Increased production of angiotensin II in the adrenal gland of stroke-prone spontaneously hypertensive rats with malignant hypertension

Angiotensin(Ang) contents in the adrenal gland of stroke-prone spontaneously hypertensive rats(SHRSP) and age-matched Wistar Kyoto rats(WKY) were determined using reverse phase high performance liquid chromatography combined with a specific radioimmunoassay. In normotensive 5 wk-old SHRSP, the adrenal renin activity was about 3 times higher than that of age-matched WKY while the adrenal Ang I and Ang II concentrations did not differ from those of WKY. In the severely hypertensive 25 wk-old SHRSP, the adrenal Ang II and Ang I, and plasma aldosterone concentrations were about 5-fold, 2-fold and 4-fold, respectively, increased compared with levels in the WKY. In the 25 wk-old SHRSP 24 h after bilateral nephrectomy, the adrenal Ang II and plasma aldosterone levels were not decreased and were 10 and 3 times, respectively, higher than those of nephrectomized control WKY. Thus, the enhanced local generation of Ang II in the adrenal gland may contribute to the increased release of aldosterone in SHRSP with malignant hypertension.     

自发性高血压大鼠中枢血管紧张素Ⅱ的变化对中枢肾上腺素...

The content of norepinephrine (NE) and epinephrine (E) in the brain of spontaneously hypertensive rats has proved abnormal, but the cause remained unknown. It was shown in the recent work that NE content in pons, posterior hypothalamus, nucleus caudatus and E concentration in medulla oblongata, anterior and posterior hypothalamus of 12-week old stroke-prone spontaneously hypertensive rats (SHRSP) were much higher than those of age-matched Wister-Kyoto rats (WKY). SHRSP also showed higher levels of systolic blood pressure (SBP) and brain angiotensin II (A II) than WKY. Intracerebroventricular (icv) perfusion of angiotensin-converting enzyme inhibitor captopril (20 micrograms for each time and three times for each day for four weeks) inhibited the synthesis of brain A II and reduced SBP and NE, E contents in all examined brain areas in SHRSP and WKY. However, the effects of chronically perfused captopril on SBP and brain NE, E levels in SHRSP were much more significant than in WKY. The results indicate that the modulatory effects of central renin-angiotensin system (RAS) on central adrenergic and noradrenergic system might be overactivated in SHRSP, which might partially responsible for the abnormally high levels of NE, E in some of the brain areas of SHRSP.     

Relative biological activities of Asn1-,Val5-angiotensin II, Ile5-angiotensin II and Sar1-angiotensin II in man

Biological activities of asn1-,val5-angiotensin II (Hypertensin, Ciba, Asn1-,Val5-ANG II), ile5-angiotensin II (human angiotensin II, Ile5-ANG II) and sar1-angiotensin II (Sar1-ANG II) were compared in man. In 7 normal men 5 pmol/kg X min each of Asn1-,Val5-ANG II, Ile5-ANG II and Sar1-ANG II was infused iv from 0900 h to 0930 h at 1-week intervals. Average increments of blood pressure at the end of the infusions were 11/12, 23/20 and 36/30 mmHg, respectively (significant differences among the 3: P less than 0.001), average decrements of plasma renin activity were 0.30, 0.32 and 0.27 ng/ml X H, respectively (no significant difference among the 3), average increments of plasma aldosterone were 1.1, 2.3 and 4.4 ng/100 ml, respectively (significant difference between the former 2: P les than 0.001, between the latter 2: P less than 0.02), and durations of blood pressure rise after the cessation of these infusions (T) were 2-5 (average 5) min, 10-25 (average 20) min and 35-60 (average 40) min, respectively (significant difference between the former 2:less than P 0.01, between the latter 2: P less than 0.001). From these results it is evident that the pressor and steroidogenic actions of Ile5-ANG II are significantly stronger than those of Asn1-,Val5-ANG II and that the duration of pressor action of the former is much longer than that of the latter. Therefore, when the activities of angiotensin II (ANG II) derivatives are compared with those of ANG II in man, Ile5-ANG II--natural human ANG II--should always be used instead of Asn1-,Val5-ANG II. The pressor and steroidogenic actions and T of Sar1-ANG II are significantly stronger or longer than those of Ile5-ANG II. The reason for this is thought to be that Sar1-ANG II is bound tightly to the vascular and adrenal ANG II receptors and is not readily metabolized.     

