Cardiovascular and renal effects of intracerebroventricular angiotensin II in conscious sheep.

Effects on systemic and pulmonary haemodynamics, renal electrolyte excretion, and plasma concentration of vasopressin, catecholamines, electrolytes and proteins in response to intracerebroventricular infusions of [Val5]-angiotensin II (ANG II) at 1, 2 and 4 pmol kg-1 min-1 in isotonic saline for 30 min were studied in conscious sheep (n = 6). Vehicle control infusions were performed in four of the animals. All three doses of ANG II were expected to increase CFS concentration of the peptide above physiological levels. All ANG II infusions were noticed to be dipsogenic, but the animals were not allowed to drink freely until at the end of the experiments (at 120 min post-infusion). The systemic arterial blood pressure increased significantly only in response to 2 and 4 pmol kg-1 min-1, concomitant with an increase of the systemic vascular resistance, whereas the cardiac output and heart rate remained unchanged. The central venous pressure increased only after administration of the highest ANG II dose, while pulmonary artery, and capillary wedge pressures were unaffected during all experiments. The plasma protein and K concentration fell in response to ANG II administration. Also here, the effects were significant only at 2 and 4 pmol kg-1 min-1. The plasma levels of vasopressin, noradrenaline, adrenaline and dopamine did not change significantly in response to any of the infusions. The renal Na excretion increased by 100-400%, but not in a strictly dose-dependent manner. Much smaller and more variable effects were seen on the renal K excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intracerebroventricular angiotensin II increases tolerance to blood loss in conscious sheep

Intracerebroventricular (i.c.v.) infusion of hypertonic NaCl improves the tolerance to haemorrhage in sheep. Since i.c.v. angiotensin II (ANG II) shares many of the effects of hypertonic NaCl on fluid balance control and blood pressure, we aimed to determine whether i.c.v. ANG II would also be effective in that regard. Six adult conscious ewes were bled from the jugular vein until the mean arterial pressure suddenly dropped to between 45 and 50 mmHg, during an i.c.v. infusion of ANG II (2 pmol kg^-1 min^-1) which commenced 30 min prior to start of blood removal and continued until end of retransfusion about 80 min after haemorrhage. A corresponding haemorrhage in the same animals during an i.c.v. infusion of 0.9% NaCl served as controls. Significantly more blood had to be withdrawn to induce hypotension when ANG II was given i.c.v. (22.3±1.8 vs. 12.6±1.2 mL kg^-1). The degree of hypotension and the recovery rate of the blood pressure did not differ between the experiments. The increased tolerance to blood loss by ANG II i.c.v. was accompanied by a reinforced elevation of the systemic vascular resistance and a larger decline of the cardiac output. The plasma norepinephrine concentration was significantly increased immediately after haemorrhage during i.c.v. ANG II, but not in control experiments. The overall vasopressin response to the hypotensive blood loss was not affected by ANG II, but high plasma levels were obtained already during the non-hypotensive stage of haemorrhage. The i.c.v. infusion of ANG II caused a significant lowering of the plasma protein concentration before start of bleeding and accentuated the haemodilution caused by the haemorrhage. We conclude that central administration of ANG II increases the tolerance to haemorrhage in sheep but with concomitant haemodynamic changes which appear unfavourable regarding cardiac load and tissue perfusion.     

Hypertension and thirst outlasting renal vasoconstriction as effects of a brief elevation of systemic angiotensin II in sheep

