Marco Antonio Peliky Fontes

Characterization of a new angiotensin antagonist selective for angiotensin-(1–7): Evidence that the actions of angiotensin-(1–7) are mediated by specific angiotensin receptors

In this study we describe a new angiotensin antagonist [Asp1-Arg2-Val3-Tyr4-Ile5-His6-D-Ala7, (A-779)] selective for the heptapeptide angiotensin-(1-7) [Ang-(1-7)]. A-779 blocked the antidiuretic effect of Ang-(1-7) in water-loaded rats and the changes in blood pressure produced by Ang-(1-7) microinjection into the dorsal-medial and ventrolateral medulla. In contrast, A-779 did not change the dipsogenic, pressor, or myotropic effects of angiotensin II (Ang II). Also, A-779 did not affect the antidiuretic effect of vasopressin or the contractile effects of angiotensin III, bradykinin, or substance P on the rat ileum. In the rostral ventrolateral medulla, the pressor effect produced by Ang-(1-7) microinjection was completely blocked by A-779 but not by AT1 or AT2 receptor antagonists (DUP 753 and CGP 42112A, respectively). Conversely, the pressor effect produced by Ang II was not changed by A-779 but was completely blocked by DUP 753. Binding studies substantiated these observations: A-779 did not compete significantly for 125I-Ang II binding to adrenocortical membranes at up to a 1 microM concentration. Low affinity binding was also observed in adrenomedullary membranes with an IC50 greater than 10 microM. Our results show that A-779 is a potent and selective antagonist for Ang-(1-7). More importantly, our data indicate that specific angiotensin receptors mediate the central and peripheral actions of Ang-(1-7).

Central mechanisms underlying short- and long-term regulation of the cardiovascular system.

1. Sympathetic vasomotor nerves play a major role in determining the level of arterial blood pressure and the distribution of cardiac output. The present review will discuss briefly the central regulatory mechanisms that control the sympathetic outflow to the cardiovascular system in the short and long term.

Evidence that angiotensin-(1-7) plays a role in the central control of blood pressure at the ventro-lateral medulla acting through specific receptors.

In this study we determined which angiotensin receptors may mediate the cardiovascular effects elicited by angiotensin-(1-7) [Ang-(1-7)] in the rostral ventrolateral medulla (RVLM) and caudal pressor area (CPA) of the ventrolateral medulla (VLM) of anesthetized rats. Furthermore the role of endogenous angiotensins in these areas was also investigated. The pressor effect produced by unilateral microinjection of Ang-(1-7) into the RVLM or CPA was not modified by either the AT1 receptor antagonist, DuP 753 or by the AT2 receptor antagonist, CGP 42112A, but was completely blocked by the Ang-(1-7) selective antagonist, A-779. In contrast, the pressor effect produced by microinjection of angiotensin II (Ang II) was completely blocked by DuP 753 but was not changed by CGP 42112A or A-779. Bilateral microinjection of A-779 into the RVLM or CPA produced a significant fall in mean arterial pressure and heart rate. Microinjection of DuP 753 produced a pressor effect comparable to bilateral injection of vehicle. These results indicate that, although Ang II acts in the VLM through an AT1 receptor subtype, the cardiovascular effects produced by microinjection of Ang-(1-7) into the RVLM and CPA are mediated by a specific angiotensin receptor (AT5?). Furthermore, our data provide evidence that endogenous Ang-(1-7) participates at the VLM in the neural control of arterial blood pressure.

Cardiovascular Responses Evoked by Leptin Acting on Neurons in the Ventromedial and Dorsomedial Hypothalamus

Abstract—Leptin, a circulating hormone produced by adipose tissue, is believed to act on the hypothalamus to increase sympathetic vasomotor activity, in addition to its well-known effects on appetite and energy expenditure. In this study, we determined the cardiovascular effects of direct application of leptin to specific cell groups within the hypothalamus that are known to be activated by circulating leptin. In rats anesthetized with urethane, microinjections of leptin (16 ng in 20 nL solution) were made into the ventromedial hypothalamic nucleus, dorsomedial hypothalamic nucleus, and paraventricular nucleus. Compared with vehicle solution, microinjections of leptin into the ventromedial hypothalamic nucleus evoked significant increases in arterial pressure and renal sympathetic nerve activity, but not heart rate. In contrast, microinjections of leptin into the dorsomedial hypothalamic nucleus evoked significant increases in arterial pressure and heart rate but not renal sympathetic nerve activity, whereas microinjections of leptin into the paraventricular nucleus had no significant effect on any of the measured cardiovascular variables. These results indicate that the ventromedial and dorsomedial hypothalamic regions might be important sites at which leptin activation leads to increases in sympathetic vasomotor activity and heart rate, as occurs in obesity-related hypertension.

