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Biomedical subjects

E E Muirhead

Publications and source records attributed to E E Muirhead.

At least 55 records · Page 3Linked to original sources
PubMed1982

Long-term captopril therapy: evolving hemodynamic effects.

Nine patients with resistant hypertension received captopril for 12 months. Five received captopril alone, four required additional therapy. In the former, mean blood pressure fell from 109 +/- 4.2 mm Hg to 84 +/- 7.5 mm Hg (P less than 0.025) after seven days. A rise to 101 +/- 19 mm Hg was noted at six and 12 months. Total peripheral resistance fell at seven days but returned to levels above control at six and 12 months. Cardiac index was 3.21 +/- 0.55 liters/min/m2 before treatment, 3.27 +/- 0.56 liters/min/m2 at seven days, and 2.17 +/- 4.0 liters/min/m2 (P less than 0.025) at 12 months. However, forearm blood flow rose from subnormal levels during the 12 months of observation, suggesting a persistent effect on the arterioles of the extremities. Plasma converting enzyme activity was significantly reduced at seven days but was above control levels at six and 12 months. However, plasma renin activity remained elevated, and plasma aldosterone concentration was significantly reduced. The fall in mean blood pressure was not related to the change in plasma converting enzyme activity in patients receiving captopril alone (five patients) or with diuretic (two patients). In the presence of beta-adrenergic blockade and volume depletion (two patients), changes in mean blood pressure appeared to be related to changes in converting enzyme activity. The data suggest that patients with essential hypertension whose blood pressure was not adequately controlled by previous medications may initially respond to captopril with a fall in blood pressure and total peripheral resistance. However, in certain individuals, these effects diminish with time despite addition of diuretics and beta-adrenergic receptor blocking agents.

Adult↗
PubMed1982

Juxtaglomerular cells grown as monolayer cell culture contain renin, angiotensin I-converting enzyme, and angiotensin I and II/III.

A monolayer cell culture of juxtaglomerular cells (JGC) was derived from the renal cortex of neonatal rats. The JGC had the characteristics of those within the kidney, including peripheral dense bodies and myofibrils indicating a smooth muscle origin; rough ER containing fluffy material consistent with protein synthesis; a prominent Golgi apparatus for packaging granules, and granules having the characteristics of secretory granules and lysosomes. Transplants of the cultured cells into syngeneic recipients survived for 2 weeks or longer and retained the features of JGC. The JGC granules fluoresced when treated with a rabbit antibody against pure rat renin, followed by fluorescein isothyocyanate conjugated F(ab')2 fragment of goat antirabbit IgG (Fc fragment) heavy chain specific. The latter indicated the presence of renin. The JGC were lysed in the presence of DFP, captopril, leupeptin, and EDTA, and were extracted in the presence of pepstatin. The lysate contained renin activity that was inhibited by a specific renin antibody. Nonspecific proteases were excluded by the antibody and its pH optimum. Angiotensin I-converting enzyme was detected in the lysate prepared without the use of EDTA and captopril. Angiotensins I and II/III were derived from the extract by additional extractions, TLC, and RIA, using highly specific antibodies. The angiotensins were confirmed by chromatography monitored by authentic angiotensins. We concluded that the cultured JGC contained renin, angiotensin I-converting enzyme, and angiotensin I and II/III.

Angiotensin I↗
PubMed1982

Cultured juxtaglomerular cells cause hypertension by secreting angiotensin.

Cultured JGC contain renin, angiotensin I, angiotensin I-converting enzyme, angiotensin II, and, by implication, the entire RAS. JGC, as transplants, appear to secrete angiotensin II/III directly into the bloodstream to cause hypertension when the renal mass is reduced. There are two main phases of the hypertensive state, an angiotensin-dependent developmental phase and a non-angiotensin-dependent maintenance phase. This model may be useful in attempts to evaluate pro-hypertensive actions of angiotensin other than those due to direct systemic vasoconstriction. Certain of these actions appear to be intrarenal and include the stimulation of sodium reabsorption, a decrease in renopapillary blood flow, the stimulation of prostaglandin synthesis, and a constraint on the antihypertensive function of the RIC.

