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Biomedical subjects

M I Phillips

Publications and source records attributed to M I Phillips.

At least 145 records · Page 8Linked to original sources
PubMed1985

Angiotensin II in rat brain comigrates with authentic angiotensin II in high pressure liquid chromatography.

Indirect evidence has implicated a role for central angiotensin II in blood pressure control. To answer directly the question of whether angiotensin II exists in the brain, independent of blood-borne angiotensin, and to quantify the amounts in different parts of the central nervous system, a sensitive radioimmunoassay was used to measure extracts of male adult rat brain hypothalamus and cortex after purification with high pressure liquid chromatography with a high recovery. The fractions coeluted with authentic angiotensin. Rats were nephrectomized bilaterally, and 24 hours later the brains were extracted in acetic acid and boiled. SepPak C-18 purification preceded reverse phase high pressure liquid chromatography. High pressure liquid chromatography revealed two peaks, one which comigrated precisely with [Ile5] angiotensin II, and another smaller peak which overlapped with [Ile5] angiotensin III. The highest levels were found in the hypothalamus (125 pg/g tissue), pituitary (190 pg/g tissue), spinal cord (199 pg/g tissue), and lower levels were found in cortex (60 pg/g tissue). The results demonstrate that the antibody which was previously used in the immunocytochemical localization of angiotensin in the hypothalamus detects authentic angiotensins. However, the study did not depend on just one antibody. A second antibody which we developed gave the same results. Molecular sieving using Sephadex G-25 with acetic acid revealed a distinct peak in the 1000 MW range and a smaller, higher molecular weight peak which needs further investigation. Spontaneously hypertensive rats did not have higher concentrations of hypothalamic angiotensin II than normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1984

Saralasin increases activity of hippocampal neurons inhibited by angiotensin II.

Angiotensin II (AII) has previously been shown to specifically excite neurons in several areas of the rat brain including the hippocampus. Using a brain slice preparation for extra- and intracellular recording, we have found a small proportion of hippocampal neurons which were inhibited by AII. By applying saralasin to those pyramidal cells which are inhibited by AII, we have tested for excitatory effects of saralasin. The results showed that saralasin antagonizes AII whether its effects are inhibitory or excitatory. Saralasin alone generally decreases spontaneous activity and the results indicate that this effect may be due to an inhibition of endogenous brain angiotensin II.

Action Potentials↗
PubMed1984

Insulin inhibits pyramidal neurons in hippocampal slices.

Recent studies have confirmed the presence of insulin receptors in the rat brain although their function has still not been well defined. The present study explores the possibility that insulin receptors in the brain can alter or contribute to central neurotransmission. Insulin caused a dose-dependent inhibition of hippocampal pyramidal neurons. The pattern of inhibition mirrored the binding kinetics of insulin in the hippocampus. Two related peptides, proinsulin and desoctapeptide insulin, had neuronal effects consistent with their binding to insulin receptors in the brain. Proinsulin was effective in doses 30-fold greater than insulin, whereas desoctapeptide insulin had little or no effect. These observations indicate that the inhibitory effect of insulin in this tissue may be insulin receptor-mediated and support a previously suggested functional role of insulin in the central nervous system.

Animals↗
PubMed1984

Angiotensin II in neuronal cultures from brains of normotensive and hypertensive rats.

Primary neuronal cultures from 1-day-old rat brains, which contain angiotensin II (ANG II) immunoreactivity within the neurons and are capable of de novo synthesis of this immunoreactivity, have been used in this study to determine the nature of this immunoreactivity by high-performance liquid chromatography (HPLC). Neuronal cultures from the brains of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats were found to contain ANG II immunoreactivity, which co-migrated with authentic ANG II on HPLC. The angiotensin detected in brain cultures was not derived from the growth medium, and its level was significantly decreased by incubating the cultures with captopril. A 71% decrease in the levels of ANG II was observed in neuronal cultures of SH rat brains compared with those from WKY controls. These observations show that differences in brain angiotensin between SH and WKY are present before differences in blood pressure are manifested.

Angiotensin II↗
PubMed1984

Cardiovascular actions of microinjections of angiotensin II in the brain stem of rats.

The blood pressure and heart rate responses to microinjection of angiotensin II (ANG II) into the brain stem of urethan-anesthetized rats were studied. Microinjection of ANG II into the area postrema (AP) resulted in significant elevation of blood pressure and significant reduction of heart rate. Microinjection into the region of the nucleus tractus solitarius (NTS) yielded a significant dose-dependent elevation in blood pressure and consistent increases in heart rate. The response to microinjection of ANG II into the region of the NTS was not due to leakage into the peripheral circulation, since intravenous administration of the ANG II antagonist, saralasin, did not attenuate the response. In fact, the cardiovascular response was increased after peripheral ANG II blockade, and the heart rate, which was consistently but not significantly elevated by NTS injection alone, was significantly elevated after saralasin pretreatment. Thermal ablation of the AP did not change the heart rate or the pressor response to microinjection of ANG II into the region of the NTS, indicating that the response was not mediated through the AP.

