Biomedical subjects

C M Ferrario

Publications and source records attributed to C M Ferrario.

At least 145 records · Page 8Linked to original sources

PubMed1991

Sympathetic stimulation-evoked overflow of norepinephrine and neuropeptide Y from the heart.

Neuropeptide Y (NPY) and norepinephrine are released together on sympathetic activation. To compare the time courses of NPY and norepinephrine washout from cardiac tissues, we measured the overflow of NPY-like immunoreactivity (NPY-LI) and norepinephrine in coronary sinus blood before, during, and after 3-minute trains of ansae subclaviae stimulation in 13 anesthetized dogs. We also measured vagally induced cardiac cycle length responses before and after ansae stimulation. Ansae stimulation increased NPY-LI and norepinephrine overflow from the heart in a frequency-dependent manner (p less than 0.02). After stimulation of the ansae at 5 and 10 Hz, the peak norepinephrine overflows decayed by 90% within 2 minutes, but the NPY-LI overflows required 17 +/- 11 and 35 +/- 21 minutes, respectively, to decay by 90%. Cardiac vagal effects were inhibited after 5- and 10-Hz ansae stimulations, and the peak inhibitions decayed by 90% after 19 +/- 7 and 39 +/- 16 minutes, respectively. The 90% decay times of the NPY-LI overflows were longer (p less than 0.003) than those of the norepinephrine overflows but did not differ significantly (p greater than 0.4) from the 90% decay times of the inhibition of vagal effects. We characterized NPY-LI in coronary sinus and arterial plasma by reversed-phase high-performance liquid chromatography. Before ansae stimulation, the main peak of NPY-LI in the plasma had a retention time similar to that of the oxidized human NPY-(1-36) standard. During ansae stimulation, however, there was a substantial increase in the peak of NPY-LI that eluted in a position similar to that of the monoxidized human NPY-(1-36) standard. These data support the hypothesis that neurally released NPY mediates the sympathetically evoked inhibition of vagal effects and indicate that the time course of removal of NPY from the heart differs substantially from that of norepinephrine. Moreover, under basal conditions, most NPY in the circulation is present in the oxidized form or as a fragment of the 36-amino-acid peptide. In contrast, cardiac sympathetic stimulation evokes the overflow of monoxidized NPY-(1-36) into the coronary sinus plasma.

Animals↗

PubMed1990

Prostaglandin production in response to angiotensin-(1-7) in rabbit isolated vasa deferentia.

Angiotensin-(1-7) is a predominant metabolite of angiotensin I in brain tissue. Its neuromodulatory and prostaglandin (PG) synthesizing capabilities were investigated in the rabbit isolated vas deferens. This metabolite had no significant effect as a neuromodulator, however it increased PGE synthesis in the vasa deferentia with a potency equivalent to that of angiotensin II. The angiotensin-(1-7) has a unique spectrum of activity among the angiotensin peptides to selectively increase PG synthesis. It could be useful in defining the relevance of angiotensin-induced PG synthesis in various systems, particularly in neuronal tissue. Angiotensin-(1-7) potentially could be useful in defining angiotensin receptor subtypes, as well.

Adrenergic Fibers↗

PubMed1990

Angiotensin II and angiotensin (1-7) excite neurons in the canine medulla in vitro.

Our group showed previously that the heptapeptide angiotensin (1-7) [Ang-(1-7)] is a bioactive product of the renin-angiotensin system, and produces dose-dependent cardiovascular effects similar to those evoked by Ang II when microinjected into the nucleus tractus solitarii (nTS) of the rat. The effects of Ang II were compared with those of Ang-(1-7) on single neuron activity recorded from the medial nTS or dorsal motor nucleus of the vagus (dmnX) in perifused horizontal slices of the canine dorsomedial medulla. Ang II excited 48% of 31 medial nTS neurons, but only activated 14% of 22 dmnX cells. Ang-(1-7) also excited half of the medial nTS cells and 14% of the dmnXl neurons. Although most medial nTS neurons excited by Ang II were also activated by Ang-(1-7), two cells were excited by Ang II but not by Ang-(1-7), and one cell was excited by Ang-(1-7) but not by Ang II. Because Ang-(1-7) lacks direct vasoconstrictor effects, neurons in the dorsomedial medulla may have different receptor characteristics than peripheral tissues. The observation of a few medial nTS neurons excited by only one Ang peptide suggests that there may be a separate Ang-(1-7) receptor that participates in the physiological effects of Ang peptides mediated by the brain.