Decreased angiotensin II binding affinity and binding capacity in the anterior pituitary gland of adult spontaneously hypertensive rats

Angiotensin II (ANG) binding sites were quantified in single pituitary glands from 4-week-old and 14-week-old male spontaneously hypertensive rats (SHR) and age-matched male normotensive Wistar-Kyoto (WKY) control rats after incubation with 125I-[Sar1]-ANG, autoradiography with computerized densitometry, and comparison to 125I-standards. The maximum binding capacity (Bmax) decreased while the dissociation constant (Kd) for ANG increased in 14-week-old SHR when compared to age-matched WKY control rats (Bmax: 265 +/- 9 and 224 +/- 4 fmol/mg protein; Kd: 0.79 +/- 0.04 and 1.14 +/- 0.08 10(-9) M in WKY and SHR, respectively). Conversely, no difference between rat strains was found in 4-week-old animals. Our results suggest that pituitary ANG binding sites may play a role in the pathophysiology of established genetic hypertension.     

Immunocytochemical and biochemical identification of angiotensin II in human nasal tissue

Angiotensin II (ANG II) was identified immunocytochemically and biochemically in biopsy samples of human nasal tissue. Staining for ANG II was predominantly found in structures similar to a string of pearls with consecutive short varicose areas, which is characteristic for neuronal tissue. The localization of ANG II in neurons was confirmed by positive staining of adjacent tissue sections with a specific antibody to neurofilament or doublestaining with both antibodies in one section. Likewise, ANG II-like material was also determined radioimmunologically in nasal tissue extracts. The concentrations of ANG II varied form 1.28 to 332.78 fmol/g wet tissue weight with an average concentration of 79.61+/-44.09 fmol ANG II/g wet tissue weight (mean+/-SEM, n=7). The ANG II-immunoreactive material was further characterized biochemically by HPLC on a reversed phase C(18) column in an acetonitrile and methanol gradient as Ile(5)-ANG II and ANG II metabolites such as Ile(4)-ANG III, Ile(3)-ANG II(3-8)hexapeptide and Ile(2)-ANG II(4-8)pentapeptide.     

Central ventilatory and cardiovascular actions of angiotensin peptides in trout

In the brains of teleosts, angiotensin II (ANG II), one of the main effector peptides of the renin-angiotensin system, is implicated in various physiological functions notably body fluid and electrolyte homeostasis and cardiovascular regulation, but nothing is known regarding the potential action of ANG II and other angiotensin derivatives on ventilation. Consequently, the goal of the present study was to determine possible ventilatory and cardiovascular effects of intracerebroventricular injection of picomole doses (5-100 pmol) of trout [Asn(1)]-ANG II, [Asp(1)]-ANG II, ANG III, ANG IV, and ANG 1-7 into the third ventricle of unanesthetized trout. The central actions of these peptides were also compared with their ventilatory and cardiovascular actions when injected peripherally. Finally, we examined the presence of [Asn(1)]-ANG II, [Asp(1)]-ANG II, ANG III, and ANG IV in the brain and plasma using radioimmunoassay coupled with high-performance liquid chromatography. After intracerebroventricular injection, [Asn(1)]-ANG II and [Asp(1)]-ANG II two ANG IIs, elevated the total ventilation through a selective stimulatory action on the ventilation amplitude. However, the hyperventilatory effect of [Asn(1)]-ANG II was threefold higher than the effect of [Asp(1)]-ANG II at the 50-pmol dose. ANG III, ANG IV, and ANG 1-7 were without effect. In addition, ANG IIs and ANG III increased dorsal aortic blood pressure (P(DA)) and heart rate (HR). After intra-arterial injections, none of the ANG II peptides affected the ventilation but [Asn(1)]-ANG II, [Asp(1)]-ANG II, and ANG III elevated P(DA) (50 pmol: +80%, +58% and +48%, respectively) without significant decrease in HR. In brain tissue, comparable amounts of [Asn(1)]-ANG II and [Asp(1)]-ANG II were detected (ca. 40 fmol/mg brain tissue), but ANG III was not detected, and the amount of ANG IV was about eightfold lower than the content of the ANG IIs. In plasma, ANG IIs were also the major angiotensins (ca. 110 fmol/ml plasma), while significant but lower amounts of ANG III and ANG IV were present in plasma. In conclusion, our study suggests that the two ANG II isoforms produced within the brain may act as a neurotransmitter and/or neuromodulator to regulate the cardioventilatory functions in trout. In the periphery, two ANG IIs and their COOH-terminal peptides may act as a circulating hormone preferentially involved in cardiovascular regulations.     

