Hypothalamic paraventricular nucleus augments baroreflex sensitivity, role of angiotensin II.

The hypothalamic paraventricular nucleus (PVN) is an important brain region involved in control of the cardiovascular system. Direct injection of angiotensin II (AngII) into the PVN produces a short or long pressor response. This study was performed in anesthetized rats to find whether the parvocellular part of the paraventricular nucleus (PVNp) affects the baroreflex. And if so, what is the effect of AngII injected into the PVNp on the baroreflex? Drugs were microinjected into the PVNp while blood pressure and heart rate were recorded continuously. We found that microinjection of AT1 and AT2 receptor antagonists into the PVNp region did not affect the baseline mean arterial pressure (MAP) and heart rate (HR) indicating that under normal conditions AngII may not provide tonic activity, at least in anaesthetized animals. Bilateral microinjections of a synaptic blocker (CoCl2) into the PVNp attenuated the baroreflex gains in responses to loading and unloading of baroreceptors, indicating that PVNp is involved in the baroreflex rate component. Microinjection of AngII into the PVNp increased MAP and HR. However, AngII slightly attenuated the baroreflex rate component using its two receptors AT1 and AT2. Collectively, these findings suggest that the PVNp as a whole is involved in the baroreflex. But AngII attenuates the heart rate response of the baroreflex through AT1 and AT2 receptors.

In the parvocellular part of paraventricular nucleus, glutamatergic and GABAergic neurons mediate cardiovascular responses to AngII.

Angiotensinergic, GABAergic, and glutamatergic neurons are present in the parvocellular region of the paraventricular nucleus (PVNp). It has been shown that microinjection of AngII into the PVNp increases arterial pressure (AP) and heart rate (HR). The presence of synapses between the angiotensinergic, GABAergic, and glutamatergic neurons has been shown in the PVNp. In this study, we investigated the possible interaction between these three systems of the PVNp for control of AP and HR. All drugs were bilaterally (100 nl/side) microinjected into the PVNp of urethane-anesthetized rats, and AP and HR were recorded continuously. Microinjection of AngII into the PVNp produced pressor and tachycardia responses. Pretreatment of PVNp with AP5 or CNQX, glutamatergic NMDA and AMPA receptors antagonists, attenuated the responses to AngII. Pretreatment of PVNp with bicuculline greatly attenuated the pressor and tachycardia responses to AngII. In conclusion, this study provides the first evidence that pressor and tachycardia responses to microinjection of AngII into the PVNp are partly mediated by both NMDA and non-NMDA receptors of glutamate. Activation of glutamatergic neurons by AngII stimulates the sympathoexcitatory neurons. We also showed that the responses to AngII were strongly mediated by GABAA receptors, probably through activation of GABAergic neurons, which in turn inhibit sympathoinhibitory neurons.

Central Nucleus of Amygdala Mediate Pressor Response Elicited by Microinjection of Angiotensin II into the Parvocellular Paraventricular Nucleus in Rats.

Background: The Paraventricular Hypothalamic Nucleus (PVN) coordinates autonomic and neuroendocrine systems to maintain homeostasis. Microinjection of angiotensin II (AngII) into the PVN has been previously shown to produce pressor and bradycardia responses. Anatomical evidence has indicated that a substantial proportion of PVN neurons is connected with the neurons in the central amygdala (CeA). The present study aimed to examine the possible contribution of the CeA in cardiovascular responses evoked by microinjection of AngII into the parvocellular portion of PVN (PVNp) before and after microinjection of cobalt chloride (CoCl2) into the CeA. Methods: The experiments were conducted at the Department of Physiology of Shiraz University of Medical Sciences, from April 2019 to November 2019. There were two groups of 21 eight-week-old urethane anesthetized male rats, namely saline (n=9 rats) and AngII (n=12 rats) groups. Drugs (100 nL) were microinjected via a single-glass micropipette into the PVNp and CeA. Their blood pressure (BP) and heart rate (HR) were recorded throughout the experiments. The mean arterial pressure (MAP) and heart rate (HR) were compared to the pre-injection values using paired t test, and to those of the saline group using independent t test. Results: Microinjection of AngII into the PVNp produced pressor response (P<0.0001) with no significant changes in HR (P=0.70). Blockade of CeA with CoCl2 attenuated the pressor response to microinjection of AngII into the PVNp (P<0.001). Conclusion: In the PVNp, Ang II increased the rats' blood pressure. This response was in part mediated by the CeA. Our study suggested that these two nuclei cooperate to perform their cardiovascular functions.

