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.     

Retardation of the development of hypertension in DOCA-salt rats by renal denervation

To determine the importance of the renal nerves in DOCA-salt hypertension, either renal denervation or a sham-operation was carried out on both DOCA-salt-treated and non-DOCA-treated rats. The systolic blood pressure of the non-DOCA rats remained within normotensive levels, in which the difference in blood pressure levels between the renal denervated and the sham-operated groups was not significant. On the other hand, the blood pressure of the rats treated with DOCA, and having intact renal nerves, began to rise by the end of the first week and rose consistently thereafter, whereas, in the renal denervated DOCA-salt rats, the blood pressure started to rise by the second week and then proceeded to increase gradually. The differences between the sham and the denervated rat groups were significant throughout the four weeks. The mean arterial pressure, directly measured from the caudal artery of conscious rats during the fourth week of this study, was 166 +/- 7 mmHg in the sham-operated and 129 +/- 4 mmHg in the renal-denervated rats (the data having an 1% significant difference). To test the effects of renal denervation on the natriuresis, pentobarbital-anesthetized rats were infused intravenously with physiological saline. The renal denervated rats which had received DOCA excreted more sodium than did the sham-operated rats. When the rats were later anesthetized with urethane to allow intracisternal injections of hypertonic saline, the mean blood pressure in renal denervated rat groups was again lower than that of the sham-denervated rat groups. However, subsequent intracisternal injections of 5% saline produced similar pressor responses as well as tachycardia in both DOCA groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Hypotensive responses to centrally administered taurine in DOCA-salt hypertensive and spontaneously hypertensive rats

The present study was designed to investigate the short-term effects of intracerebroventricularly-administered taurine in DOCA-salt hypertensive (DOCA), spontaneously hypertensive (SHR) and their respective normotensive control rats anesthetized with urethane. Blood pressure, heart rate and sympathetic nerve activity were consistently decreased following the injection of taurine 150 micrograms per rat in hypertensive rats as well as in normotensive controls of the two groups. Percent changes from the baselines in blood pressure, heart rate and sympathetic nerve activity were significantly larger in DOCA-salt hypertensive rats than those in sham operated rats. In contrast, percent changes in blood pressure and sympathetic nerve activity were not significantly different between spontaneously hypertensive rats and normotensive wistar kyoto rats. These result show that the responses of blood pressure, heart rate and sympathetic nerve activity to intracerebroventricular taurine are different between spontaneously hypertensive rats and DOCA-salt hypertensive rats. It appears that augmented vasodepressor responses to taurine in DOCA-salt hypertensive rats, as compared to spontaneously hypertensive rats, are due to enhanced inhibition of the sympathetic outflow.     

Augmented central cholinergic mechanisms in spontaneously hypertensive rats. Involvement of deranged noradrenergic mechanisms in the brain

Intracerebroventricular (ICV) injections of carbachol produced biphasic blood pressure responses consisting of initial vasodepression of short duration followed by a sustained pressor phase, which were accompanied by corresponding changes in sympathetic nerve activity in normotensive outbred-Wistar rats (NT) under urethane-anesthesia. In both normotensive Kyoto Wistar rats (WKY) and spontaneously hypertensive rats (SHR), on the other hand, carbachol elicited purely pressor responses, and accompanying sympathetic nerve activity was little affected. The magnitude of the pressor responses was larger in SHR than in WKY or NT rats. Spinal sectioning did not affect the magnitude of the pressor responses. Vasopressor responses to intravenous injections of arginine-vasopressin were not significantly different between WKY and SHR. These results indicate that carbachol injected intracerebroventricularly produces vasopressor effects mainly by releasing pituitary hormones, probably vasopressin, and that augmented pressor responses in SHR may be due to excessive release of vasopressin. When central noradrenergic neurons had been destroyed with ICV injections of 6-hydroxydopamine in both NT and WKY rats, carbachol-induced vasopressor responses were markedly augmented and resulted in responses similar to those of SHR. These findings indicate that central noradrenergic vasodepressive neurons are deficient and that the augmented vasopressor responses to carbachol resulted from deranged central noradrenergic mechanisms in SHR.     

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.     

