Biomedical subjects

C M Ferrario

Publications and source records attributed to C M Ferrario.

At least 127 records · Page 7Linked to original sources

PubMed1991

Hypertensive mechanisms and converting enzyme inhibitors.

The introduction of angiotensin-converting enzyme (ACE) inhibitors marks a new era in the understanding and treatment of high blood pressure. Although the benefits of therapy with ACE inhibitors are documented, it is more difficult to isolate the principal mechanisms that account for their effective actions in the treatment of hypertension. Recent data suggest that these agents affect both the pressor and depressor mechanisms that regulate vascular tone and cardiac function. For example, ACE inhibitors decrease angiotensin II-mediated vasoconstriction, reduce adrenal medullary catecholamine release, restore baroreceptor activity, and normalize vasomotor sympathetic activity. Experimental work indicates that ACE inhibitors also act on hypertensive mechanisms via actions on the central nervous system. Cardiovascular centers in the brain have receptor sites for angiotensin II and contain the proteins required for local synthesis of angiotensins. Vasomotor neurons possess such receptors and exhibit ACE activity. In addition, angiotensin II receptors involved in the regulation of baroreceptor activity are present in neuronal elements of the baroreflex arc. It is suggested that ACE inhibitors reach the brain via circumventricular organs to reduce sympathetic activity and enhance baroreceptor sensitivity. New studies suggest that depressor actions of ACE inhibitors include enhanced biosynthesis of vasodilator prostaglandins. From animal experiments it is deduced that enhanced production of angiotensin-(1-7) after inhibition of ACE stimulates release of vasodilator prostaglandins. These investigations clarify the function of tissue renin-angiotensin systems in the control of blood pressure in both normal and hypertensive states.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1991

Pressor effect of centrally administered sodium chloride: role of the ventral third ventricle region and the area postrema.

To determine the site(s) responsible for the central cardiovascular effect of hypertonic saline, 0.2 ml of 1.5 M NaCl was administered to anesthetized dogs via three routes, a lateral ventricle, the third ventricle and the cisterna magna. Intracisternal administration of hypertonic NaCl produced much prompter pressor and tachycardic responses than did administration via the other two routes. Covering the ventral third ventricle region with a petroleum jelly plug had the effect of abolishing the pressor response to lateral ventricular hypertonic NaCl but did not modify the response to intracisternal hypertonic NaCl. By contrast, electrolytic lesion of the area postrema attenuated the rise in blood pressure produced by the intracisternal NaCl without affecting the response to lateral ventricular NaCl. These results indicate that at least two sites, the ventral third ventricle region in the hypothalamus and the area postrema in the lower brainstem, are responsible for the acute hypertension induced by an increase in NaCl concentration in the cerebrospinal fluid of the dog.

Animals↗

PubMed1991

The nonpeptide angiotensin II antagonist DuP 753 is a potent stimulus for prostacyclin synthesis.

In an attempt to define the angiotensin II receptor subtype responsible for prostaglandin release, we studied the effects of the nonpeptide, subtype 1 (or B) selective angiotensin II antagonist, DuP 753. Release of prostaglandin E2 produced by angiotensin II from rat C6 glioma, human astrocytoma, or porcine aortic smooth muscle cells in culture was blocked by the addition of the 10(-7) M of DuP 753. In contrast, the release of prostacyclin, as assessed by measurement of the stable metabolite 6-keto PGF1 alpha, was not attenuated by addition of Du P 753. However, DuP 753 either alone or in combination with angiotensin II, produced dose-dependent increases in prostacyclin release with doses as low as 10(-8) M. In the absence of angiotensin II, DuP 753 also increased prostaglandin E2 release at high doses but the magnitude of the potentiation was substantially less than for prostacyclin release (50 to 250% v 400 to 2800% above basal). Thus, we clearly show that angiotensin II stimulates PGE2 release via subtype 1 (or B) angiotensin receptors. Whether the effect of DuP 753 on prostaglandin release is a result of agonistic properties or intrinsic effects unrelated to blockage of angiotensin II receptors remains to be determined. The marked stimulatory effect of DuP 753 release precludes characterization of the receptor subtype that mediates the Ang II-induced release of prostacyclin. Nonetheless, potent stimulation of prostacyclin release by DuP 753, especially in vascular smooth muscle cells, requires reevaluation of the mechanisms that participate in the anti-hypertensive effects of the compound.

