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Biomedical subjects

C M Ferrario

Publications and source records attributed to C M Ferrario.

270 records · Page 15Linked to original sources
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Cardiac pumping ability following reversal of hypertrophy and hypertension in spontaneously hypertensive rats.

Direct measurements of arterial pressure, stroke volume (SV), and cardiac output (CO) were obtained in ether-anesthetized rats with established spontaneous hypertension (SHR) treated with alpha-methyldopa and compared to both untreated hypertensive and normotensive Wistar-Kyoto (WKY) rats. Left ventricular pumping ability was determined by the maximum levels of SV and CO reached during rapid intravenous volume loading with blood. Treatment with methyldopa reduced the SHR arterial blood pressure (average 57 mm Hg) and reversed the cardiac hypertrophy toward normal. In comparison to untreated SHR, therapy increased heart rate and CO and decreased peripheral resistance. During volume-loading, the levels of SV and CO at matched left ventricular end-diastolic pressures were significantly higher in treated vs untreated SHR. To evaluate the role of blood pressure in the improved peak pumping ability observed in treated rats, a phenylephrine infusion was used to equalize pressures while repeating cardiac function studies. In normotensive WKY and untreated SHR, left ventricular pump function was not greatly affected. A pronounced depression in peak SV and peak CO was observed only in treated SHR. The data indicate that treatment with methyldopa is associated with improved ventricular function in part related to the reduction in arterial pressure.

Animals↗
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Effect of chronic sodium depletion on cerebrospinal fluid and plasma catecholamines.

To test the role of central neurogenic factors in sodium-depleted states, cerebrospinal fluid (CSF) norepinephrine, epinephrine, and dopamine were measured in mongrel dogs first on a normal sodium intake (65 mEq sodium/day) and then on a 21-day regime of low sodium diet (4 mEq/day combined with diuretics). Plasma catecholamines were measured in the same group of dogs. Three weeks of sodium depletion supplemented with diuretics caused a 24-fold increase in plasma renin activity, hemoconcentration, and elevated serum protein concentration. Both plasma and CSF sodium decreased significantly. After sodium depletion, plasma norepinephrine rose 76% but epinephrine and dopamine did not change. The same pattern was observed whether samples were obtained in conscious or anesthetized animals. In CSF, norepinephrine rose 44% during sodium depletion, while epinephrine and dopamine remained unchanged. The CSF norepinephrine was related inversely to the CSF sodium concentration and directly to plasma renin activity. These observations support the view that the combined procedure of restricted dietary sodium intake and diuretic therapy causes alterations in CSF norepinephrine in a direction compatible with possible overactivity of central noradrenergic neurons.

Animals↗
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Central opiate system modulation of the area postrema pressor pathway.

Angiotensin II, when given into the vertebral arteries, acts at the area postrema to augment central sympathetic vasomotor activity. The mechanism of action is unknown but recent evidence implicates an interaction with the opiate system. In dogs anesthetized with chloralose either alone or in combination with morphine, naloxone blunted the pressor response to vertebrally administered angiotensin II by 50%. Addition of morphine to dogs anesthetized with chloralose only doubled the pressor response to identical doses of angiotensin II. On the other hand, the magnitude of the pressor responses to intravenously infused angiotensin II were unaltered by either naloxone or morphine. Likewise, responses to norepinephrine given vertebrally and intravenously were not similarly affected. Therefore, naloxone-induced changes in vascular responsiveness were not responsible for the altered sensitivity of the area postrema to angiotensin II following blockade of endogenous opiates. The data suggest that there exists a previously unrecognized interaction of the endogenous opiate system in the medulla in mediating the pressor effects of angiotensin II at the level of the area postrema.

Angiotensin II↗
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Collagen metabolism and reversal of aortic medial hypertrophy in spontaneously hypertensive rats treated with methyldopa.

