Sympathetic Hyperactivity during Hypothalamic Stimulation in Spontaneously Hypertensive Rats

Takeda, Kazuo; Buñag, Ruben D.

doi:10.1172/jci109171

Cited by 109 publications

(31 citation statements)

References 26 publications

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“…Studies in our laboratory have demonstrated that bilateral dorsal rhizotomy (T-10 to L-2) prevents the development of hypertension and the increase in NE turnover rate and release in the posterior hypothalamic nuclei in CRF rats (41). This suggests that afferent impulses from damaged kidneys may activate areas of the brain involved in the noradrenergic regulation of blood pressure and contribute to the development of hypertension (42)(43)(44)(45)(46)(47). This notion is supported by the study of Converse et al (48) who showed that the decrease in arterial pressure after bilateral nephrectomy in uremic patients on chronic dialysis, was associated with lower sympathetic nerve firing and regional vascular resistance.…”

Section: Discussionmentioning

confidence: 94%

“…There is also substantial evidence that an increase in noradrenergic activity in the posterior hypothalamus is associated with increased peripheral SNS activity and blood pressure. Electrical stimulation of the posterior hypothalamic areas increases blood pressure in the rat (42, 43,54), and destruction of these areas decrease blood pressure in SHR rats (55). Local perfusion of hypertonic saline or phenylephrine in the posterior hypothalamus elicited increased blood pressure, heart rate, and NE release (56).…”

Section: Discussionmentioning

confidence: 99%

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Nitric oxide (NO) modulates the neurogenic control of blood pressure in rats with chronic renal failure (CRF).

Ye¹,

Nosrati²,

Campese³

1997

J. Clin. Invest.

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Increased sympathetic nervous system (SNS) activity plays a role in the genesis of hypertension in rats with chronic renal failure (CRF). Because nitric oxide (NO) modulates the activity of the SNS, a deficit of NO synthesis could be responsible for the increased SNS activity in these animals.In the present study, we evaluated the effects of L -arginine and L-NAME on blood pressure and SNS activity in Sprague Dawley 5/6 nephrectomized or sham-operated rats. SNS activity was determined by measuring norepinephrine turnover rate in several brain nuclei involved in the regulation of blood pressure. In the same brain nuclei, we measured NO content and nitric oxide synthase (NOS) gene expression by semiquantitative measurements of NOS mRNA reverse transcription polymerase chain reaction.In CRF rats, norepinephrine turnover rate was increased in the posterior hypothalamic nuclei, locus coeruleus, paraventricular nuclei, and the rostral ventral medulla, whereas NOS mRNA gene expression and NO 2 /NO 3 content were increased in all brain nuclei tested. L-NAME increased blood pressure and NE turnover rate in several brain nuclei of both control and 5/6 nephrectomized rats.In CRF rats, a significant relationship was present between the percent increment in NOS mRNA gene expression related to the renal failure, and the percent increase in norepinephrine turnover rate caused by L-NAME. This suggests that endogenous NO may partially inhibit the activity of the SNS in brain nuclei involved in the neurogenic regulation of blood pressure, and this inhibition is enhanced in CRF rats.In

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Nitric oxide (NO) modulates the neurogenic control of blood pressure in rats with chronic renal failure (CRF).

Ye¹,

Nosrati²,

Campese³

1997

J. Clin. Invest.

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“…7,15 A central disturbance in NE release by the hypothalamus is related to increased SNS activity. 8 Accordingly, augmented NE release and catecholamine synthesis as well as tyrosine hydroxylase gene expression have been reported at central sites related to blood pressure regulation in adult SHR.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-(1–7) Inhibitory Mechanism of Norepinephrine Release in Hypertensive Rats

et al. 2004

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Abstract-Release of norepinephrine (NE) by the hypothalamic nuclei may contribute to regulation of sympathetic nervous system (SNS) activity. Angiotensin-(1-7) [Ang-(1-7)] has an antihypertensive effect and may decrease SNS activity. We tested the hypothesis that Ang-(1-7) inhibits the release of NE in hypothalami, via the Ang-(1-7) and angiotensin II type 2 (AT 2 ) receptors, acting through a bradykinin (BK)/NO-dependent mechanism. Hypothalami from normotensive controls and spontaneously hypertensive rats (SHR) were isolated and endogenous NE stores labeled by incubating the tissues with [ 3 H]NE. [ 3 H]NE release from the hypothalami was stimulated by KCl in the presence or absence of Ang-(1-7) alone or combined with various antagonists and inhibitors. Ang-(1-7) significantly attenuated K ϩ -induced NE release by hypothalami from normotensive rats but was more potent in SHR. The Ang-(1-7) receptor antagonist ]Ang-(1-7), the AT 2 receptor antagonist PD 123319, and the BK B 2 receptor antagonist icatibant all blocked the inhibitory effect of Ang-(1-7) on K ϩ -stimulated NE release in SHR. The inhibitory effect of Ang-(1-7) disappeared in the presence of the NO synthase inhibitor N G -nitro-L-arginine methyl ester and was restored by the precursor of NO, L-arginine. The diminished NE release caused by Ang-(1-7) was blocked by a soluble guanylyl cyclase inhibitor as well as by a cGMP-dependent protein kinase (PKG). We concluded that Ang-(1-7) decreases NE release from the hypothalamus via the Ang-(1-7) or AT 2 receptors, acting through a BK/NO-mediated mechanism that stimulates cGMP/PKG signaling. In this way, Ang-(1-7) may decrease SNS activity and exert an antihypertensive effect. ] has been shown to be the most pleiotropic bioactive component of the renin-angiotensin system because it exerts effects that may be identical to, different from, or opposite from those displayed by angiotensin II (Ang II). 1 For instance, it lacks the vasoconstrictor aldosterone secretagogue or dipsogenic effects of Ang II. 1,2 However, it mimics Ang II stimulation of vasopressin and prostaglandin release 1 as well as peripheral norepinephrine (NE) outflow. 3 In contrast, Ang-(1-7) causes natriuresis, diuresis, and vasodilatation and inhibits angiogenesis and cellular growth, 1,2 suggesting that in many cases, this peptide may act as an endogenous antagonist of Ang II. In fact, Ang-(1-7) has been suggested as having an antihypertensive effect as well as counterbalancing the pressor and proliferative actions of Ang II because some of its effects that oppose those of Ang II are enhanced in rat models of hypertension. 1,4 It has been demonstrated that the Mas proto-oncogene, originally considered to be an "orphan" G-protein-coupled receptor involved in phospholipase C activation, 5 binds Ang-(1-7) and is involved in the biological actions of this heptapeptide. 6 Genetic deletion of the Mas receptor abolishes not only binding of Ang-(1-7) to mouse kidneys but also Ang-(1-7)-induced relaxation and antidiuretic responses, suggesting that ...

