Biomedical subjects

C M Ferrario

Publications and source records attributed to C M Ferrario.

At least 163 records · Page 9Linked to original sources

PubMed1989

Malignant hypertension, fibrinoid deposition, and fibrinogen electrophoresis.

Electrophoretic profiles of the molecular weight distributions of fibrinogen derivatives in blood provide a tool for combined assessment of coagulation and fibrinolysis in the course of vascular disease. Profiles obtained in studies on an experimental model of hypertension and in humans with occlusive vascular disease are discussed. In the experimental studies elevations in the level of cross-linked dimers provided a more reliable means for predicting development of malignant hypertension than did many other criteria, especially near the outset when blood pressure changed to similar degrees in rats with malignant and benign hypertension. Similarly, we find that levels of dimeric and occasionally trimeric forms of fibrinogen are more prominently elevated than degraded forms of fibrinogen in patients with occlusive vascular disease.

Animals↗

PubMed1988

Distribution of catecholaminergic neuronal systems in the canine medulla oblongata and pons.

The distribution of catecholamine-containing neurons, fibers, and varicosities in the brainstem of both adult and juvenile dogs was mapped in detail with glyoxylic acid histofluorescence. Four separate groups of catecholamine-fluorescent neurons were identified within the canine medulla and pons in locations comparable to the A1, A2, A5, and A6 regions reported in other species. However, aspects of the pattern and density of the catecholaminergic neuronal systems appeared to be unique to the dog. The A1 neurons of the caudal ventrolateral medulla were much more scattered than in rats or rabbits, but relatively similar to cats. In the A2 region of the dorsomedial medulla, catecholaminergic cells and fibers were uniquely distributed compared to other species: fluorescent neurons were scattered only within the dorsal motor nucleus of the vagus, and a distinctive pattern of fibers and varicosities outlined the nucleus of the solitary tract and dorsal motor nucleus of the vagus. The A5 neurons of the rostral ventrolateral medulla appeared at the rostral limit of the A1 region. Fluorescent A5 cells were more sparse than in rats or primates, and were patterned similarly to cats and rabbits. The canine A6 region contained the most extensive and dense grouping of catecholamine neurons and was similar in pattern to the rabbits but less extensive than that seen in cats or primates. An ascending catecholaminergic fiber pathway was traced through the central tegmental field of the canine medulla and pons, with features similar to the primate. The present study provides the first description of the catecholaminergic neuronal systems of the canine medulla.

Animals↗

PubMed1988

Release of vasopressin from the rat hypothalamo-neurohypophysial system by angiotensin-(1-7) heptapeptide.

We have recently shown that hydrolysis of labeled angiotensin I in canine brainstem homogenate causes a rapid accumulation of the heptapeptide angiotensin-(1-7) [Ang-(1-7)]. Although this angiotensin fragment has no vasopressor activity, its consistent generation in brain homogenate led us to study its potential neurosecretory effects in the rat hypothalamo-neurohypophysial system (HNS) in vitro. Ang-(1-7) or angiotensin II (Ang II) was added to HNS perifusate in concentrations of 0.04, 0.4, and 4 microM, and release of arginine vasopressin (AVP) during each treatment was quantified as a percentage of the AVP release detected in the preceding collection period. Base-line release of AVP averaged 281 +/- 47 pg per 15 min (mean +/- SEM) in HNS explants (five experiments, five explants per chamber) perifused in Krebs solution at 37 degrees C, after a 1-hr equilibration period. At 0.04 microM, Ang II or Ang-(1-7) did not stimulate AVP release. Ang II increased AVP release over the control value by 172% +/- 44% and 268% +/- 66% at 0.4 and 4 microM, respectively; the same concentrations of Ang-(1-7) increased AVP release by 134% +/- 12% and 216% +/- 45%. The responses to Ang II and Ang-(1-7) at the highest concentration were both significant (P less than 0.05), and comparison by two-way analysis of variance indicated that Ang II and Ang-(1-7) were equipotent in stimulating AVP release over the range of concentrations studied. In the presence of the competitive Ang II antagonist [Sar1,Thr8]Ang II (20 microM), the release of AVP increased approximately equal to 2-fold. Neither Ang II nor Ang-(1-7) (4 microM) caused a further enhancement of AVP release in the presence of [Sar1,Thr8]Ang II. These data suggest that a hydrophobic residue in position 8 of the angiotensin peptide is not essential for activation of angiotensin receptors in the rat HNS. Moreover, the equipotence of Ang II and Ang-(1-7) indicates that Ang-(1-7) may participate in the control of AVP release.

