Differential regulation of central vasopressin receptors in transgenic rats with low brain angiotensinogen (original) (raw)
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AJP: Regulatory, Integrative and Comparative Physiology, 2013
Grobe JL. Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent. An indispensable role for the brain renin-angiotensin system (RAS) has been documented in most experimental animal models of hypertension. To identify the specific efferent pathway activated by the brain RAS that mediates hypertension, we examined the hypothesis that elevated arginine vasopressin (AVP) release is necessary for hypertension in a double-transgenic model of brain-specific RAS hyperactivity (the "sRA" mouse model). sRA mice experience elevated brain RAS activity due to human angiotensinogen expression plus neuronspecific human renin expression. Total daily loss of the 4-kDa AVP prosegment (copeptin) into urine was grossly elevated (Ն8-fold). Immunohistochemical staining for AVP was increased in the supraoptic nucleus of sRA mice (ϳ2-fold), but no quantitative difference in the paraventricular nucleus was observed. Chronic subcutaneous infusion of a nonselective AVP receptor antagonist conivaptan (YM-087, Vaprisol, 22 ng/h) or the V2-selective antagonist tolvaptan (OPC-41061, 22 ng/h) resulted in normalization of the baseline (ϳ15 mmHg) hypertension in sRA mice. Abdominal aortas and secondorder mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V1A receptor mRNA, but no significant changes in V2 receptor expression in kidney were observed. Chronic tolvaptan infusion also normalized the (5 mmol/l) hyponatremia of sRA mice. Together, these data support a major role for vasopressin in the hypertension of mice with brainspecific hyperactivity of the RAS and suggest a primary role of V2
Altered cardiovascular regulation in arginine vasopressin-overexpressing transgenic rat
American journal of physiology. Endocrinology and metabolism, 2003
Although arginine vasopressin (AVP), an antidiuretic hormone, has been widely acknowledged to play an important role in cardiovascular regulation via V1a receptors (V1aR), its precise significance remains unclear. In this study, we investigated the effects of long-standing high plasma AVP status on cardiovascular regulation in the AVP-overexpressing transgenic (Tg) rat. Adult male homozygous Tg rats were compared with age-matched normal Sprague-Dawley rats as controls. There were no significant differences in mean arterial blood pressure (BP; MABP) or heart rate between Tg and control rats in the basal state. Subcutaneous injection of AVP significantly increased MABP in controls but did not cause any apparent increase in MABP in Tg rats. BP recovery from hemorrhage-induced hypotension was significantly delayed in Tg compared with control rats. Pretreatment with a selective V1aR antagonist, OPC-21268, which is thought to restore the downregulation of V1aR, markedly improved both of t...
Vasopressinergic mechanisms in the nucleus reticularis lateralis in blood pressure control
Brain Research, 1993
We sought to determine whether arginine vasopressin (AVP) modulates arterial pressure (AP) by a receptor-mediated action in the nucleus reticularis rostroventrolateralis (nRVL). Immunocytochemical labeling with an antiserum against a synthetic AVP conjugate revealed a discrete although modest presumptive neuropeptidergic innervation of the nRVL. Electron microscopic analysis of vasopressinergic processes in the nRVL revealed that AVP-like immunoreactivity (AVP-LI) was primarily in axons and axon terminals. Immunoreactive terminals contained numerous small clear vesicles and large dense core vesicles and formed synapses with unlabeled dendrites. In the nRVL, retrograde transport-immunofluorescence data demonstrated close appositions between vasopressinergic beaded processes and a compact subambigual column of reticulospinal neurons labeled by deposits of cholera toxin /3-subunit into the thoracic spinal cord. Similar methods were used to define the origins of the AVP-afferent projection to nRVL. These retrograde transport-immunofluorescence studies demonstrated numerous retrogradely labeled neurons in the hypothalamus, including the paraventricular nucleus (PVN), after injections of a retrograde tracer, Fluoro-Gold into the ventrolateral medulla. However, double-labeled neurons were rare and confirmed a diffuse AVP afferent innervation of the sympathoexcitatory area. Microinjection of AVP into the nRVL in anesthetized rats produced a large dose-related increase in AP different from control at a dose of 1 pmol or higher. AVP injected intravenously elevated AP only at significantly higher doses. Microinjections of AVP into the nucleus tractus solitarii (NTS) had a smaller effect whereas into the caudal ventrolateral medulla exerted no effect on AP. Bilateral microinjections of an AVP antagonist, d(CH2)5[Tyr(Me)Z]AVP into the nRVL produced no change in AP but blocked the increase produced by subsequent injections of AVP. An acute hemorrhage produced by withdrawal of 2 ml of blood from the femoral vein did not alter AP. However, bilateral microinjections of the AVP antagonist into the nRVL 5 min after hemorrhage decreased AP. In contrast, the AVP-antagonist injected intravenously after hemorrhage had no effect on AP. Our data suggest that under conditions demanding increased sympathetic drive to maintain AP, such as hemorrhage, a functional AVP receptor mechanism via terminals in the nRVL may be activated to restore normal levels of AP.
