V1a and V1b Vasopressin Receptors Within the Paraventricular Nucleus Contribute to Hypertension in Male Rats Exposed to Chronic Mild Unpredictable Stress

2020 ◽  
Author(s):  
Dragana Komnenov ◽  
Harrison Quaal ◽  
Noreen F. Rossi
Keyword(s):  
Heart Rate ◽  
Paraventricular Nucleus ◽  
Rat Model ◽  
Pressor Response ◽  
Traditional Risk Factor ◽  
Male Rats ◽  
Mild Stress ◽  
Renal Nerve ◽  
Renal Sympathetic Nerve Activity ◽  
Vasopressin Receptors

Depression is an independent non-traditional risk factor for cardiovascular disease and mortality. The chronic unpredictable mild stress (CMS) rat model is a validated model of depression. Within the paraventricular nucleus (PVN), vasopressin (VP) via V1aR and V1bR have been implicated in stress and neurocardiovascular dysregulation. We hypothesized that in conscious, unrestrained CMS rats vs control, unstressed rats, PVN VP results in elevated arterial pressure (MAP), heart rate and renal sympathetic nerve activity (RSNA) via activation of V1aR and/or V1bR. Male rats underwent four weeks of CMS or control conditions. They were then equipped with hemodynamic telemetry transmitters, PVN cannula, and left renal nerve electrode. V1aR or V1bR antagonism dose-dependently inhibited MAP after VP injection. V1aR or V1bR blockers at their ED50 doses did not alter baseline parameters in either control or CMS rats, but attenuated the pressor response to VP microinjected into PVN by ~50%. Combined V­1aR and V1bR inhibition completely blocked the pressor response to PVN VP in control but not CMS rats. CMS rats required combined maximally inhibitory doses to block either endogenous VP within the PVN or responses to microinjected VP. Compared with unstressed control rats, CMS rats had higher plasma VP levels and greater abundance of V1aR and V1bR transcripts within PVN. Thus, the CMS rat model of depression results in higher resting MAP, heart rate and RSNA which can be mitigated by inhibition of vasopressinergic mechanisms involving both V1aR and V1bR within the PVN. Circulating VP may also play a role in the pressor response.

Abstract MP45: Deletion Of The Transient Receptor Vanilloid-1 (TRPV1) Channel In Rats Attenuates 2 Kidney 1 Clip Hypertension

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Sean D Stocker ◽  
Leon J DeLalio
Keyword(s):  
Heart Rate ◽  
Renovascular Hypertension ◽  
Sensory Nerve ◽  
Experimental Models ◽  
Sensory Nerves ◽  
Male Rats ◽  
Wild Type ◽  
Renal Nerve ◽  
Trpv1 Channels ◽  
Arterial Blood

Renal denervation lowers arterial blood pressure (ABP) in both clinical populations and multiple experimental models of hypertension. This therapeutic effect is partly attributed to the removal of overactive renal sensory nerves that increase sympathetic efferent activity and ABP. Renal sensory nerves highly express TRPV1 channels, and administration of the TRPV1 agonist capsaicin increases renal sensory nerve activity. However, the extent by which TRPV1 channels directly contribute to renal nerve dependent models of hypertension has not been tested. To test this hypothesis, we generated a novel TRPV1 -/- rat using CRISPR/Cas9 and deletion of exon 3. Male and female TRPV1 -/- and wild-type littermates (8-12 weeks) were instrumented with telemetry. At 2 weeks later, renovascular hypertension via renal stenosis was produced by placement of a PTFE cuff (0.16 x 0.22 inches, 1mm long) around the right renal artery. Male TRPV1 -/- and wild-type rats had no differences in baseline mean ABP (99±2 vs 98±3 mmHg, respectively; n=7-9) or heart rate (390±7 vs 400±8 bpm, respectively). Renal stenosis significantly increased mean ABP in both groups; however, mean ABP was significantly lower at Day 28 in male TRPV1 -/- versus wild-type rats (125±8 vs 155±2 mmHg, respectively: P<0.01). Ganglionic blockade with chlorisondamine (2.5mg/kg, sc) at Day 28 produced a smaller fall in mean ABP of male TRPV1 -/- versus wild-type rats (-53±4 vs -86±3 mmHg, respectively; P<0.001). On the other hand, female TRPV1 -/- and wild-type rats had no differences in baseline mean ABP (102±2 vs 104±1 mmHg, respectively; n=6-9) or heart rate (419±8 vs 410±7 bpm, respectively). Renal stenosis significantly increased mean ABP in both groups; however, there were no differences at Day 28 between female TRPV1 -/- versus wild-type rats (117±8 vs 122±6 mmHg, respectively). Moreover, the increase in mean ABP was smaller in females versus males. The ganglionic blocker chlorisondamine produced similar depressor responses in female TRPV1 -/- versus wild-type rats (-64±7 vs -65±7 mmHg, respectively). These findings illustrate a sex difference in renovascular hypertension in rats, but importantly indicate that TRPV1 channels contribute to the established phase of renovascular hypertension in male rats.