The influence of 10 min intracarotid (i.e.) and intravenous (i.v.) infusions of angiotensin II (Ang II; 20 pmol kg^-1 min^-1) on carotid blood pressure (cBP) and renal blood flow (RBF) was studied in unanaesthetized ewes without and with pre-treatment with the α₁-and β-adrenoceptor blocker labetalol. RBF was also monitored during 30 min intracerebroventricular (ICV) infusions of Ang II at 2 pmol kg^-1 min^-1. The i.e. infusions of Ang II induced about 50 mmHg rise in cBP. A steep decline occurred during 5 min post-infusion, followed by a much slower reduction with the cBP remaining above control level at 40 min post-infusion. The pressure elevation induced by i.v. Ang II was less pronounced but exhibited a similar pattern. Labetalol significantly reduced the pressor response to i.e. as well as i.v. Ang II. The i.e. and i.v. infusions of Ang II conspicuously reduced the RBF regardless of whether the ewes were labetalol-treated or not. At 5 min after the infusions RBF had returned to control level. The ICV infusions did not influence the RBF. Ang II i.e. elicited thirst in 50% of the ewes with the urge to drink remaining at 40 min post-infusion. The dipsogenic response was not reduced by labetalol pre-treatment. The results imply that no cerebral component contributes to the reduction in RBF induced by systemic Ang II. However, a centrally mediated action seems to be the cause of the long-lasting post-infusion cBP elevation and dipsogenic response. It suggests that, once bound at brain sites, Ang II may have a sustained action, alternatively may initiate cerebral processes of long duration.     

Effects of losartan,prazosin and a vasopressin V1‐receptor antagonist on renal and femoral blood flow in conscious sheep

The regulation of blood flow to different organs is determined by the autonomic nervous system and systemic and/or local vasoactive substances. Although the cardiovascular effects of the renin‐angiotensin system (RAS), the sympathoadrenal system and vasopressin (AVP) have been thoroughly studied, there are relatively few investigations on these systems with concomitant measurements of systemic haemodynamics and regional blood flow in conscious unstressed individuals. We therefore studied effects of pharmacological blockade of AVP V₁‐, angiotensin II (ANG II) AT₁‐and adrenergic α‐receptors on central and regional (renal and femoral blood flow) haemodynamics in adult conscious ewes. Eight adult cross‐bred ewes were chronically intrumented with peri‐vascular ultrasonic flow probes implanted unilaterally around the renal and the femoral artery. While standing in their habitual environment, systemic and regional haemodynamics were measured before and after the following treatments as single intravenous injections. Animals in group A (n=6) were given isotonic saline (NaCl) followed by the AT₁‐receptor blocker losartan (LOS, 10 mg kg^–1) 30 min later; group B (n=6) animals were given the α‐adrenoceptor blocker prazosin (PRAZ, 0.2 mg kg^–1); and group C (n=6) the vasopressin V₁ receptor antagonist [d(CH₂)₅Tyr(Me)AVP] (AVP‐a, 10 μg kg^–1). PRAZ reduced mean arterial pressure (MAP) by 11% concomitant with an increase in heart rate (HR) (32%), whereas the other substances where without effect on those variables. Femoral blood flow (FBF) was enhanced (increased by 82%) by injection of PRAZ only. Administration of LOS increased the renal blood flow (RBF) by 11% while the other drugs were without effect on that parameter. We conclude that basal renal vascular tone in conscious unstressed sheep is dependent on angiotensinergic mechanism and that blockade of this influence causes a local increase in flow without concomitant effects on systemic haemodynamics.     

Cardiovascular and adrenal sensitivity to angiotensin II in essential hypertension