Collagen synthesis, content, and concentration were determined in the hypertrophied intima media of thoracic aortas from 10-, 15-, and 20-week-old spontaneously hypertensive rats (SHR). Although the rates of aortic collagen synthesis declined with age, the dry weight of the intima media and the total collagen content increased proportionally. Collagen concentration thus remained unchanged. Methyldopa was administered orally to SHR when they were 12 to 15 weeks of age, when their body weight were identical to the untreated group. Blood pressure and the degree of aortic medial hypertrophy, judged by medial dry weight per kilogram body weight, were significantly lower compared with untreated SHR. Collagen synthesis was likewise decreased to a mean rate not significantly higher than age-matched normotensive Wistar-Kyoto controls. This reduction in collagen synthesis, however, was not sufficient to decrease measurably the total collagen content of the aortas compared with untreated SHR. Since medial dry weights were lower in the treated rats, collagen concentration in aortas from SHR given methyldopa for 3 weeks was actually increased. The increase in collagen concentration also suggests that medial hypertrophy was reversed.

Aging↗
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Neurogenic hypertension produced by lesions of the nucleus tractus solitarii alone or with sinoaortic denervation in the dog.

The cardiovascular effects of bilateral lesions of the nucleus tractus solitarii (NTS) were compared with those of subsequent sinoaortic denervation in the same dogs. Destruction of the lateral but not the medial component of the NTS between + 0.5 and 3 mm anterior to the obex produces mild hypertension and tachycardia, not always sustained for more than 2 weeks. Rises in pressure were accompanied by increased lability which was not present regularly in all dogs but correlated with the baseline level of arterial pressure. On the other hand, sinoaortic denervation following lateral NTS lesions produced the first demonstration of fulminant hypertension in the dog, which led to death within hours. These data suggest that, while NTS lesions in the dog probably only partially interrupt central baroreceptor pathways, the addition of sinoaortic denervation completely disrupts baroreceptor inputs to the central nervous system, thus releasing central sympathetic outflow completely from baroreceptor inhibition.

Animals↗
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Catecholamines and serotonin in the area postrema of normal and sodium-depleted dogs.

Sodium depletion, a maneuver that is accompanied by a 14-fold elevation of plasma renin activity (PRA), alters the norepinephrine concentration of the canine area postrema (AP), a circumventricular organ of the 4th ventricle known to be sensitive to circulating angiotensin II. The norepinephrine concentration of the AP after 3 weeks of sodium depletion decreased by 43%, whereas the concentration of epinephrine and dopamine and the activity of phenylethanolamine-N-methyltransferase (PNMT) did not change. In the pyramidal tract (PT) and choroid plexus (CP) catecholamines were present in significantly lower amounts than in the AP; their concentrations were unaffected by sodium depletion in the PT, but in the CP the norepinephrine concentration was reduced. Serotonin was present in the AP but its concentration was unaltered by sodium depletion. These findings provide evidence that sodium depletion produced an alteration in the concentration of norepinephrine of the area postrema without any change in the concentration of epinephrine, dopamine or serotonin.

Animals↗
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Rat (Ile5) but not bovine (Val5) angiotensin raises plasma norepinephrine in rats.

A part of the vasoconstrictor activity of angiotensin II (AII) may result from its ability to enhance norepinephrine (NE) release from sympathetic noradrenergic nerve terminals. To investigate this proposed pressor mechanism of AII, the effects of intravenous (i.v.) infusion of AII on blood pressure and plasma catecholamines in pithed rats were determined. Two naturally occurring angiotensins, valine5 AII (bovine) and isoleucine5 AII (rat), were administered in equal (72 ng/min) doses. Valine5 AII caused an 80% increase in mean arterial pressure (MAP) from 54 +/- 4 to 97 +/- 19 mm Hg. Isoleucine5 AII caused an 82% increase in MAP from 49 +/- 5 to 89 +/- 18 mm Hg. Neither angiotensin caused a change in heart rate, suggesting that pithing completely destroyed the central baroreceptor reflex mechanism. Plasma catecholamines were differentially affected by the peptides:isoleucine5 AII significantly increased plasma NE concentration by 82% compared to saline-infused rats (p less than 0.01). Valine5 AII did not significantly affect plasma NE concentration. Plasma dopamine and epinephrine concentrations were not significantly altered by infusion of either analog. Despite the significant increases in plasma NE concentrations with isoleucine5 in AII-infusion rats, there was no correlation between plateau MAP or the percent increase in MAP and plasma NE concentrations of individual animals within this group. The ability of angiotensin to elevate MAP, increase NE release from sympathetic nerve terminals, as well as potential differences in the actions of angiotensins in different species, and angiotensin receptor heterogeneity, are discussed.