Action Potentials↗

PubMed1990

Astrocyte cultures derived from human brain tissue express angiotensinogen mRNA.

We have identified human cultured cell lines that are useful for studying angiotensinogen gene expression and its regulation in the central nervous system. A model cell system of human central nervous system origin expressing angiotensinogen has not previously been available. Expression of angiotensinogen has not previously been available, Expression noninduced human astrocytes, since astrocytic cell lines derived from human glioblastomas or nonneoplastic human brain tissue invariably produced angiotensinogen mRNA. In situ hybridization histochemistry revealed that angiotensinogen mRNA production was not limited to a subpopulation of astrocytes because greater than 99% of cells in these cultures contained angiotensinogen mRNA. These cell lines will be useful in studies of the molecular mechanisms controlling angiotensin synthesis and the role of biologically active angiotensin in the human brain by allowing us to examine regulation of expression of the renin-angiotensin system in human astrocyte cultures.

Angiotensinogen↗

PubMed1990

Cardiovascular actions of vasopressin at the ventrolateral medulla.

Vasopressin acts at a number of sites in the central nervous system to alter arterial pressure. This study investigated the hypothesis that vasopressin acts at the rostral ventrolateral medulla to increase arterial pressure. The rostral pressor area of the medulla oblongata was exposed in urethane-anesthetized rats prepared for topical application of vasopressin. A 3-minute application of vasopressin (range 10(-8) to 10(-3) M) produced dose-dependent increases in arterial pressure that averaged between 2 +/- 1 and 65 +/- 11 mm Hg (p less than 0.01). Tachycardia was not a consistent response at any concentration of vasopressin. Intravenous administration of a V1 vasopressin antagonist did not modify the pressor response produced by topical application of vasopressin (10(-4) M). Application of the V1 antagonist to the rostral pressor area, however, prevented the production of a pressor effect to subsequent topical application of vasopressin (10(-4) M). These experiments suggest that vasopressin stimulates the activity of vasomotor neurons in the rostral ventrolateral medulla by a mechanism that involves a neuronal V1 receptor.

Animals↗

PubMed1990

The renin-angiotensin system during acute myocardial ischemia in dogs.

We used the technique of high-performance liquid chromatography combined with radioimmunoassay to establish the profile of angiotensin peptides in the periphery and across the circulation of the dog's heart. Data were obtained before and after blockade of angiotensin converting enzyme, and after acute myocardial ischemia produced by occlusion of the left anterior descending coronary artery. Baseline values of plasma renin activity and immunoreactive angiotensin II were higher in the aortic root than in the coronary sinus but concentrations of angiotensin I and angiotensin-(1-7) were similar. In untreated animals, coronary occlusion produced significant increases in renin activity and arterial and venous levels of angiotensin I and angiotensin II. Inhibition of converting enzyme with benazeprilat (CGS-14,831) increased baseline circulating levels of angiotensin I, whereas angiotensin II and its carboxyl terminal fragments were reduced markedly. Baseline plasma levels of angiotensin-(1-7) and its fragments did not change. Myocardial ischemia in benazeprilat-treated dogs increased plasma renin activity and circulating levels of angiotensin I. Concentrations of angiotensin II and angiotensin-(1-7) did not change either in peripheral blood or across the coronary circulation. These results indicate that angiotensin peptides can be formed endogenously by enzymatic pathways alternate to converting enzyme. Furthermore, these data provide the basis for a further understanding of the role of the renin-angiotensin system after myocardial ischemia.

Acute Disease↗

PubMed1990

Pathways of angiotensin formation and function in the brain.

