edema through increased hydraulic conductivity.     

Neurons of the rostral ventrolateral medulla contribute to obesity-induced hypertension in rats

Activation of the sympathetic nervous system contributes to the pathogenesis of obesity-induced hypertension. The present study sought to determine whether sympathetic regulatory neurons of the rostral ventrolateral medulla contribute to the elevated blood pressure in obese rats. Male Sprague-Dawley rats (350 to 425 g) were placed on a moderately high-fat diet (32% kcal as fat) or a low-fat (LF) diet (10.6% kcal as fat). After 13 weeks, rats fed the moderately high-fat diet segregated into obesity-prone (OP) and obesity-resistant (OR) groups based on their body weight (OP: 839+/-22 g; OR: 668+/-15 g; LF: 680+/-18 g; n=15 for all groups; P<0.01). Under isoflurane anesthesia, baseline mean arterial blood pressure was significantly elevated in the OP rats versus the OR and LF rats (OP: 108+/-2 mm Hg; OR: 100+/-2 mm Hg; LF: 97+/-3 mm Hg; n=7; P<0.05). Inhibition of the rostral ventrolateral medulla with bilateral microinjection of the GABA(A) receptor agonist muscimol (200 pmol/100 nL) decreased mean arterial blood pressure to similar levels across the groups (OP: 49+/-1 mm Hg; OR: 50+/-2 mm Hg; LF: 49+/-1 mm Hg), but the magnitude of this decrease was significantly greater in the OP versus the OR and LF rats (OP: -58+/-2 mm Hg; OR: -49+/-1 mm Hg; LF: -48+/-3 mm Hg; P<0.01). These differences in mean arterial blood pressure cannot be explained by changes in vascular reactivity as the ED(50) in response to phenylephrine and norepinephrine was similar across the groups. The present findings suggest that the elevated sympathetic nerve activity and arterial blood pressure in obese rats depends on the tonic activity of rostral ventrolateral medulla sympathetic neurons.     

Cardiovascular depression and stabilization by central vasopressin in rats

The role of endogenous vasopressin in cardiovascular homeostasis was examined using vasopressin-deficient rats (Brattleboro) (n = 194) and their parent strain, Long-Evans rats (n = 181). Mean arterial pressure (blood pressure) and heart rate were measured every 4 seconds with or without infusion of drug solution for 21 hours, and mean values and their standard deviations (lability) were calculated. Blood pressure in Brattleboro rats (116 +/- 1.1 mm Hg, mean +/- SEM) was significantly higher than that in Long-Evans rats (96 +/- 0.7 mm Hg, p less than 0.001), whereas heart rates (381 +/- 3.3 and 375 +/- 2.9 beats/min, respectively) were similar. The lability of blood pressure and heart rate in Brattleboro rats (9.2 +/- 0.1 mm Hg and 42.3 +/- 0.7 beats/min) was also greater than that in Long-Evans rats (6.7 +/- 0.1 mm Hg, p less than 0.001 and 38.4 +/- 0.8 beats/min, p less than 0.01, respectively). In Brattleboro rats, intravenous vasopressin (0.1 ng/kg/min or 0.6 ng/kg/min) did not affect blood pressure, although it did reduce heart rate and decreased lability of blood pressure and heart rate. Intracerebroventricular (central) infusion of vasopressin (2 pg/kg/min) in Brattleboro rats induced initial hypertension and tachycardia followed by long-lasting hypotension and bradycardia, whereas in Long-Evans rats it induced only hypertension and tachycardia. In both strains, central vasopressin dramatically decreased the lability of blood pressure and heart rate. Neither intravenous (0.2 ng/kg/min) nor central desmopressin (2 pg/kg/min or 0.2 ng/kg/min), a V2 renal receptor agonist, changed any of these parameters in Brattleboro rats, although both diminished urinary volume. Neither intravenous (50 ng/kg/min) nor central (3.3 pg/kg/min) d(CH2)5-Tyr(Me)-arginine vasopressin, a vasopressin V1 receptor antagonist, modulated any of these parameters in Long-Evans rats. These results suggest that endogenous as well as exogenous vasopressin acts centrally as a cardiovascular inhibitor and stabilizer through a receptor mechanism other than V1 or V2 receptor mechanisms.