Angiotensin II↗

PubMed1991

Evidence that prolyl endopeptidase participates in the processing of brain angiotensin.

In order to understand angiotensin metabolism in the canine brain, we determined the molecular forms of angiotensin peptides present in the hypothalamus of the dog and carried out measurements of the metabolism of 125I-angiotensin I in homogenates of that tissue. Angiotensin peptides were extracted from canine hypothalamic tissue and quantified by specific radioimmunoassays combined with high-performance liquid chromatography. The major angiotensin peptides detected were angiotensin-(2-7) (391.2 +/- 16.8 pg/g tissue) and angiotensin-(3-7) (864.8 +/- 128.1 pg/g). Angiotensin II immunoreactivity was mainly composed of angiotensin-(3-8) (117.5 +/- 64 pg/g) and trace amounts of angiotensin II and angiotensin III. Angiotensin I immunoreactivity was composed of angiotensin I (52.3 +/- 5.8 pg/g). In separate experiments, addition of 125I-angiotensin I into supernatants (18,000 g for 2 min) of canine hypothalamic homogenates resulted in the accumulation of 125I-angiotensin-(1-7) as the major peptide product (14% of the total 125I-radioactivity) at 2 min. Incubation of the homogenate supernatants with enalaprilat (1 mumol/l), phosphoramidon (10 mumol/l), or ethylenediamine tetraacetic acid (1 mmol/l) did not inhibit the production of 125I-angiotensin-(1-7). In contrast, addition of Z-Pro-Prolinal (1 mumol/l), a specific inhibitor of prolyl endopeptidase, prevented the generation of 125I-angiotensin-(1-7) from 125I-angiotensin I by 47.0 +/- 8.0% (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗

PubMed1991

Evidence for an intrinsic angiotensin system in the canine pancreas.

Increasing evidence suggests an association between hypertension and abnormalities of glucose metabolism. Since components of the renin-angiotensin system exist in a variety of tissues consistent with paracrine actions of the peptide, we sought to determine whether the pancreas contains a local angiotensin system. We report the presence of angiotensinogen messenger (m) RNA, angiotensinogen protein, angiotensin II and high-affinity binding sites for angiotensin II in the canine pancreas. These novel findings establish a foundation for future studies to evaluate whether angiotensin acts as a paracrine regulator of endocrine and/or exocrine functions of the pancreas.

Angiotensin II↗

PubMed1991

Characterization of angiotensin receptors mediating prostaglandin synthesis in C6 glioma cells.

The heptapeptide angiotensin (ANG)-(1-7) mimics some but not all the central actions of ANG II, suggesting that receptor subtypes may exist. The effects of ANG-(1-7), ANG II, and ANG I on prostaglandin (PG) E2 and prostacyclin (PGI2) synthesis were investigated in neurally derived rat C6 glioma cells. All three ANG peptides stimulated PG release in a dose-dependent manner with the order of potency ANG-(1-7) greater than ANG I greater than ANG II. PGE2 release induced by ANG-(1-7) (10(-7) M) was partially blocked by [Sar1,Ile8]ANG II (10(-6) M), [Sar1,Thr8]ANG II (10(-6) M), or the subtype 1 selective antagonist Du Pont 753 (10(-5) M) but not by the subtype 2 selective antagonist CGP 42112A (10(-7)-10(-5) M). PGI2 release was inhibited only by [Sar1,Thr8]ANG II. ANG II-induced PGE2 release was blocked by [Sar1,Thr8]ANG II (10(-6) M), [Sar1,Ile8]ANG II (10(-6) M), or Du Pont 753 (10(-7) M) but not by CGP 42112A (10(-7)-10(-5) M). In contrast, ANG II-induced PGI2 release was blocked by Du Pont 753 (10(-7) M) as well as [Sar1,Ile8]ANG II (10(-6) M) but not by [Sar1,Thr8]ANG II or CGP 42112A. Thus ANG II-stimulated PGE2 and PGI2 syntheses in C6 glioma cells are mediated via receptor subtype 1. ANG-(1-7)-induced PGE2 synthesis is also mediated via subtype 1 receptors; however, PGI2 release was blocked by [Sar1,Thr8]ANG II only.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗

PubMed1991

Effect of angiotensin II in ventrolateral medulla of spontaneously hypertensive rats.