Agonistic activities of isoleucine8-angiotensin II in man

In order to clarify the importance of C-terminal phenylalanine in angiotensin II (ANG II) molecule, agonistic activities of a C-terminal substituted peptide, isoleucine8-angiotensin II (Ile8-ANG II), were studied in comparison with those of sarcosine1-, isoleucine8-angiotensin II (Sar1-, Ile8-ANG II) and isoleucine5-angiotensin II (Ile5-ANG II) in 5 normal men. When infused iv at a rate of 600 pmol/kg X min for 30 min, Ile8-ANG II and Sar1-, Ile8-ANG II raised the blood pressure to the same extent (15/15 mmHg on the average), while the average blood pressure increase was 21/21 mmHg after an iv infusion of Ile5-ANG II at a rate of 5 pmol/kg X min for 30 min. Duration of the pressor action after the cessation of each infusion was 50-90, 90-120 and 10-25 min, respectively. In each case plasma renin activity (PRA) decreased and plasma aldosterone (PA) increased. When infused iv at a rate of 10 pmol/kg X min (maximum non-pressor dose) for 120 min, both Ile8-ANG II and Sar1-, Ile8-ANG II lowered PRA and increased PA gradually, but 100 mg oral captopril given immediately before these infusions caused no significant increase in PRA or no significant decrease in PA but again a decrease in PRA and an increase in PA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sympathetic hyperreactivity to air-jet stress in the chromosome 1 blood pressure quantitative trait locus congenic rats

A chromosome 1 blood pressure quantitative trait locus (QTL) was introgressed from the stroke-prone spontaneously hypertensive rats (SHRSP) to Wistar-Kyoto (WKY) rats. This congenic strain (WKYpch1.0) showed an exaggerated pressor response to both restraint and cold stress. In this study, we evaluated cardiovascular and sympathetic response to an air-jet stress and also examined the role of the brain renin-angiotensin system (RAS) in the stress response of WKYpch1.0. We measured mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to air-jet stress in WKYpch1.0, WKY, and SHRSP. We also examined effects of intracerebroventricular administration of candesartan, an ANG II type 1 receptor blocker, on MAP and HR responses to air-jet stress. Baseline MAP in the WKYpch1.0 and WKY rats were comparable, while it was lower than that in SHRSP rats. Baseline HR did not differ among the strains. In WKYpch1.0, air-jet stress caused greater increase in MAP and RSNA than in WKY. The increase in RSNA was as large as that in SHRSP, whereas the increase in MAP was smaller than in SHRSP. Intracerebroventricular injection of a nondepressor dose of candesartan inhibited the stress-induced pressor response to a greater extent in WKYpch1.0 than in WKY. Intravenous injection of phenylephrine caused a presser effect comparable between WKYpch1.0 and WKY. These results suggest that the chromosome 1 blood pressure QTL congenic rat has a sympathetic hyperreactivity to an air-jet stress, which causes exaggerated pressor responses. The exaggerated response is at least partly mediated by the brain RAS.     

Angiotensin stimulates oxytocin release

A sensitive and specific radioimmunoassay for oxytocin (OT) was developed to study the effect of angiotensin II (ANG II) upon neurohypophyseal OT release in conscious rats. ANG II injected into the lateral cerebral ventricle (i.c.v.) produced within 60 seconds a steep increase in plasma OT concentration from a control value of 10.46 ± 1.35 fmol/ml to 88.95 ± 5.06 fmol/ml and 119.56 ± 11.46 fmol/ml following 10 and 100 ng i.c.v. ANG II, respectively. Inhibition of OT release by simultaneous application of the ANG II antagonist {Sar¹, Ile⁸}-ANG II suggests that ANG II acted via specific angiotensin receptors in the brain.     

