Frederick Mendelsohn - Academia.edu (original) (raw)
Papers by Frederick Mendelsohn
Journal of Neurochemistry, Jan 18, 2002
Journal of Cardiovascular Pharmacology, 1986
ABSTRACT
Journal of Hypertension, Jul 1, 1991
Angiotensin converting enzyme (ACE) inhibitors lead to induction of ACE in animals and humans. Th... more Angiotensin converting enzyme (ACE) inhibitors lead to induction of ACE in animals and humans. This complicates the use of ACE enzymatic activity as an index of inhibition in plasma or tissues after chronic administration of ACE inhibitors. We have, therefore, developed a method for ACE measurement by in vitro autoradiography using an 125I-labelled inhibitor to quantitate total ACE and the concentration of free (not inhibited) ACE in tissues after prolonged administration of ACE inhibitors to rats. Measurements made on unprocessed tissue sections reflect residual free ACE activity in the presence of the unlabelled inhibitor. In a parallel series of adjacent sections, the ACE inhibitor is dissociated from the enzyme by reversibly denaturing the enzyme by zinc chelation. This is followed by reconstitution of the active enzyme by zinc ion replacement and measuring total enzyme concentration. This technique permits measurement of the extent of ACE inhibition and induction. This method was evaluated in tissues of rats following chronic oral administration of lisinopril (10 mg/kg per day) for 2 weeks. The pattern of ACE inhibition was similar to that seen in our previous acute studies. However, induction of ACE was found to be organ specific; plasma total ACE increased 1.75-fold and total ACE in the lung increased by 30% compared with untreated animals, but there was no demonstrable change in total ACE concentration in the kidney, adrenal or aorta. Despite this, during chronic treatment with lisinopril, ACE activity in all of these organs was inhibited with low levels of free ACE.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension, Mar 1, 1988
Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after ... more Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after administration of lisinopril, an ACE inhibitor. Tissue ACE was assessed by quantitative in vitro autoradiography using the ACE inhibitor [ I25 I]351A, as a ligand, and serum ACE was measured by a fluorimetric method. Following oral administration of lisinopril (10 mg/kg), serum ACE activity was acutely reduced but recovered gradually over 24 hours. Four hours after lisinopril administration, ACE activity was markedly inhibited in kidney (11% of control level), adrenal (8%), duodenum (8%), and lung (33%; p<0.05). In contrast, ACE in testis was little altered by lisinopril (96%). In brain, ACE activity was markedly reduced 4 hours after lisinopril administration in the circumventricular organs, including the subfornical organ (16-22%) and organum vasculosum of the lamina terminalis (7%; p < 0.05). In other areas of the brain, including the choroid plexus and caudate putamen, ACE activity was unchanged. Twenty-four hours after administration, ACE activity in peripheral tissues and the circumventricular organs of the brain had only partially recovered toward control levels, as it was still below 50% of control activity levels. These results establish that lisinopril has differential effects on inhibiting ACE in different tissues and suggest that the prolonged tissue ACE inhibition after a single oral dose of lisinopril may reflect targets involved in the hypotensive action of ACE inhibitors. (Hypertension 11: 230-238, 1988) KEY WORDS • angiotensin converting enzyme inhibitors • hypotensive action lisinopril • blood-brain barrier • renin ANGIOTENSIN converting enzyme (ACE; / \ EC3.4.15.1) is a peptidyl dipeptidase that is X \. responsible for the conversion of angiotensin I to angiotensin II. High concentrations of ACE are found in vascular endothelial cells, 1 renal proximal tubules, 2 intestinal mucosa, 3 the male reproductive system, 4 and some specific areas of the brain. 5-6 Recently, ACE inhibitors such as captopril and enalapril have been found to be effective for the treatment of hypertension and congestive heart failure. 7 The mechanism of the hypotensive action of these drugs is unclear. Although the circulating renin-angiotensin system was initially considered the primary target for ACE inhibitors, this possibility must be reevaluated
European Journal of Pharmacology, 1989