Contribution of paraventricular nucleus to afferent renal nerve pressor response

1988 ◽  
Vol 254 (3) ◽  
pp. R531-R543 ◽  
Author(s):  
M. M. Caverson ◽  
J. Ciriello
Keyword(s):  
Paraventricular Nucleus ◽  
Pressor Response ◽  
Sensory Information ◽  
Sympathetic Nerves ◽  
Firing Frequency ◽  
Procaine Hydrochloride ◽  
Renal Nerve ◽  
Neurosecretory Neurons ◽  
Electrolytic Lesions ◽  
Alpha Chloralose

Experiments were done in alpha-chloralose-anesthetized, paralyzed, and artificially ventilated cats to determine the effect of afferent renal nerve (ARN) stimulation on the firing frequency of neurons in the paraventricular nucleus of the hypothalamus (PVH), whose axons project directly to the neurohypophysis (NH), and the contribution of these neurons to the pressor response elicited by ARN stimulation. In the first series of experiments, 474 single units were extracellularly recorded in the PVH region. Of these units 86 were antidromically excited by stimulation of the NH. Seventeen of the antidromic units (20%) responded orthodromically to ARN stimulation; 10 responded to ARN stimulation only, and 7 units responded to both ARN and buffer nerve stimulation. All PVH-NH-projecting neurons that responded to ARN stimulation were excited. In the second series the contribution of PVH neurons to the pressor response elicited by ARN stimulation was investigated in animals with the aortic depressor, carotid sinus, vagus, and cervical sympathetic nerves cut bilaterally. The ARN pressor response has previously been shown to be due to the activation of the sympathetic nervous system and to the release of arginine vasopressin (AVP). The primary and secondary (AVP component) components of the pressor response were attenuated by 51 and 69%, respectively, by bilateral injections of procaine hydrochloride into PVH or bilateral electrolytic lesions of PVH. Control injections of saline into PVH or electrolytic lesions of hypothalamic regions anterior, dorsal, or ventral to PVH did not alter the ARN pressor response. These experiments demonstrate that sensory information originating in renal receptors excites magnocellular neurosecretory neurons in PVH and suggest that this renal-paraventricular reflex loop may contribute to the elevated arterial pressure and AVP release during conditions when ARN are activated.

Aging is not accompanied by sympathetic hyperresponsiveness to air-jet stress

1996 ◽  
Vol 271 (2) ◽  
pp. H768-H775 ◽  
Author(s):  
H. M. Stauss ◽  
D. A. Morgan ◽  
K. E. Anderson ◽  
M. P. Massett ◽  
K. C. Kregel
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Low Frequency ◽  
Nerve Activity ◽  
Renal Nerve ◽  
Renal Sympathetic Nerve Activity ◽  
Fischer 344 ◽  
Air Jet ◽  
Renal Nerve Activity ◽  
Renal Sympathetic

It has been postulated that sympathetic nervous system reactivity to acutely applied stress is increased with age. We investigated the autonomic and hemodynamic adjustments to air-jet stress in 9 mature (12-mo-old) and 11 senescent (24-mo-old) Fischer 344 rats. Rats were instrumented with arterial and venous catheters, flow probes around the renal artery, and nerve electrodes on the ipsilateral renal nerve. After the rats recovered from surgery, blood pressure, heart rate, renal blood flow, and renal sympathetic nerve activity were recorded during control conditions and during an 8-min continuous air-jet application. Renal resistance and the low (0.01-0.20 Hz)- and mid-frequency (0.20-0.50 Hz) power of blood pressure were computed off-line. The air jet induced an increase in blood pressure, heart rate, renal resistance, renal nerve activity, and blood pressure power in the low- and mid-frequency ranges in both groups. Blood pressure and low-frequency blood pressure power increased less, and the elevations in renal resistance and renal nerve activity were of shorter duration in senescent compared with mature rats. These data suggest that sympathetic responsiveness to air-jet stress is not enhanced with increasing age.