Summary Regulation of aldosterone secretion by sodium chloride is impaired in a group of essential hypertensives: high-salt diet fails to suppress aldosterone in these patients despite low renin values. The mechanism of this impaired regulation of aldosterone has not been clarified so far. We tested the sensitivity of aldosterone secretion and blood pressure to A II in 20 normotensive controls (aged 20–60, MAP 92±3 mm Hg), in ten normotensives with one or two parents with hypertension, and in 21 patients with essential hypertension (aged 17–65, MAP 119±4 mm Hg). After a period of 6 days on high-salt intake (300–320 mEq Na⁺/day), A II (0.1, 0.5, 1.0 and 2.0 ng/kg/min) was infused, each concentration for 30 min. According to aldosterone excretion during sodium loading, patients were divided into group A with complete suppression (n=12, aldosterone excretion 3.6±0.4 µg/day) and in group B with insufficient suppression (n=9, aldosterone excretion 15.5±2.3 µg/day). Despite similarly low plasma renins, rise of serum aldosterone levels during A II infusion was significantly higher in group B patients than in group A patients and normotensive controls. Rise in mean arterial blood pressure, however, brought about by graded A II infusion was similar in both groups of hypertensives and in normotensive controls. The results demonstrate an increased adrenal sensitivity to A II in a subgroup of essential hypertensives only. A similar adrenal hypersensitivity to A II found by others in patients with hyperaldosteronism due to adrenal hyperplasia supports the hypothesis that the same mechanism underlies both disorders.Abbreviations MAP mean arterial blood pressure - A II Angiotensin II Dedicated to Prof. Dr. W. Kaufmann on the occasion of his 60^th birthday     

Tolerance to haemorrhage during vasopressin antagonism and/or captopril treatment in conscious sheep

The effect of separate and combined blockade of vasopressin (AVP) V₁-receptors and angiotensin II formation on resistance to a slow venous haemorrhage (0.7 ml kg^-1 min^-1) was studied in six conscious adult sheep by bleeding to the point of an abrupt fall in the mean systemic arterial pressure (MSAP). Intravenous administration of the V₁-receptor antagonist [d(CH₂)₅Tyr(Me)AVP] (10 μg kg^-1) and/or the angiotensin I converting enzyme inhibitor captopril (20 mg+1 mg h^-1) did not cause any significant haemodynamic changes in the normovolaemic animal. The volume of haemorrhage necessary to induce acute hypotension (MSAP < 50 mmHg) was significantly smaller after AVP blockade alone (13.8±0.7 ml kg^-1; P < 0.01) but not after captopril treatment (14.7±1.6 ml kg^-1; n.s.) compared to control animals receiving no drug treatment (16.8±0.6 ml kg^-1). The combined treatment with the AVP antagonist and captopril caused a further decrease in tolerance to haemorrhage (9.4±1.2 ml kg^-1; P < 0.001). Blockade of AVP V₁-receptors was associated with an attenuated increase in systemic vascular resistance immediately after the end of haemorrhage, concomitant with an accentuated lowering of the central venous pressure. In contrast, captopril treatment decreased the degree of vasoconstriction mainly during the second half of the post-haemorrhage observation period of 1 hour. It is concluded that both AVP and angiotensin II contribute to the maintenance of the MSAP during haemorrhage in conscious sheep. During the spontaneous recovery after hypotensive blood loss, a vasoconstrictor effect of AVP is evident mainly during the initial 15 min, whereas at later stages angiotensin II appears to be of relatively greater importance.     

Genetic deletion and overexpression of angiotensin II receptors

Angiotensin II receptors are essential components of the renin-angiotensin system transducing angiotensin II mediated signals across the plasma membrane of many cell types in the cardiovascular system. To date, three subtypes of angiotensin II receptors have been identified by molecular cloning, termed angiotensin II type 1 (AT_1A, AT_1B) and type 2 (AT₂) receptors. This review focuses on recent transgenic animal models which have been generated to study the in vivo significance of angiotensin receptor diversity. AT_1A receptors are the major blood pressure regulators and have a potent growth-stimulatory effect on cardiac myocytes in vivo. The AT_1B receptor subtype may participate in the control of vascular tone if AT_1A receptors are absent. AT₂ receptors are abundantly expressed during embryonic development and may also play a role in blood pressure regulation by influencing vascular development and differentiation. Received: 16 February 1998 / Accepted: 10 August 1998     

Lactation affects pressor,volumetric and natriuretic responses to angiotensin II in goats