Angiotensin I↗

PubMed1988

Hemodynamic and neurohormonal changes in the development of DOC hypertension in the dog.

In this article we summarize studies of the hemodynamic and endocrine effects of desoxycorticosterone (DOC)-induced hypertension in dogs and also review new data of the action of this steroid on baroreceptors. The hemodynamic effect of subcutaneous injections of DOC to dogs, without supplementation of salt in their diet, consisted of increases in arterial pressure that were sustained for a 28-day observation period and associated with augmented cardiac output. At the early stage of the hypertensive response there was a rise in plasma Na+ concentration accompanied by increases in the plasma and cerebrospinal fluid (CSF) levels of vasopressin. The activity of the peripheral renin angiotensin system, as evaluated by the longitudinal changes in plasma renin activity and plasma immunoreactive angiotensin II (irAng-II), was markedly depressed in the hypertensive dogs. In contrast, the concentration of irAngII in the CSF did not change. Additional studies of the carotid occlusion reflex in anesthetized dogs revealed an enhanced buffering baroreceptor capacity in the early (less than day 10), but not the late (greater than day 28), stages of the hypertension. The abnormality in baroreflex function may be mediated by an effect of the steroid on an activity of brain angiotensin II that influences the inhibitory interaction between high and low pressure baroreceptors. The data acquired in these studies agree with the notion that excess mineralocorticoid production causes hypertension by mechanisms that influence the neurohormonal control of blood pressure by the central nervous system.

Angiotensin II↗

PubMed1988

Bidirectional transport of angiotensin II binding sites in the vagus nerve.

We previously showed that specific angiotensin II (Ang II) binding sites are present in the canine nodose ganglion and peripheral vagus nerve, and that unilateral removal of the nodose ganglion results in loss of binding in the ipsilateral nucleus tractus solitarii and the dorsal motor nucleus of the vagus. An association of Ang II binding sites with both afferent and efferent vagal fibers is consistent with actions of the peptide on cardiac vagal tone and the baroreceptor reflex. To investigate possible transport of Ang II binding sites, quantitative in vitro receptor autoradiography was used to visualize binding after double ligation of the peripheral process of the cervical vagus nerve. One ligature was tied 0.2 to 0.5 cm distal to the nodose ganglion; the second ligature was tied on the same nerve 1.0 to 1.5 cm from the nodose ganglion. Twenty-four hours later, high-affinity Ang II binding sites (Ka = 0.46 +/- 0.08 nM) accumulated at the first ligature (the side nearest the nodose ganglion), indicating anterograde transport. Since accumulations of similar affinity sites were seen distal to the second ligature, retrograde transport of binding sites also occurred. These data reveal the existence of a mechanism for the bidirectional axonal transport of Ang II binding sites in the cervical portion of the vagus nerve.

Angiotensin II↗

PubMed1988

Converting enzyme activity and angiotensin metabolism in the dog brainstem.

The concentrations of angiotensin converting enzyme (ACE) activity, norepinephrine, and serotonin were measured in microdissected regions of the dog's brainstem and spinal cord. In addition, we determined the in vitro metabolism of 125I-angiotensin I (Ang I) in homogenates of the same brain punch regions. High ACE-specific activity was found in the monoamine-containing regions of the brainstem and in the intermediolateral column of the spinal cord. In brainstem homogenates 125I-Ang I was metabolized to angiotensin II (Ang-[1-8]) and the N-terminal heptapeptide Ang-(1-7). In the presence of MK 422 (50 microM), Ang-(1-7) was still generated, while the production of Ang-(1-8) was inhibited. This study revealed the presence of high ACE activity in monoamine regions of dog brainstem and spinal cord, and showed that the metabolite Ang-(1-7) is the major product generated from Ang I in the presence and absence of ACE inhibition.