Stimulation of parabrachial neurons elicits a sympathetically mediated pressor response in cats

1988 ◽  
Vol 255 (6) ◽  
pp. H1349-H1358 ◽  
Author(s):  
J. S. Hade ◽  
S. W. Mifflin ◽  
T. S. Donta ◽  
R. B. Felder
Keyword(s):  
Heart Rate ◽  
Electrical Stimulation ◽  
Arterial Pressure ◽  
Pressor Response ◽  
Electrical Stimulus ◽  
Respiratory Drive ◽  
Nerve Activity ◽  
Renal Nerve ◽  
Low Intensity ◽  
Stimulation Of

We examined the role of the parabrachial neuronal mass in mediating the pressor response to electrical stimulation of parabrachial nucleus (PBN). In anesthetized cats, 100 mM L-glutamate (L-glu) was microinjected into PBN at sites from which low-intensity (25 microA) electrical stimulation evoked a pressor response. Arterial pressure, heart rate, and, in some animals, renal or phrenic nerve activity were monitored. Microinjection of L-glu caused an increase in arterial pressure that was comparable with that elicited by low-intensity electrical stimulation. Electrical stimulation, and to a lesser extent L-glu microinjection, caused an increase in renal sympathetic nerve activity but no significant change in heart rate. No consistent change in central respiratory drive accompanied the pressor response. These responses were preserved after baroreceptor denervation but were blocked by intravenous administration of the alpha-adrenergic receptor antagonist phentolamine. Microinjection into PBN of 2 mM kainic acid, which selectively depolarizes neurons but spares axons, reversibly blocked the arterial pressure and renal nerve responses to the 25-microA electrical stimulus. We conclude that the pressor response elicited by electrical stimulation of PBN in the anesthetized cat is mediated by cellular elements in PBN, not by fibers of passage. Because phentolamine completely blocked the pressor response, we suggest that it is subserved peripherally by sympathetic alpha-adrenergic rather than humoral (e.g., angiotensin, vasopressin) vasoconstrictor mechanisms. Finally, our data indirectly suggest that PBN stimulation may differentially engage efferent components of the sympathetic nervous system to elicit the pressor response.

Increased ganglionic responses to substance P in hypertensive rats due to upregulation of NK1 receptors

2000 ◽  
Vol 279 (5) ◽  
pp. R1685-R1694 ◽  
Author(s):  
Robert V. Schoborg ◽  
Donald B. Hoover ◽  
John D. Tompkins ◽  
John C. Hancock
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Substance P ◽  
Intravenous Injection ◽  
Pressor Response ◽  
Sympathetic Ganglia ◽  
Hypertensive Rats ◽  
Renal Nerve ◽  
Functional Studies ◽  
Wistar Kyoto

Intravenous injection of substance P (SP) increases renal nerve firing and heart rate in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) by stimulating sympathetic ganglia. Blood pressure is increased in SHRs but lowered in WKYs. This study assesses the role of neurokinin-1 (NK1) receptors in mediating the ganglion actions of SP. Rats for functional studies were anesthetized and then treated with chlorisondamine. Renal nerve, blood pressure, and heart rate responses to intravenous injection of the NK1 receptor agonist GR-73632 were similar but less than those to equimolar doses of SP in SHRs. GR-73632 only slightly increased renal nerve firing and heart rate and lowered blood pressure in WKYs. The NK1receptor antagonist GR-82334 (200 nmol/kg iv) blocked the ganglionic actions of GR-73632 and the pressor response to SP in SHRs. It reduced the renal nerve and heart rate responses by 52 and 35%. This suggests that the pressor response to SP is mediated by ganglionic NK1 receptors and that NK1 receptors also have a prominent role in mediating the renal nerve and heart rate responses to SP. Quantitative autoradiography showed that NK1receptors are more abundant in the superior cervical ganglia of SHRs. RT-PCR showed increased abundance of NK1 receptor mRNA in SHRs as well. These observations suggest that the greater ganglionic stimulation caused by SP in SHRs is due to upregulation of NK1 receptors.

Interaction between glutamate and GABA systems in the integration of sympathetic outflow by the paraventricular nucleus of the hypothalamus

2006 ◽  
Vol 291 (6) ◽  
pp. H2847-H2856 ◽  
Author(s):  
Yi-Fan Li ◽  
Keshia L. Jackson ◽  
Javier E. Stern ◽  
Brandon Rabeler ◽  
Kaushik P. Patel
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Paraventricular Nucleus ◽  
Sympathetic Nerve Activity ◽  
Excitatory Input ◽  
Sympathetic Outflow ◽  
Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Dose Dependent ◽  
Renal Sympathetic