Another controller system for arterial pressure. AngII-vasopressin neural network of the parvocellular paraventricular nucleus may regulate arterial pressure during hypotension.

Angiotensin II (AngII) immunoreactive cells, fibers and receptors, were found in the parvocelluar region of paraventricular nucleus (PVNp) and AngII receptors are present on vasopressinergic neurons. However, the mechanism by which vasopressin (AVP) and AngII may interact to regulate arterial pressure is not known. Thus, we tested the cardiovascular effects of blockade of the AngII receptors on AVP neurons and blockade of vasopressin V1a receptors on AngII neurons. We also explored whether the PVNp vasopressin plays a regulatory role during hypotension in anesthetized rat or not. Hypovolemic-hypotension was induced by gradual bleeding from femoral venous catheter. Either AngII or AVP injected into the PVNp produced pressor and tachycardia responses. The responses to AngII were blocked by V1a receptor antagonist. The responses to AVP were partially attenuated by AT1 antagonist and greatly attenuated by AT2 antagonist. Hemorrhage augmented the pressor response to AVP, indicating that during hemorrhage, sensitivity of PVNp to vasopressin was increased. By hemorrhagic-hypotension and bilateral blockade of V1a receptors of the PVNp, we found that vasopressinergic neurons of the PVNp regulate arterial pressure towards normal during hypotension. Taken together these findings and our previous findings about angII (Khanmoradi and Nasimi, 2017a) for the first time, we found that a mutual cooperative system of angiotensinergic and vasopressinergic neurons in the PVNp is a major regulatory controller of the cardiovascular system during hypotension.

Role of the Kölliker-Fuse nucleus in cardiovascular responses to hypoxia and baroreceptor activation in anesthetized rats.

Introduction: Parabrachial Kölliker-Fuse (KF) complex, located in dorsolateral part of the pons, is involved in the respiratory control, however, its role in the baroreflex and chemoreflex responses has not been established yet. This study was performed to test the contribution of the KF to chemoreflex and baroreflex and the effect of microinjection of a reversible synaptic blocker (Cocl2) into the KF in urethane anesthetized rats. Methods: Activation of chemoreflex was induced by systemic hypoxia caused by N2 breathing for 30 seconds "hypoxic- hypoxia methods" and baroreflex was evoked by intravenous injection (i.v.) of phenylephrine (Phe, 20 µg /kg/0.05-0.1 mL). N2 induced generalized vasodilatation followed by tachycardia reflex and Phe evoked vasoconstriction followed by bradycardia. Results: Microinjection of Cocl2 (5 mM/100 nL/side) produced no significant changes in the Phe-induced hypertension and bradycardia, whereas the cardiovascular effect of N2 was significantly attenuated by the injection of CoCl2 to the KF. Conclusion: The KF played no significant role in the baroreflex, but could account for cardiovascular chemoreflex in urethane anesthetized rats.

An Experimental Study on Spinal Cord µ-Opioid and α2-Adrenergic Receptors mRNA Expression Following Stress-Induced Hyperalgesia in Male Rats.