Angiotensin II↗
PubMed1984

Localization of the central pressor action of bradykinin to the cerebral third ventricle.

Bradykinin injected into the lateral ventricle produces a rise in blood pressure. Cream plugs selectively localized to discrete regions of the ventricular system were used to block drug access to periventricular sites. Third ventricular plugs blocked the pressor response to lateral ventricular injections of 5 micrograms bradykinin (27 +/- 5 before vs. 5 +/- 5 mmHg after plug, n = 7) and 100 ng angiotensin II (22 +/- 3 before vs. 4 +/- 2 mmHg after plug, n = 5). Third ventricular plugs also suppressed the drinking response to angiotensin II (3.7 +/- 0.6 before vs. 0.9 +/- 0.6 ml after plug, n = 5). However, plugs that occluded the fourth ventricle failed to suppress the central bradykinin pressor response (27 +/- 8 before vs. 35 +/- 9 mmHg after plug, n = 5). The data suggest that the central bradykinin pressor response has a site of action similar to that of angiotensin II in the ventral third ventricle.

Angiotensin II↗
PubMed1984

Mechanism of pressor effects by angiotensin in the nucleus tractus solitarius of rats.

We recently reported that microinjection of angiotensin II (ANG II) into the nucleus tractus solitarius (NTS) results in an increase in mean arterial pressure (MAP) in urethan-anesthetized rats in a dose range of 50-500 ng. To investigate the mechanism of this response, hexamethonium (20 mg/kg iv) was used to inhibit sympathetic activation. There was a highly significant (P less than 0.001) reduction in the magnitude of the pressor response (4.7 +/- 1.1 mmHg) compared with preblockade ANG II (500 ng) responses (15.5 +/- 1.6 mmHg). A vasopressin antagonist and hypophysectomized rats were used to study the contribution of pituitary vasopressin. Injection of 500 ng ANG II in hypophysectomized rats produced a pressor response (14.8 +/- 3.2 mmHg) indistinguishable from that in intact controls (15.5 +/- 1.6 mmHg). Pretreatment with the vasopressin antagonist d(CH2)5Tyr(Me)AVP (1 microgram iv) in intact rats also had no effect on the magnitude of the pressor response (15.7 +/- 1.7 mmHg). Microinjection of ANG I and II produces an increase in arterial pressure. It is concluded that the angiotensin pressor response in the NTS is mediated by activation of descending sympathetic fibers and is not dependent on release of blood-borne pressor agents from the pituitary.

Angiotensin I↗
PubMed1983

The opposite effects of central and peripheral vasoactive intestinal polypeptide on blood pressure in rats.

In conscious normotensive rats catheterized for continuous recording of blood pressure, intracerebroventricular injections of vasoactive intestinal polypeptide (VIP) produced pressor responses in contrast to depressor effects when given intravenously. The pressor effect was not mediated by angiotensin II since pretreatment with an angiotensin antagonist failed to block the response. These findings show that there are separate mechanisms for central versus peripheral effects of VIP.

Angiotensin II↗
PubMed1983

Angiotensin II stimulates changes in the norepinephrine content of primary cultures of rat brain.

Interactions between norepinephrine and angiotensin II were investigated in neuron-enriched primary brain cell cultures, which have been demonstrated to contain catecholamines, angiotensin II-like immunoreactivity and specific receptors for angiotensin II. Angiotensin II (7.5 and 15.0 micrograms/ml) caused significant increases in both neuronal and growth media norepinephrine levels, which were inhibited by saralasin. These observations suggest that angiotensin acts at its specific receptors to alter neuronal norepinephrine levels.

Angiotensin II↗
PubMed1983

Rat brain cells in primary culture: visualization and measurement of catecholamines.

Catecholamines have been visualized and quantified in primary cultures of whole rat brain. Twenty-one-day old cultures treated with glyoxylic acid and viewed under a fluorescence microscope revealed neurons stained specifically with blue-green catecholamine fluorescence. Brightly stained multipolar cell bodies were seen, along with stained neurites and varicosities, and there was no staining associated with the non-neuronal portion of the culture. Twenty-one-day-old non-neuron-enriched cultures contained 10-20 times less norepinephrine and dopamine than cytosine arabinoside-treated neuron-enriched cultures. The latter cultures contained 10-12 times more norepinephrine than 1-day-old rat brains, demonstrating maturation and differentiation of the cultured neurons. Norepinephrine levels of neuron-enriched cultures were, however, 3 times less than those in 21-day-old rat brains. The cultured neurons had the ability to synthesize catecholamines since levels were decreased with alpha-methyl-p-tryosine. On the other hand, the growth medium contained significant amounts of norepinephrine, but did not have the ability to synthesize catecholamines. It may be concluded that the cellular catecholamines are not derived from the medium in any great amounts. This study provides the basis of a system in which to examine catecholaminergic neurotransmission and peptide catecholamine interactions at the cellular level under semi-defined conditions.