Demands on cardiovascular function and fluid turnover increase during lactation and pregnancy in the goat, but the hormonal status is different. This study is aimed at investigating the effects of hypertensive angiotensin II (ANGII) in lactating goats. The results were compared with those of pregnancy and control conditions. ANGII (0.5 pg min^-1) was infused intravenously for 60 min (n = 6). The rise in blood pressure in response to ANGII was attenuated during lactation as in pregnancy (P < 0.001 vs control period). ANGII caused reflex bradycardia. Plasma protein concentration decreased by 7.5% during infusions in lactating goats (pregnancy: 9%; control period: 4.5%). Renal Na excretion increased by 260% (lactation), by 400% (pregnancy; n.s. vs. lactation), and by 800% (control period; P < 0.01 vs. lactation). The glomerular filtration rate was unchanged during ANGII infusions in lactating animals, but increased in the other periods. Effective renal plasma flow decreased. ANGII raised aldosterone from < 34.5 pmol 1^--¹ to 539 ± 80 pmol l^-1 (lactation) and to 428 ± 41 pmol l^-1 (control; P < 0.05 vs. lactation), and from 72 ± 9 to 651 ± 103 pmol l^-1 (pregnancy; P < 0.01 vs. lactation). Plasma progesterone was undetectable during lactation, but varied from 0 to 17 nmol l^-1 during control conditions and was 16 ± 1 nmol l^-1 during pregnancy. Oestradiol 17β was 181± 22 pmol l^-1 in pregnant goats, and undetectable in lactating animals. In conclusion, lactation affects ANGII-induced changes in cardiovascular and fluid regulation, but in this period the effects were not related to progesterone or oestradiol 17 β.     

血管紧张素Ⅱ受体拮抗剂对高血压肾小动脉重建的影响

目的:研究血管紧张素II(AngII)受体拮抗剂对高血压肾小动脉重建的影响。方法:18只4周龄雄性大鼠分为:正常血压大鼠(WKY)组、自发性高血压大鼠(SHR)组、SHR口服losartan组,均饲养至16周。在肾组织切片上分别用光镜和电镜配合计算机图像分析法观测肾组织内小动脉的几何形态学指标和小动脉平滑肌及其间隙,离体肾脏灌流法测定最小肾血管阻力。结果:Losartan组的尾动脉收缩压、肾小动脉壁厚、壁面积、壁厚内径比和中层血管平滑肌细胞宽度以及最小肾血管阻力,均显著低于高血压对照组。结论:AngII受体拮抗剂losartan能预防SHR肾小动脉的重建。     

Segmental distribution of vascular resistances during ureteral occlusion: The vasoconstrictive effects of angiotensin and CaCl2 differ from those of catecholamines and renal nerve stimulation

Examinations of renal autoregulation and renin release suggest that α-adrenergic agonists, in contrast to other vasoconstrictors, preferentially constrict the preglomerular arteries. To examine this hypothesis, experiments were performed in anesthetized dogs during ureteral occlusion. At a ureteral pressure (UP) of 100 mmHg the afferent arterioles are dilated and mechanical constriction of the renal artery does not alter intrarenal vascular resistances. Whereas angiotensin and CaCl₂ infused into the renal artery reduced renal blood flow (RBF) by 25–30% without reducing UP, renal nerve stimulation reduced RBF and UP in proportion. During angiotensin and catecholamine infusion, measurements of UP and intrarenal venous pressure permitted calculations of preglomerular, efferent vascular and intrarenal venous resistances. Until RBF was reduced by 25%, angiotensin raised both preglomerular and efferent vascular resistances, whereas norepinephrine and the α-adrenergic agonists, phenylephrine and methoxamine raised preglomerular more than efferent vascular resistance. When RBF was reduced by more than 25%, all vasoconstrictors showed a similar pattern with large increments both in preglomerular and efferent vascular resistances. Conclusions: Humoral and nervous stimulation of α-adrenergic receptors reduce glomerular capillary pressure by preferentially constricting the preglomerular arteries and may affect renal autoregulation and renin release by reducing the transmural pressure of the afferent arterioles.     