Journal of Renin-Angiotensin-Aldosterone System, 2008
I In nt tr ro od du uc ct ti io on n. . Brain arginine 8 -vasopressin (AVP), through the V 1a -and V 2 -receptors, is essential for the maintenance of mean arterial pressure (MAP). Central AVP interacts with the components of the renin-angiotensin system, which participate in MAP regulation. This study aimed to determine the effects of V 1a -, V 2 -and V 1a /V 2 -AVP selective antagonists and AT 1 -and AT 2 -angiotensin II (Ang II) selective antagonists on the MAP induced by AVP injected into the medial septal area (MSA) of the brain. M Ma at te er ri ia al ls s a an nd d m me et th ho od ds s. . Male Holtzman rats with stainless steel cannulae implanted into the MSA were used in experiments. Direct MAP was recorded in conscious rats. R Re es su ul lt ts s. . AVP administration into the MSA caused a prompt and potent pressor response in a dose-dependent fashion. Pretreatment with the V 1a -and V 2 -antagonists reduced, whereas prior injection of the V 1a /V 2 -antagonist induced a decrease in the MAP that remained below the baseline. Both AT 1 -and AT 2 -antagonists elicited a decrease, while simultaneous injections of two antagonists were more effective in decreasing the MAP induced by AVP. C Co on nc cl lu us si io on n. . These results indicate there is a synergism between the V 1a -and V 2 -AVP and AT 1and AT 2 -Ang II receptors in the MSA in the regulation of MAP.
of the renin-angiotensin system at the RVLM of transgenic rats with low brain angiotensinogen. Am J Physiol Regulatory Integrative Comp Physiol 280: R428-R433, 2001.-The transgenic rats TGR(ASrAOGEN) (TGR) with low levels of brain angiotensinogen were analyzed for cardiovascular reactivity to microinjections of ANG II and angiotensin receptor (AT 1) antagonists [CV-11974, AT 1 specific; A-779, ANG-(1-7) selective; sarthran, nonspecific] into the rostral ventrolateral medulla (RVLM) of conscious rats. Microinjec-tion of ANG II resulted in a significantly higher increase in the mean arterial pressure (MAP) of TGR than control [Sprague-Dawley (SD)] rats, suggesting an upregulation of ANG II receptors in TGR. CV-11974 produced an increase in MAP of SD but not in TGR rats. A-779 produced a depressor response in SD but not in TGR rats. Conversely, sarthran produced a similar decrease of MAP in both rat groups. The pressor effect of the AT 1 antagonist may indicate an inhibi-tory role of AT 1 receptors in the RVLM. On the other hand, ANG-(1-7) appears to have a tonic excitatory role in this region. The altered response to specific angiotensin antagonists in TGR further supports the functionally relevant decrease in angiotensins in the brains of TGR and corroborates the importance of the central renin-angiotensin system in cardiovascular homeostasis. brain renin-angiotensin system; rostral ventrolateral me-dulla; blood pressure THE EXISTENCE OF A LOCAL renin-angiotensin system (RAS) in the central nervous system is generally acknowledged (4, 10). Although different approaches indicate multiple roles for the brain RAS, its relative significance in the proposed processes remains of interest (27). A variety of studies has focused on distinguishing the contribution of the brain RAS to the regulation of cardiovascular and fluid-electrolyte ho-meostasis, as classically described functions of the en-docrine RAS. Brain ANG II increases blood pressure, thirst, sodium appetite, and vasopressin release; and it causes sympathetic activation and modulates the baroreflex control. These functions are mediated by interactions of ANG II with specific receptors located at important brain sites involved in cardiovascular and fluid-electrolyte regulation (5). In the past few years, it has become evident that other biologically active an-giotensin peptides, including ANG-(1-7), are capable of influencing mean arterial pressure (MAP) and barore-flex control of heart rate (HR) acting centrally (8, 11). The rostral ventrolateral medulla (RVLM) represents the main relay for the sympathetic output and contains angiotensin receptors (12). Considered an important component of the neural circuitry regulating