Endothelin (ET) is one of the most potent known vasoconstrictors (Yanagisawa et al., 1988). Howev... more Endothelin (ET) is one of the most potent known vasoconstrictors (Yanagisawa et al., 1988). However its physiological role and distribution of its receptors are still unknown. In the present study the radioligand, 125I-endothelin, was used to map receptors for ET in rat kidney using in vitro autoradiography and computerized densitometry (Mendelsohn et al., 1987). Porcine endothelin (Protein Research Foundation, Osaka, Japan) was radioiodinated with ~25I using Iodogen and purified by gradient elution from C18 cartridges. Autoradiographs were generated by incubating 20 /tm frozen sections of rat kidneys with 0.3 /~Ci/ml (= 20 pM) 125I-ET in 20 mM HEPES buffer, pH 7.4, containing 135 mM NaC1, 2 mM CaC12, 0.2% bovine serum albumin and 0.01% bacitracin for 1 h at 20 o C. Nonspecific binding was determined in the presence of 1 /.tM unlabelled ET. After incubation, the sections were washed, and exposed to X-ray film for 12-24 h at room temperature. Optical density of the X-ray films was quantitated by computerized densitometry (Mendelsohn et al., 1987). A very high density of ET-receptor binding occurs overlying glomeruli in the cortex, and over the inner medulla (fig. 1). A high density of binding occurs over longitudinal bands in the inner stripe of outer medulla, corresponding to vasa recta bundles, and also in the inter bundle zone of
American Journal of Hypertension, Jun 1, 1994
ABSTRACT We developed an in vitro autoradiographic method to localize and quantify active renin i... more ABSTRACT We developed an in vitro autoradiographic method to localize and quantify active renin in primate tissues. Active renin in monkey kidney sections was labeled with the primate specific renin inhibitor, 3H-CGP29287, and quantitated with autoradiography and computerized densitometry. Microscopic emulsion autoradiography was carried out to clarify the detailed localization of the binding. Non-specific binding to aspartyl proteases other than renin was blocked using 1 mumol/L of N-acetyl-pepstatin. To assess the usefulness of this procedure, binding of 3H-CGP29287 was examined both by film and emulsion autoradiography in the kidneys of monkeys (Macaca fuscata) that were given chronically either an angiotensin converting enzyme inhibitor (trandolapril), an angiotensin II receptor antagonist (E4177), or vehicle. 3H-CGP29287 was found to bind very selectively to the juxtaglomerular apparatus (JGA) under control conditions. In monkeys treated with trandolapril or E4177, 3H-CGP29287 binding was increased in proportion to the increase in renal renin concentration determined enzymatically; in these kidneys, emulsion autoradiography revealed radioinhibitor binding extending far from the JGA. The potency of a series of unlabeled renin inhibitor in competing for 3H-CGP29287 binding in the autoradiographic system closely paralleled their potencies, as determined in inhibiting renin by an enzymatic assay. This technique permits specific labeling of the catalytic site of renin in the monkey kidney sections.
Birkhäuser Boston eBooks, 1991
Angiotensin II (ANG II) regulates numerous brain functions including drinking and salt appetite, ... more Angiotensin II (ANG II) regulates numerous brain functions including drinking and salt appetite, release of both anterior and posterior pituitary hormones, and regulation of cardiovascular function through interactions with central control of efferent autonomic activity (see Phillips, 1987) as well as the well characterized actions on peripheral tissues (see Peach, 1977). The central actions are probably mediated by both systemic and endogenous neuronal angiotensin.
Endocrinology, Jun 1, 1980
ABSTRACT
The Medical Journal of Australia, 1971
A brief review of the biochemistry and physiological functions of the renin‐angiotensin system is... more A brief review of the biochemistry and physiological functions of the renin‐angiotensin system is presented. A critical analysis is given of the various methods, both bioassay and radioimmunoassay, for measuring plasma renin and angiotensin levels. With the development of radioimmunoassay, specific, precise and rapid measurements of renin and angiotensin levels may now be made. Various factors that may influence the plasma level of renin are discussed, and the clinical applications for plasma renin measurements are listed.