Angiotensin II↗
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Effects of chronic sodium depletion on canine brain renin and cathepsin D activities.

The activities of brain renin and cathepsin D were measured in brain regions of 10 dogs on a normal sodium intake (65 mEq Na+/day) and 10 other dogs placed on a low sodium diet (less than 4 mEq Na+/day) for 21 days and given a diuretic. The purpose of this study was twofold: to assess the effect of sodium depletion on brain renin activity; and to assess in the same regions alterations in brain renin and cathepsin D activities. Sodium depletion caused a ninefold increase in plasma renin activity, hemoconcentration, and hyponatremia. In the presence of marked hyperreninemia, the average cerebral renin activity was reduced significantly; the most pronounced changes occurred in the upper and lower brain-stem regions. Cerebrospinal fluid renin was increased by 30%, but this change was not significant in sodium-depleted dogs. There were no significant alterations in cathepsin D activity whether assessed in total or regional brain areas. These observations support the view that there is an inverse relationship between plasma and brain renin activity in chronically sodium-depleted dogs. Additionally, evidence is provided that brain renin activity is modified independently from cathepsin D activity.

Animals↗
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Alterations in plasma and cerebrospinal fluid norepinephrine and angiotensin II during the development of renal hypertension in conscious dogs.

The levels of norepinephrine (NE), epinephrine (E), and angiotensin II immunoreactivity (AIIir) in plasma and in cerebrospinal fluid (CSF) were measured in eight conscious dogs before and during a 28-day period in the development of two-kidney, one clip (2K1C) hypertension produced by a two-step procedure. The early phase (less than 7 days) of hypertension following partial constriction of the renal artery was accompanied by tachycardia and increases in concentrations of NE and AIIir in both plasma and CSF; E did not change. One week later blood pressure remained elevated (107 +/- 2 after vs 88 +/- 2 mm Hg before clipping, p less than 0.05), but other variables returned to control values. Occlusion of the partially constricted renal artery caused severe hypertension that was initially associated with a transient decrease in levels of NE in both plasma and CSF and a sustained rise in plasma and CSF concentrations of AIIir that persisted for as long as 2 weeks after the second operation. None of these effects was seen in nine sham-operated dogs. Since activation of the renal pressor system is associated with time-related changes in the concentrations of NE and AII in both plasma and CSF, these observations indicate early involvement of both sympathetic and renin-angiotensin systems in the pathogenesis of renovascular hypertension.

Angiotensin II↗
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Basal levels of plasma epinephrine and norepinephrine in the dog.

Conscious (n = 62) and anesthetized (n = 34) dogs were studied to establish basal levels and ranges for plasma epinephrine (E) and norepinephrine (NE) in this species. Trained conscious dogs were familiarized to recording conditions and personnel for 2 to 3 weeks and acclimatized to the laboratory for at least 15 minutes prior to blood sampling from a chronically implanted catheter. Their basal values were 65 +/- 47 pg/ml for E and 145 +/- 58 pg/ml for NE, which were significantly lower (p less than 0.05) than values in a second group of conscious dogs trained in the same manner but sampled soon after arrival to the laboratory (E = 144 +/- 93 pg/ml; NE = 193 +/- 86 pg/ml). Catecholamine levels in dogs anesthetized with one of three different regimes commonly used in cardiovascular studies were shown to be similar to the basal values found in conscious dogs acclimatized to the laboratory. The weak correlations found between basal plasma catecholamines and hemodynamic variables in all groups of conscious dogs reflect the complexity of factors interacting with the sympathetic nervous system in the maintenance of arterial pressure. These results document the variability that can be expected when using catecholamine levels as an index of sympathetic nervous system activity and the necessity of standardizing conditions for sample collection.

Acclimatization↗
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Neurogenic actions of angiotensin II.

It has become increasingly evident that blood-borne angiotensin II has major effects upon brain cardiovascular centers. With the discovery of an angiotensin I-forming enzyme or isoenzymes in the central nervous system of mammals, alternative concepts have emerged regarding the role of this peptide in the regulation of central adrenoreceptor activity, pituitary function, and hydromineral metabolism. These concepts are reviewed, and a framework for future research is suggested by the author.