The paraventricular nucleus (PVN) of the hypothalamus is a central site known to modulate sympathetic outflow. Excitatory and inhibitory neurotransmitters within the PVN dictate final outflow. The goal of the present study was to examine the role of the interaction between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA in the regulation of sympathetic activity. In α-chloralose- and urethane-anesthetized rats, microinjection of glutamate and N-methyl-d-aspartate (NMDA; 50, 100, and 200 pmol) into the PVN produced dose-dependent increases in renal sympathetic nerve activity, blood pressure, and heart rate. These responses were blocked by the NMDA receptor antagonistdl-2-amino-5-phosphonovaleric acid (AP-5). Microinjection of bicuculline, a GABAA receptor antagonist, into the PVN (50, 100, and 200 pmol) also produced significant, dose-dependent increases in renal sympathetic nerve activity, blood pressure, and heart rate; AP-5 also blocked these responses. Using microdialysis and HPLC/electrochemical detection techniques, we observed that bicuculline infusion into the PVN increased glutamate release. Using an in vitro hypothalamic slice preparation, we found that bicuculline increased the frequency of glutamate-mediated excitatory postsynaptic currents in PVN-rostral ventrolateral medullary projecting neurons, supporting a GABAA-mediated tonic inhibition of this excitatory input into these neurons. Together, these data indicate that 1) glutamate, via NMDA receptors, excites the presympathetic neurons within the PVN and increases sympathetic outflow and 2) this glutamate excitatory input is tonically inhibited by a GABAA-mediated mechanism.

Increase in sympathetic outflow by paraventricular nucleus stimulation in awake rats

1989 ◽  
Vol 256 (6) ◽  
pp. R1325-R1330 ◽  
Author(s):  
H. Kannan ◽  
Y. Hayashida ◽  
H. Yamashita
Keyword(s):  
Heart Rate ◽  
Arterial Pressure ◽  
Paraventricular Nucleus ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Sympathetic Outflow ◽  
Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Renal Sympathetic Nerve ◽  
Renal Sympathetic

Our previous studies demonstrated that stimulation of the hypothalamic paraventricular nucleus (PVN) in anesthetized rats evoked a depressor response accompanied with a decrease in sympathetic outflow (H. Kannan, A. Niijima, and H. Yamashita, J. Auton. Nerv. Syst. 19: 83-86, 1987; H. Yamashita, H. Kannan, M. Kasai, and T. Osaka, J. Auton. Nerv. Syst. 19: 229-234, 1987). Because anesthesia may alter cardiovascular responses, we examined in conscious rats the effects of PVN stimulation on arterial pressure, heart rate, and renal sympathetic nerve activity. Electrical stimulation through chronically implanted electrodes evoked increases in arterial pressure and renal sympathetic nerve activity with a slight decrease in heart rate. The magnitude of responses was dependent on the frequency and the intensity of the stimulus. Latency of the excitatory response of the renal sympathetic nerve activity was approximately 70 ms. Microinjection of L-glutamate (0.5 M, 200 nl) into the PVN area also elicited increases in blood pressure and renal sympathetic nerve activity. These results suggest that activation of PVN neurons in conscious rats produces pressor responses due to an increase in the sympathetic outflow. These findings contrast with those obtained previously in anesthetized rats.

Central control of cardiac baroreflex responses during peripheral hyperosmolality

2000 ◽  
Vol 278 (5) ◽  
pp. R1157-R1163 ◽  
Author(s):  
Steven L. Bealer
Keyword(s):  
Heart Rate ◽  
Hypertonic Saline ◽  
Pressor Response ◽  
Isotonic Saline ◽  
Male Rats ◽  
Central Control ◽  
Preoptic Nucleus ◽  
Median Preoptic Nucleus ◽  
Saline Loading ◽  
Acid Administration

Acute increases in peripheral osmolality evoke a pressor response and baroreflex-mediated bradycardia. These experiments were designed to determine if the fall in heart rate during peripheral sodium loading is 1) equivalent to bradycardia accompanying phenylephrine (PE) infusion, 2) mediated by the parasympathetic (PSNS) or sympathetic (SNS) nervous system, and 3) controlled by the median preoptic nucleus (MnPO). Male rats received an intravenous infusion of isotonic saline, hypertonic saline (2.5 M NaCl), or PE for 30 min. Blood pressure increased equivalently in the hypertonic NaCl and PE groups. However, heart rate fell more in animals infused with PE. Furthermore, pretreatment with methylatropine to block the PSNS had no effect on bradycardia, whereas blocking SNS influences on cardiac function significantly attenuated the fall in heart rate during peripheral hyperosmolality. Finally, kainic acid administration in the MnPO before testing increased bradycardia observed during hypertonic saline loading. Taken together, these data suggest that acute peripheral hyperosmolality acts at the MnPO to reduce cardiac SNS withdrawal during the pressor response that reduces the associated baroreflex bradycardia.