Nerve stimulation induced overflow of neuropeptide Y and modulation by angiotensin II in spontaneously hypertensive rats

The sympathetic nervous system and renin-angiotensin system are both thought to contribute to the development and maintenance of hypertension in experimental models such as the spontaneously hypertensive rat (SHR). We demonstrated that periarterial nerve stimulation (NS) increased the perfusion pressure (PP) and neuropeptide Y (NPY) overflow from perfused mesenteric arterial beds of SHRs at 4-6, 10-12, and 18-20 wk of age, which correspond to prehypertensive, developing hypertensive, and maintained hypertensive stages, respectively, in the SHR. NS also increased PP and NPY overflow from mesenteric beds of Wistar-Kyoto (WKY) normotensive rats. NS-induced increases in PP and NPY were greater in vessels obtained from SHRs of all three ages compared with WKY rats. ANG II produced a greater increase in PP in preparations taken from SHRs than WKY rats. ANG II also resulted in a greater increase in basal NPY overflow from 10- to 12-wk-old and 18- to 20-wk-old SHRs than age-matched WKY rats. ANG II enhanced the NS-induced overflow of NPY from SHR preparations more than WKY controls at all ages studied. The enhancement of NS-induced NPY overflow by ANG II was blocked by the AT1 receptor antagonist EMD-66684 and the angiotensin type 2 receptor antagonist PD-123319. In contrast, ANG II greatly enhanced norepinephrine overflow in the presence of PD-123319. Both captopril and EMD-66684 decreased neurotransmitter overflow from SHR mesenteric beds; therefore, we conclude that an endogenous renin-angiotensin system is active in this preparation. It is concluded that the ANG II-induced enhancement of sympathetic nerve stimulation may contribute to the development and maintenance of hypertension in the SHR.     

Metabolism of Angiotensin Peptides by Neuronal and Glial Cultures from Rat Brain

The degradation pattern and rate of [Ile5]-Angiotensin (Ang) I, II, and III were studied in neuron-enriched and glia-enriched cells in primary cultures from rat brain. Metabolites were separated by HPLC, and their identities were evaluated by comparison of their retention times with those of synthetic Ang peptide fragments and by analysis of their amino acid composition. Major metabolites were identified as des-Asp1-[Ile5]-Ang I, des-Asp1-[Ile5]-Ang II, [Ile5]-Ang II (3-8) hexapeptide, [Ile5]-Ang II (4-8) pentapeptide, and [Ile5]-Ang II (5-8) tetrapeptide. Glia-enriched cells degraded [Ile5]-Ang I and [Ile5]-Ang III significantly faster than neuron-enriched cells, whereas no difference between the two types of cells was found in the degradation rate of [Ile5]-Ang II. Although the half-lives of [Ile5]-Ang I and [Ile5]-Ang III in neuron-enriched cells from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were not significantly different, neuron-enriched cultures from WKY rats metabolized [Ile5]-Ang II about 2.6 times faster than neuron-enriched cells derived from SHR.     

Sar1Ile7]angiotensin III, a new selective antagonist of the pressor effect of angiotensin III in conscious rats

Two analogues of angiotensin III were compared as antagonists of the pressor response to angiotensin II (ANG II) and angiotensin III (ANG III) in conscious, unrestrained rats. Dose-mean arterial pressure (MAP) response curves were obtained for ANG II and ANG III in the absence or presence of [Ile7]ANG III (1.3 x 10(-7) mol/kg) or [Sar1 Ile7]ANG III (1.2 x 10(-7) mol/kg). In the presence of [Ile7]ANG III, the dose-MAP response curves for ANG II and ANG III were significantly displaced to the right. [Ile7]ANG III behaved as a partial agonist on ANG II but not ANG III receptors. In the presence of [Sar1 Ile7]ANG III, the dose-MAP response curve for ANG III but not ANG II was significantly displaced to the right. This suggests that [Sar1 Ile7]ANG III is a selective antagonist of ANG III in the vasculature. [Ile7]ANG III, on the other hand, antagonizes both ANG II and ANG III receptors. Our results support the hypothesis of the existence of a sub-class of angiotensin receptors activated by ANG III in the vascular smooth muscle.     