Inefficiency of intracerebroventricular ANP to alter haemodynamic,plasma vasopressin and renin responses to haemorrhage in sheep

Whether intracerebroventricular (i.e.v.) infusion of atrial natriuretic peptide (human-ANP, 1–28) 25 pmol min^-1 influences the tolerance to blood loss and haemorrhage induced cardiovascular, vasopressin and renin responses were studied in five conscious sheep. The i.e. v. infusion was started 60 min prior to a slow (0.7 ml kg^-1 min^-1) venous haemorrhage, was run concurrently with bleeding, and for 90 min thereafter. Venous blood was removed until the mean systemic arterial pressure suddenly fell to about 50 mmHg. There were no statistically significant differences in either the bleeding volume necessary to induce the sudden decrease in blood pressure, or in cardiovascular parameters measured by venous heart thermodilution catheterization, compared with control experiments with i.e.v. infusion of artificial CSF. The plasma protein and vasopressin concentrations and renin activity were unaffected by the i.c.v. infusion of ANP as were the changes in these parameters occurring during the subsequent haemorrhage. The same negative findings were obtained with a three times higher dose of ANP(l-28) (75 pmol min^-1), tested in three of the animals. Thus the i.c.v. infusion of ANP(l-28), in amounts expected to elevate the CSF concentration far above basal levels does apparently not influence normal blood pressure regulation or alter haemodynamic, vasopressin and renin responses to haemorrhage in conscious sheep.     

Atrial natriuretic peptide attenuates pressor but enhances natriuretic responses to angiotensin II in pregnant conscious goats

This study was designed to examine the actions of ANP in acute, ANGII-mediated hypertension during pregnancy. Effects on blood pressure, blood volume, and renal Na and K excretion were evaluated in conscious goats (n= 6). ANP (2 μrg min^-1), ANGII (0.5 μg min^-1), or ANGII + ANP (doses the same as for each peptide alone) was infused intravenously for 60 min. The pressor response to ANGII was reduced in pregnant goats. This reduction was seen in systolic, but not in diastolic pressure. ANP decreased pressure by 5–10 mmHg both in pregnancy and in non-pregnancy. When ANGII + ANP was infused, blood pressure initially rose as with ANGII but then declined. ANP suppressed only the elevated systolic pressure. Plasma protein concentration and haematocrit was reduced by ANGII but increased by ANP alone or together with ANGII, thereby implying fluid shift into the vasculature by ANGII and opposite movement by ANP. ANGII increased renal Na excretion to 1500 μmol min^-1in non-pregnancy, but only to half of that in pregnancy. ANP alone caused small natriuresis, but enhanced ANGII-induced natriuresis to near 3000 μmol min^-1in both non-pregnant and pregnant goats. In summary, ANP further attenuated the blunted blood-pressure rise due to ANGII in pregnant goats, and reduced plasma volume, but enhanced renal Na excretion as in non-pregnant goats. This implies that with the present combination ANP and ANGII caused a near maximal natriuretic response that was not modified by the systemic cardiovascular changes occurring in pregnant goats.     

Central inhibition of opioid receptor subtypes and its effect on haemorrhagic hypotension in conscious sheep