Angiotensin I↗

PubMed1988

In vivo release of angiotensin II from the rat hypothalamus.

Recent studies suggest that angiotensin II is released from neuronal tissue in vitro, but the occurrence of this phenomenon in the intact brain has not yet been demonstrated. To characterize the in vivo release of immunoreactive angiotensin II, push-pull cannulas were positioned in the anterior hypothalamus in 47 Sprague-Dawley rats (200-250 g) anesthetized with Inactin (100 mg/kg i.p.). Artificial cerebrospinal fluid was perfused at 20 microliters/min, and effluent samples were collected for 15-minute periods over 2 hours. Angiotensin II was detectable (greater than 2.5 pg/ml) in the push-pull cannula perfusate of the majority (76%) of the rats. Spontaneous release of immunoreactive angiotensin II was constant for 2 hours in 11 rats at values averaging from 4.4 +/- 1.5 to 8.2 +/- 2.2 pg/ml. In addition, bilateral nephrectomy performed 48 hours before did not affect the detection of angiotensin II (n = 3). Angiotensin immunoreactivity in the rat hypothalamus was further characterized by high performance liquid chromatography. The analysis showed that the perfusate contained authentic angiotensin II as well as other angiotensin metabolites. The effect of beta-adrenergic modulation on the release of angiotensin II was assessed in 20 rats by adding isoproterenol (10(-10), 10(-8), and 10(-6) M), propranolol (10(-6) M), or a combination of both. Neither activation nor inhibition of hypothalamic beta-receptors altered the spontaneous release of angiotensin II. These data demonstrate that angiotensin II and congener peptides are detectable in the microenvironment of the anterior hypothalamus of the anesthetized rat and that the release of angiotensin II immunoreactivity in the anterior hypothalamus is not modified by beta-adrenergic receptors.

Angiotensin II↗

PubMed1988

The ventrolateral medulla. A new site of action of the renin-angiotensin system.

High-affinity binding sites for angiotensin II (Ang II) in the ventrolateral medulla suggest that Ang II may act at cell groups that are known to modulate blood pressure. This hypothesis was investigated by the topical application of angiotensin I (Ang I), Ang II, the Ang II antagonist [Sar1, Thr8]Ang II, and the Ang I converting enzyme inhibitor MK 422 to a restricted region of the ventral medullary surface known as the glycine-sensitive area. Both Ang I (100 pmol) and Ang II (100 pmol) produced significant (p less than 0.01) increases in blood pressure (+20 +/- 4 and +31 +/- 5 mm Hg, respectively) that were associated with no change in heart rate. Furthermore, the relationship between the peak increases in blood pressure and Ang II was dose-dependent. Blockade of endogenous Ang II by [Sar1, Thr8]Ang II (13 nmol) produced a significant decrease in baseline blood pressure (-8 +/- 1 mm Hg; p less than 0.001). Similarly, topical application of MK 422 prevented the pressor effect of Ang I. Taken together, these experiments indicate that at least some components of the renin-angiotensin system exist in the ventrolateral medulla and they may modulate vasomotor outflow.

Angiotensin I↗

PubMed1988

Baroreceptor reflex modulation by angiotensin II at the nucleus tractus solitarii.

This study characterized the effect of nucleus tractus solitarii (NTS) microinjection of the angiotensin II (Ang II) antagonist [Sar1, Thr8]Ang II on the baroreceptor control of heart rate in anesthetized rats. Reflex changes in heart rate were elicited by bolus intravenous injections of either phenylephrine or sodium nitroprusside before and after bilateral microinjection of [Sar1, Thr8]Ang II (100 pmol) or vehicle into the NTS. The slope of the relationship between the change in pulse interval and the change in mean arterial pressure was used as an index of baroreceptor reflex sensitivity. Bradycardia elicited by phenylephrine-induced increases in pressure was significantly greater after NTS injection of [Sar1, Thr8]Ang II. The slope of the pulse interval-arterial pressure relationship was 0.60 +/- 0.09 ms/mm Hg after injection, as compared with 0.42 +/- 0.07 ms/mm Hg before. In contrast, the baroreceptor reflex sensitivity index generated by decreases in pressure with nitroprusside was similar before and after injection. Vehicle injections did not alter the baroreceptor reflex index. Collectively, the data suggest that inhibition of endogenous Ang II in the NTS facilitates the baroreceptor reflex sensitivity to increases, but not decreases, in pressure. This new finding reveals the NTS as one site of action for the tonic effects of endogenous Ang II.