cardiovascular homeostasis by modulating vasomotor tone, the RVLM is situated inside the blood-brain barrier and thus receives solely locally produced angio-tensins (26). The relative role of angiotensin peptides in this region for central control of blood pressure is still unclear. Microinjection of the nonspecific angio-tensin antagonist sarthran into the RVLM of anesthe-tized animals produced a significant fall in blood pressure (2, 17, 19), suggesting an excitatory role for ANG II in this region. However, microinjection of losartan or other angiotensin receptor (AT 1) antagonists into the RVLM did not change blood pressure in anesthetized animals (14, 18) and produced a pressor response in freely moving rats (13). On the other hand, microinjec-tion of the ANG-(1-7) antagonist A-779 (29) produced significant decreases in MAP in anesthetized (14) or awake (13) rats. To further clarify the role of angioten-sin peptides at the RVLM, we aimed in the present study to test the cardiovascular responsiveness to an-giotensin receptor stimulation or blockade at the RVLM of conscious transgenic rats with low brain AOGEN, TGR(ASrAOGEN) (TGR). TGR rats exhibit up to 90% reduced angiotensinogen levels throughout the brain, hypotension, low plasma vasopressin levels, and decreased hypertensive response to peripheral infusion of slow-pressor doses of ANG II (6, 30).
Arginine vasopressin modulates the central action of angiotensin II in the dog
Hypertension, 1983
Endogenous vasopressin may interact with central autonomic nervous system factors in the regulation of cardiovascular function. In 25 morphine/chloralose-anesthetized dogs, we studied the magnitude of the pressor response produced by an infusion of angiotensin II (All) into the vertebral arteries (VA), before and after intracisternal (n = 10), intravertebral (n = 9), or intravenous (n = 6) administration of a competitive antagonist of arginine vasopressin (AVP) [d(CH 2)5iyr(Me) AVP]. The dose response curve to vertebral artery infusion of AH (range 2-20 ng/ kg/mih) was significantly (p < 0.05) shifted to the right of control after injection of the AVP antagonist (10 Mg/kg) into the cisterna magna; the ED at 20 mm Hg being almost double after central AVP blockade. This effect of AVP blockade was confined only to the cardiovascular response mediated by All via the vertebral arteries. When pressor doses of All were injected into either a vein (i.v.) or the cisterna magna of these same dogs, the increases in mean blood pressure were the same before and after AVP antagonist treatment. In another group of anesthetized dogs, we investigated whether the reduced reactivity to intravertebral All could be duplicated by giving the AVP antagonist either via the vertebral artery or i.v. Only the cisterna magna route was effective in causing a blunting of the pressor response to vertebral artery AH. These data demonstrate a previously unknown interaction between vasopressin and the centrally mediated pressor response to intravertebral AH. (Hypertension 5 (supp V): V-94-V-100, 1983) KEY WORDS • blood pressure • angiotensin II • vasopressin • neuropeptides area postrema • central autonomic function • baroreceptor reflexes • neuroendocrine mechanisms I T is well established that in the dog the area postrema of the fourth ventricle has a role in the neural control of cardiovascular function by acting, in part, to enhance central vasomotor sympathetic activity in response to increased blood levels of angiotensin II (All). 1 " 5 In addition, recent data suggest that the effects of AH at the dog's area postrema may depend upon the activity of endogenous brain peptides such as the opioid system. 6 Other studies have indicated that there are reciprocal direct connections between the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus and the nucleus tractus solitarii (NTS) in the brain stem. 7 8 Long descending projections from PVN to the dorsal motor nuclei of the vagus nerve (DMV), the NTS and upper spinal cord have
The Journal of Physiology, 2010