Angiotensin II↗
PubMed1982

Derivation of antihypertensive neutral renomedullary lipid from renal venous effluent.

The ANRL was derived from the renal venous effluent as the kidney exerted its nonexcretory antihypertensive function. This was made possible by three developments: (1) improvement in the extraction of ANRL from fresh renal medulla; (2) the fact that purified ANRL caused an acute vasodepressor effect (acted as a vasodilator); and (3) experience with unclipping the one-kidney, one-clip hypertensive rat. Unclipping after an anastomosis between the ureter and the vena cava caused the MAP to return to normal levels in an average of 20 hr. At an average of 5 hr, when the MAP had dropped an average of 34 mm Hg (from approximately 190), an exchange infusion was started and blood was collected from the renal vein. The plasma was separated, lyophilized, and extracted for total lipids. The lipids were subjected to two TLC procedures and tested for vasodepressor activity. Renal venous effluent, under those conditions, yielded a considerable amount of vasodepressor lipid that was similar to that derived from fresh renal medulla. Controls (normal, nephrectomized, and hypertensive animals) yielded little or no such lipid. Indomethacin did not interfere with the derivation of the vasodepressor lipid. As the MAP was lowered and the ANRL-like lipid appeared in the renal venous blood, the RICs degranulated. The RICs appear to be the source of the antihypertensive lipid.

Animals↗
PubMed1982

Effect of platelet-activating factor (PAF) on human platelets.

The effect of pure synthetic PAF (1-0-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) was studied in human platelets. PAF (0.2--2.0 micrograms/ml) produced a dose-dependent aggregation in human platelet-rich plasma (PRP) or platelet suspension obtained by gel-filtration (GFP). In addition, PAF (0.8 microgram/ml) induced secretion of 14C-serotonin (45% +/- 10%; mean +/- SD, n = 9) and platelet factor 4 (PF4) (12.89 +/- 3.81 micrograms/10(9) platelets; n = 9) in PRP. Similar results were obtained in GFP. Aggregation and release of 14C-serotonin and PF4 were inhibited by the metabolic inhibitors 2-deoxyglucose (16.7 mM) and antimycin-A (8.3 micrograms/ml), by the membrane-active drugs mepacrine (10 microM) and chlorpromazine (0.025 mM), by PGI2 (5.34 nM), which elevates intracellular c-AMP, by indomethacin (10 microM) or aspirin (100 microM). The ADP scavengers, creatine phosphate and creatine phosphokinase (CP/CPK), inhibited the second wave of aggregation but not secretion. These data suggest that the major effect of PAF on human platelets is mediated through the cyclo-oxygenase pathway and not through a third pathway.

Animals↗
PubMed1982

Morphometric studies of the renomedullary interstitial cells of Dahl hypertension-prone and hypertension-resistant rats.

Two strains of rats, one genetically sensitive (the Dahl S rat) and the other resistant (the Dahl R rat) to the hypertensive effect of a high-salt diet were studied morphometrically for determination of whether any anatomic differences were present in the renomedullary interstitial cells (RICs) that might help explain these strain differences. The rats resistant to the hypertensive effects of sodium chloride had more RIC than those from the sensitive strain. In addition, they were more heavily granulated. These findings may be related to the known antihypertensive function of the RICs and may help explain observed differences in the prostaglandin metabolism of the Dahl S and R rats.

Animals↗
PubMed1981

Derivation of neutral antihypertensive lipid from renal venous effluent in rats.

1. The antihypertensive neutral renomedullary lipid (ANRL) is a natural product derived from fresh renal medulla and from venous blood. 2. ANRL appears to be an antihypertensive hormone secreted when the kidney exerts its antihypertensive function after unclipping. 3. The kidney appears to be the main source of ANRL, maintaining a basal rate of secretion of ANRL. 4. The kidney of the one-kidney, one-clip hypertensive rat appears to secrete an inappropriate amount of ANRL. Thus a deficiency of the secretion of the antihypertensive hormone may play a role in the pathogenesis of the one-kidney, one-clip hypertensive model. 5. Degranulation of the renomedullary interstitial cells (RIC) occurs as the kidney exerts its antihypertensive action after unclipping, supporting these cells as the source of ANRL. 6. Channels between collecting duct cells may encourage water reabsorption while the clip is in place; conversely, the closure of these channels when the clip is removed may encourage the diuresis that is observed.