Angiotensin II↗

PubMed1988

Characteristics of hormonal and neurogenic mechanisms of deoxycorticosterone-induced hypertension.

We characterized the hemodynamic and endocrine changes associated with the evolution of steroid-induced hypertension in conscious, trained, instrumented dogs given intramuscular injections of deoxycorticosterone (DOC) pivalate on Days 1 (20 mg/kg) and 14 (10 mg/kg) of the study. Because hypertension could be produced in these dogs without salt loading and unilateral nephrectomy, the research afforded a novel opportunity to determine the primary effects of DOC excess on the renin-angiotensin and sympathetic nervous systems, and on vasopressin levels. Both before and during 28 days of DOC treatment, regular measurements of mean arterial pressure, heart rate, cardiac output, and total peripheral resistance were coupled with serial determinations of plasma and cerebrospinal fluid levels of angiotensin II, vasopressin, norepinephrine, and electrolytes. DOC induced a progressive rise in mean arterial pressure associated with increased cardiac output and no change in heart rate. These hemodynamic changes were accompanied by sustained decreases in plasma renin activity, and in plasma, but not cerebrospinal fluid, angiotensin II. In contrast, plasma and cerebrospinal fluid vasopressin rose transiently on the 7th and 14th days of the study, respectively. After anesthesia with morphine and chloralose, the hemodynamic response to occlusion of a sole innervated carotid artery was evaluated on the 5th week before and after cervical vagotomy. Compared to normal animals, dogs with DOC-induced hypertension showed a reduced pressor response to carotid occlusion associated with suppression of reflex tachycardia; vagotomy partially restored the pressor response to normal levels. The data suggest that DOC-induced hypertension changes central hormonal influences of cardiovascular function, and also alters cardiopulmonary baroreceptor reflex control of peripheral sympathetic nerve activity.

Angiotensin II↗

PubMed1988

Neuronal responses to angiotensin II in the in vitro slice from the canine medulla.

The present studies utilized the in vitro slice preparation of the canine dorsomedial medulla, which we have recently developed, to obtain direct evidence for the effects of angiotensin II (Ang II) on the activity of single neurons in this region. Horizontally oriented slices (300 micron) containing the area postrema, nucleus tractus solitarii (NTS), and dorsal motor nucleus of the vagus were perifused with oxygenated artificial cerebrospinal fluid. The effects of microdrop application of Ang II and its antagonist [Sar1,Thr8]Ang II on spontaneous firing rate were determined in 27 extracellularly recorded neurons. Ang II substantially increased the firing rate of 13 neurons located in the medial NTS, but it did not alter the spontaneous activity of the remaining 14 neurons. In most cases Ang II elicited a slowly developing, prolonged excitatory response. The effects of both Ang II and [Sar1,Thr8]Ang II were tested in 13 neurons. [Sar1,Thr8]Ang II produced a short latency, brief excitation in three neurons, marked inhibition of spontaneous firing in two cells, and no effect on the other eight neurons. Administration of [Sar1,Thr8]Ang II blocked the excitatory effects of subsequent administration of Ang II in three neurons. To our knowledge, these observations provide the first evidence for direct actions of both Ang II and [Sar1,Thr8]Ang II on neurons in the canine NTS and for the specificity of the neuronal effects of Ang II as documented by blockade of the excitatory response to Ang II by [Sar1,Thr8]Ang II.

Action Potentials↗

PubMed1988

A hypothesis regarding the function of angiotensin peptides in the brain.