European journal of endocrinology, Jun 1, 1981
Normal human serum markedly stimulated aldosterone production from rat adrenal glomerulosa cells ... more Normal human serum markedly stimulated aldosterone production from rat adrenal glomerulosa cells incubated in Krebs Ringer bicarbonate medium (KRBGA). The effect was dose-related. In [K+] 3.6 mM KRBGA medium, serum stimulated aldosterone output to higher levels than those produced by maximal doses of serotonin (5 HT), angiotensin II (All) or high [K+] (8.4 mM). Cells maximally stimulated by high [K+], 5 HT or All in KRBGA medium were further stimulated by serum. The angiotensin analogue, [Sar1, Ala8]-AII abolished the effect of All but not that of high [K+] or serum. Basal and ACTH-stimulated corticosterone outputs of rat fasciculata cells were not significantly affected by sera known to stimulate glomerulosa cells. Aldosterone stimulating activity of serum was dialysable and fully recovered in a serum ultrafiltrate. The serotonin blockers methysergide and metergoline abolished the aldosterone stimulating activity of serum but also depressed basal aldosterone output and methysergide reduced K+-stimulated output. Chymotrypsin digestion abolished the aldosterone stimulating activity of All but not that of serotonin or serum.
Neuroscience Letters, Jun 1, 1996
There is increasing evidence that neuropeptides have trophic functions during embryogenesis. We e... more There is increasing evidence that neuropeptides have trophic functions during embryogenesis. We examined the ability of angiotensin II, substance P, soraatostatin-28 and luteinising hormone-releasing hormone to influence neurite outgrowth from embryonic chick sympathetic neurons in culture. Nanomolar concentrations of angiotensin II inhibited neurite outgrowth, whereas the other peptides had no effect at similar concentrations. The effect of angiotensin II on neurite outgrowth is likely to be mediated by an atypical angiotensin receptor, as it was only weakly inhibited by [sarl,ala8]angiotensin II, and was not inhibited by losartan, an inhibitor of mammalian AT 1 receptors, or PD123319, an AT 2 inhibitor. Neurite outgrowth was also inhibited by angiotensin III and angiotensin IV but not by angiotensinogen I1_14. The study provides further evidence that angiotensin peptides, like classical neurotransmitters, may have trophic functions during embryogenesis.
Neuropharmacology, Sep 1, 1992
ABSTRACT
Clinical and Experimental Hypertension, 1997
We have previously demonstrated that angiotensin II stimulates the release of dopamine from the n... more We have previously demonstrated that angiotensin II stimulates the release of dopamine from the normotensive rat striatum via the AT1 receptor. In this study, the effect of angiotensin II-stimulated striatal dopamine release in the spontaneous hypertensive rat was compared to normotensive controls. In the spontaneous hypertensive rat, angiotensin II stimulated dopamine release to 169 +/- 13% (P < 0.05) in the experimental period, with levels remaining high in the recovery phase, 158 +/- 16% (P < 0.05). This effect was not significantly different from the response in normotensive controls, in which angiotensin II stimulated dopamine release to 149 +/- 18% (P < 0.05) in the experimental period, with the effect also persisting through the recovery period, 244 +/- 62% (P < 0.05). Thus, despite reports of increased activity of the brain angiotensin II and dopamine systems in the spontaneous hypertensive rat, there is no evidence of abnormal regulation of the striatonigral dopamine system.
American Journal of Physiology-regulatory Integrative and Comparative Physiology, Jul 1, 1983
Preference for 0.9% saline was examined, using two-bottle preference tests over 6-7 days, in the ... more Preference for 0.9% saline was examined, using two-bottle preference tests over 6-7 days, in the spontaneously hypertensive rat (SHR) and normotensive Wistar Kyoto rat (WK) of the Okamoto strain, the genetically hypertensive (GHR) and normotensive rat (NT) of the Smirk strain, and the Sprague-Dawley (SD), Dark Agouti (DA), and hooded Long-Evans or Brattleboro (BB) rat. Only the SHR exhibited a sustained and marked preference for 0.9% saline on each test day. The WK, GHR, NT, and SD preferred saline in the first 24-48 h of testing but thereafter showed neither a preference for, nor aversion to, saline. The BB showed neither a preference for, nor aversion to, saline in the first 24 h of testing and thereafter showed a significant aversion to saline on each test day. Saline preference was further examined in both the SHR and WK offered a choice of water and 0.9%, 2.0, or 2.7% saline. While preference for saline decreased in both SHR and WK with increasing saline concentration, the SHR maintained a significantly greater preference for saline and greater total sodium intake than the WK at each concentration. Hydralazine (5 mg . kg-1 . day-1, po) administered to SHR, while they were offered a choice of water and 0.9% saline, significantly lowered blood pressure over a 4-day period but failed to alter their saline preference significantly. We conclude that of the seven strains of rats examined only the SHR exhibited a preference for saline in extended two-bottle preference tests. Furthermore this preference for saline appears to be maintained independently of the blood pressure of the SHR.