Centrally inhibitory effect of adrenaline on cardiovascular and sympathetic nerve system in urethane anesthetized rat

The present study was undertaken to determine the central effect of adrenaline. Adrenaline was administered to the cisterna magna in urethane anesthetized rats. Following the intracisternal injections, the blood pressure dropped and reached a plateau after 15 min, the hypotensive effect continuing for at least 30 min. The heart rate also slowed concomitantly with the depressor effect. The vehicle treated rats did not show any cardiovascular responses. The cardiovascular responses in the experimental rats were accompanied by an inhibition of the sympathetic nerve activity. Pressor responses to electrical stimulation of the posterior hypothalamus were partly inhibited, while pressor responses to intravenous injections of noradrenaline remained unchanged. In DOCA hypertensive rats, the depressor responses to intracisternal injections of adrenaline were augmented. These findings suggest that adrenaline in the brain could contribute to the inhibitory mechanism of the cardiovascular system accompanied by inhibition of the sympathetic nerve system, and that this mechanism may be attenuated in DOCA hypertensive rats.     

KCl inhibits hypothalamic activity to attenuate hypertension in DOCA-salt rats

Potassium supplementation attenuated the development of hypertension in DOCA-salt rats but did not affect blood pressure in control rats. However, it caused a decrease in body weight in both groups of rats. Sympathetic nerve and pressor responses either to electrical stimulation of the hypothalamus or to intracisternal injections of hypertonic NaCl were enhanced in DOCA-salt rats but were normalized by KCl supplementation. Since the pressor responses to injected norepinephrine or tyramine remained unaltered by KCl treatment, a peripheral inhibition of cardiovascular reactivity was considered unlikely. Pretreatment with methyclothiazide also attenuated the elevation in blood pressure but did not affect the responsiveness to hypothalamic stimulation; hence increased natriuresis or diuresis alone could not account for the effects induced by KCl. These findings are consistent with the conclusion that KCl supplementation attenuates the development of DOCA-salt hypertension in rats by acting on the central nervous system to reduce sympathetic output.     

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.     

Effect of AV3V lesions on development of DOCA-salt hypertension and vascular Na+-pump activity

We studied the effects of anteroventral third ventricle (AV3V) lesions on the vascular Na+-pump activity of deoxycorticosterone acetate-salt (DOCA-salt) treated rats. Blood pressures and Na+-pump activity of the isolated tail arteries, measured as ouabain-sensitive 86Rb-uptake, were determined in untreated control rats, DOCA-salt treated rats, rats with AV3V lesions, and rats with AV3V lesions which were treated with DOCA-salt. Control rats receiving DOCA treatment developed higher blood pressures than rats receiving no DOCA treatment. Placement of AV3V lesions prior to administration of DOCA prevented the increase in blood pressure. Vascular Na+-pump activity in the DOCA-treated group was reduced by 20% compared to all other groups. The AV3V lesions prevented the suppression of Na+-pump activity caused by DOCA treatment. Suppression of vascular Na+-pump activity was due to a humoral substance since Na+-pump activity of tail arteries from control rats incubated in plasma from DOCA-salt treated rats was suppressed by 25% when compared to those incubated in control plasma. Our findings support the hypothesis that a circulating pressor substance is at least partially responsible for the development of DOCA-salt hypertension and that the mechanism by which AV3V lesions prevent DOCA hypertension may be through the interruption of secretion, transport, or synthesis of this factor.     

Suppression of renal sympathetic activity with potassium supplement in DOCA-salt rats

We studied the involvement of renal sympathetic nervous system activity in the antihypertensive and natriuretic effects of potassium supplement in DOCA-salt treated rats. Systolic blood pressure of DOCA-salt rats rose substantially, reaching 181 +/- 3 mmHg after 4 weeks of DOCA-salt administration. In contrast, the supplement of 1% KCl solution attenuated the development of the hypertension until the fourth week (120 +/- 1 mmHg). After the 4-week treatments, renal norepinephrine turnover rate was calculated from the decline in specific activity after the injection of dl-3H-norepinephrine. It was markedly accelerated in DOCA-salt rats as compared to control rats. In contrast, 1% KCl supplement significantly restored to normal the increased renal norepinephrine turnover rate in DOCA-salt rats. Taken together, evidence presented suggests that the normalization of the increased renal sympathetic tone may be involved in the natriuretic and antihypertensive effects of potassium supplement in DOCA-salt hypertensive rats.     

