Abstract
Our objective was to investigate in conscious Sprague-Dawley (6-8 weeks, 250-300 g) female rats (N = 7 in each group) the effects of intracerebroventricularly (icv) injected adrenomedullin (ADM) on blood pressure and heart rate (HR), and to determine if ADM and calcitonin gene-related peptide (CGRP) receptors, peripheral V1 receptors or the central cholinergic system play roles in these cardiovascular effects. Blood pressure and HR were observed before and for 30 min following drug injections. The following results were obtained: 1) icv ADM (750 ng/10 µL) caused an increase in both blood pressure and HR (ΔMAP = 11.8 ± 2.3 mmHg and ΔHR = 39.7 ± 4.8 bpm). 2) Pretreatment with a CGRP receptor antagonist (CGRP8-37) and ADM receptor antagonist (ADM22-52) blocked the effect of central ADM on blood pressure and HR. 3) The nicotinic receptor antagonist mecamylamine (25 µg/10 µL, icv) and the muscarinic receptor antagonist atropine (5 µg/10 µL, icv) prevented the stimulating effect of ADM on blood pressure. The effect of ADM on HR was blocked only by atropine (5 µg/10 µL, icv). 4) The V1 receptor antagonist [β-mercapto-β-β-cyclopentamethylenepropionyl1, O-me-Tyr2,Arg8]-vasopressin (V2255; 10 µg/kg), that was applied intravenously, prevented the effect of ADM on blood pressure and HR. This is the first study reporting the role of specific ADM and CGRP receptors, especially the role of nicotinic and muscarinic central cholinergic receptors and the role of peripheral V1 receptors in the increasing effects of icv ADM on blood pressure and HR.
Highlights
Adrenomedullin (ADM), a calcitonin/calcitonin generelated peptide (CGRP) with vasodilatory properties, has multiple functions in regulating cardiovascular homeostasis, and is of particular interest in the pathophysiology of hypertension [1,2,3]
Microinjection of ADM into the hypothalamic paraventricular nucleus (PVN) induced a significant decrease of blood pressure [23], whereas microinjection of ADM into the rostral www.bjournal.com.br ventrolateral medulla caused a significant increase of blood pressure accompanied by an increase of renal sympathetic output [24,25]
We observed that icv ADM administered at a dose of 750 ng/10 μL increased blood pressure and heart rate (HR) in rats and these increased values did not return to basal values after 30 min
Summary
Adrenomedullin (ADM), a calcitonin/calcitonin generelated peptide (CGRP) with vasodilatory properties, has multiple functions in regulating cardiovascular homeostasis, and is of particular interest in the pathophysiology of hypertension [1,2,3]. Some of the central effects of this peptide are thought to be mediated by specific receptors and CGRP1 receptors, similar to the peripheral mechanism [5,6]. Many studies have demonstrated that icv ADM increased blood pressure and heart rate (HR) via central sympathetic stimulation. Previous studies have shown that central cholinergic stimulation or central cholinomimetic injection causes increases in blood pressure via the activation of sympathetic discharge [17,18,19,20]. The action of centrally administered ADM might involve other mechanisms with peripheral V1 receptors since there are several reports that icv administration of ADM increased c-fos mRNA and FOS protein in many areas of the hypothalamus, including the paraventricular nucleus (PVN) and supraoptic nucleus
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