The spontaneously hypertensive rat (SHR) exhibits an enhanced activity of the peripheral sympathetic and brain renin-angiotensin systems. In the present experiments, we evaluated the cardiovascular response of angiotensin II (ANG II) microinjected in the rostral (RVLM) and the caudal (CVLM) ventrolateral medulla of age-matched (14-16 wk old) SHR and Wistar-Kyoto (WKY) rats. Responses of mean arterial pressure (MAP) and heart rate (HR) to microinjection of ANG II (5, 20 and 100 pmol) into histologically verified sites of the RVLM and CVLM were compared with those obtained by injections of the excitatory agent L-glutamate (2 nmol) at the same site. In both strains, ANG II elicited dose-dependent pressor responses in the RVLM and depressor responses in the CVLM, both of which peaked at a dose of 20 pmol. The magnitude of the fall in MAP produced by injections of ANG II into the CVLM were significantly (P less than 0.01) greater in SHR than in WKY group. In contrast, peak pressor responses elicited by injection of ANG II into the RVLM were of similar magnitude in the two groups. When compared with the MAP response produced by L-glutamate injections, responses to ANG II microinjection were slower in onset, and the latency to the peak response was longer. Ganglionic blockade with hexamethonium bromide prevented the effect of ANG II injection in the RVLM. This study provides evidence that ANG II acts as an excitatory agent at sites within the ventrolateral medulla that determine the vasomotor control of blood pressure in both normotensive and hypertensive rats.

Angiotensin II↗

PubMed1991

Effects of chronic intraventricular sodium on blood pressure and fluid balance.

To examine if chronic sodium loading on the brain produces sustained increases in blood pressure, water intake, and sodium excretion, hypertonic (0.5 M and 1.5 M) and isotonic (0.15 M) NaCl solutions were infused into the third ventricle of Sprague-Dawley rats at a rate of 5.5 microliters/hr for 7 days. Intracerebroventricular infusion of 1.5 M NaCl significantly increased systolic blood pressure during the entire infusion period (+23 +/- 5 mm Hg on day 1 and +15 +/- 2 mm Hg on day 7, n = 10, mean +/- SEM). Blood pressure rose insignificantly in the 0.5 M NaCl group, whereas it remained at the baseline levels in the 0.15 M NaCl group. The increases in water intake (day 2), positive water balance (day 2), and negative sodium balance (day 3) were observed in the 1.5 M NaCl group. On day 7, the 1.5 M NaCl group showed hyponatremia and low plasma osmolality and had higher plasma norepinephrine but not vasopressin compared with the 0.15 M NaCl group. In another series of study, depressor response to intravenous hexamethonium (20 mg/kg) in the 1.5 M NaCl group was greater than that in the 0.15 M NaCl group on both day 1 and 7. The depressor response to d(CH2)5Tyr(Me)-arginine vasopressin (10 micrograms/kg) in the 1.5 M NaCl group was greater on day 1 but not on day 7. These results indicate that sustained sodium stimulus on the central nervous system causes mild hypertension and alters water and sodium balance. The sympathetic nervous system but not vasopressin may play an important role in the chronic phase of central NaCl-induced hypertension.

Animals↗

PubMed1991

Neurovascular mechanisms and sodium balance in the pathogenesis of hypertension.

Physiological studies have clarified the role that the brain has in the interplay between salt balance and hypertension. Neural mechanisms and endocrine secretions play a pivotal role in the adaptation of mammals to changes in the intake and excretion of sodium. Maneuvers that alter the concentration of sodium in the plasma modify the sensitivity of baroreceptor reflexes and alter vascular reactivity. These changes may be mediated in part by the release of vasopressin. The research also suggests that the brain indirectly modulates the ability of the vascular endothelium to release vasoactive factors. Collectively, these studies illustrate the multiple effects of the sodium ion on the peripheral neural and central endocrine mechanisms that participate in the regulation of arterial pressure.

