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.     

Amino acids with central pressor effect in conscious rats

Intracisternal injection of arginine, proline, cysteine, aspartic acid, and asparagine increased blood pressure in conscious rats. Proline markedly decreased heart rate, but the rate was raised by arginine, cysteine, and aspartic acid. In addition, intravenous administration of these amino acids failed to increase blood pressure in the same pattern.     

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 micrograms min-1), ANGII (0.5 microgram 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 mumol min-1 in non-pregnancy, but only to half of that in pregnancy. ANP alone caused small natriuresis, but enhanced ANGII-induced natriuresis to near 3000 mumol min-1 in 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.     

Inhibitory effect of central calcitonin-gene related peptide (CGRP) on pancreatic secretion in conscious rats

The inhibitory effect of central administration of calcitonin-gene related peptide (CGRP) on pancreatic secretion stimulated by bile-pancreatic juice diversion was determined in conscious rats. Rats were prepared with separate cannulae for draining bile and pancreatic juice and with a duodenal cannula and an extrajugular vein cannula. In addition, another cannula was stereotactically implanted into the left lateral cerebral ventricle. Rats were placed in restraint cages and experiments were conducted 4 d after the operation without anesthesia. An injection of CGRP (1 nmol/10 microl) into the left lateral cerebral ventricle (i.c.v.) inhibited pancreatic secretion as well as cholecystokinin (CCK) release induced by bile-pancreatic juice diversion. Intravenous infusion of alpha- and beta-adrenergic receptor antagonist, phentolamine and propranolol did not reverse the inhibition of pancreatic secretion. Intravenous infusion of CGRP did not affect pancreatic secretion or plasma CCK concentrations. The inhibitory action of central CGRP (i. c.v.) on pancreatic secretion and CCK release stimulated by bile-pancreatic juice diversion is partially mediated by an alpha-adrenergic mechanism, although its precise mechanism has not been elucidated.     

Intracerebroventricular injection of brain natriuretic peptide inhibits vasopressin secretion in conscious rats

The effect of intracerebroventricular (i.c.v.) injection of brain natriuretic peptide (BNP), a novel peptide purified from the porcine brain, on arginine vasopressin (AVP) secretion was studied in conscious, unrestrained rats and was compared with that of atrial natriuretic polypeptide (ANP). I.c.v. administration of BNP (0.01, 0.1 or 1 nmol) significantly inhibited basal AVP secretion and the effect of BNP was comparable to that of ANP. The AVP secretion induced by i.c.v. injection of angiotensin II (0.1 nmol) was significantly suppressed by the pretreatment with BNP (0.1 or 1 nmol). These results suggest that BNP is involved in the central control of AVP secretion either alone or in combination with brain ANP.     

A pressor response to vibration in conscious rats

Cardiovascular response in an alerted state induced by vibration was studied in conscious rats by giving a to-and-fro movement to their cages for 30 sec. Cardiac output, superior mesenteric flow, and hindquarter flow were observed with chronically implanted electromagnetic flow probes and arterial pressure with an indwelling catheter. Arterial pressure, heart rate, cardiac output and hindquarter flow increased and superior mesenteric flow decreased with vibration. The increase in heart rate was still present after adrenalectomy, but was abolished by beta-adrenoceptor blockade propranolol. The increase in hindquarter flow was greatly diminished by propranolol or after adrenalectomy, but was still present in adrenalectomized rats after alpha-adrenoceptor blockade phentolamine. The decrease in superior mesenteric flow in vibration was abolished by phentolamine. It was diminished by adrenalectomy. These findings indicate that the cardiovascular response to vibration includes excitation of the cardiac sympathetic nerves, adrenomedullary secretion, and excitation of sympathetic vasoconstrictor fibers and exercise hyperemia in skeletal muscles.     

Central nitric oxide blocks vasopressin, oxytocin and atrial natriuretic peptide release and antidiuretic and natriuretic responses induced by central angiotensin II in conscious rats