New findings from this laboratory suggest that fragments of angiotensin derived from the amino (N-)terminus are biologically active end products of the renin-angiotensin system. In vitro and in vivo experiments revealed that the heptapeptide angiotensin-(1-7) [Ang-(1-7)] is a major endogenous product of the renin-angiotensin system cascade in the brains of rats and dogs. Additional studies with enzyme inhibitors showed that Ang-(1-7) is produced directly from angiotensin I by an enzyme other than the angiotensin converting enzyme. Immunocytochemical fibers within the hypothalamo-neurohypophyseal vasopressinergic system of the rat. Although Ang-(1-7) is as potent as angiotensin II (Ang II) in stimulating release of vasopressin from superperfused hypothalamo-neurohypophyseal explants, the heptapeptide has no dipsogenic or vasoconstrictor activity. In contrast, Ang-(1-7) mimics the effects of Ang II in augmenting the intrinsic discharge rate of neurons within the vagal-solitary complex and in causing monophasic depressor responses after microinjection into the medial region of the nucleus tractus solitarii. The evidence obtained in these experiments suggests novel mechanisms for the generation of angiotensin peptides in the brain. Additionally, the findings suggest that some of the biological actions ascribed to Ang II might be conveyed by the endogenous production of other angiotensin peptides that are generated by enzymatic pathways alternate to those described in the peripheral circulation.

Angiotensin I↗

PubMed1990

Actions of angiotensin peptides after partial denervation of the solitary tract nucleus.

We determined the excitatory effects of direct nucleus tractus solitarii injection of angiotensin peptides after the sinoaortic nerves were cut unilaterally in rats under halothane anesthesia. Twenty-four hours later, recordings of mean arterial pressure and heart rate were obtained during injections of 2.5 ng angiotensin II or angiotensin-(1-7) in chloralose-urethane-anesthetized rats. Both peptides caused reductions in pressure and heart rate after nucleus tractus solitarii injections. In unilateral sinoaortic denervated rats, the hypotension and bradycardia produced with angiotensin II injections in either the ipsilateral (denervated) or contralateral (nondenervated) nucleus tractus solitarii were comparable. Angiotensin-(1-7), however, produced a larger decrease in pressure on the denervated side when compared with the nondenervated side. There were no differences in baseline pressure or heart rate between control rats and those with unilateral sinoaortic denervations. The effects of both angiotensin II and angiotensin-(1-7) were blocked by previous administration of the angiotensin II antagonist [Sar1,Thr8]angiotensin II into the nucleus tractus solitarii. Assessment of angiotensin II binding sites in the solitary-vagal complex 24 hours after denervation showed a 13% reduction in angiotensin receptors. These findings confirm that both angiotensin II and angiotensin-(1-7) express biological activity through receptor-mediated actions in the dorsal medulla oblongata. That the effects produced by angiotensin II do not require the integrity of baroreceptor input further suggests that the receptors responsible for the acute cardiovascular actions of this peptide reside on postsynaptic elements in the vagal-solitary complex.

Angiotensin I↗

PubMed1990

Role of vasopressin in cardiovascular and neurohormonal responses to intracerebroventricular hypertonic NaCl.

To determine the significance of vasopressin in cardiovascular and neurohormonal responses caused by centrally administered hypertonic NaCl, we examined the effects of a vasopressin antagonist on blood pressure, heart rate, plasma levels of catecholamines, cortisol and renin activity in anesthetized dogs. Intracerebroventricular (ICV) injections of 0.2 ml of 1.5 M NaCl increased mean arterial blood pressure (+29.7 +/- 3.0 mmHg, mean +/- SE), heart rate (+27.9 +/- 7.0 beats/min), plasma concentrations of vasopressin (+48.9 +/- 8.2 pg/ml), norepinephrine (+40.0 +/- 6.2 pg/ml), epinephrine (+231.4 +/- 21.4 pg/ml) and cortisol (+5.3 +/- 1.1 micrograms/dl) and decreased plasma renin activity (-2.0 +/- 0.4 ng/ml/hr). An intravenous vasopressin antagonist, d(CH2)5Tyr(Me)AVP, at a dose of 10 micrograms/kg, attenuated the pressor response and augmented the heart rate response to ICV 1.5 M NaCl. The vasopressin antagonist also augmented the change in plasma norepinephrine and significantly attenuated the responses of cortisol and renin. Baseline levels of these variables were not altered by the vasopressin antagonist except for an increase in renin activity. Two injections of hypertonic NaCl without any pretreatment produced similar cardiovascular and hormonal responses. These results suggest that vasopressin contributes not only to an increase in blood pressure, but also to changes in the sympathetic nervous system, the hypothalamo-adrenocortical axis and the peripheral renin-angiotensin system in response to a central sodium stimulus.