Angiotensin II↗

PubMed1991

Angiotensin-(1-7). A member of circulating angiotensin peptides.

We measured the concentrations of three principal products of the renin-angiotensin system and seven of their metabolites in the plasma of anesthetized normal dogs and in dogs 24 hours after bilateral nephrectomy. The levels of the angiotensin peptides were measured by high-performance liquid chromatography combined with radioimmunoassay using three specific antibodies that recognized different epitotes in the sequences of angiotensin I, angiotensin II, and angiotensin-(1-7). The analysis revealed that angiotensin-(1-7) is present in the plasma of intact (4.9 +/- 2.2 fmol/ml) and nephrectomized (0.5 +/- 0.5 fmol/ml) dogs. An intravenous injection of purified hog renin (0.01 Goldblatt unit/kg) increased plasma levels of angiotensin I, angiotensin II, and angiotensin-(1-7) both before and after nephrectomy. These changes were associated with parallel increases in the concentrations of fragments of the three parent peptides. Administration of MK-422 led to the disappearance of circulating angiotensin II and its fragments both before and after a second injection of the same dose of renin. In contrast, MK-422 augmented the plasma levels of both angiotensin I and angiotensin-(1-7). The concentrations of these two peptides, but not the blood pressure, were again augmented by a second injection of renin given after blockade of converting enzyme. These effects were observed both before and after bilateral nephrectomy. These findings show that angiotensin-(1-7) circulates in the blood of normal and nephrectomized dogs. In addition, we found that angiotensin-(1-7) is generated in the blood from the cleavage of angiotensin I through a pathway independent of converting enzyme (EC 3.4.15.1).

Angiotensin I↗

PubMed1991

Neurophysiological responses to angiotensin-(1-7).

The aim of this study was to investigate the action of the heptapeptide angiotensin-(1-7) on the spontaneous activity of paraventricular neurons using microiontophoresis. Recent immunocytochemical investigations have shown that this product of angiotensin I is predominantly located in cells and fibers of the forebrain and brain stem. Our results show that most neurons in the paraventricular nucleus are excited by angiotensin-(1-7) at a dose of 50-80 nA. In comparison with angiotensin II or angiotensin III, the onset of response and the occurrence of the maximal effect were significantly delayed. With higher doses of angiotensin-(1-7), there was a decrease in latency and a dose-dependent increase in firing frequency. Of all the angiotensin compounds tested, angiotensin III was the most potent. Preliminary results obtained with an angiotensin antagonist show that the action of angiotensin II, angiotensin III, and angiotensin-(1-7) is blocked by the angiotensin receptor subtype 2 antagonist CGP 42112A. Because the angiotensin-(1-7) system in the brain is associated with central vasopressinergic pathways, vasopressin was tested in a similar way. Neurons in the paraventricular nucleus that were excited by iontophoretically applied angiotensins showed a weak response to vasopressin. Occasionally, a small excitatory action was observed. Our results support the hypothesis that the heptapeptide angiotensin-(1-7) is a biologically active neuropeptide. The data also suggest that amino terminal fragments of angiotensin II are not inactive degradation products.

Angiotensin I↗

PubMed1991

Subtype 2 angiotensin receptors mediate prostaglandin synthesis in human astrocytes.

We have identified two distinct cellular responses that occur in human astrocytes in the presence of angiotensin (Ang) peptides and are linked to specific receptor subtypes. Ang II and the N-terminal heptapeptide Ang-(1-7) stimulated release of prostaglandin (PG) E2 and PGI2 (measured as the stable metabolite 6-keto-PGF1 alpha). In contrast, only Ang II but not Ang-(1-7) activated phosphoinositide-specific phospholipase C, leading to mobilization of intracellular calcium. The Ang II-induced PGE2 and PGI2 syntheses were attenuated by [Sar1,Ile8]Ang II but not by [Sar1,Thr8]Ang II. Ang-(1-7)-induced PGE2 and PGI2 syntheses were not inhibited by either of these two classical antagonists. DuP 753, a subtype 1-selective Ang receptor antagonist, blocked the Ang II-induced release of PGE2 but not PGI2. In contrast, CGP 42112A, the subtype 2-selective antagonist, totally blocked the Ang II-induced PGI2 release and partially attenuated the PGE2 release. Ang-(1-7)-induced PGE2 and PGI2 release was not altered by DuP 753; however, CGP 42112A totally blocked the effects of Ang-(1-7) on PG stimulation. Calcium mobilization in response to Ang II was blocked by [Sar1,Thr8]Ang II, [Sar1,Ile8]Ang II, and DuP 753 but not by CGP 42112A. These data suggest that human astrocytes contain both Ang receptor subtypes. The subtype 1 Ang receptor participates both in the release of PGs and in the mobilization of calcium, whereas the subtype 2 receptor is coupled to the release of PGs only. In addition, PG release coupled to subtype 2 Ang II receptors occurs through a calcium-independent mechanism and responds uniquely to Ang-(1-7).