American Journal of Physiology-regulatory Integrative and Comparative Physiology, May 1, 1982
Chronic intracerebroventricular (icv) infusion of angiotensin II (ANG II) (6 micrograms/h) in rat... more Chronic intracerebroventricular (icv) infusion of angiotensin II (ANG II) (6 micrograms/h) in rats resulted in a sustained 70-mmHg rise in blood pressure during 7 days of treatment. A marked dipsogenic response preceded the maximal rise in blood pressure, peaked at 24 h, and returned to control by the 5th day. Urinary sodium excretion rose on the 1st day of infusion but thereafter was not different from that of vehicle-infused rats. ANG II-infused rats showed a small but significant kaliuresis, a fall in serum osmolality (5.5 mosmol/kg), but no change in plasma Na+, K+, or glucose. Rats infused with the same dose of ANG II intravenously showed a small, 8-mmHg rise in blood pressure, but none of the changes noted after icv ANG II. Plasma renin activity was suppressed in rats infused with ANG II by both routes. We conclude that the pressor, dipsogenic, and renal excretory effects of icv ANG II are mediated centrally and cannot be explained by leakage of the peptide into the systemic circulation. Furthermore, the pressor and dipsogenic effects of ANG II become clearly dissociated during chronic icv infusion.
Hypertension, Sep 1, 1982
Angiotensin-converting enzyme (ACE) in rat brain closely resembled that in lung in its kinetics w... more Angiotensin-converting enzyme (ACE) in rat brain closely resembled that in lung in its kinetics with the substrate Hip-His Leu, the inhibitors SQ 20,881 and SQ 14,225, and in its Cl" activation profile. Modification of dietary NaCI intake was associated with marked changes in brain ACE activity. Sodium-loaded rats had lower activity of ACE in hypothalamus, striatum, and midbrain, and higher activity in spinal cord compared to controls. In sodium-restricted rats, ACE was elevated in pituitary and depressed in spinal cord. Chronic intravenous infusion of angiotensin (AH) was associated with a pattern of changes partly resembling sodium loading: ACE was depressed in hypothalamus and striatum but elevated in midbrain. After chronic intracerebroventricular infusion of AH, ACE was elevated in striatum and hippocampus, and depressed in spinal cord; a pattern of changes quite different from those associated with intravenous All. These results show that ACE in several brain regions is sensitive to dietary sodium intake and support the hypothesis that angiotensincontaining neurons in these areas might be responsive to NaCI status of the animal. The observed changes in brain ACE do not seem to be explained in any simple manner by changes in circulating or central angiotensin II. (Hypertension 4: 590-596, 1982) KEY WORDS • sodium status • kininase II • osmotic minipumps * renin-angiotensin system • thirst * blood pressure
Clinical and Experimental Pharmacology and Physiology, Nov 1, 1998
1. Angiotensin IV (AngIV), the (3-8) fragment of AngII, was previously believed to be an inactive... more 1. Angiotensin IV (AngIV), the (3-8) fragment of AngII, was previously believed to be an inactive metabolite. However, specific binding sites, termed AT4 receptors, have been identified in the brain and peripheral organs and the peptide has been reported to enhance memory recall in passive avoidance studies and to dilate pial and renal cortical vessels. 2. AT4 receptors are distinct from AngII AT1 and AT2 receptors with respect to function, ligand specificity and distribution. 3. In the brain, AT4 receptors are abundant in cerebral and cerebellar cortex, hippocampal formation and cholinergic systems, as well as sensory and motor systems. However, the peptide AngIV is low or undetectable in the central nervous system. This led us to search for an alternative peptide ligand of the AT4 receptor. 4. The decapeptide LVVYPWTQRF was isolated from cerebral cortex and binds with high affinity to brain AT4 receptors. This peptide sequence corresponds to an internal sequence of P-globin and has previously been named LVV-haemorphin 7. 5. Haemorphin may represent a new class of endogenous neuropeptides, some of which interact potently with the brain AT4 receptor to elicit a range of actions.