BACKGROUND: Intense stress can change pain perception and induce hyperalgesia; a phenomenon called stress-induced hyperalgesia (SIH). However, the neurobiological mechanism of this effect remains unclear. The present study aimed to investigate the effect of the spinal cord µ-opioid receptors (MOR) and α2-adrenergic receptors (α2-AR) on pain sensation in rats with SIH. METHODS: Eighteen Sprague-Dawley male rats, weighing 200-250 g, were randomly divided into two groups (n=9 per group), namely the control and stress group. The stress group was evoked by random 1-hour daily foot-shock stress (0.8 mA for 10 seconds, 1 minute apart) for 3 weeks using a communication box. The tail-flick and formalin tests were performed in both groups on day 22. The real-time RT-PCR technique was used to observe MOR and α2-AR mRNA levels at the L4-L5 lumbar spinal cord. Statistical analysis was performed using the GraphPad Prism 5 software (San Diego, CA, USA). Student's t test was applied for comparisons between the groups. P<0.05 was considered statistically significant. RESULTS: There was a significant (P=0.0014) decrease in tail-flick latency in the stress group compared to the control group. Nociceptive behavioral responses to formalin-induced pain in the stress group were significantly increased in the acute (P=0.007) and chronic (P=0.001) phases of the formalin test compared to the control group. A significant reduction was also observed in MOR mRNA level of the stress group compared to the control group (P=0.003). There was no significant difference in α2-AR mRNA level between the stress and control group. CONCLUSION: The results indicate that chronic stress can affect nociception and lead to hyperalgesia. The data suggest that decreased expression of spinal cord MOR causes hyperalgesia.

Effects of Post-Weaning Chronic Stress on Nociception, Spinal Cord µ-Opioid, and α2-Adrenergic Receptors Expression in Rats and Their Offspring.

Stressful situations can change biological process in human and animal, and some of these changes may transfer to the next generations. We used a communication box to induce chronic electrical foot-shock stress in rats. Tail flick latency and formalin test were done to determine the level of pain sensation. Real-time RT-PCR was used to measure the level of spinal cord µ-opioid (MOR) and α2-adrenergic receptors (α2-AR) mRNA. We demonstrate that chronic stress can change nociception and leads to hyperalgesia. Moreover, spinal cord MOR mRNA level decreased following chronic stress. We did not observe any significant changes in the level of spinal cord α2-AR mRNA between stressed and non-stressed rats. In addition, non-stressed sons of stressed mothers showed hyperalgesia compared to the control group. They showed lesser level of MOR mRNA level in comparison to the control rats. Furthermore, stressed sons of stressed mothers illustrated more hyperalgesia than the other stressed groups. We indicate that chronic stress can reduce spinal cord MOR mRNA level and lead to hyperalgesia. Additionally, these changes can transfer to offspring.

Effect of testosterone on Cisplatin-induced nephrotoxicity in surgically castrated rats.

BACKGROUND: Cisplatin (CP) is an important antitumor drug with serious side effects such as nephrotoxicity. Estrogens can affect CP-induced nephrotoxicity; however, the role of testosterone (TS), the main male sex hormone, is not clear. OBJECTIVES: This study aimed to investigate the effect of TS on CP-induced nephrotoxicity in castrated male rats. MATERIALS AND METHODS: A total of 54 male Wistar rats were castrated and allocated into eight groups. Groups 1 through 3 respectively received 10, 50, and 100 mg/kg/wk of TS and group 4 received sesame oil for four weeks; then all four groups received 2.5 mg/kg/d CP for one week. Groups 5 through 8 received the same treatment regimen as groups 1 through 4 during first four weeks but instead of CP, they received saline for one week. Then the animals were sacrificed for biochemical and histopathologic studies. RESULTS: CP increased the serum levels of blood urea nitrogen (BUN), creatinine (Cr), and malondialdehyde (SMDA) as well as kidney weight (KW), bodyweight (BW) loss, and kidney tissue damage score (KTDS). It significantly decreased the serum and kidney levels of nitrite and serum level of TS in comparison with the control group (P < 0.05). However, coadministration of CP and low dose of TS significantly decreased the serum levels of BUN as well as Cr and KTDS (P < 0.05). Administration of high-dose TS alone increased the SMDA level, KTDS, and KW while decreased the BW significantly (P < 0.05). CONCLUSIONS: It seems that testosterone in low dose, i.e. physiologic dose, protects kidneys against CP-induced nephrotoxicity; however, special care is needed in CP therapy of patients with high levels of TS.