Aim: To investigate the contribution of cerebral μ‐, κ‐ and δ‐opioid receptors in causing the hypotension, bradycardia and renal hypoperfusion evoked by haemorrhage. Methods: Adult conscious ewes were bled continuously from a jugular vein until mean arterial blood pressure (MAP) was reduced to below 50 mmHg. Starting 30 min before and continuing until 60 min after haemorrhage either artificial cerebrospinal fluid (control), d ‐Phe‐Cys‐Tyr‐d ‐Trp‐Orn‐Thr‐Pen‐Thr‐NH₂ (CTOPμ‐receptor antagonist), ICI 174,864 (δ‐receptor antagonist) or nor‐binaltorphimine dihydrochloride (nor‐BNI, κ‐receptor antagonist) were infused intracerebroventricularly. In a randomized crossover fashion the effect of antagonizing one central opioid receptor subtype was compared to control experiments in the same animal (n = 6 in all groups). Results: Compared to corresponding controls, nor‐BNI and ICI 174,864 significantly increased the haemorrhage volume needed to reduce MAP to below 50 mmHg (+4.7 mL kg^?1, SD 1.8 and +3.1 mL kg^?1, SD 3.0 respectively). In the nor‐BNI group this was accompanied by a significantly augmented tachycardia before MAP fell. Both nor‐BNI and ICI 174,864 also postponed haemorrhagic bradycardia and prolonged adequate blood flow to the kidney. The infusions did not affect the circulation per se or the recovery after haemorrhage. The μ‐opioid receptor blockade had no effect on baseline circulation or the response to haemorrhage. Conclusion: Activation of κ‐ and δ‐opioid receptors adjacent to the ventricular compartment contributes to initiating haemorrhagic hypotension and bradycardia in conscious sheep. However, other parts of the brain and different receptors are likely to play a role as well.     

Cardiovascular effects of parathyroid hormone in conscious sheep

The cardiovascular effects of the synthetic amino terminal fragment of parathyroid hormone, PTH(1-34), were studied in intact conscious sheep. Physiological doses of bovine (b) PTH(1-34), 0.188, 0.376, 0.56 and 0.75 micrograms kg-1 h-1 were infused in random order into conscious sheep for periods of 1 h each. Isotonic saline was infused as a control. Mean arterial blood pressure (MABP) decreased from 99.2 +/- 1.2 mmHg during the control infusion to 88.9 +/- 1.4 mmHg during infusion of the highest dose of PTH. Heart rate (HR) increased from 81.6 +/- 7.3 beats min-1 during the control infusion to 142.3 +/- 14.0 beats min-1 at the highest PTH dose and plasma renin activity (PRA) increased from 0.33 +/- 0.15 ng ml-1 h-1 to 1.54 +/- 0.46 ng ml-1 h-1. Cardiac output (CO), calculated by an indirect method, increased to 176 +/- 28% of the control values. The changes in all four parameters were dose dependent. Renal blood flow (RBF) increased during the PTH infusion period.     

Impaired drinking to angiotensin II after subdiaphragmatic vagotomy in rats

Rats received total bilateral subdiaphragmatic vagotomy and, one month later, were fitted with chronic intravenous or intracerebroventricular cannulas. The vagotomized rats showed much reduced drinking compared with controls during intravenous infusion of angiotensin II. Their drinking to intracerebroventricularly administered angiotensin II was, however, less affected. The possible role of the vagus nerve in the mediation of angiotensin and other types of drinking is discussed.     

血管紧张素II及其受体在血管平滑肌细胞迁移中的作用

目的:探讨血管紧张素II(AngII)及其受体(ATRs)在局部血管损伤后血管平滑肌细胞(VSMC)迁移中的作用及其机制。方法:以体外培养VSMC为基础,采用细胞化学和改良Boyden'schamber的方法,观察AngⅡ干预VSMC后AngII受体的表达、VSMC迁移能力的变化、肌动蛋白纤维丝的动态组装变化,并探讨AT₁R拮抗剂、AT₂R拮抗剂对上述观测指标的影响。结果:AngII10^-7mol/L可以刺激VSMC发生迁移,该作用是通过影响VSMC内应力纤维动态组装而实现的;AngII干预VSMC后可使AT₁R表达上调,随着作用时间延长AT₁R表达水平下降。AT₁R拮抗剂可下调AT₁R表达。AngII通过AT₁R的介导发挥其影响VSMC迁移能力的生物学效应。AT₂R对此无明显影响。结论:AngII通过AT₁R介导来调节VSMC内肌动蛋白微丝的动态组装,进而改变VSMC的迁移能力,从而发挥其介导VSMC迁移的生物学效应。     

Graded levels of hemorrhage, thirst and angiotensin II in the rat.