Angiotensin II↗
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Arginine vasopressin modulates the central action of angiotensin II in the dog.

Endogenous vasopressin may interact with central autonomic nervous system factors in the regulation of cardiovascular function. In 25 morphine/chloralose-anesthetized dogs, we studied the magnitude of the pressor response produced by an infusion of angiotensin II (AII) into the vertebral arteries (VA), before and after intracisternal (n = 10), intravertebral (n = 9), or intravenous (n = 6) administration of a competitive antagonist of arginine vasopressin (AVP) [d(CH2)5Tyr(Me) AVP]. The dose response curve to vertebral artery infusion of AII (range 2-20 ng/kg/min) was significantly (p less than 0.05) shifted to the right of control after injection of the AVP antagonist (10 micrograms/kg) into the cisterna magna; the ED at 20 mm Hg being almost double after central AVP blockade. This effect of AVP blockade was confined only to the cardiovascular response mediated by AII via the vertebral arteries. When pressor doses of AII were injected into either a vein (i.v.) or the cisterna magna of these same dogs, the increases in mean blood pressure were the same before and after AVP antagonist treatment. In another group of anesthetized dogs, we investigated whether the reduced reactivity to intravertebral AII could be duplicated by giving the AVP antagonist either via the vertebral artery or i.v. Only the cisterna magna route was effective in causing a blunting of the pressor response to vertebral artery AII. These data demonstrate a previously unknown interaction between vasopressin and the centrally mediated pressor response to intravertebral AII.

Angiotensin II↗
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Location of the area postrema pressor pathway in the dog brain stem.

Electrical stimulation of the dog's area postrema (AP) induces a response that mimics the pressor response produced by intravertebral infusion of low-dose angiotensin II, which causes an increase in mean arterial pressure associated with transient tachycardia and increased peripheral resistance. The present study investigated in morphine-chloralose anesthetized dogs whether: 1) the characteristics of the AP pressor response are influenced by the presence of carotid sinus afferents; 2) structures rostral to the medulla influence the AP pressor response; and 3) the pressor pathway is initiated by neurons within the AP. Since bilateral cervical sinovagal denervation, which potentiated the phenylephrine pressor response, did not affect the pressor response to AP stimulation, the data provide evidence for an inhibitory influence exerted upon the central baroreflex mechanism by the AP pressor mechanism. The unaltered AP pressor response after midcollicular transection suggests that the efferent pathway is contained within the brain stem caudal to the pons. Finally, the elimination of the pressor response following kainic acid microinjection into the AP provides evidence that the AP pressor mechanism is initiated by neurons within the AP, rather than by fibers of passage from other pressor centers. These results suggest that the AP produces its facilitation of central sympathetic vasomotor outflow via a pathway contained within the medulla.

Animals↗
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Cerebrospinal fluid angiotensin II immunoreactivity is not derived from the plasma.

To elucidate whether the presence of angiotensin II immunoreactivity (ANG II-ir) in the cerebrospinal fluid (CSF) of the dog is in part due to passage of the peptide across the CSF-blood-brain barrier, [Ile5] angiotensin II (ANG II) was infused intravenously for 7 days in conscious, trained dogs at a rate of 10 micrograms/kg/day. Mean arterial pressure (MAP) and heart rate were monitored each day, and samples of arterial blood and CSF (with a catheter secured into the cisterna magna) were drawn at regular intervals for determination of catecholamine levels, ANG II-ir, and electrolyte levels. Within 2 days after ANG II infusion, MAP stabilized at 35 +/- 1 mm Hg (mean +/- SE, p less than 0.001) above control values. The hypertension was associated with bradycardia, suppressed plasma renin activity, and a fall in both plasma and CSF Na+ concentrations. These changes coincided with a considerable and sustained decrease in the levels of plasma and CSF norepinephrine. On the other hand, levels of epinephrine and K+ in the two compartments remained unchanged. Although concentration of ANG II-ir in plasma was augmented markedly (368% above control values, p less than 0.001), ANG II-ir in the CSF remained within the low values measured in the control period.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
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The anteroventral third ventricle region. Participation in the regulation of blood pressure in conscious dogs.