The presence of nitric oxide synthase (NOS), the enzyme that catalyses the formation of nitric oxide (NO), in the circumventricular organs and magnocellular neurones suggests an important role of NO in the modulation of vasopressin (AVP) and oxytocin (OT) release. Intracerebroventricular (I.C.V.) injection of angiotensin II (Ang II) stimulates the release of AVP, OT and atrial natriuretic peptide (ANP), with the resultant antidiuretic and natriuretic effects. This study investigated the interaction between nitrergic and angiotensinergic pathways on the release of AVP, OT and ANP and on urinary volume and sodium excretion in water-loaded rats. Unanaesthetized, freely moving, male Wistar rats received two water loads followed by an injection into the lateral ventricle of an inhibitor of NOS (L-NAME), a NO donor [3-morpholinylsydnoneimine chloride (SIN-1) or S-nitroso-N-acetyl penicillamine (SNAP)] or vehicle (isotonic saline) and, 20 min after, they received a second I.C.V. injection of Ang II or vehicle. Injections of L-NAME or Ang II produced an increase in plasma levels of AVP, OT and ANP, a reduction in urinary volume and an increase in sodium excretion. Pretreatment with L-NAME enhanced the Ang II-induced increase in AVP, OT and ANP release, as well as the antidiuresis and natriuresis. Injection of SIN-1 or SNAP did not modify hormonal plasma levels and urinary parameters. In contrast SNAP blocked the AVP, OT and ANP release, as well as antidiuretic and natriuretic responses induced by ANG-II. Thus, the central nitrergic system can act to inhibit AVP, OT and ANP secretion and the antidiuretic and natriuretic effects in response to Ang II.     

Effects of atrial natriuretic peptide,brain natriuretic peptide and urodilatin on histamine induced bronchoconstriction in the conscious guinea pig

Inflammation Research -     

Renal nerve blunts natriuretic and diuretic response to atrial natriuretic peptide in conscious rabbits

The contribution of the renal nerve to the natriuretic and diuretic responses to rat atrial natriuretic peptide (rAMP) was investigated in conscious rabbits with unilateral renal denervation. Renal nerve activity (RNA) was measured at the contralateral innervated kidney. Catheters were bilaterally implanted into the ureters. Urine samples were collected from each kidney by gravity drainage at 10-min clearance intervals. In rabbits with all baroreflexes intact, infusion of rANP at 0.3 micrograms/(kg.min) for 30 min decreased mean arterial pressure by 8 +/- 4 mmHg and increased RNA by 53 +/- 13%. After sinoaortic baroreceptor denervation (SAD), hypotensive response to infusion of rANP was greater than that in intact rabbits, while RNA did not change. After SAD plus vagotomy, infusion of rANP lowered mean arterial pressure by 21 +/- 4 mmHg and RNA by 19 +/- 6%. In the denervated kidney, infusion of rANP increased Na+ excretion by 16.1 +/- 4.5 from 3.5 +/- 1.0 muEq/min and water excretion by 0.17 +/- 0.05 from 0.08 +/- 0.02 ml/min. In the contralateral innervated kidney, infusion of rANP increased the amount of Na+ and water excretion by 4.5 +/- 3.2 muEq/min and 0.07 +/- 0.04 ml/min, which were significantly less than those in the denervated kidney. These results indicate that infusion of rANP increases RNA, due to baroreceptor reflexes, and that this increase in RNA blunts natriuretic and diuretic action of rANP.     

Changes in atrial natriuretic peptide and brain natriuretic peptide associated with hypobaric hypoxia-induced pulmonary hypertension in rats

Experimental pulmonary hypertension induced in a hypobaric hypoxic environment (HHE) is characterized by structural remodeling of the heart and pulmonary arteries. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) both have diuretic, natriuretic, and hypotensive effects, and both are involved in cardiovascular homeostasis as cardiac hormones. To study the effects of HHE on the natriuretic peptide synthesis system, 170 male Wistar rats were housed in a chamber at the equivalent of the 5500-m altitude level for 1-12 weeks. After 1 week of HHE, pulmonary arterial pressure was significantly raised, and the ratio of left ventricle plus septum over right ventricle of the heart showed a significant decrease (compared with those of ground-level control rats). In both ventricular tissues, the expression of ANP messenger (m)RNA and BNP mRNA increased after exposure to HHE. The amounts of ANP and BNP had decreased significantly in right atrial tissue at 12 weeks of HHE (compared with those of the controls), whereas in ventricular tissues at the same time point, both levels had increased significantly. In in situ hybridization and immunohistochemical studies, the staining of the mRNAs for ANP and BNP and of ANP and BNP themselves was more intense in both ventricular tissues after exposure to HHE than before (i.e., in the controls). The results suggest that, in response to HHE, the changes in ventricular synthesis are similar for ANP and BNP. These changes may play a role in modulating pulmonary hypertension in HHE. However, under our conditions, pulmonary hypertension increased progressively throughout the HHE period.     

Possible involvement of central atrial natriuretic polypeptide in regulation of hypothalamo-pituitary-adrenal axis in conscious rats

The effects of intracerebroventricular (i.c.v.) administration of angiotensin II (AII) and atrial natriuretic polypeptide (ANP) on the plasma corticosterone level were studied in conscious, unrestrained rats. Although i.c.v. injection of ANP had no apparent effect on the basal plasma corticosterone level, it attenuated the plasma corticosterone increase induced by centrally injected AII dose-dependently. These results suggest that ANP in the brain is involved in the regulation of the hypothalamo-pituitary-adrenal axis.     