Journal of Neurochemistry, Jan 18, 2002
Journal of Cardiovascular Pharmacology, 1986
ABSTRACT
Journal of Hypertension, Jul 1, 1991
Angiotensin converting enzyme (ACE) inhibitors lead to induction of ACE in animals and humans. Th... more Angiotensin converting enzyme (ACE) inhibitors lead to induction of ACE in animals and humans. This complicates the use of ACE enzymatic activity as an index of inhibition in plasma or tissues after chronic administration of ACE inhibitors. We have, therefore, developed a method for ACE measurement by in vitro autoradiography using an 125I-labelled inhibitor to quantitate total ACE and the concentration of free (not inhibited) ACE in tissues after prolonged administration of ACE inhibitors to rats. Measurements made on unprocessed tissue sections reflect residual free ACE activity in the presence of the unlabelled inhibitor. In a parallel series of adjacent sections, the ACE inhibitor is dissociated from the enzyme by reversibly denaturing the enzyme by zinc chelation. This is followed by reconstitution of the active enzyme by zinc ion replacement and measuring total enzyme concentration. This technique permits measurement of the extent of ACE inhibition and induction. This method was evaluated in tissues of rats following chronic oral administration of lisinopril (10 mg/kg per day) for 2 weeks. The pattern of ACE inhibition was similar to that seen in our previous acute studies. However, induction of ACE was found to be organ specific; plasma total ACE increased 1.75-fold and total ACE in the lung increased by 30% compared with untreated animals, but there was no demonstrable change in total ACE concentration in the kidney, adrenal or aorta. Despite this, during chronic treatment with lisinopril, ACE activity in all of these organs was inhibited with low levels of free ACE.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension, Mar 1, 1988
Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after ... more Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after administration of lisinopril, an ACE inhibitor. Tissue ACE was assessed by quantitative in vitro autoradiography using the ACE inhibitor [ I25 I]351A, as a ligand, and serum ACE was measured by a fluorimetric method. Following oral administration of lisinopril (10 mg/kg), serum ACE activity was acutely reduced but recovered gradually over 24 hours. Four hours after lisinopril administration, ACE activity was markedly inhibited in kidney (11% of control level), adrenal (8%), duodenum (8%), and lung (33%; p<0.05). In contrast, ACE in testis was little altered by lisinopril (96%). In brain, ACE activity was markedly reduced 4 hours after lisinopril administration in the circumventricular organs, including the subfornical organ (16-22%) and organum vasculosum of the lamina terminalis (7%; p < 0.05). In other areas of the brain, including the choroid plexus and caudate putamen, ACE activity was unchanged. Twenty-four hours after administration, ACE activity in peripheral tissues and the circumventricular organs of the brain had only partially recovered toward control levels, as it was still below 50% of control activity levels. These results establish that lisinopril has differential effects on inhibiting ACE in different tissues and suggest that the prolonged tissue ACE inhibition after a single oral dose of lisinopril may reflect targets involved in the hypotensive action of ACE inhibitors. (Hypertension 11: 230-238, 1988) KEY WORDS • angiotensin converting enzyme inhibitors • hypotensive action lisinopril • blood-brain barrier • renin ANGIOTENSIN converting enzyme (ACE; / \ EC3.4.15.1) is a peptidyl dipeptidase that is X \. responsible for the conversion of angiotensin I to angiotensin II. High concentrations of ACE are found in vascular endothelial cells, 1 renal proximal tubules, 2 intestinal mucosa, 3 the male reproductive system, 4 and some specific areas of the brain. 5-6 Recently, ACE inhibitors such as captopril and enalapril have been found to be effective for the treatment of hypertension and congestive heart failure. 7 The mechanism of the hypotensive action of these drugs is unclear. Although the circulating renin-angiotensin system was initially considered the primary target for ACE inhibitors, this possibility must be reevaluated
European Journal of Pharmacology, 1989