Studies of the in vivo and in vitro metabolism of angiotensin peptide precursors, and of angiotensin II (Ang II) in tissues, has revealed the possibility that some of the fragments formed through specific enzymatic pathways are bioactive. There is evidence that Ang III is as potent as Ang II in stimulating thirst and causing aldosterone secretion. New findings from this laboratory have led us to reevaluate the concept that fragments of angiotensins derived from the amino (N-) terminus are devoid of biological activity. Using in vitro and in vivo techniques, we showed that Ang-(1-7) is processed from Ang I in amounts equal to or greater than Ang II. In addition, Ang-(1-7) generation is not dependent upon Ang I converting enzyme (ACE) activity in homogenates of canine brain stem. This heptapeptide promotes release of vasopressin from perifused hypothalamo-neurohypophysial explant and stimulates neural responses when microinjected into the vagal-solitary complex. The data supporting these findings are discussed below.

Angiotensin II↗

PubMed1988

Effect of Na+/H+ exchange inhibitors on agonist-induced contraction of rat aorta.

A number of vasoconstrictor agonists activate the Na+/H+ antiport system in vascular smooth muscle, leading to alkalinization of the cytosol and influx of Na+. It is believed that agonist-induced Na+/H+ exchange may play an important role in contraction. We have evaluated this hypothesis by determining the effect of inhibition of Na+/H+ exchange on phenylephrine (PE)-induced contraction of rat aorta. Preincubation of rat aorta with the Na+/H+ exchange inhibitor amiloride (0.5 mM) inhibited subsequent PE-induced contraction. However, the more potent and specific Na+/H+ exchange inhibitor hexamethylene amiloride (10 microM) did not inhibit PE-induced contraction. Inhibition of Na+/H+ exchange by removal of extracellular Na+ and substitution with N-methyl-D-glucamine only moderately reduced PE-induced contraction. Hexamethylene amiloride (10 microM) and methyl-isobutyl amiloride (30 microM), another potent and specific inhibitor of Na+/H+ exchange, caused a slow, sustained and reversible contraction of rat aorta which was 114.7 and 86.6%, respectively, of maximal PE-induced contraction. Hexamethylene amiloride-induced contraction was dose-dependent, dependent on extracellular calcium and inhibited by nifedipine. We conclude that the vasorelaxant effects of amiloride are unrelated to inhibition of Na+/H+ exchange, and may be mediated by inhibition of kinases involved in contraction. These results demonstrate that inhibition of Na+/H+ exchange has no major effect on agonist-induced contraction of rat aorta, and suggest that vasoconstrictor activation of Na+/H+ exchange does not play a major role in agonist-induced contraction of rat aorta.

Amiloride↗

PubMed1987

Pressor responses of angiotensin II microinjected into the dorsomedial medulla of the dog.

Angiotensin II (Ang II) was injected into regions of the dorsomedial medulla of dogs where both specific Ang II binding and neural elements containing this peptide are found. Picomole amounts of the peptide were delivered simultaneously from a linear array of 3 micropipettes with tips positioned concurrently in either the area postrema (ap), nucleus tractus solitarii (nTS), dorsal motor nucleus of the vagus (dmnX), or hypoglossal nucleus (nXII). Significant increases in blood pressure occurred with Ang II injections into the medial nTS (+12 +/- 2 mm Hg), the ap(+9 +/- 3 mm Hg), and the nXII (+6 +/- 2 mm Hg). In both the medial nTS and the nXII, the pressor responses were accompanied by significant increases in heart rate (+13 +/- 3 beats/min and +8 +/- 3 beats/min, respectively). Ang II injected into the dmnX did not produce consistent effects on blood pressure or heart rate. These data demonstrate that unilateral injections of picomole amounts of Ang II produce changes in blood pressure and heart rate which involve neural elements in the ap and medial nTS.

Angiotensin II↗

PubMed1987

Chronic sodium depletion suppresses the area postrema pressor pathway.

Sodium depletion in dogs is known to affect both the renin-angiotensin as well as the sympathetic nervous system. The effect of this dietary regime upon the area postrema pressor pathway, as evaluated by the cardiovascular responses to centrally acting angiotensin II, has not been determined previously. With this in mind, male mongrel dogs were maintained on either a normal or a sodium restricted diet supplemented with furosemide and dose-response curves for intravertebral and intravenous angiotensin II (range: 1-20 ng/kg/min) were obtained. Sodium depletion results in not only a blunted intravenous pressor response to angiotensin II but also the abolition of the centrally mediated pressor responses mediated by the area postrema. Because accumulating evidence indicates that in sodium depleted dogs sympathetic nerve activity is reduced while central noradrenergic inhibitory activity is increased the reduced effects of angiotensin II upon the central sympathetically mediated pressor response may in part be related to decreases in sympathetic nerve activity.