Animals↗

PubMed1990

Importance of the renin-angiotensin-aldosterone system (RAS) in the physiology and pathology of hypertension. An overview.

Current leading theories of the mechanisms of essential hypertension include the participation of the renin-angiotensin-aldosterone system (RAS). Recent advances provide means for a critical reassessment of this system in the physiology and pathology of hypertension. The expression of the proteins of the RAS in organs other than the kidneys suggests that angiotensin II also acts as a modulator of cell function. This paper discusses the role of tissue angiotensin peptides in the regulation of blood pressure and suggests new ideas with regard to the importance of the brain RAS in the development of essential hypertension.

Angiotensin II↗

PubMed1990

The renin-angiotensin system: importance in physiology and pathology.

In recent years, the role of the renin-angiotensin system (RAS) in the development of hypertension has been investigated extensively. Studies have shown that there are actually two systems: a tissue and a circulating RAS. The control of hypertension is focused primarily in the RAS in the cardiovascular system and the brain. By manipulating the RAS with angiotensin converting enzyme (ACE) inhibitors, researchers have learned that the cardiovascular neuronal centers in the brain have receptor sites for the actions of angiotensin II (Ang II). Receptors for Ang II are found in the medulla oblongata in neurons involved in the regulation of baroceptor activity. Since studies in both animals and hypertensive patients indicate that ACE inhibitors reduced sympathetic activity and enhanced baroceptor sensitivity, it is possible that the primary hypotensive mechanism of these agents is through blockage of Ang II formation in the cardiovascular centers of the brain.

Angiotensin II↗

PubMed1990

Angiotensin-[1-7]: evidence for novel actions in the brain.

Structure-activity studies of angiotensin II (Ang II) have clearly established that the carboxyl-terminal phenylalanine is crucial for activation of angiotensin receptors associated with a broad range of effects including vasoconstriction, aldosterone release, and dipsogenesis. Thus, the heptapeptide angiotensin-[1-7] (Ang-[1-7]) has been classified as an inactive metabolite of the hormone Ang II. This assumption was seriously questioned in light of the report from our laboratory that Ang-[1-7] is the major metabolite of dog brainstem homogenates both in the absence and in the presence of angiotensin-converting enzyme inhibitors. These data raised the possibility of a functional role for Ang-[1-7] in the brain. Subsequent studies in the in vitro hypothalamoneurohypophysial system of the rat demonstrated that Ang-[1-7] is equipotent with Ang II in its activation of AVP release. Other Ang II-like actions have since been identified for Ang-[1-7] in the brain. For example, microinjection of Ang-[1-7] into brainstem nuclei of the rat promotes bradycardia and hypotension; in addition, Ang-[1-7] mimics the effect of Ang II in augmenting the intrinsic discharge rate of neurons within the vagal-solitary complex of the dog. Our laboratory has also provided evidence for synthesis and storage of Ang-[1-7] in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1990

Selective blockade of angiotensin responses in the rabbit isolated vas deferens by angiotensin receptor antagonists.