Endothelin (ET) is one of the most potent known vasoconstrictors (Yanagisawa et al., 1988). Howev... more Endothelin (ET) is one of the most potent known vasoconstrictors (Yanagisawa et al., 1988). However its physiological role and distribution of its receptors are still unknown. In the present study the radioligand, 125I-endothelin, was used to map receptors for ET in rat kidney using in vitro autoradiography and computerized densitometry (Mendelsohn et al., 1987). Porcine endothelin (Protein Research Foundation, Osaka, Japan) was radioiodinated with ~25I using Iodogen and purified by gradient elution from C18 cartridges. Autoradiographs were generated by incubating 20 /tm frozen sections of rat kidneys with 0.3 /~Ci/ml (= 20 pM) 125I-ET in 20 mM HEPES buffer, pH 7.4, containing 135 mM NaC1, 2 mM CaC12, 0.2% bovine serum albumin and 0.01% bacitracin for 1 h at 20 o C. Nonspecific binding was determined in the presence of 1 /.tM unlabelled ET. After incubation, the sections were washed, and exposed to X-ray film for 12-24 h at room temperature. Optical density of the X-ray films was quantitated by computerized densitometry (Mendelsohn et al., 1987). A very high density of ET-receptor binding occurs overlying glomeruli in the cortex, and over the inner medulla (fig. 1). A high density of binding occurs over longitudinal bands in the inner stripe of outer medulla, corresponding to vasa recta bundles, and also in the inter bundle zone of
American Journal of Hypertension, Jun 1, 1994
ABSTRACT We developed an in vitro autoradiographic method to localize and quantify active renin i... more ABSTRACT We developed an in vitro autoradiographic method to localize and quantify active renin in primate tissues. Active renin in monkey kidney sections was labeled with the primate specific renin inhibitor, 3H-CGP29287, and quantitated with autoradiography and computerized densitometry. Microscopic emulsion autoradiography was carried out to clarify the detailed localization of the binding. Non-specific binding to aspartyl proteases other than renin was blocked using 1 mumol/L of N-acetyl-pepstatin. To assess the usefulness of this procedure, binding of 3H-CGP29287 was examined both by film and emulsion autoradiography in the kidneys of monkeys (Macaca fuscata) that were given chronically either an angiotensin converting enzyme inhibitor (trandolapril), an angiotensin II receptor antagonist (E4177), or vehicle. 3H-CGP29287 was found to bind very selectively to the juxtaglomerular apparatus (JGA) under control conditions. In monkeys treated with trandolapril or E4177, 3H-CGP29287 binding was increased in proportion to the increase in renal renin concentration determined enzymatically; in these kidneys, emulsion autoradiography revealed radioinhibitor binding extending far from the JGA. The potency of a series of unlabeled renin inhibitor in competing for 3H-CGP29287 binding in the autoradiographic system closely paralleled their potencies, as determined in inhibiting renin by an enzymatic assay. This technique permits specific labeling of the catalytic site of renin in the monkey kidney sections.
Birkhäuser Boston eBooks, 1991
Angiotensin II (ANG II) regulates numerous brain functions including drinking and salt appetite, ... more Angiotensin II (ANG II) regulates numerous brain functions including drinking and salt appetite, release of both anterior and posterior pituitary hormones, and regulation of cardiovascular function through interactions with central control of efferent autonomic activity (see Phillips, 1987) as well as the well characterized actions on peripheral tissues (see Peach, 1977). The central actions are probably mediated by both systemic and endogenous neuronal angiotensin.
Endocrinology, Jun 1, 1980
ABSTRACT
The Medical Journal of Australia, 1971
A brief review of the biochemistry and physiological functions of the renin‐angiotensin system is... more A brief review of the biochemistry and physiological functions of the renin‐angiotensin system is presented. A critical analysis is given of the various methods, both bioassay and radioimmunoassay, for measuring plasma renin and angiotensin levels. With the development of radioimmunoassay, specific, precise and rapid measurements of renin and angiotensin levels may now be made. Various factors that may influence the plasma level of renin are discussed, and the clinical applications for plasma renin measurements are listed.
