Experimental hypertension group - Ribeirão Preto campus of University of São Paulo

• Grant number: 95/04685-8
• Support Opportunities: Research Projects - Thematic Grants
• Start date: June 01, 1996
• End date: September 30, 2000
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Maria Cristina de Oliveira Salgado
• Grantee: Maria Cristina de Oliveira Salgado
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant(s): 00/06163-9 - Pressure response to bilateral carotid occlusion in conscious chronic diabetic rats: effect of insulin therapy., AR.EXT; 00/01564-5 - 1) involvement of paraventricular nucleus of hypothalamus and parabrachial nucleus in the cardiovascular responses of chemoreflex in awake rats. 2)evaluation of the gain of the baroreflex after..., AR.EXT; 00/01585-2 - 1) effects of voltage-gated ca channels activation and inhibition in aortas from 2k-1c hypertensive rats. 2) relaxing effect to atrial natriuretic peptide in tail arteries pre-contracted with endothelin.., AR.EXT; + associated grants 99/02015-6 - Nae J. Dun | East Tennessee State University - Estados Unidos, AV.EXT; 98/04249-1 - Kenneth Michael Spyer | Royal Free Hospital - Inglaterra, AV.EXT; 97/03632-3 - Hemodynamic responses to eletrical stimulation of the aortic depressor nerve and chemoreflex activation with potassium cyanide in unanesthetized rats., AR.EXT; 97/03368-4 - Steven Wayne Mifflin | University of Texas - United States, AV.EXT; 97/00004-1 - 1) nitric oxide is involved in the blunted sympathetic vasoconstriction of rat mesenteric arteries in pregnancy., AR.EXT; 96/06863-3 - Mark W. Chapleau | University of Iowa College of Medicine - Estados Unidos, AV.EXT - associated grants

Abstract

The studies of neuro-humoral mechanisms involved in the cardiocirculatory control and in the physiopathogeny of hypertension, proposed in this thematic team project, will be tackled by means of in vivo techniques, as well as in vitro and biochemical methods. The experience of the group in electroneuronographic recording of the activity of the aortic baroreceptors and in hemodynamic studies and of reflex regulation of the cardiac frequency and arterial pressure, will, now (annex I), be applied in two experimental models of peripheral neuropathy, namely, diabetes caused by the administration of streptozotocin and the model of Chagas disease caused by the inoculation of the y do T. cruzi strain. We will study in these models, in mice, the baroreceptor function and its rapid adaptation to levels of hypertension induced by the narrowing of the aorta. We will also investigate in these models the adaptation of the regulation reflex of arterial pressure and cardiac frequency, as a whole, to levels of hypertension. In the model of Chagas disease in mice, we will also study hemodynamic aspects of the acute and chronic phases of the inoculation and also the histological (morphological morphometric) alterations of the aortal baroreceptors. Another important aspect of the signaling reference the SNC, for the modulation of the cardio-circulatory regulation, is the study of the neurotransmission of the afferences of peripheral receptors (presso- and chemical receptors) in the bulbar structures that compose the reflex arc (annex II). It is hoped to study the mechanisms involved in the neurotransmission in NTS of sympatho-inhibitory components of the baroreflex and sympatho-excitatory of the chemoreflex, in non anaesthetized mice. Specifically it is intended: 1) to characterize the sympatho-inhibitory component activated by the electrical stimulation of the afferences of the aortal baroreceptors and by the micro injection of L-glutamate in the lateral commissural NTS; 2) to evaluate the participation of the receptors of excitatory aminoacids (EAA) in the neurotransmission of the sympatho-inhibitory component of the baroreflex, as well as the subtypes of EAA receptors involved; 3) to evaluate if the cardiovagal component of the chemoreflex presents characteristics of neurotransmission and subtypes of serotinergic receptors similar to the cardiovagal component of the baroreflex; 4) to evaluate the role of the different subtypes of serotinergic receptors, especially those of the subtype 5-HT3, in the neuromodulation of the excitatory cardiovagal components of the baroreflex and of the excitatory cardiovagal and sympatho-excitatory component of the chemoreflex. The studies of cardio-circulatory regulation and of the models of arterial hypertension involve, also, humoral factors, which significantly control arterial pressure, through the control of cardiac output and peripheral resistance. We will evaluate the participation of the endogenous cinines, a potent vasodilator and natriuretic, in cardio-circulatory control in normotense mice and with chronic renal hypertension of the type one-kidney, a clip (annex III). To this end, we will investigate the mechanism of the vasodilatory action of bradykinin, both in vitro (resistance vessels) and in vivo (arterial pressure). The importance of endogenous cinines on the renal excretory function will also be analyzed by means of the use of specific inhibitors. The contribution of the different cininases, in vivo and in vitro, will also be analyzed. Since neuro-humoral factors exercise an important control on the degree of contraction of the vascular smooth muscle, with direct repercussion on the degree of peripheral resistance, experiments will be carried out to identify the participation of the different factors in the conditions of the altered pressure reactivity, such as pregnancy and models of hypertension (annex IV). Parts of the research of the team will be concentrated on the study of the cell mechanisms determining vascular reactivity. These studies will use in vitro models which include isolated and perused vascular beds, isolated arterial segments and isolated muscle cells. The experiments proposed aim to elucidate the ionic mechanisms involved in the contractile response of vascular smooth muscle to adrenergic or peptidergic agonists, as well as identify possible alterations in the same, associated with the decrease in vascular reactivity which occurs in normal pregnancy of the female mouse or the alteration of the reactivity to adrenergic agonists which occurs in models of renal hypertension (1R, 1K). Specifically, we will quantitatively characterize the dependent channels for calcium voltage, the channels of potassium and the calcium membrane ionic fluxes, as well as the modification in the intracellular concentration of hydrogen. Although part of these experiments uses classical methodologies in pharmacology and physiology, it is the interest of the group to implement also more modern techniques that permit the direct analysis of the ionic fluxes in vascular smooth muscle (annex V) and the location and quantification of the calcium and potassium channels. Finally, this series of experiments seeks to clarify the participation of endothelium in the alterations of vascular reactivity which occur in pregnancy and in the 1R, 1K model of hypertension and which mechanisms are involved. (AU)