scholarly journals Effects of nNOS antisense in the paraventricular nucleus on blood pressure and heart rate in rats with heart failure

2005 ◽  
Vol 288 (1) ◽  
pp. H205-H213 ◽  
Author(s):  
Yu Wang ◽  
Xue-Fei Liu ◽  
Kurtis G. Cornish ◽  
Irving H. Zucker ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Heart Rate ◽  
Paraventricular Nucleus ◽  
Antisense Oligonucleotides ◽  
Pressor Response ◽  
No Synthase ◽  
Coronary Ligation ◽  
Nos Inhibitor

Using neuronal NO synthase (nNOS)-specific antisense oligonucleotides, we examined the role of nitric oxide (NO) in the paraventricular nucleus (PVN) on control of blood pressure and heart rate (HR) in conscious sham rats and rats with chronic heart failure (CHF). After 6–8 wk, rats with chronic coronary ligation showed hemodynamic and echocardiographic signs of CHF. In sham rats, we found that microinjection of sodium nitroprusside (SNP, 20 nmol, 100 nl) into the PVN induced a significant decrease in mean arterial pressure (MAP). SNP also induced a significant decrease in HR over the next 10 min. In contrast, the NOS inhibitor NG-monomethyl-l-arginine (l-NMMA, 200 pmol, 100 nl) significantly increased MAP and HR over the next 18–20 min. After injection of nNOS antisense, MAP was significantly increased in sham rats over the next 7 h. The peak response was 27.6 ± 4.1% above baseline pressure. However, in the CHF rats, only MAP was significantly increased. The peak magnitude was 12.9 ± 5.4% of baseline, which was significantly attenuated compared with sham rats ( P < 0.01). In sham rats, the pressor response was completely abolished by α-receptor blockade. HR was significantly increased from hour 1 to hour 7 in sham and CHF rats. There was no difference in magnitude of HR responses. The tachycardia could not be abolished by the β1-blocker metoprolol. However, the muscarinic receptor antagonist atropine did not further augment the tachycardia. We conclude that NO induces a significant depressor and bradycardiac response in normal rats. The pressor response is mediated by an elevated sympathetic tone, whereas the tachycardia is mediated by withdrawal of parasympathetic tone in sham rats. These data are consistent with a downregulation of nNOS within the PVN in CHF.

Activation of 5-hydroxytryptamine-1A receptors suppresses cardiovascular responses evoked from the paraventricular nucleus

2011 ◽  
Vol 301 (4) ◽  
pp. R1088-R1097 ◽  
Author(s):  
Jouji Horiuchi ◽  
Alp Atik ◽  
Kamon Iigaya ◽  
Lachlan M. McDowall ◽  
Suzanne Killinger ◽  
...  
Keyword(s):  
Heart Rate ◽  
Paraventricular Nucleus ◽  
Sympathetic Nerve Activity ◽  
Cardiovascular Responses ◽  
Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Dorsomedial Hypothalamus ◽  
Way 100635 ◽  
Renal Sympathetic ◽  
Stimulation Of

Activation of central 5-hydroxytryptamine-1A (5-HT1A) receptors powerfully inhibits stress-evoked cardiovascular responses mediated by the dorsomedial hypothalamus (DMH), as well as responses evoked by direct activation of neurons within the DMH. The hypothalamic paraventricular nucleus (PVN) also has a crucial role in cardiovascular regulation and is believed to regulate heart rate and renal sympathetic activity via pathways that are independent of the DMH. In this study, we determined whether cardiovascular responses evoked from the PVN are also modulated by activation of central 5-HT1A receptors. In anesthetized rats, the increases in heart rate and renal sympathetic nerve activity evoked by bicuculline injection into the PVN were greatly reduced (by 54% and 61%, respectively) by intravenous administration of (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), an agonist of 5-HT1A receptors, but were then completely restored by subsequent administration of WAY-100635, a selective antagonist of 5-HT1A receptors. Microinjection of 8-OH-DPAT directly into the PVN did not significantly affect the responses to bicuculline injection into the PVN, nor did systemic administration of WAY-100635 alone. In control experiments, a large renal sympathoexcitatory response was evoked from both the PVN and DMH but not from the intermediate region in between; thus the evoked responses from the PVN were not due to activation of neurons in the DMH. The results indicate that activation of central 5-HT1A receptors located outside the PVN powerfully inhibits the tachycardia and renal sympathoexcitation evoked by stimulation of neurons in the PVN.

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