Hypotension and hypothalamic depression produced by intracerebroventricular injections of GABA in spontaneously hypertensive rats

To determine the central effects of 4-Amino-n-butyric acid (GABA), pressor and sympathetic nerve responses to electrical stimulation of the ventromedial hypothalamus were recorded following the intracerebroventricular (ICV) injection of GABA. In normotensive Wistar rats, anesthetized with urethane, ICV injections of GABA (50-200 micrograms) reduced sympathetic nerve activity, arterial blood pressure, and heart rate in a dose-dependent manner. Graded electrical stimulation of the ventromedial hypothalamus (50, 100, 150 microA) increased not only mean blood pressure but also the rate of sympathetic nerve firing, and both responses were attenuated by GABA pretreatment (100, 200 micrograms, ICV). In spontaneously hypertensive rats (SHR), ICV-injected GABA also reduced sympathetic and cardiovascular activity, but the magnitude of depressor responses was significantly larger in SHR than in normotensive Wister Kyoto controls (WKY). Pressor and sympathetic nerve responses elicited by ventromedial hypothalamic stimulation were initially larger in SHR than in WKY, but upon subsequent ICV injection of GABA, hypothalamic responsiveness in SHR was inhibited more prominently and became comparable to that in WKY. These results suggest that by depressing hypothalamic function, centrally injected GABA decreases sympathetic nerve activity to thereby lower blood pressure and heart rate, and in SHR, ICV-injected GABA reversed hypothalamo-sympathetic hyperactivity and thus attenuated hypertension.     

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.     

Central attenuation of aortic baroreceptor reflex in prehypertensive DOCA-salt-loaded rats

To determine whether the arterial baroreceptor reflex can act to oppose the development of hypertension, deoxycorticosterone acetate (DOCA)-salt hypertension was produced in sinoaortic-denervated and sham-operated rats. Systolic blood pressure measured by tail cuff started to increase in both sinoaortic-denervated and sham-operated rats 7 days after DOCA treatment, and the hypertension developed identically in both denervated and sham-operated rats. These findings suggest that the baroreceptor reflex cannot act against the development of hypertension. To determine whether the baroreceptor reflex is attenuated before the development of hypertension, bradycardiac and sympathoinhibitory responses to i.v. injections of norepinephrine were examined. Bradycardic and sympathoinhibitory responses were significantly smaller in DOCA-salt-treated rats in both prehypertensive (5th day after DOCA-salt treatment) and hypertensive stages (21st day after treatment). In urethane-anesthetized DOCA-loaded and control rats on the 5th day after treatment, aortic depressor nerve stimulation elicited frequency-dependent depressor and bradycardic responses accompanied by inhibition of sympathetic nerve activity in both DOCA-loaded and control rats. However, those responses were significantly smaller in DOCA-loaded rats than in control rats. These results suggest that the central component of the baroreceptor reflex mediated by the aortic depressor nerve is impaired before hypertension develops and that this impairment may contribute to the development of hypertension in DOCA-salt-treated rats.     

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.     

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.     

Central action of increased osmolality to support blood pressure in deoxycorticosterone acetate-salt rats

To test the hypothesis that increased osmolality contributes to hypertension in deoxycorticosterone acetate (DOCA)-salt-hypertensive rats by acting in the brain, DOCA-salt and Sham-salt rats were instrumented with bilateral, nonoccluding intracarotid and femoral catheters. Two weeks prior, rats were uninephrectomized and received subcutaneous implants with or without DOCA (65 mg) and began drinking salt water (1% NaCl and 0.2% KCl). DOCA-salt rats (n=28) exhibited elevated blood pressure (159+/-4 mm Hg; P<0.05) and heart rate (392+/-10 bpm; P<0.05) compared with Sham-salt animals (n=5; blood pressure: 107+/-5 mm Hg; heart rate: 355+/-10 bpm). Bilateral intracarotid infusion of hypotonic fluid (osmolality: approximately 40 mOsm/L), which lowers osmolality of blood to the brain by approximately 2%, rapidly decreased blood pressure in DOCA-salt rats (-22+/-4 mm Hg after 15 minutes; P<0.05; n=7) but not Sham-salt rats (2+/-2 mm Hg; n=5). Hypotonic fluid infused intravenously did not lower blood pressure (0+/-2 mm Hg) in DOCA-salt rats (n=7). In DOCA-salt rats pretreated with a V(1) vasopressin antagonist (Manning compound, 5 microg, IV), intracarotid hypotonic infusion still decreased blood pressure (-10+/-3 mm Hg; P<0.05; n=9), but the response was smaller (P<0.05). Finally, in DOCA-salt rats (n=4) pretreated with the V(1) antagonist and the ganglionic blocker hexamethonium, decreasing osmolality of blood to the brain did not reduce blood pressure. These data indicate that, in DOCA-salt rats, hypertonicity acts in the brain to support blood pressure, in part by stimulating vasopressin secretion and in part by stimulating another rapidly reversible mechanism, likely the sympathetic nervous system.     