1-Sarcosine-8-Isoleucine Angiotensin II↗

PubMed1991

Functional interactions between angiotensin II and substance P in the dorsal medulla.

Low doses of either angiotensin (Ang) II or substance P (SP) microinjected into the medial nucleus tractus solitarii (NTS) produce hypotension and bradycardia, mimicking activation of the baroreceptor reflex. Anatomical evidence suggests that Ang II binding sites in the medial NTS are located presynaptically on vagal afferent fibers that may contain SP and are codistributed with SP binding sites located postsynaptically on intrinsic medial NTS neurons. To evaluate whether the similar cardiovascular effects of Ang II and SP in the medial NTS could involve Ang II-evoked release of SP, we compared the effects of these peptides on the spontaneous activity of medial NTS neurons recorded in vitro and determined whether Ang II evoked release of SP from rat medulla slices. Both Ang II and SP (1 microM in artificial cerebrospinal fluid) excited 11 of 40 medial NTS neurons. In these cells, the peak response latency was significantly longer to Ang II than to SP (59.5 +/- 4.7 versus 26.5 +/- 2.4 seconds, p less than 0.0001). When rat medulla slices were perfused with Ang II (2 microM in Krebs' bicarbonate), release of SP immunoreactivity was increased by 400% over control perfusion with Krebs' solution alone (p less than 0.05). We have provided the first evidence for an excitatory action of Ang II on neurons in the NTS of the rat and for excitation by both Ang II and SP of a subset of neurons in the medial NTS. Moreover, we have shown for the first time that Ang II can stimulate the release of SP immunoreactivity from the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1991

Identification and regulation of angiotensin II receptor subtypes on NG108-15 cells.

NG108-15 cells, a neurally derived clonal cell line, express various components of the renin-angiotensin system and thus serve as a model of the cellular action of angiotensin (Ang) II. NG108-15 cells contain a high-affinity binding site for Ang II, with a Kd of 1.1 nM and a Bmax of 6.5 fmol/mg protein. Ang peptides competed for 125I-Ang II binding with an order of potency of Ang II greater than Ang-(2-8) much greater than Ang-(1-7). The subtype 1 (or B)-selective Ang II receptor antagonist DuP 753 as well as [Sar1,Ile8]Ang II and [Sar1,Thr8]Ang II competed for Ang II binding with high affinity, whereas the subtype 2 (or A)-selective Ang receptor antagonist CGP 42112A was partially effective only at a 300-fold higher concentration. When NG108-15 cells were induced to differentiate by treatment with dibutyryl cyclic adenosine 3',5'-monophosphate, the density of Ang II receptors increased dramatically, with little change in affinity (1.1 versus 4.2 nM) or competition by Ang peptides. In marked contrast to undifferentiated cells, CGP 42112A became a potent competitor (IC50, 1 nM) for the majority (90-95%) of Ang II binding, whereas DuP 753 competed for only 5-10% of the binding sites. Ang II caused a dose-dependent mobilization of cytosolic Ca2+ in undifferentiated NG108-15 cells through activation of phospholipase C and the production of inositol 1,4,5-trisphosphate. In these cells, Ca2+ mobilization was blocked by either DuP 753 or the sarcosine Ang II analogues, whereas CGP 42112A was ineffective. Ang II also mobilized intracellular Ca2+ in differentiated NG108-15 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Sarcosine-8-Isoleucine Angiotensin II↗

PubMed1991

Human astrocytes contain two distinct angiotensin receptor subtypes.

