Biomedical subjects

Debra I Diz

Publications and source records attributed to Debra I Diz.

21 records · Page 2Linked to original sources

PubMed2003

Angiotensin receptors contribute to blood pressure homeostasis in salt-depleted SHR.

This study evaluated the contribution of angiotensin peptides acting at various receptor subtypes to the arterial pressure and heart rate of adult 9-wk-old male conscious salt-depleted spontaneously hypertensive rats (SHR). Plasma ANG II and ANG I in salt-depleted SHR were elevated sevenfold compared with peptide levels measured in sodium-replete SHR, whereas plasma ANG-(1-7) was twofold greater in salt-depleted SHR compared with salt-replete SHR. Losartan (32.5 micromol/kg), PD-123319 (0.12 micromol. kg(-1). min(-1)), [d-Ala(7)]ANG-(1-7) (10 and 100 pmol/min), and a polyclonal ANG II antibody (0.08 mg/min) were infused intravenously alone or in combination. Combined blockade of AT(2) and AT((1-7)) receptors significantly increased the blood pressure of losartan-treated SHR (+15 +/- 1 mmHg; P < 0.01); this change did not differ from the blood pressure elevation produced by the sole blockade of AT((1-7)) receptors (15 +/- 4 mmHg). On the other hand, sole blockade of AT(2) receptors in losartan-treated SHR increased mean arterial pressure by 8 +/- 1 mmHg (P < 0.05 vs. 5% dextrose in water as vehicle), and this increase was less than the pressor response produced by blockade of AT((1-7)) receptors alone or combined blockade of AT((1-7)) and AT(2) receptors. The ANG II antibody increased blood pressure to the greatest extent in salt-depleted SHR pretreated with only losartan (+11 +/- 2 mmHg) and to the least extent in salt-depleted SHR previously treated with the combination of losartan, PD-123319, and [d-Ala(7)]ANG-(1-7) (+7 +/- 1 mmHg; P < 0.01). Losartan significantly increased heart rate, whereas other combinations of receptor antagonists or the ANG II antibody did not alter heart rate. Our results demonstrate that ANG II and ANG-(1-7) act through non-AT(1) receptors to oppose the vasoconstrictor actions of ANG II in salt-depleted SHR. Combined blockade of AT(2) and AT((1-7)) receptors and ANG II neutralization by the ANG II antibody reversed as much as 67% of the blood pressure-lowering effect of losartan.

Angiotensin I↗

PubMed2002

Vasopeptidase inhibition and Ang-(1-7) in the spontaneously hypertensive rat.

BACKGROUND: Omapatrilat, a new vasopeptidase inhibitor, inhibits the activity of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). Because these two enzymes participate in the degradation of the vasodilator and natriuretic peptide, angiotensin-(1-7) [Ang-(1-7)], we assessed whether omapatrilat treatment is associated with changes in the plasma and urinary excretion rates of the angiotensins. METHODS: We investigated in spontaneously hypertensive rats (SHR) (0.24 kg body weight) the effect of omapatrilat on plasma and urinary concentrations of angiotensin (Ang) I, Ang II and Ang-(1-7) during 17 days of administration of either the drug (N = 15, 100 micromol/kg/day) or vehicle (N = 14) in the drinking water. Hemodynamic and renal excretory function studies were associated with histological examination of the expression of Ang-(1-7) in the kidneys of both vehicle and omapatrilat-treated SHRs. RESULTS: Omapatrilat induced a sustained lowering of systolic blood pressure (-68 mm Hg) without changes in cardiac rate. The mild positive water balance produced by omapatrilat did not cause natriuresis or kaliuresis, although it was associated with a significant decrease in urine osmolality. Blood pressure normalization was accompanied by increases in plasma Ang I (2969%), Ang II (57%), and Ang-(1-7) (163%) levels, paralleling pronounced increases in urinary excretion rates of Ang I and Ang-(1-7) but not Ang II. Detection of Ang-(1-7) immunostaining in the kidneys of five other SHR exposed either to vehicle (N = 3) or omapatrilat (N = 2) ascertained the source of the Ang-(1-7) found in the urine. Intense Ang-(1-7) staining, more pronounced in omapatrilat-treated SHR, was found in renal proximal tubules throughout the outer and inner regions of the renal cortex and the thick ascending loop of Henle, whereas no Ang-(1-7)-positive immunostaining was found in glomeruli and distal tubules. CONCLUSIONS: Omapatrilat antihypertensive effects caused significant activation of the renin-angiotensin system associated with increases in urinary excretion rates of Ang I and Ang-(1-7). Combined studies of Ang-(1-7) metabolism in urine and immunohistochemical studies in the kidney revealed the existence of an intrarenal source, which may account for the pronounced increase in the excretion rate of the vasodilator heptapeptide. These findings provide further evidence for a contribution of Ang-(1-7) to the regulation of renal function and blood pressure.

Angiotensin I↗

PubMedDate not supplied

Angiotensin peptides as neurotransmitters/neuromodulators in the dorsomedial medulla.

1. The present review provides an update on evidence of the neurotransmitter pathways and location of receptors within the nucleus tractus solitarii (NTS) mediating the baroreflex and other haemodynamic actions of angiotensin (Ang) II. 2. A series of studies suggests a significant role for substance P in the acute cardiovascular and carotid sinus chemoreceptor facilitatory actions of AngII in the NTS. The use of antisense oligonucleotides to AT1 receptors indicates both pre- and post-synaptic AngII receptors are likely to be involved in these actions. 3. With respect to baroreceptor reflex actions, it is clear that endogenous AngII impairs the gain for operation of the baroreceptor reflex, because AT1 receptor antagonists facilitate reflex function. This effect is either independent of substance P or involves inhibition of release. Moreover, initial data obtained using antisense oligonucleotides to AT1 receptors suggest that, in the NTS, the effect of endogenous AngII on the baroreceptor reflex is mainly due to presynaptic actions on vagal or carotid sinus afferent fibres. In contrast, the level of endogenous AngII within the NTS appears to have variable effects on activation of cardiopulmonary vagal afferent fibres by phenylbiguanide. These results indicate a divergence of effects of AngII on reflexes evoked by these two different types of sensory input. 4. Use of transgenic rats with alterations in brain angiotensin peptides allowed us to assess the effect of long-term alterations in brain Ang peptides on reflex function. We studied (mRen2)27 transgenic rats (TGR(mRen2)) with high brain medulla AngII levels and transgenic rats with angiotensinogen (Aogen) antisense linked to glial fibrillary acidic protein promoter (TGR(ASrAogen)) with greatly reduced brain Aogen. The reflex evoked by activation of cardiac vagal chemosensitive afferent fibres was enhanced in TGR(ASrAogen), whereas the baroreceptor reflex control of heart rate was attenuated in TGR(mRen2), further confirming a divergence of effects of AngII on these two sensory modalities. 5. The overall results are consistent with a sustained inhibitory effect of AngII on the baroreceptor reflexes, with dose-dependent or activation-dependent effects on cardiac vagal afferent fibre activation. Moreover, alterations in substance P pathways may contribute to the actions of AngII on reflex function.

Angiotensin II↗