The anteroventral third ventricle (AV3V) region plays an important role in fluid and electrolyte balance and cardiovascular control in the rat; however, experiments in other species have raised questions about the universality of findings in the rat. The effects of discrete lesions placed within the AV3V area on hydromineral balance, the pressor response to angiotensin II given intravenously, and the initiation of a renin-dependent model of hypertension were examined in the dog. A transpharyngeal approach to the optic chiasm enabled us to destroy only the anterior aspects of the AV3V region (aAV3V group) or to include the entire nucleus medianus (NM) as well (aAV3V + NM group). Lesions of the aAV3V caused polydipsia and transient hypernatremia and hyperosmolality. In contrast, adipsia and a sustained increase in plasma sodium levels and osmolality were observed in dogs with lesions of the aAV3V plus the entire NM. Neither lesion altered baseline arterial pressure, heart rate, plasma levels of catecholamines and vasopressin, or total plasma protein levels. Only in aAV3V + NM lesioned dogs was there a tendency for plasma angiotensin II immunoreactivity to be elevated above control values at 2 and 4 days after operation. Neither lesion attenuated the pressor response to intravenous angiotension II or the initiation of renal hypertension induced by aortic coarctation. As observed in other species, structures within the AV3V region participate in hydromineral balance in the dog; however, in the dog portions of the NM dorsal to the AV3V region are essential for the mediation of drinking behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
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Angiotension-(1-7) and antihypertensive mechanisms.

Of the active fragments studied to-date, Ang-(l-7) is the most pleiotropic of the Ang I metabolities because it exerts effects that may be identical or opposite to those of Ang II. While much research remains to be done, accumulating evidence suggests that Ang-(1-7) stimulates the synthesis and release of vasodilator prostaglandins, augments the metabolic actions of bradykinin, and increases the release of nitric oxide. This explains why Ang-(1-7) activates antihypertensive mechanisms, particularly in situations of increased Ang II activity. In other words, Ang-(1-7) may act as a negative feedback hormone of the pressor and trophic actions of Ang II. The enzymes forming Ang-( 1-7) reinforce the idea that this peptide is a component of a vasodepressor system that regulates blood pressure. Both neprilysin and metalloendopeptidase 24.15 form Ang-(1-7) but also cleave bradykinin and atrial natriuretic peptide to smaller fragments. Our recent discovery that Ang-(1-7) is a major substrate for angiotensin converting enzyme (ACE) adds a new and important dimension to the understanding of the biochemical physiology of the renin angiotensin system. Moreover, these data explain why Ang-(1-7) augmentes the hypotensive effects of bradykinin and contributes to the antihypertensive actions of ACE inhibitors. While the bulk of the research in hypertension continues to emphasize the investigation of the cellular actions of Ang II, our research has introduced new concepts and uncovered new mechanisms through which angiotensin peptides control homeostasis and influence the pathogenesis of cardiovascular disease.

Angiotensin I↗
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Altered neural control of cardiovascular function in sodium-depleted dogs.

Sodium restriction affects sympathetic control mechanisms by blunting of the reflex pressor response to carotid sinus hypotension, which is reversible by section of vagal afferents. To obtain more direct evidence, sympathetic nerve activity was recorded from a renal nerve (RNA) in 16 normal (NS) and 13 sodium-depleted (SD) dogs anesthetized with morphine-pentobarbital. Integrated RNA was measured during changes in mean arterial pressure (MAP) produced by i.v. infusion of sodium nitroprusside (100 micrograms/kg/min) or phenylephrine (20 micrograms/kg/min). The classical inverse relationship between MAP and integrated RNA was found before and after bilateral vagotomy (VAGT) in both NS and SD dogs. However, RNA in SD dogs, expressed as % of maximal neural firing, was significantly less at any blood pressure level when compared to NS dogs. In addition, the critical pressure (point at which RNA ceased) was reduced in SD vs NS dogs (p less than 0.002). The decreased sympathetic neural firing in SD dogs was abolished after bilateral VAGT, confirming the pronounced buffering effects of vagal afferents on RNA in salt-depleted dogs.

Afferent Pathways↗