Hemorrhage was evaluated as a stimulus to drink in rats prepared with chronically implanted jugular cannulae and bled either 20, 30, 40 or 50 percent of their total blood volume. Hourly observations of water intake for 5 hr after hemorrhage revealed that the volume drunk was proportional to the degree of hemorrhage. Drinking induced by 20 percent hemorrhage did not differ significantly from control values, and intake was greatest and most persistent after 50 percent blood loss. The onset of maximal drinking at 1 hr after 40 percent hemorrhage was preceded by a twofold increase in plasma concentrations of angiotensin II. This is compatible with previous suggestions that angiotensin plays a role in hypovolemic thirst.     

The effect of angiotensin AT1 receptor blockade in the brain on the maintenance of blood pressure during haemorrhage in sheep

The effect of systemic or intracerebroventricular (ICV) infusion of the angiotensin AT₁ receptor antagonist losartan on blood pressure during hypotensive haemorrhage was investigated in five conscious sheep. Mean arterial pressure (MAP) was measured during haemorrhage (15 mL kg^?1 body wt). Losartan (1 or 0.33 mg h^?1) was given to sheep by ICV, intravenous or intracarotid administration, beginning 60 min before and continuing during the haemorrhage. During control infusion of ICV artificial cerebrospinal fluid, MAP was maintained until 13.16 ± 0.84 mL kg^?1 blood loss, when a rapid reduction of at least 15 mmHg in arterial pressure occurred (the decompensation phase). ICV infusion of losartan at 1 mg h^?1 caused an early onset of the decompensation phase after only 9.8 ± 0.8 mL kg^{? 1} of blood loss compared with control. Intravenous infusion of losartan (1 mg h^?1) also caused an early onset (P < 0.05) of the decompensation phase at 10.2 ± 1.0 mL kg^?1 blood loss. This dose of losartan inhibited the pressor response to ICV angiotensin II, but not to intravenously administered angiotensin II, indicating that only central AT₁ receptors were blocked. Bilateral carotid arterial administration of losartan at 0.33 mg h^?1 caused an early onset of the decompensation phase during haemorrhage at 11.06 ± 0.91 mL kg^?1 blood loss (P < 0.05), which did not occur when infused by intravenous or ICV routes. The results indicate that an angiotensin AT₁-receptor-mediated mechanism is involved in the maintenance of MAP during haemorrhage in sheep. The locus of this mechanism appears to be the brain.     

An electrophysiological study of angiotensin II regulation of Na-HCO3 cotransport and K conductance in renal proximal tubules

The effect of picomolar concentrations of angiotensin II (AII) was investigated in isolated perfused rabbit renal proximal tubules using conventional or pH-sensitive intracellular microelectrodes. Under control conditions cell membrane potential (V _b) and cell pH (pH_i) averaged –53.8±1.9 mV (mean±SEM,n=49) and 7.24±0.01 (n=10), respectively. AII (at 10^–11 mol/l), when applied from the bath (but not when applied from the lumen perfusate), produced the following effects: approximately 85% of the viable tubules responded with a small depolarization (+ 5.5±0.4 mV,n=43) which was accompanied in half of the pH_i measurements by a slow acidification (pH_i=–0.03±0.01,n=5). The remaining 15% responded with a small hyperpolarization (V_b=–3.1±0.4 mV,n=6). All changes were fully reversible and repeatable. Experiments with fast changes in bath HCO₃ or K concentrations, as well as measurements of the basolateral voltage divider fraction in response to transepithelial current flow, explain these observations as stimulation of a basolateral Na-HCO₃ cotransporter and of a basolateral K conductance. Both counteract in their effect onV _b, but can be individuated by blocker experiments with 4,4-diisothiocyanatostilbene-2,2-disulphonic acid (DIDS) and barium. Both the stimulation of Na-HCO₃ cotransport and the stimulation of the K conductance may result from down-regulation of the level of cyclic adenosine monophosphate in the cell.