Animals↗
PubMed1981

Vasopressin in the rat with partial nephrectomy-salt hypertension.

The role of vasopressin in the pathogenesis of partial nephrectomy (PN)-salt hypertension was examined in the rat. Hypertension was produced by reducing renal mass 70% and substituting 1% saline for drinking water 2 to 4 days after surgery. PN alone resulted in an increase in systolic blood pressure. Subsequent salt loading led to a further large increase in arterial pressure. On the second to third day after substitution of saline for drinking water, urinary vasopressin excretion (UADHV) was increased six-fold and the plasma vasopressin concentration was increased two and one-half-fold. UADHV then fell to a level that was three-fold greater than control values 5 days later. Although there was a marked stimulation of vasopressin release during the period of salt loading, a vasopressin pressor antagonist had only a small effect on arterial pressure. This suggests vasopressin is not a major pressor agent in PN-salt hypertension.

Animals↗
PubMed1981

Possible link between converting enzyme inhibition and renomedullary interstitial cells.

The kidney exerts both prohypertensive and antihypertensive functions. Part of the anti-hypertensive function of the kidney is mediated by the renomedullary interstitial cells (RIC), as an endocrine-type function. Six experimental models of hypertension and their relation to the antihypertensive function of the RIC are discussed. It is proposed that the anti-hypertensive function of the RIC may be deficient by the three mechanisms: 1) absence of the cells (as in the renoprival state); 2) severe damage to the cells (as in partial nephrectomy-salt hypertension of the rat and late malignant hypertension of the rabbit); and 3) constraint of the function of these cells (as in angiotensin-salt hypertension due to a lower salt intake). The constraint may result from excessive angiotensin, either by a direct effect or via a hemodynamic mechanism. The converting enzyme inhibitors (CEI) fail to exert their antihypertensive function when the RIC are absent or damaged. Conversely, the CEI are effective in those models associated with intact RIC. CEI appear to exert their antihypertensive action partly through an effect on RIC.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1981

Antihypertensive lipids from the kidney: alkyl ether analogs of phosphatidylcholine.

Four types of lipids with potential antihypertensive properties have recently been derived from the kidney. These consist of prostaglandins (PG), a renin inhibitor, a neutral lipid, and alkyl ether analogs of phosphatidylcholine. PGI2, mostly renocortical, and PGE2, mostly renomedullary, may aid the antihypertensive function of the kidney by decreasing renal vascular resistance and shunting blood toward the juxtamedullary zone and the renal papilla, where the renomedullary interstitial cells (RIC) are located. Several analogs of the renin inhibitor are available. The neutral lipid is a natural product derived from fresh renal medulla and from RIC grown as monolayer tissue culture. The alkyl ether analogs of phosphatidylcholine (formerly designated as the antihypertensive polar renomedullary lipid or APRL) are orally active vasodilators. They cause a prolonged depressor effect due to a decrease in peripheral vascular resistance. The latter may be partly due to alpha-adrenergic antagonism.

Animals↗
PubMed1980

Antihypertensive action of captopril in angiotensin-salt hypertension.

Captopril (SQ 14225), a converting enzyme inhibitor, significantly lowered the arterial pressure (AP) of rats with angiotensin-salt hypertension, a hypertensive state associated with sodium retention, volume expansion, and suppression of both renin and aldosterone secretion. While captopril was acting, there was no increase in sodium, potassium, or water excretion. Thus, the antihypertensive effect was not due to natriuresis or diuresis. Moreover, as the AP was lowered, there was no change in plasma renin concentrtion, the pulse rate was lowered, and the lack of potassium retention suggested minimal or no effect on aldosterone secretion. The mechanism of action of captopril in a sodium-volume-expanded, renin-aldosterone-suppressed state is unknown.

Animals↗
PubMed1979

Short-term therapy of severe hypertension. Hemodynamic correlates of the antihypertensive response in man.