The ability of angiotensin peptides to stimulate prostaglandin release and raise intracellular calcium levels by activating a phosphoinositide-specific phospholipase C was assessed in three human astrocytoma cell lines (CRTG3, STTG1, and WITG2). The addition of angiotensin II to CRTG3 cells resulted in a dose-dependent release of prostaglandin E2 and prostacyclin, the production of inositol 1,4,5-trisphosphate, and the mobilization of intracellular calcium. Angiotensin-(1-7), previously considered to be an inactive metabolite of angiotensin II, was as potent as angiotensin II for prostaglandin release but did not activate phospholipase C or mobilize intracellular calcium. In contrast, angiotensin-(2-8) caused only a slight increase in prostaglandin release, even though it was as effective as angiotensin II in augmenting inositol 1,4,5-trisphosphate production and calcium mobilization. Moreover, neither the release of prostaglandins in response to angiotensin II or angiotensin-(1-7) nor the mobilization of intracellular calcium in response to angiotensin II required extracellular calcium. Angiotensin II and angiotensin-(1-7) caused the release of prostaglandins from all three human astrocytoma cell lines, but changes in the level of intracellular calcium in response to angiotensin II only occurred in CRTG3 cells. Although previous studies have provided evidence for angiotensin receptor subtypes on the basis of selectivity of antagonists or signal transduction mechanisms, these data suggest that human astrocytes contain multiple angiotensin receptor subtypes on the basis of their response to different angiotensin heptapeptides--angiotensin-(1-7) and angiotensin-(2-8).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗

PubMed1991

Attenuated vascular reactivity in dogs with anteroventral third ventricle lesions.

Lesion of the anteroventral portion of the third cerebral ventricle causes hypernatremia, adipsia, and attenuation of the pressor response to intravenous administration of angiotensin II and norepinephrine. In addition, these lesions prevent the development of several experimental models of hypertension. In this study, a lesion of the third cerebral ventricle region was made in 14 dogs. In seven dogs in which hypernatremia developed the lesions included the organum vasculosum of the lamina terminalis; seven animals in which the circumventricular organ was spared by the lesion remained normonatremic. Vascular responsiveness of isolated right carotid artery rings to angiotensin II and phenylephrine was assessed 3 days after lesioning the anteroventral portion of the third cerebral ventricle. In endothelium-denuded ring vessels, vasoconstrictor responses to phenylephrine were significantly decreased in animals both with and without inclusion of the organum vasculosum of the lamina terminalis. A similar effect was observed in intact vessels of dogs in which the circumventricular organ was spared but not in those with lesions that included this area. In contrast, angiotensin II-induced vasoconstriction was significantly decreased in the arteries with intact endothelium of both groups of lesioned animals. These data show that lesion of the anteroventral third ventricle area alters alpha 1-adrenergic and angiotensin II vascular responsiveness in isolated carotid artery rings with the possible participation of the endothelium.

Acetylcholine↗

PubMed1991

Do primary dysfunctions in neural control of arterial pressure contribute to hypertension?

This article is a summary of the physiological and clinical evidence that links the cause of essential hypertension to the brain. We stress the potential importance of a biochemical disturbance in the central role of angiotensin II in the regulation of arterial pressure. While the evidence is compelling, we acknowledge the need for further complete studies on this timely subject.

Animals↗

PubMed1991

Angiotensin-(1-7): a new hormone of the angiotensin system.

We provide a new foundation for an alternative interpretation of the biochemical physiology of the brain and other tissue angiotensin systems on the basis of research done in our laboratory. This perspective is prompted by the discovery that angiotensin-(1-7) has cellular functions that differ from those established for angiotensin II. Although angiotensin-(1-7) is not an agonist in terms of activating vasoconstriction, stimulating thirst, or promoting aldosterone release, the heptapeptide caused neuronal excitation and vasopressin release with a potency similar to that found with angiotensin II. Furthermore, angiotensin-(1-7) enhances the production of prostanoids by a receptor-mediated event that causes no associated rise in intracellular Ca2+. These actions of angiotensin-(1-7) provide a new understanding of the heterogeneous functions of angiotensin peptides as modulators of a wide range of regulatory functions in mammals.

Angiotensin I↗