Cross-tachyphylaxis of the pressor response to angiotensins in conscious rabbits

The effect of tachyphylasix to angiotensin II amide on the pressor potency of angiotensin I, II and III and noradrenaline was investigated in conscious rabbits with indwelling cannulae. No significant difference was observed between the reduction in responses to angiotensin II (58±4%) and angiotensin III (42 ±6%) but angiotensin I (15±5%) and noradrenaline (17±10%) responses were less markedly inhibited. If all angiotensin I pressor activity was mediated through its conversion to angiotensin II one would expect an equivalent degree of cross-tachyphylaxis to occur with the two peptides. Our results suggest that angiotensin I may have significant inherent pressor activity of its own, independent of conversion. This compound is already known to have activity at other target tissues. The absence of a significant difference in the degree of tachyphylaxis with angiotensin II and III may indicate they have substantially common pathways as pressor agents.     

The progressive pressor response to angiotensin in the rabbit

1. The threshold for any detectable rise of systemic arterial pressure during the prolonged intravenous administration of angiotensin to conscious rabbits was observed to be an infusion rate of 0·003-0·006 μg.kg^-1.min^-1.

2. At infusion rates between threshold and 0·04 μg.kg^-1.min^-1 the systemic arterial pressure rose progressively over a 3- to 7-day period to a plateau.

3. On stopping the angiotensin infusion the blood pressure fell rapidly back to its base line much faster than it rose during the infusion. The time taken to reach control values was approximately related to the duration of the infusion.

4. At infusion rates of about 0·05 μg.kg^-1.min^-1 the full rise of blood pressure developed within a few minutes, and could be sustained without change for many days. At higher rates the blood pressure diminished with time.

5. Diurnal fluctuations of blood pressure were often seen during prolonged infusions of angiotensin at low rates; and more rapid fluctuations of blood pressure over an hour or two were frequently encountered immediately after an infusion was turned off.

6. The possible role of angiotensin in producing chronic renal hypertension is discussed in the light of these observations.

     

Inhibition of central angiotensin II-induced pressor responses by hydrogen peroxide

Hydrogen peroxide (H₂O₂), important reactive oxygen species produced endogenously, may have different physiological actions. The superoxide anion (O₂^·−) is suggested to be part of the signaling mechanisms activated by angiotensin II (ANG II) and central virus-mediated overexpression of the enzyme superoxide dismutase (that dismutates O₂^·− to H₂O₂) reduces pressor and dipsogenic responses to central ANG II. Whether this result might reflect elevation of H₂O₂ rather than depletion of O₂^·− has not been addressed. Here we investigated the effects of H₂O₂ injected intracerebroventricularly (i.c.v.) or ATZ (3-amino-1,2,4-triazole, a catalase inhibitor) injected intravenously (i.v.) or i.c.v. on the pressor responses induced by i.c.v. injections of ANG II. Normotensive male Holtzman rats (280–320 g, n=5–13/group) with stainless steel cannulas implanted in the lateral ventricle were used. Prior injection of H₂O₂ (5 μmol/1 μl) or ATZ (5 nmol/1 μl) i.c.v. almost abolished the pressor responses induced by ANG II (50 ng/1 μl) also injected i.c.v. (7±3 and 5±3 mm Hg, respectively, vs. control: 19±4 mm Hg). Injection of ATZ (3.6 mmol/kg b.wt.) i.v. also reduced central ANG II-induced pressor responses. Injections of H₂O₂ i.c.v. and ATZ i.c.v. or i.v. alone produced no effect on baseline arterial pressure. Central ANG II, H₂O₂ or ATZ did not affect heart rate. The results show that central injections of H₂O₂ and central or peripheral injections of ATZ reduced the pressor responses induced by i.c.v. ANG II, suggesting that exogenous or endogenous H₂O₂ may inhibit central pressor mechanisms activated by ANG II.     

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.     