Inhibition of norepinephrine release by presynaptic alpha 2-adrenoceptors in mesenteric vasculature preparations from chronic DOCA-salt hypertensive rats

This study investigated norepinephrine release during electrical nerve stimulation and inhibitory characteristics of presynaptic alpha 2-adrenoceptors in perfused mesenteric vasculature from deoxycorticosterone acetate (DOCA)-salt hypertensive rats (7-8 weeks after surgery). Electrical stimulation of sympathetic innervation caused a significantly greater release of endogenous norepinephrine into the mesenteric vasculature of DOCA-salt hypertensive rats than in age-matched normotensive controls. Pressor responses to electrical nerve stimulation were also enhanced in DOCA-salt hypertension. Yohimbine, a potent alpha 2-adrenoceptor blocking agent, potentiated the stimulation-evoked release of norepinephrine into the vasculature in normotensive rats. This effect was blunted in DOCA-salt hypertension. These results suggest that increased norepinephrine release from the sympathetic nerve endings in DOCA-salt hypertension might partly reflect an impaired presynaptic alpha 2-adrenoceptor-mediated inhibition, which could enhance vascular sympathetic tone in this model of hypertension.     

Neurotransmitter Release,Vascular Responsiveness and Their Suppression by Ca-Antagonist in Perfused Mesenteric Vasculature of Doca-Salt Hypertensive Rats

To investigate the role of norepinephrine release from the sympathetic nerve endings and vascular responsiveness in the pathogenesis of hypertension, the perfused mesenteric preparations were used in DOCA-salt hypertensive rats (acute phase: 10 days after operation, chronic phase: 7–8 weeks).

In addition, the effects of a Ca-antagonist (verapamil) on the norepinephrine release and vascular responsiveness were also examined.

Vasoconstrictor responses to the electrical nerve stimulation were significantly greater in DOCA-salt hypertension in the chronic phase than the age-matched normotensive controls. The pressor responses to exogenous norepinephrine were significantly enhanced in DOCA-salt hypertension both in acute and chronic phases.

Endogenous norepinephrine overflow from the sympathetic nerve endings during the electrical nerve stimulation was enhanced in the chronic phase of DOCA-salt hypertension, but not in the acute phase, compared with the age-matched normotensive controls.

After infusion of verapamil, the pressor responses and norepinephrine overflow by the electrical nerve stimulation were significantly inhibited, and the suppression was greater in chronic DOCA-salt hypertension than in the normotensive controls.

These results demonstrate that the vascular responsiveness was increased in both acute and chronic phases of DOCA-salt hypertensive rats, while the norepinephrine overflow from the adrenergic nerve terminals was enhanced only in the chronic phase. More marked inhibition of the vasoconstrictor responses and norepinephrine overflow in the presence of a Ca-antagonist in chronic DOCA-salt hypertension might represent the higher Ca-dependency in the neurotransmission of the peripheral resistance vessels, especially in the mechanism of presynaptic norepinephrine release, than their normotensive controls, and it could partly contribute to the development and maintenance of DOCA-salt hypertension.     

Endogenous brain angiotensin II-mediated sympathetic nerve responses are not augmented in mature spontaneously hypertensive rats

Conjugated estrogens injected into the lateral brain ventricle in awake rats elicited behavioral excitation and vasopressor responses. Magnitude of pressor responses was greater in spontaneously hypertensive rats (SHR) than in normotensive Kyoto Wistar rats (WKY). Pressor responses in SHR were abolished by central pretreatments of either captopril or angiotensin II analog. Under urethane anesthesia, conjugated estrogens still produced greater pressor responses in SHR, but accompanying increases in sympathetic nerve firings were the same in both WKY and SHR. These results suggest that while centrally-administered estrogens may activate the brain renin-angiotensin system to increase sympathetic nerve firing and thereby elevated blood pressure, SHR have larger pressor responses only because peripheral vascular reactivity has been increased.