Comparative studies on the extractability of collagen from aortas of stroke-prone spontaneously hypertensive and normotensive rats.

The molecular states of collagen in the aortas of age-matched stroke-prone spontaneously hypertensive (SHRSP) and normotensive Wistar Kyoto rats (WKY) were studied by analyzing its extractability under defined conditions. The monomeric and oligomeric collagen extractable with 0.5 M acetic acid/6 M urea from aortic homogenates of 9-month-old SHRSP and WKY comprised approx. 0.6 and 2.0%, respectively, of the total collagen. On incubation of the acetic acid/urea-extracted residues with pepsin at 4 degrees C, the levels of the collagen alpha 1(I) and alpha 2(I) chains solubilized from the SHRSP residues were both less than 50% of those from the WKY residues. When the residues were incubated with pepsin at 15 or 25 degrees C, the differences became smaller. When the acetic acid/urea residues were hydrolyzed with cyanogen bromide, nearly identical peptide maps were obtained for SHRSP and WKY. The aortas from 2-month-old SHRSP and WKY contained much larger proportions of acid/urea-extractable collagen than those of the older rats (8.2 and 13% of the respective total collagen). The levels of the alpha 1(I) and alpha 2(I) chains solubilizable from the respective residues by pepsin at 4 degrees C were similar to each other. These results indicate that aortic collagen fibrils in SHRSP are stiffened more prominently than those in WKY.     

Differential Signal Transduction Efficacy and Biological Activity of Triprolyl and Pentasarcosyl Angiotensin II In Adrenal Cortex and Vascular Smooth Muscle

Abstract

Two synthetic analogues of angiotensin II (ANG II) with an extended N-terminus, (Sar)₅-ANG II and (Pro)₃-ANG II, have been tested in vitro for their ability to bind to ANG II receptors, to raise cytosolic free calcium concentration, (Ca⁺⁺]_i, and to induce a biological response in bovine adrenal zona glomerulosa cells and in cultured rat aortic smooth muscle cells. The results indicate that the two analogues did not behave identically In these two target cells for ANG II. On one hand, in the adrenal cortex, (Sar)₅-ANG II and (Pro)₃-ANG II were very weak agonists and (Sar)₅-ANG II could even be used as an antagonist of ANG II-induced aldosterone production. On the other hand, both peptides were almost as potent as ANG II in vascular smooth muscle cells, with respect to signal messenger generation and prostacyclin synthesis. Such peptides may be useful tools in the elucidation of the differences among ANG II receptors from various target tissues.     

Central hypertensive actions of angiotensin I, II and III in conscious rats

The effects of intracerebroventricular administrations of three natural angiotensins, angiotensin I (ANG I 3.8 X 10-11-9.4 X10-10 mol/kg body weight), II (9.6 X 10-12-2.4 X 10-10 mol/kg body weight) and III (2.7 X 10-10 2.5 X 10-9 mol/kg body weight) on systemic blood pressure were investigated in conscious rats. Angiotensin II (ANG II), ANG I and angiotensin III (ANG III), increased blood pressure in a dose-related manner. The order of potency of angiotensins was ANG II greater than ANG I greater than ANG III. The intraventricular administration of a converting enzyme inhibitor (SQ 14225, 6.9 X10-8 mol/kg) abolished the central effect of ANG I, while an angiotensin II analogue ([Sar1-Ala8]ANG II, 1.1 X 10-8 mol/kg) administered intraventricularly inhibited the central pressor effects of these three angiotensins. These results suggest that ANG II is a main mediator of the renin-angiotensin system in the central nervous system.     