We examined the effect of two angiotensin receptor antagonists on neuromodulatory and prostaglandin-producing effects of angiotensin II in the rabbit isolated vas deferens because prior studies have established that angiotensins selectively influence the two neural events, one being adrenergic and the other nonadrenergic. Angiotensin II increased adrenergic neurotransmission and prostaglandin E synthesis in a concentration-dependent manner while depressing nonadrenergic neurotransmission. The [1-Sarcosine, 8-Alanine]-angiotensin II preferentially antagonized adrenergic neuromodulatory effects of angiotensin II. In contrast, the nonadrenergic neuromodulatory and prostaglandin E-releasing effects of angiotensin II were suppressed by [1-Sarcosine, 8-Alanine]-angiotensin II to a lesser extent. The nonpeptide angiotensin receptor antagonist, Dupont 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2(1)-(1-H-tetrazol-5-yl) biphenyl-4-yl)methyl] imidazole, potassium salt, exhibited the opposite selectivity. It eliminated the depression of nonadrenergic neurotransmission without significantly altering the potentiation of adrenergic neurotransmission caused by angiotensin II. The angiotensin-induced stimulation of prostaglandin E synthesis was also eliminated by this antagonist. These data suggest that angiotensin effects in the vas deferens are mediated by at least two types of angiotensin receptors.

Angiotensin II↗

PubMed1989

Identification of angiotensin-(1-7) in rat brain. Evidence for differential processing of angiotensin peptides.

Tissue and plasma forms of angiotensin (Ang) peptides were characterized by reverse-phase high performance liquid chromatography and three specific radioimmunoassays. This method allowed resolution of 10 Ang peptides and revealed distinctive distributions for the three principal Ang peptides in the brain, adrenal gland, and plasma. In extracts from the rat hypothalamus, approximately equimolar amounts of Ang-(1-7), Ang-II, and Ang-I were detected (1.10, 1.18, and 1.45 pmol/g of tissue, respectively). A similar profile was observed in the medulla oblongata and amygdala, although the content of these three peptides was 40-70% less than that seen in the hypothalamus. In the adrenal gland, the predominant peptide was Ang-II (1.07 pmol/g); levels of Ang-(1-7) (0.19 pmol/g) and Ang-I (0.14 pmol/g) were approximately 20% that of Ang-II. In plasma, the major angiotensin was Ang-I (0.13 pmol/ml), with lower levels of Ang-(1-7) and Ang-II (0.01-0.02 pmol/ml). This study is the first demonstration of the endogenous presence of Ang-(1-7) in central and peripheral tissues of the rat. Moreover, the data suggest tissue-specific processing of angiotensins, with Ang-(1-7) being a predominant Ang peptide in the central nervous system. In light of the recent biological properties described for this peptide, Ang-(1-7) may represent an active member of Ang peptides in the brain.

Adrenal Glands↗

PubMed1989

Activation of renal sympathetic outflow by intracisternal hypertonic NaCl in dogs.

The neurohormonal and sympathetic nervous system responses to injection of hypertonic NaCl (1.5 M) into the cisterna magna were investigated in morphine-pentobarbital-anesthetized dogs (n = 8). Mean arterial blood pressure (MAP), heart rate (HR), and integrated efferent renal sympathetic nerve activity (ERSNA) were recorded, and blood samples were taken for the determination of plasma concentrations of epinephrine (Epi), norepinephrine (NE), arginine vasopressin (AVP), osmolality, plasma renin activity (PRA), and serum sodium and potassium. By 2 min after injection of hypertonic NaCl into the cisterna magna, significant increases were observed for MAP (+47 +/- 5 mmHg, P less than 0.01), HR (+59 +/- 11 beats/min, P less than 0.01), and ERSNA (+47 +/- 16%, P less than 0.01) above base line. The increased activity of the sympathetic nervous system was not accompanied by changes in PRA, Epi, NE, or AVP. Hypertonic NaCl was injected into the cisterna magna of six dogs before and after intravenous administration of the AVP antagonist [d(CH2)5Tyr(Me)]AVP. The time course for increases in MAP, HR, and ERSNA was not affected by AVP blockade. Subsequent administration of hexamethonium chloride abolished the pressor, tachycardic, and ERSNA responses elicited by cisterna magna injection of hypertonic NaCl. These experiments indicate that hypertonic NaCl acts at the lower brain stem to activate the sympathetic nervous system. Further, the pressor and tachycardic responses evoked by hypertonic NaCl acting at the lower brain stem do not appear to involve the hypothalamic-hypophysial-adrenal axis.