European journal of endocrinology, Jun 1, 1981
Normal human serum markedly stimulated aldosterone production from rat adrenal glomerulosa cells ... more Normal human serum markedly stimulated aldosterone production from rat adrenal glomerulosa cells incubated in Krebs Ringer bicarbonate medium (KRBGA). The effect was dose-related. In [K+] 3.6 mM KRBGA medium, serum stimulated aldosterone output to higher levels than those produced by maximal doses of serotonin (5 HT), angiotensin II (All) or high [K+] (8.4 mM). Cells maximally stimulated by high [K+], 5 HT or All in KRBGA medium were further stimulated by serum. The angiotensin analogue, [Sar1, Ala8]-AII abolished the effect of All but not that of high [K+] or serum. Basal and ACTH-stimulated corticosterone outputs of rat fasciculata cells were not significantly affected by sera known to stimulate glomerulosa cells. Aldosterone stimulating activity of serum was dialysable and fully recovered in a serum ultrafiltrate. The serotonin blockers methysergide and metergoline abolished the aldosterone stimulating activity of serum but also depressed basal aldosterone output and methysergide reduced K+-stimulated output. Chymotrypsin digestion abolished the aldosterone stimulating activity of All but not that of serotonin or serum.
Neuroscience Letters, Jun 1, 1996
There is increasing evidence that neuropeptides have trophic functions during embryogenesis. We e... more There is increasing evidence that neuropeptides have trophic functions during embryogenesis. We examined the ability of angiotensin II, substance P, soraatostatin-28 and luteinising hormone-releasing hormone to influence neurite outgrowth from embryonic chick sympathetic neurons in culture. Nanomolar concentrations of angiotensin II inhibited neurite outgrowth, whereas the other peptides had no effect at similar concentrations. The effect of angiotensin II on neurite outgrowth is likely to be mediated by an atypical angiotensin receptor, as it was only weakly inhibited by [sarl,ala8]angiotensin II, and was not inhibited by losartan, an inhibitor of mammalian AT 1 receptors, or PD123319, an AT 2 inhibitor. Neurite outgrowth was also inhibited by angiotensin III and angiotensin IV but not by angiotensinogen I1_14. The study provides further evidence that angiotensin peptides, like classical neurotransmitters, may have trophic functions during embryogenesis.
Neuropharmacology, Sep 1, 1992
ABSTRACT
Clinical and Experimental Hypertension, 1997
We have previously demonstrated that angiotensin II stimulates the release of dopamine from the n... more We have previously demonstrated that angiotensin II stimulates the release of dopamine from the normotensive rat striatum via the AT1 receptor. In this study, the effect of angiotensin II-stimulated striatal dopamine release in the spontaneous hypertensive rat was compared to normotensive controls. In the spontaneous hypertensive rat, angiotensin II stimulated dopamine release to 169 +/- 13% (P < 0.05) in the experimental period, with levels remaining high in the recovery phase, 158 +/- 16% (P < 0.05). This effect was not significantly different from the response in normotensive controls, in which angiotensin II stimulated dopamine release to 149 +/- 18% (P < 0.05) in the experimental period, with the effect also persisting through the recovery period, 244 +/- 62% (P < 0.05). Thus, despite reports of increased activity of the brain angiotensin II and dopamine systems in the spontaneous hypertensive rat, there is no evidence of abnormal regulation of the striatonigral dopamine system.
American Journal of Physiology-regulatory Integrative and Comparative Physiology, Jul 1, 1983
Preference for 0.9% saline was examined, using two-bottle preference tests over 6-7 days, in the ... more Preference for 0.9% saline was examined, using two-bottle preference tests over 6-7 days, in the spontaneously hypertensive rat (SHR) and normotensive Wistar Kyoto rat (WK) of the Okamoto strain, the genetically hypertensive (GHR) and normotensive rat (NT) of the Smirk strain, and the Sprague-Dawley (SD), Dark Agouti (DA), and hooded Long-Evans or Brattleboro (BB) rat. Only the SHR exhibited a sustained and marked preference for 0.9% saline on each test day. The WK, GHR, NT, and SD preferred saline in the first 24-48 h of testing but thereafter showed neither a preference for, nor aversion to, saline. The BB showed neither a preference for, nor aversion to, saline in the first 24 h of testing and thereafter showed a significant aversion to saline on each test day. Saline preference was further examined in both the SHR and WK offered a choice of water and 0.9%, 2.0, or 2.7% saline. While preference for saline decreased in both SHR and WK with increasing saline concentration, the SHR maintained a significantly greater preference for saline and greater total sodium intake than the WK at each concentration. Hydralazine (5 mg . kg-1 . day-1, po) administered to SHR, while they were offered a choice of water and 0.9% saline, significantly lowered blood pressure over a 4-day period but failed to alter their saline preference significantly. We conclude that of the seven strains of rats examined only the SHR exhibited a preference for saline in extended two-bottle preference tests. Furthermore this preference for saline appears to be maintained independently of the blood pressure of the SHR.