Angiotensin II↗

PubMed1987

Projections of the carotid sinus nerve to the medulla in the dog.

The afferent and efferent projections of the carotid sinus nerve were examined within the medulla of the dog with axonal transport of horseradish peroxidase (HRP), and compared with the projections of the glossopharyngeal nerve. The carotid sinus nerve was identified electrophysiologically prior to injection of tracer. Carotid sinus nerve afferent fibers entered the medulla as part of the glossopharyngeal nerve root near the caudal limits of the cochlear nuclei. Labeled axons entered the solitary tract and ran caudally to about 3 mm anterior to the obex, where they began to enter the nucleus tractus solitarii (nTS). Carotid sinus afferent fibers and presumptive terminals were discretely localized within limited portions of the ipsilateral dorsal, medial, and lateral nTS as far as 3 mm caudal to the obex. A few fibers entered the dorsolateral area postrema ipsilateral to HRP injection. Labeled fibers in the commissural nTS crossed the midline and entered the contralateral medial nTS. Efferent neurons were observed only in half of the cases, and were limited to one to three labeled perikarya in the periphery of the retrofacial nucleus. Comparison of the carotid sinus distribution with the previously described vagal afferent projections to the canine nTS revealed partially overlapping, but clearly distinctive patterns, which support a viscerotopic organization of the nTS.

Afferent Pathways↗

PubMed1987

Role of area postrema pressor mechanisms in the regulation of arterial pressure.

This article discusses the data which established that angiotensin II modulates the tonic and reflex control of cardiovascular function by actions on the nuclear regions of the dorsal medulla oblongata. Although physiological evidence for the modulatory actions of angiotensin II in structures of the lower brainstem has been gathered over the past 16 years, only the recent application of new neurobiological techniques has allowed a more definitive understanding of its role. The identification of high affinity angiotensin II binding sites within the parenchyma of the area postrema with the technique of in vitro receptor autoradiography has provided anatomical validity for a role of angiotensin II in the central nervous system. The added discovery of angiotensin II binding sites in subnuclear components of the nucleus tractus solitarii and the motor nucleus of the tenth cranial nerve provides additional information on the various mechanisms through which angiotensin II may affect the intrinsic activity of the brainstem neuronal circuits involved in the integration of baroreceptor and sensory visceromotor function.

Angiotensin II↗

PubMed1987

Effect of area postrema lesion on low-frequency arterial pressure oscillations in dogs.

To explore the possibility that chronic inactivation of the area postrema (AP) may alter the frequency distribution of oscillations in blood pressure, the power spectra for mean arterial pressure (MAP) were evaluated in conscious dogs before and after heat coagulation (n = 4) or sham lesions (n = 6) of the AP. No significant changes in MAP were observed in either group of dogs after surgery. Tachycardia was seen in AP-lesioned animals after surgery; no consistent changes in heart rate were found in sham-lesioned dogs. Spectra were averaged to provide a group spectral estimate for the AP-lesioned and sham-lesioned groups, respectively, for each experimental period. In the sham-lesioned group a variance peak was observed at approximately 0.03 Hz both before and after surgery. The same peak was seen in the AP-lesioned group during the control period but disappeared following AP lesion, apparently because a greater proportion of the variance was shifted toward frequencies below 0.03 Hz. In addition, a peak related to respiratory rate was present in both groups before surgery but was selectively abolished by AP lesion. AP lesion also substantially reduced the power associated with frequencies between 0.1 and 0.4 Hz. The use of spectral analysis has allowed us to demonstrate that a low-frequency oscillation of MAP in conscious, resting dogs requires the integrity of the AP and that the 0.1- to 0.4-Hz components of the variability of MAP are attenuated after removal of the AP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