Cardiovascular effects produced by microinjection of angiotensins and angiotensin antagonists into the ventrolateral medulla of freely moving rats

In this study we determined the cardiovascular effects produced by microinjection of angiotensin peptides [Angiotensin-(1-7) and Angiotensin II] and angiotensin antagonists (losartan, L-158,809, CGP 42112A. Sar1-Thr8-Ang II, A-779) into the rostral ventrolateral medulla of freely moving rats. Microinjection of angiotensins (12.5-50 pmol) produced pressor responses associated to variable changes in heart rate, usually tachycardia. Unexpectedly, microinjection of both AT1 and AT2 ligands produced pressor effects at doses that did not change blood pressure in anesthetized rats. Conversely, microinjection of Sar1-Thr8-Ang II and the selective Ang-(1-7) antagonist, A-779, produced a small but significant decrease in MAP an HR. These findings suggest that angiotensins can influence the tonic activity of vasomotor neurons at the RVLM. As previously observed in anesthetized rats, our results further suggest a role for endogenous Ang-(1-7) at the RVLM. The pressor activity of the ligands for AT1 and AT2 angiotensin receptor subtypes at the RVLM, remains to be clarified.

Role of angiotensin II receptors in the regulation of vasomotor neurons in the ventrolateral medulla.

1. There is a high density of angiotensin type 1 (AT1) receptors in various brain regions involved in cardiovascular regulation. The present review will focus on the role of AT1 receptors in regulating the activity of sympathetic premotor neurons in the rostral part of the ventrolateral medulla (VLM), which are known to play a pivotal role in the tonic and phasic regulation of sympathetic vasomotor activity and arterial pressure.

Cardiovascular effects produced by micro-injection of angiotensin-(1–7) on vasopressor and vasodepressor sites of the ventrolateral medulla

In this study, we determined the cardiovascular effects produced by micro-injection of the heptapeptide Angiotensin-(1-7) [Ang-(1-7)] into the rat ventrolateral medulla (VLM). Micro-injection of Ang-(1-7) into the rostral VLM and the caudal pressor area of the VLM produced significant increases in arterial pressure, comparable to that observed with micro-injection of Ang II. The changes in arterial pressure were associated with more variable changes in heart rate (HR) (usually tachycardia). On the other hand, micro-injection of Ang-(1-7) into the caudal depressor area induced decreases in arterial pressure and HR. The results suggest that, besides Ang II, Ang-(1-7) is involved in the mediation of the cardiovascular actions of the renin-angiotensin system in the VLM.

Cardiovascular and thermal responses evoked from the periaqueductal grey require neuronal activity in the hypothalamus.

Stimulation of neurons in the lateral/dorsolateral periaqueductal grey (l/dlPAG) produces increases in heart rate (HR) and mean arterial pressure (MAP) that are, according to traditional views, mediated through projections to medullary autonomic centres and independent of forebrain mechanisms. Recent studies in rats suggest that neurons in the l/dlPAG are downstream effectors responsible for responses evoked from the dorsomedial hypothalamus (DMH) from which similar cardiovascular changes and increase in core body temperature (Tco) can be elicited. We hypothesized that, instead, autonomic effects evoked from the l/dlPAG depend on neuronal activity in the DMH. Thus, we examined the effect of microinjection of the neuronal inhibitor muscimol into the DMH on increases in HR, MAP and Tco produced by microinjection of N‐methyl‐d‐aspartate (NMDA) into the l/dlPAG in conscious rats. Microinjection of muscimol alone modestly decreased baseline HR and MAP but failed to alter Tco. Microinjection of NMDA into the l/dlPAG caused marked increases in all three variables, and these were virtually abolished by prior injection of muscimol into the DMH. Similar microinjection of glutamate receptor antagonists into the DMH also suppressed increases in HR and abolished increases in Tco evoked from the PAG. In contrast, microinjection of muscimol into the hypothalamic paraventricular nucleus failed to reduce changes evoked from the PAG and actually enhanced the increase in Tco. Thus, our data suggest that increases in HR, MAP and Tco evoked from the l/dlPAG require neuronal activity in the DMH, challenging traditional views of the place of the PAG in central autonomic neural circuitry.

Role of periaqueductal gray on the cardiovascular response evoked by disinhibition of the dorsomedial hypothalamus

Activation of neurons in the region of the dorsomedial hypothalamus (DMH), by microinjection of the GABA(A) receptor antagonist bicuculline methiodide (BMI) results in increases in arterial pressure, heart rate as well as behavioral changes similar to those evoked by acute emotional stress. Previous anatomic studies clearly demonstrated projections from the DMH to the midbrain periaqueductal gray (PAG), a brain region implicated in the organization of behavioral strategies associated with specific cardiovascular responses. In this study, physiological experiments in conscious rats were used to investigate the functional significance of this pathway. Unilateral inhibition of the lateral dorsolateral region of the PAG (l/dlPAG) with the GABA(A) receptor agonist, muscimol (1 nmol/100 nl) largely reduced the tachycardia and the pressor response produced by microinjection of BMI (10 pmol/100 nl) into the ipsilateral DMH. In contrast, inhibition of the ventrolateral PAG (vlPAG) region had no significant effect on the cardiovascular response evoked from disinhibition of the ipsilateral DMH. Our present results indicate that the l/dlPAG region is an important synaptic relay in the descending cardiovascular pathways from the DMH.

What Drives The Tonic Activity Of Presympathetic Neurons In The Rostral Ventrolateral Medulla

1. The present review discusses the mechanisms that maintain the tonic activity of presympathetic cardiovascular neurons in the rostral part of the ventrolateral medulla.