Animals↗

PubMed1989

Cardiovascular effects of angiotensin-(1-7) injected into the dorsal medulla of rats.

The amino terminal angiotensin heptapeptide, Asp-Arg-Val-Tyr-Ile-His-Pro [ANG-(1-7)], is the major product formed during incubation of 125I-labeled ANG I or 125I-labeled ANG II with homogenates obtained from canine dorsomedial medulla oblongata. To determine whether ANG-(1-7) has central-mediated cardiovascular effects, this heptapeptide was microinjected into the dorsal medulla of chloralose-urethan-anesthetized rats. Unilateral injections of ANG-(1-7) into the medial nucleus tractus solitarii caused depressor and bradycardic effects at doses between 0.1 and 12.5 ng. Similar hypotensive responses accompanied with bradycardia were produced by injections of ANG-(1-7) into the dorsal motor nucleus of the vagus. In both nuclei, the monophasic depressor responses elicited by ANG-(1-7) were qualitatively similar to those found with injections of ANG II. Biphasic depressor-pressor responses of variable magnitude were produced by the injection of either angiotensin peptide at a high dose (250 ng). Because ANG-(1-7) has no direct vascular or dipsogenic effects, our findings suggest important differences in the receptor requirements for vascular and neural tissue of the dorsal medulla. Moreover, the data support the concept of tissue specific formation and action of angiotensin peptides in the brain.

Angiotensin I↗

PubMed1989

Alternative mechanism for attenuated pressor responses in AV3V-lesioned dogs.

We lesioned the periventricular tissue of the anteroventral portion of the third cerebral ventricle (AV3V) of dogs to evaluate the mechanism that accounts for blunting of the pressor activity of angiotensin II (ANG II). AV3V lesions were done with a microknife using a transbuccal approach; the procedure denervated the organum vasculosum of the laminae terminalis, the nucleus medianus, and the medial preoptic nucleus. Two to four days after surgery, the conscious AV3V-lesioned dogs showed adipsia and their blood contained increased quantities of Na+ (175 +/- 2 meq/l) and an elevated osmolality (352 +/- 5 mosmol/kg). Cardiac rate was faster (131 +/- 8 beats/min) in AV3V-lesioned dogs, but their mean arterial pressure (MAP) was within normal values (99 +/- 4 mmHg). These changes were accompanied by an almost 18-fold increase in the plasma levels of immunoreactive ANG II (irANG II). In contrast, plasma vasopressin (AVP) levels fell to nondetectable values. Pressor responses produced by intravenous infusions of ANG II or injections of norepinephrine (NE) were significantly blunted 3 days after AV3V ablation. Short-term treatment of eight AV3V-lesioned dogs with the synthetic AVP analogue, 1-desamino-8-D-arginine vasopressin, reduced plasma Na+ and irANG II levels. The pressor activity of peripheral infusions of ANG II was restored to prelesion values, whereas pressor responsiveness to NE remained depressed. These data suggest that the blunting of the pressor action of ANG II in AV3V-lesioned dogs is an expression of a disorder in the regulation of renal and behavioral mechanisms maintaining fluid balance and AVP secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1989

The renin angiotensin system: importance in physiology and pathology.

Angiotensin II has long been recognized as a key factor in cardiovascular regulation. The effectiveness of angiotensin-converting enzyme (ACE) inhibitors in controlling essential hypertension suggests that angiotensin II plays a key role in its pathology. The tools of molecular biology have provided the means for a critical reassessment of the renin-angiotensin-aldosterone system in physiology and pathology. The analysis has shown that angiotensin peptides are also synthesized and processed locally in a variety of tissues, including the vascular wall, adrenal glands, heart, and brain. Since angiotensin II is a potent modulator of cardiovascular control centers in the brain, the hypothesis is now advanced that a defect in the brain renin-angiotensin-aldosterone system contributes to the development of hypertensive disease.

Angiotensin II↗