A co-morbidity of sleep apnoea is hypertension associated with elevated sympathetic nerve activity (SNA) which may result from conditioning to chronic intermittent hypoxia (CIH). Our hypothesis is that SNA depends on input to the rostral ventrolateral medulla (RVLM) from neurons in the paraventricular nucleus (PVN) that release arginine vasopressin (AVP) and specifically, that increased SNA evoked by CIH depends on this excitatory input. In two sets of neuroanatomical experiments, we determined if AVP neurons project from the PVN to the RVLM and if arginine vasopressin (V 1A ) receptor expression increases in the RVLM after CIH conditioning (8 h per day for 10 days). In the first set, cholera toxin β subunit (CT-β) was microinjected into the RVLM to retrogradely label the PVN neurons. Immunohistochemical staining demonstrated that 14.6% of CT-β-labelled PVN neurons were double-labelled with AVP. In the second set, sections of the medulla were immunolabelled for V 1A receptors, and the V 1A receptor-expressing cell count was significantly greater in the RVLM (P < 0.01) and in the neighbouring rostral ventral respiratory column (rVRC) from CIH-than from room air (RA)-conditioned rats. In a series of physiological experiments, we determined if blocking V 1A receptors in the medulla would normalize blood pressure in CIH-conditioned animals and attenuate its response to disinhibition of PVN. Blood pressure (BP), heart rate (HR), diaphragm (D EMG ) and genioglossus muscle (GG EMG ) activity were recorded in anaesthetized, ventilated and vagotomized rats. The PVN was disinhibited by microinjecting a GABA A receptor antagonist, bicuculline (BIC, 0.1 nmol), before and after blocking V 1A receptors within the RVLM and rVRC with SR49059 (0.2 nmol). In RA-conditioned rats, disinhibition of the PVN increased BP, HR, minute D EMG and GG EMG activity and these increases were attenuated after blocking V 1A receptors. In CIH-conditioned rats, a significantly greater dose of blocker (0.4 nmol) was required to blunt these physiological responses (P < 0.05). Further, this dose normalized the baseline BP. In summary, AVP released by a subset of PVN neurons modulates cardiorespiratory output via V 1A receptors in the RVLM and rVRC, and increased SNA in CIH-conditioned animals depends on up-regulation of V 1A receptors in the RVLM.
Brain Research, 1988
In order to determine if the decreased hypothalamic and increased posterior pituitary content of vasopressin (VP) observed previously in spontaneously hypertensive rats (SHR) were a secondary consequence of the hypertension, the effect of preventing the development of hypertension on VP content of the hypothalamoneurohypophyseal system was evaluated. Two methods for preventing the hypertension were used: (l) chronic angiotensin-converting enzyme inhibition (oral captopril, 100 mg/kg/day at 4-12 weeks of age); and (2) intraventricular 6-hydroxydopamine (6-OHDA, 200/~g at 4 and 5 weeks of age). Both of these treatments markedly attenuated the increase in systolic blood pressure in SHRs at 5-11 weeks of age. The captopril-treated rats had a significant elevation in serum renin activity at 12 weeks of age indicating the presence of chronic converting enzyme inhibition, and the 6-OHDA-treatment resulted in a depletion of hypothalamic (86%) and brainstem (76%) norepinephrine content. Hypothalamic VP content was reduced in untreated SHRs compared to normotensive Wistar-Kyoto rats (WKYs, P = 0.0015). It was not significantly altered in either strain by the 6-OHDA treatment. Captopril caused a reduction in hypothalamic VP content in both SHRs and WKYs (P < 0.01). Posterior pituitary VP content was elevated in untreated SHRs compared to WKYs (P < 0.001), and remained elevated with captopril and 6-OHDA treatments. These data indicate that the abnormalities in VP content in the hypothalamus and posterior pituitary of SHRs are not a response to the hypertension. Therefore, they may represent primary abnormalities in the SHR. In contrast, the suppression of renal renin concentration previously observed in SHRs was abolished when the hypertension was prevented by 6-OHDA treatment suggesting that the reduced renin concentration in mature SHR is a secondary response to the hypertension.