Animals↗
PubMed1983

Central injection of angiotensin II alters catecholamine activity in rat brain.

Centrally injected angiotensin II (ANG II) produces a pressor response. The effect of ANG II injected intracerebroventricularly on catecholamine utilization in specific rat brain regions was examined. A pressor dose of ANG II stimulated an increase in norepinephrine (NE) utilization in the locus coeruleus, raphe magnus and AI regions of the brain stem, and in the hypothalamus. These increases in NE utilization were selective, and dopamine utilization was not altered in the same regions. Also, the changes in NE utilization were direct and not due to the rise in blood pressure caused by ANG II, since a similar pressor effect caused by intravenously injected hypertonic saline did not alter NE utilization in any of the above regions. Areas such as the subfornical organ and organum vasculosum of the lamina terminalis that contain both catecholamines and ANG II receptors did not show a substantial change in catecholamine utilization after intracerebroventricularly injected ANG II. This study demonstrates that specific brain NE rich regions are activated by intracerebroventricular injection of ANG II. Some of these regions correlate with known blood pressure control centers and the data points to brain catecholaminergic regions which are involved in the central ANG II pressor response.

Angiotensin II↗
PubMed1983

Angiotensin II and bradykinin: interactions between two centrally active peptides.

Two neuropeptides, bradykinin (BK) and angiotensin II (ANG II), produce an increase in blood pressure when injected into the brain ventricles. This study is an example of central peptide-peptide interaction and was carried out to determine if BK and ANG II share a common mechanism in the brain to control blood pressure and drinking in rats. Prior injection of saralasin [10 micrograms intraventricularly (ivt)] was found to enhance the pressor response to ivt BK (5 micrograms) by 44%. The same dose of saralasin attenuated the pressor response to ivt ANG II (200 ng) by 55%. 50 ng ANG II and 5 micrograms BK given together ivt did not significantly alter blood pressure or urine conductance compared to 50 ng ANG II alone. Drinking to ivt infusions of ANG II (14 ng/min) was significantly attenuated when combined with BK (0.7 micrograms or 2.8 micrograms/min). Pretreatment with 10 micrograms indomethacin ivt diminished the pressor response to 5 micrograms ivt BK. Prostaglandin E2 (1.4 micrograms/min), but not prostaglandin A2, inhibited drinking to 14 ng/min ivt infusions of ANG II. The results suggest that ANG II and BK share an interrelationship with respect to their central actions: ANG II inhibits the BK pressor response and BK acts to inhibit drinking induced by ANG II. Prostaglandins of the E series may mediate these central actions of bradykinins.

Angiotensin II↗
PubMed1983

Primary cultures from fetal rat brain incorporate [3H]-isoleucine and [3H]-valine into immunoprecipitable angiotensin II.

Primary cultures from fetal rat brain contain angiotensin II immunoreactivity in neurons. To study the origin of this immunoreactivity, primary cultures were incubated with [3H]-valine or [3H]-isoleucine. A time-dependent incorporation of radioactivity into immunoprecipitable angiotensin II was observed. Incubation of cultures with Captopril, an inhibitor of the converting enzyme, resulted in a significant inhibition of [3H]-valine incorporation into immunoreactive [3H]-angiotensin II. These results demonstrate that primary cultures from fetal rat brain can synthesize an angiotensin II-like immunoreactivity and support a concept that angiotensin II may be synthesized in fetal rat brain.

Angiotensin II↗
PubMed1983

New evidence for brain angiotensin and for its role in hypertension.

Twenty years ago it was demonstrated that angiotensin II (Ang II) acts on the brain, which results in an elevation of blood pressure. Ten years later, reninlike activity was discovered in the brain of the rat and dog, which gave rise to the concept of an endogenous brain renin-angiotensin system. In the periphery, the kidney, liver, and lungs work in unison to produce Ang II. Evidence for brain renin, substrate, converting enzyme, and angiotensins is reviewed. New data indicate that the enzyme system for the synthesis of Ang II within the brain may in fact be contained in the cell. All the components for a renin-angiotensin system have now been found in neuroblastoma/glioma cell lines and Ang II is present in primary cell culture of rat brain neurons. The significance of angiotensin in the brain for hypertension is that it may be a stimulus for vasopressin release and sympathetic activation, which can maintain high blood pressure. In the spontaneously hypertensive rat, there is evidence of increased brain angiotensin. Also, experiments with angiotensin-converting enzyme inhibitors show that blockade of brain angiotensin production leads to a long-lasting lowering of blood pressure. The activity of the inhibitors in part appears to be directly on the brain.

Angiotensin II↗