Functions of AT1 and AT2 angiotensin receptors in the paraventricular nucleus of the rat, correlating single-unit and cardiovascular responses.

The paraventricular hypothalamic nucleus (PVN) is a complex structure with both neuroendocrine and autonomic functions including cardiovascular control. The PVN contains angiotensin II (AngII) immunoreactive cells, fibers, as well as AT1 and AT2 receptors of AngII. We microinjected AngII into the PVN of normotensive anesthetized rats and simultaneously recorded blood pressure, heart rate (HR) and single-unit responses. The roles of AT1 and AT2 receptors in these responses were also evaluated. Microinjection of AngII into the PVN produced a short excitatory single-unit response and two types of pressor responses: short duration with a decrease in HR and long with an increase in HR. Microinjection of losartan, an AT1 antagonist, into the PVN produced two response types, attenuation and augmentation of the pressor and firing rate responses to AngII. Microinjection of PD123319, an AT2 antagonist, into the PVN greatly attenuated pressor and single-unit response to AngII, indicating that the pressor response was mediated through AT2 receptors too. In conclusion, microinjection of AngII into the PVN stimulates neurons resulting in an increase in firing rate and consequently produces a short or long pressor response. These responses were mediated through AT1 and AT2 receptors; however, AT1 receptor may produce inhibition too. The results suggest that AngII of the PVN may be a neurotransmitter playing a role in arterial pressure regulation.

Endogenous angiotensin II in the paraventricular nucleus regulates arterial pressure during hypotension in rat, a single-unit study.

The hypothalamic paraventricular nucleus (PVN) controls cardiovascular regulation through vasopressin and sympathetic system. The PVN contains angiotensin II (AngII) and AngII receptors. We have already shown that microinjection of AngII into PVN produced a pressor response concomitant with an increase in firing rate of some PVN neurons. This study was performed to find if PVN AngII plays a regulatory function during hypotension. Hypovolemic-hypotension was induced and the possible role of the PVN AngII in returning arterial pressure toward normal was assessed by monitoring cardiovascular response and single-unit activity of the PVN neurons. Hemorrhage augmented the pressor, tachycardic and single-unit responses to AngII. After-hemorrhage injection of PD123319, an AT2 antagonist, into PVN resulted in a significant decrease in firing rate of some neurons, indicating that AngII was released into the PVN due to hemorrhage. Using single-unit recording, we found that PVN receives electrical signals from baroreceptors and from circulating AngII through circumventricular organs. In addition, by producing hemorrhagic-hypotension and bilateral blockade of AT2 receptors of the PVN, we found that AngII regulates arterial pressure toward normal during hypotension. So for the first time, it was verified that brain renin-angiotensin system is also a major regulatory system of the cardiovascular system.

Angiotensin II in the paraventricular nucleus stimulates sympathetic outflow to the cardiovascular system and make vasopressin release in rat.

The hypothalamic paraventricular nucleus (PVN) plays essential roles in neuroendocrine and autonomic functions, including cardiovascular regulation. It was shown that microinjection of angiotensin II (AngII) into the PVN produced a pressor response. In this study, we explored the probable mechanisms of this pressor response. AngII was microinjected into the PVN and cardiovascular responses were recorded. Then, the responses were re-tested after systemic injection of a ganglionic blocker, Hexamethonium, or a vasopressin V1 receptor blocker. Hexamethonium pretreatment (i.v.) greatly and significantly attenuated the pressor response to AngII, with no significant effect on heart rate, indicating that the sympathetic system is involved in the cardiovascular effect of AngII in the PVN. Systemic pretreatment (i.v.) with V1 antagonist greatly and significantly attenuated the pressor response to AngII, with no significant effect on heart rate, indicating that vasopressin release is involved in the cardiovascular effect of AngII in the PVN. Overall, we found that AngII microinjected into the PVN produced a pressor response mediated by the sympathetic system and vasopressin release, indicating that other than circulating AngII, endogenous AngII of the PVN increases the vasopressin release from the PVN.

The role of S-methylisothiourea hemisulfate as inducible nitric oxide synthase inhibitor against kidney iron deposition in iron overload rats.

BACKGROUND: Iron dextran is in common use to maintain iron stores. However, it is potentially toxic and may lead to iron deposition (ID) and impair functions of organs. Iron overload can regulate the expression of inducible nitric oxide synthase (iNOS) in some cells that has an important role in tissue destruction. S-methylisothiourea hemisulfate (SMT) is a direct inhibitor of iNOS, and this study was designed to investigate the effect of SMT against kidney ID in iron overload rats. MATERIALS AND METHODS: 24 Wistar rats (male and female) were randomly assigned to two groups. Iron overloading was performed by iron dextran 100 mg/kg/day every other day for 2 weeks. In addition, during the study, groups 1 and 2 received vehicle and SMT (10 mg/kg, ip), respectively. Finally, blood samples were obtained, and the kidneys were prepared for histopathological procedures. RESULTS: SMT significantly reduced the serum levels of creatinine and blood urea nitrogen. However, SMT did not alter the serum levels of iron and nitrite, and the kidney tissue level of nitrite. Co-administration of SMT with iron dextran did not attenuate the ID in the kidney. CONCLUSION: SMT, as a specific iNOS inhibitor, could not protect the kidney from ID while it attenuated the serum levels of kidney function biomarkers.

The protective activity of noscapine on renal ischemia-reperfusion injury in male Wistar rat.

OBJECTIVES: Bradykinin is a part of the kinin-kallikrein system which is involved in ischemia-reperfusion injury via B1 and B2 receptors. Noscapine is a non-competitive antagonist of bradykinin receptors. Noscapine has been reported to to be able to protect some organs against ischemia-reperfusion injury but its effect on renal ischemia-reperfusion injury (RIR) in rats is unknown. Therefore, the present study was designed to evaluate the effect of noscapine on renal ischemia-reperfusion injury in rats. MATERIALS AND METHODS: Twenty four rats were randomly assigned to four groups; sham, RIR control, pre-and post-treatment with noscapine. To induce RIR injury, 20 days after right nephrectomy, animals underwent a midline laparotomy and the renal artery was clamped for 40 min to induce ischemia, and the clamp was then removed to allow reperfusion for 48 hr. Animals received noscapine or vehicle 1 hr before RIR or just prior to reperfusion. At the end of the experiment, animals were killed by cardiac exsanguination. Blood samples were collected to assess blood urea nitrogen (BUN) and creatinine. The kidneys were also removed for histopathlogical and western-blot analysis. RESULTS: Noscapine treatment 1 hr before RIR or just prior to reperfusion protects the renal tissue structure as compared with the control. The expression levels of the studied inflammatory mediators, TNF-α and MCP-1in pretreated-, and treated-noscapine groups decreased as compared with the control group. The levels of BUN and creatinine in pre-, and post-treated noscapine groups were significantly lower than in control animals. CONCLUSION: Noscapine protects renal tissue structure and function against RIR through down-regulation of the inflammatory mediators.