Atrial natriuretic factor increases albumin extravasation in conscious rats

Atrial natriuretic factor (ANF) lowers blood volume in intact and anephric experimental animals. The latter observation suggests extravasation of plasma at the level of the microcirculation. In view of the differential regional hemodynamic responses to ANF, the present study investigates possible regional differences in plasma extravasation measured as regional albumin clearances in skeletal muscle, lung, brain, ileum, and skin.In control animals, there were pronounced regional differences in clearances with highest values in ileum (0.248±0.015 l/min.g tissue) and lowest in brain (0.010±0.002 l/min.g tissue). Plasma-volume was 3.58±0.07 ml/100 g b.w. ANF (1 g/kg.min) significantly reduced plasma-volume (3.20±0.06 ml/100 g b.w.). This was associated with significantly increased albumin clearances in skeletal muscle and ileum, but not in other tissues examined.The data indicate that ANF increases albumin extravasation. This suggests that, besides effects on renal function and vascular tone, ANF also affects blood volume through influencing the relationship between intra- and extravascular volume.     

Separation of drinking and pressor responses to central angiotensin by monoamines

This study investigated the neurotransmitters involved in the increase in blood pressure and drinking produced when angiotension II is injected intraventricularly (ivt). Using pharmacologic manipulations of the monoamines norepinephrine, dopamine, and serotonin it has been possible to separate the pressor response from dipsogenic responses to angiotension II. Alpha-adrenergic blockade with phentolamine restricted to the brain blocked the pressor response to angiotensin II in a dose-related manner, while drinking remained unaffected. Norepinephrine alone, injected into the ventricles elevated blood pressure, but did not produce drinking. The norepinephrine effect was also blocked by phentolamine by the same ventricular route. Other monoamines were not involved. Dopamine alone did not produce thirst. Cardiovascular effects with dopamine were observed only with large doses. The dopaminergic agonist apomorphine produced no change in blood pressure or drinking. Reduction of central serotonin stores by p-chlorophenylalanine intraperitoneally or 5,7-dihydroxytryptamine intraventricularly had no effect on the pressor or dipsogenic effects of angiotensin II. The serotonin agonist N,N-dimethyl-5-methoxytryptamine ivt did not produce a rise in blood pressure or drinking. It is concluded that the pressor effect of angiotensin II, but not the drinking effect is mediated by noradrenergic stimulation of alpha-receptors. The drinking response does not appear to be mediated by the monoamines.     

Inhibitory effect of angiotensin on renal sodium reabsorption

Zusammenfassung Am isolierten Frosch-Sartorius wurde die isometrische Spannungsentwicklung und die Konzentration an Phosphorylkreatin (PKr) in isotonischer KCl-Lösung in Funktion der Zeit gemessen. Dabei sollte die Ursache für das spontane Einsetzen der Erschlaffung und der Regeneration der Bestände an PKr während der Dauerdepolarisation aufgeklärt werden.Vorbehandlung des Muskels in Ringer-Lösung mit 4,5 mM Ca⁺⁺ (statt normal 1,8 mM) unterdrückte die schnelle Phase der KCl-Kontraktur und führte zur Verlängerung der Kontrakturdauer. Der Wiederanstieg der Konzentration an PKr vollzog sich dabei langsamer als in KCl-Lösung mit normalem Ca⁺⁺-Gehalt.Kühlung des Muskels von 20° C auf 0° C bewirkte eine auffällige Erschlaffungs-verzögerung in isotonischer KCl-Lösung bei gleichzeitiger Hemmung der Regeneration der Bestände an PKr.In Gegenwart bekannter in vitro-Inhibitoren der Ca⁺⁺-Aufnahme in die Vesikel des sarkoplasmatischen Reticulums (wie SCN^–, Thymol und Coffein) kam es zu einer Verstärkung der KCl-Kontraktur hinsichtlich Höhe und Dauer sowie zur Ausbildung eindeutiger Verkürzungsrückstände. Die Regeneration der Bestände an PKr verlief dabei stark verzögert und war bei gleichzeitiger Anwesenheit von SCN^– und Thymol vollständig blockiert.Die Untersuchungen zeigen, daß bei funktioneller Ausschaltung der Oberflächenmembran durch K⁺-Depolarisation das Einsetzen der Erschlaffung und der Regeneration der Bestände an PKr abhängt von der Ca⁺⁺-Rückbindung in die Vesikel des sarkoplasmatischen Reticulums. Der Prozeß der Erschlaffung würde demnach kontrolliert durch die Funktion intracellulärer Membranstrukturen und nicht durch den elektrischen Zustand der Oberflächenmembran.Die Frage der Funktion einzelner Membranabschnitte sowie die Frage der morphologischen Komponenten des intracellulären Ca⁺⁺-Turnovers werden im Hinblick auf die Kompartmentierung der Muskelzelle diskutiert.Wesentliche Teile der vorliegenden Arbeit wurden von Fräulein Ch. Petzoldt der Medizinischen Fakultät Freiburg i. Br. als Dissertation vorgelegt.