Ten severely hypertensive patients were randomized into five treatment groups: vasodilators; vasodilators plus diuretics; sympatholytics; sympatholytics plus diuretics; and sympatholytics, diuretics, and vasodialtors. Cardiac index was measured daily by echocardiography, and total peripheral resistance (TPR) calculated. Plasma renin activity (PRA) and creatinine clearance (CCR) were measured every other day. There was no difference in antihypertensive response. Seven patients, whose initial TPR was high, responded to treatment with a fall in TPR, regardless of regimen. Three patients with a high pretreatment cardiac index responded with a fall in cardiac index. Changes in TPR or cardiac index were not related to changes in CCR. There was no correlation between PRA and either blood pressure or TPR. It is concluded that the pretreatment hemodynamic status of severely hypertensive patients is the major determinant of the hemodynamic response to antihypertensive therapy.

Adolescent↗
PubMed1978

Case for a renomedullary blood pressure lowering hormone.

Ablation of renal tissue makes the subject sensitive to hypertension-inducing mechanisms, especially those due to fluid expansion, either by Na-volume or whole blood. Such hypertensive mechanisms are prevented by deviation of urine flow into a vein. Ablation of the renal medulla, by acute hydronephrosis or chemically, also potentiates the hypertensive state. Transplantation of either the renal medulla or its interstitial cells (RIC) can prevent or reverse hypertension. Under the latter conditions, the protective mechanism appears to result from the secretion of an antihypertensive hormone by the RIC. Lipid extracts of renal medulla not only prevent and reverse the hypertensive state in the same manner as medullary transplants but, under certain conditions, exert an acute depressor effect. The RIC can undergo hyperplastic changes much in the manner of an endocrine structure. For these reasons, it is proposed that the RIC represent an antihypertensive endocrine organ whose putative hormone may be termed the renomedullary antihypertensive hormone (ARH). Additional data in support of these contentions are presented.

Animals↗
PubMed1978

Cyclic 3',5'-nucleotide phosphodiesterase; cytochemical localization in rat renomedullary interstitial cells.

The localization of cyclic 3', 5' -nucleotide phosphodiesterase activity in rat renal papillae was examined by utilizing cytochemical methods. Renal medullary interstitial cells had predictable phosphodiesterase activity predominantly on the cytoplasmic border of dilated cisternal membranes. Cells of the collecting tubule and loop of Henle contained diffuse reaction product. Capillaries had reaction product localized in pinocytic vesicles. Addition of theophylline resulted in no deposition of reaction product in interstitial cells and in cells of the collecting tubule and loop of Henle, suggesting an inhibition of phosphodiesterase activity. Since the membranes of dilated cisternae of renal medullary interstitial cells have been shown to be related to prostaglandin synthesis and probably to the anti-hypertensive function of these cells, the finding of phosphodiesterase activity on these membranes suggests a possible role of cyclic AMP in these two functions.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1977

Reversal of hypertension by transplants and lipid extracts of cultured renomedullary interstitial cells.

Transplants and lipid extracts of the same monolayer tissue culture of renomedullary interstitial cells from murine renal medulla exerted a similar antihypertensive action in rats having hypertension of the sodium-volume-dependent-type. The antihypertensive action resembled that caused by lipid extracts of rabbit renal medulla and extracts of lapine renomedullary interstitial cells grown in tissue culture. The recession of the arterial pressure of the hypertensive animals usually occurred slowly and steadily to a maximum within 6 to 12 hours. On occasions, a substantial acute depressor effect preceded the slow and steady decline of the pressure. As the pressure was lowered, there was either minimal or no change in the pulse rate. The lowering of the hypertensive pressure before there was vascularization of the transplant appears to support the view that the transplanted cells secreted and/or liberated an antihypertensive substance(s) that seeped out and was absorbed by nearby capillaries and/or lymphatics and circulated and acted in the manner of a hormone. The extracted and purified lipid from the same cells as used for transplantation is proposed as a candidate for such hormonal action. Evidence is presented that minimizes the possibility of the classic renomedullary prostaglandins as this antihypertensive lipid. The findings add support to the concept that the kidney exerts a hormonal antihypertensive action that opposes the well known hormonal prohypertensive renal actions.

Angiotensin II↗