Biological activities of angiotensin II-(1-6)-hexapeptide and angiotensin II-(1-7)-heptapeptide in man

Biological activities of angiotensin II-(1-6)-hexapeptide [ANG-(1-6)] and angiotensin II-(1-7)-heptapeptide [ANG-(1-7)] were studied in 5 normal men and 3 patients with Bartter's syndrome. The angiotensins were infused iv in each subject from 0900 h to 0915 h at a rate of 21 nmol(16.8 micrograms)/kg X min and 18 nmol(16.2 micrograms)/kg X min for ANG-(1-6) and ANG-(1-7), respectively. In the normal men a significant rise in blood pressure was observed by the infusions of both peptides. Average increments of blood pressure for ANG-(1-6) were 17/14, 23/18, 22/15 and 17/14 mmHg at 2, 5, 10 and 15 min, respectively, and those for ANG-(1-7) were 19/15, 20/17, 13/13 and 15/13 mmHg at 2, 5, 10 and 15 min, respectively. The duration of pressor actions after the cessation of the infusions (T) was 10 min for ANG-(1-6) and 20 (for systolic) and 30 (for diastolic) min for ANG-(1-7). T for ANG-(1-6) was shorter than and T for ANG-(1-7) was similar to T for Ile5-angiotensin II (Ile5-ANG II) reported previously in 7 normal men 5 of whom were the same as examined in the present study. On the other hand, both peptides did not cause a rise in blood pressure in the 3 patients with Bartter's syndrome. Both angiotensins did not cause an increase in plasma aldosterone but did cause a significant decrease in plasma renin activity both in the normal men and in the patients. From these results and our previous observations of inactivity of angiotensin II-(5-8)-tetrapeptide, a pressor action of angiotensin II-(4-8)-pentapeptide, and pressor, renin-suppressing and steroidogenic actions of angiotensin II-(3-8)-hexapeptide in normal men, it is thought that ANG-(1-6) and ANG-(1-7) are bound to angiotensin II (ANG II) receptor in the peripheral arterioles and show pressor actions (less than 0.024% and less than 0.028% of Ile5-ANG II, respectively) and suppress renin mainly via short loop feedback and that the shortest biologically active ANG II molecules for pressor, renin-suppressing and steroidogenic actions are Tyr-Ile-His, Val-Tyr-Ile-His and Val-Tyr-Ile-His-Pro-Phe, respectively, in man. It is also evident that ANG-(1-6) is more rapidly metabolized than ANG-(1-7) or Ile5-ANG II in man.     

Angiotensin stimulates respiration in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) have an activated brain angiotensin system. We hypothesized 1) that ventilation (V) would be greater in conscious SHR than in control Wistar-Kyoto (WKY) rats and 2) that intravenous infusion of the ANG II-receptor blocker saralasin would depress respiration in SHR, but not in WKY. Respiration and oxygen consumption (VO(2)) were measured in conscious aged-matched groups (n = 16) of adult female SHR and WKY. For protocol 1, rats were habituated to a plethysmograph and measurements obtained over 60-75 min. After installation of chronic intravenous catheters, protocol 2 consisted of 30 min of saline infusion ( approximately 14 microliter. kg(-1). min(-1)) followed by 40 min of saralasin (1.3 microgram. kg(-1). min(-1)). V, tidal volume (VT), inspiratory flow [VT/inspiratory time (TI)], breath expiratory time, and VO(2) were higher, and breath TI was lower in "continuously quiet" SHR. In SHR, but not in WKY rats, ANG II-receptor block decreased V, VT, and VT/TI and increased breath TI. During ANG II-receptor block, an average decrease in VO(2) in SHR was not significant. About one-half of the higher V in SHR appears to be accounted for by an ANG II mechanism acting either via peripheral arterial receptors or circumventricular organs.     

Abnormal renal medullary response to angiotensin II in SHR is corrected by long-term enalapril treatment