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“…The number of individual pulses per second was counted with a rate analyzer whose output was recorded as a histogram on an ink-writing recorder converted to digital form using a computer interface, and printed by a programmed calculator. 21 …”

Section: Sympathetic and Pressor Responsiveness In Anesthetized Ratsmentioning

confidence: 99%

Streptozotocin diabetic rats are hypertensive despite reduced hypothalamic responsiveness.

Buñag¹,

Tomita²,

Sasaki³

1982

Hypertension

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SUMMARY To determine whether diabetes predisposes rats to hypertension, tail-cuff systolic pressures were measured in male rats made diabetic by pretreatment with streptozotocin. From Weeks 2 through 7, diabetic rats weighed less but had higher systolic pressures than nondiabetic ones. Further comparisons made while the rats were anesthetized with urethane showed that pressor and sympathetic nerve responses to ventromedial hypothalamic stimulation, as well as pressor responses to injected vasopressin, were significantly reduced in the diabetic group. A generalized reduction of cardiovascular reactivity was considered unlikely because systemic pressor responses to norepinephrine and tyramine were unimpaired. Yet reflex bradycardia elicited by norepinephrine was enhanced indicating that baroreceptor resetting had not occurred. Thus, diabetic rats were characterized by hypertension, narrowed pulse pressure, bradycardia with increased reflex responses to norepinephrine, and reduced pressor responses to hypothalamic stimulation and to vasopressin. The successful induction of diabetes was confirmed not only by the presence of hyperglycemia, hypoinsulinemia, glycosuria, and abnormal glucose tolerance, but also by reductions in pancreatic weight, insulin, and /3-cell content. Although our results suggest that diabetic rats are predisposed to become hypertensive, other mechanisms such as hypothalamic depression may be activated to restrict further elevations in blood pressure. H YPERTENSION is generally believed to be more prevalent among diabetics than nondiabetics, 1 -2 but why this might be so is uncertain. Previous attempts to record blood pressure in rats with experimental diabetes have yielded equivocal results. Although blood pressure in normotensive rats is usually elevated by either alloxan 2 " 1 or streptozotocin, 5 -6 it has also been found unaffected 7 or even slightly decreased by streptozotocin. 8 In spontaneously hypertensive rats (SHR), blood pressure falls during the first few weeks after alloxan diabetes is induced, 4 6 9 but several months later becomes even higher than before. 3 From the Department of Pharmacology, College of Health Sciences and Hospital, University of Kansas Medical Center, Kansas City, Kansas.Supported by Research Grant AM 27660 from the National Institute of Arthritis, Metabolism, and Digestive Diseases.An abstract of this paper was published in Federation Proceedings 40: 391, 1981. Dr. Susumu Sasaku is a postdoctoral research fellow from the Second Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.Address for reprints: Dr. Ruben D. Bunag, Department of Pharmacology, University of Kansas Medical Center, 39th and Rainbow Boulevard, Kansas City, Kansas 66103.Received May 27, 1981; revision accepted December 7, 1981. While trying to characterize the cardiovascular changes occurring in normotensive rats that had been pretreated with streptozotocin, we found the ensuing diabetes accompanied by mild hypertension. Both blood pressure 10 and blood sugar" a...

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Sympathetic Hyperactivity during Hypothalamic Stimulation in Spontaneously Hypertensive Rats

Cited by 109 publications

References 26 publications

Nitric oxide (NO) modulates the neurogenic control of blood pressure in rats with chronic renal failure (CRF).

Nitric oxide (NO) modulates the neurogenic control of blood pressure in rats with chronic renal failure (CRF).

Angiotensin-(1–7) Inhibitory Mechanism of Norepinephrine Release in Hypertensive Rats

Streptozotocin diabetic rats are hypertensive despite reduced hypothalamic responsiveness.

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