American Journal of Physiology-regulatory Integrative and Comparative Physiology, May 1, 1982
Chronic intracerebroventricular (icv) infusion of angiotensin II (ANG II) (6 micrograms/h) in rat... more Chronic intracerebroventricular (icv) infusion of angiotensin II (ANG II) (6 micrograms/h) in rats resulted in a sustained 70-mmHg rise in blood pressure during 7 days of treatment. A marked dipsogenic response preceded the maximal rise in blood pressure, peaked at 24 h, and returned to control by the 5th day. Urinary sodium excretion rose on the 1st day of infusion but thereafter was not different from that of vehicle-infused rats. ANG II-infused rats showed a small but significant kaliuresis, a fall in serum osmolality (5.5 mosmol/kg), but no change in plasma Na+, K+, or glucose. Rats infused with the same dose of ANG II intravenously showed a small, 8-mmHg rise in blood pressure, but none of the changes noted after icv ANG II. Plasma renin activity was suppressed in rats infused with ANG II by both routes. We conclude that the pressor, dipsogenic, and renal excretory effects of icv ANG II are mediated centrally and cannot be explained by leakage of the peptide into the systemic circulation. Furthermore, the pressor and dipsogenic effects of ANG II become clearly dissociated during chronic icv infusion.
Hypertension, Sep 1, 1982
Angiotensin-converting enzyme (ACE) in rat brain closely resembled that in lung in its kinetics w... more Angiotensin-converting enzyme (ACE) in rat brain closely resembled that in lung in its kinetics with the substrate Hip-His Leu, the inhibitors SQ 20,881 and SQ 14,225, and in its Cl" activation profile. Modification of dietary NaCI intake was associated with marked changes in brain ACE activity. Sodium-loaded rats had lower activity of ACE in hypothalamus, striatum, and midbrain, and higher activity in spinal cord compared to controls. In sodium-restricted rats, ACE was elevated in pituitary and depressed in spinal cord. Chronic intravenous infusion of angiotensin (AH) was associated with a pattern of changes partly resembling sodium loading: ACE was depressed in hypothalamus and striatum but elevated in midbrain. After chronic intracerebroventricular infusion of AH, ACE was elevated in striatum and hippocampus, and depressed in spinal cord; a pattern of changes quite different from those associated with intravenous All. These results show that ACE in several brain regions is sensitive to dietary sodium intake and support the hypothesis that angiotensincontaining neurons in these areas might be responsive to NaCI status of the animal. The observed changes in brain ACE do not seem to be explained in any simple manner by changes in circulating or central angiotensin II. (Hypertension 4: 590-596, 1982) KEY WORDS • sodium status • kininase II • osmotic minipumps * renin-angiotensin system • thirst * blood pressure
Clinical and Experimental Pharmacology and Physiology, Nov 1, 1998
1. Angiotensin IV (AngIV), the (3-8) fragment of AngII, was previously believed to be an inactive... more 1. Angiotensin IV (AngIV), the (3-8) fragment of AngII, was previously believed to be an inactive metabolite. However, specific binding sites, termed AT4 receptors, have been identified in the brain and peripheral organs and the peptide has been reported to enhance memory recall in passive avoidance studies and to dilate pial and renal cortical vessels. 2. AT4 receptors are distinct from AngII AT1 and AT2 receptors with respect to function, ligand specificity and distribution. 3. In the brain, AT4 receptors are abundant in cerebral and cerebellar cortex, hippocampal formation and cholinergic systems, as well as sensory and motor systems. However, the peptide AngIV is low or undetectable in the central nervous system. This led us to search for an alternative peptide ligand of the AT4 receptor. 4. The decapeptide LVVYPWTQRF was isolated from cerebral cortex and binds with high affinity to brain AT4 receptors. This peptide sequence corresponds to an internal sequence of P-globin and has previously been named LVV-haemorphin 7. 5. Haemorphin may represent a new class of endogenous neuropeptides, some of which interact potently with the brain AT4 receptor to elicit a range of actions.