This study tested the hypotheses that renal medullary blood flow (MBF) in spontaneously hypertensive rats (SHR) has enhanced responsiveness to angiotensin (ANG) II and that long-term treatment with enalapril can correct this. MBF, measured by laser Doppler flowmetry in anesthetized rats, was not altered significantly by ANG II in Wistar-Kyoto (WKY) rats, but was reduced dose dependently (25% at 50 ng. kg(-1). min(-1)) in SHR. Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) into the renal medulla unmasked ANG II sensitivity in WKY rats while L-arginine given into the renal medulla abolished the responses to ANG II in SHR. In 18- to 19-wk-old SHR treated with enalapril (25 mg. kg(-1). day(-1) when 4 to 14 wk old), ANG II did not alter MBF significantly, but sensitivity to ANG II was unmasked after L-NAME was infused into the renal medulla. Endothelium-dependent vasodilation (assessed with aortic rings) was significantly greater in treated SHR when compared with that in control SHR. These results indicate that MBF in SHR is sensitive to low-dose ANG II and suggest that this effect may be due to an impaired counterregulatory effect of nitric oxide. Long-term treatment with enalapril improves endothelium-dependent vascular relaxation and decreases the sensitivity of MBF to ANG II. These effects may be causally related to the persistent antihypertensive action of enalapril in SHR.     

Vascular receptors for angiotensin, vasopressin, and atrial natriuretic peptide in experimental hypertension

Angiotensin II (ANG II) and vasopressin (AVP) are two powerful vasoconstrictors, and atrial natriuretic peptide (ANP) is a potent vasorelaxant. The changes in the density or affinity of binding sites for these agents that may alter target organ responsiveness in hypertension are reviewed. ANG II binding in mesenteric arteries was unaltered in one-kidney, one-clip (1-K, 1-C) and in 2-K, 1-C hypertensive rats, while in deoxycorticosterone acetate (DOCA)-salt hypertensive rats ANG II binding to blood vessels was significantly increased. A role of mineralocorticoids to increase the number of vascular ANG II sites in some hypertensive models is suggested. In spontaneously hypertensive rats (SHR) ANG II receptors were increased in young rats in the prehypertensive stage with respect to Wistar-Kyoto (WKY) control rats, but normal in older rats. AVP binding in the vasculature of hypertensive rats was uniformly decreased in inverse correlation to plasma AVP levels, but vascular responsiveness to AVP was exaggerated. Inositol trisphosphate production by blood vessels of SHR in response to AVP showed that increased AVP receptor-coupled phospholipase C activity may mediate in part the exaggerated pressor response in spite of reduced or normal density of receptors for vasoconstrictor peptides. Vascular ANP sites in 2-K, 1-C, 1-K,1-C, and DOCA-salt hypertensive rats varied inversely with plasma concentrations of ANP. Normal densities of ANP receptors in saralasin-sensitive 2-K, 1-C hypertensive rats correlated with ANP sensitivity, while saralasin-insensitive 2-K, 1-C hypertensive rats, which did not respond to ANP, had significantly decreased density of ANP vascular receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin-(1-7) attenuates the chronotropic response to angiotensin II via stimulation of PTEN in the spontaneously hypertensive rat neurons

Several studies have focused on the beneficial effects of peripheral angiotensin-(1-7) [Ang-(1-7)] in the regulation of cardiovascular function, showing its counterregulatory effect against the actions of angiotensin II (ANG II). However, its actions in the central nervous system are not completely understood. In the present study, we investigated the intracellular mechanisms underlying the action of ANG-(1-7) using the patch-clamp technique in neurons cultured from the hypothalamus of neonatal spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Superfusion of neurons with ANG II (100 nM) significantly increased neuronal firing in both strains of rats, and this chronotropic effect of ANG II was significantly enhanced in prehypertensive SHR neurons compared with WKY rat neurons. The enhanced chronotropic effect of ANG II was attenuated by a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY 294002 (10 μM). Superfusion of neurons with ANG-(1-7) (100 nM) did not alter the neuronal firing rate in either SHR or WKY neurons; however, it significantly attenuated the chronotropic action of ANG II exclusively in prehypertensive SHR neurons. This counterregulatory effect of ANG-(1-7) on ANG II action in prehypertensive SHR neurons was attenuated by cotreatment with either A-779, a Mas receptor antagonist, or bisperoxovanadium, a phosphatase and tensin homologue deleted on chromosome ten (PTEN) inhibitor. In addition, incubation of WKY and prehypertensive SHR neurons with ANG-(1-7) significantly increased PTEN activity. The data demonstrate that ANG-(1-7) counterregulates the chronotropic action of ANG II via a PTEN-dependent signaling pathway in prehypertensive SHR neurons.