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Biomedical subjects

J C McGiff

Publications and source records attributed to J C McGiff.

34 records · Page 2Linked to original sources
PubMed1977

Contribution of prostaglandins to the renal circulation in conscious, anesthetized, and laparotomized dogs.

The effects of an inhibitor of prostaglandin (PG) synthetase, indomethacin, were studied on renal blood flow (RBF) and mean aortic blood pressure (MABP) and related to changes in concentrations of PGs in renal venous blood under widely different experimental conditions. Although levels of PGE-like material ("PGE") in renal venous blood of the chloralose-anesthetized-laparotomized dog were 8-fold greater than in conscious dogs, viz., 0.39 vs. 0.05 ng/ml of blood, respectively, RBF and MABP were similar for each group. Indomethacin in doses as high as 10 mg/kg, iv, affected neither RBF, MABP, nor PG levels either in the conscious dog or in the anesthetized dog. However, in the anesthetized-laparotomized dog, smaller doses of indomethacin (2 mg/kg, iv) decreased RBF by more than 40% and increased MABP by 15%. This was associated with a decline in concentration of renal venous PGs to those levels observed in conscious dogs. The principal renal PG varied according to the experimental conditions. The venous levels of "PGF" were greater than "PGE" in conscious dogs, whereas in acutely stressed dogs the renal venous concentrations of "PGE" were more than 2-fold those of "PGF". Plasma renin activity was highly correlated with "PGE" levels in renal venous blood, but not with "PGF" levels. Thus, in the acutely stressed dog, the renal circulation is supported by a major PG component, withdrawal of which results in a decline in RBF. In contrast, in the conscious dog at rest, renal PGs do not appear to contribute significantly to RBF. The significance of the small basal release of PGs into the renal venous effluent of the conscious dog, which is not affected by indomethacin, remains to be determined.

Anesthesia↗
PubMed1977

Bartter's syndrome results from an imbalance of vasoactive hormones.

Bartter's syndrome may result from a disturbance of the interrelations of three vasoactive hormonal systems: the kallikrein-kinin, renin-angiotensin, and prostaglandin systems. Although kinin and angiotensin have opposing effects on renal function, each hormone increases the levels of prostaglandins within the kidney. Elevated renal prostaglandin levels are primarily responsible for some of the major features of the syndrome. The effectiveness of indomethacin in the treatment of Bartter's syndrome derives in large part from the ability of the drug to inhibit prostaglandin production. Indomethacin also decreases the activity of the renin-angiotensin system and the excretion of renal kallikrein, perhaps related to inhibition of prostaglandin mechanisms that may participate in the release of renin and kallikrein. However, additional actions of indomethacin must be considered, such as an effect of the drug on a naturally occurring renin inhibitor.

Angiotensin II↗
PubMed1976

Contribution of prostaglandins to the renal vascular supersensitivity to vasoconstrictor agents exhibited by New Zealand genetic hypertensive rats.

1. Studies were made of the effects on responses to vasoconstrictor agents of prostaglandins released from Krebs perfused isolated kidneys of genetic hypertensive and normotensive rats. 2. Prostaglandin E-like activity, detected by bioassay, was released from kidneys of both groups of rats during the vasoconstriction produced by noradrenaline, angiotensin or prostaglandin F2alpha. 3. In preparations obtained from hypertensive rats, responses to higher doses of noradrenaline or angiotensin were initially greater than those from normotensive rats and these were then reduced to a greater extent by infusion of indomethacin, which abolished release of prostaglandin E-like activity. Thereafter, in kidneys of either group, vasoconstriction to noradrenaline was potentiated by infusion of prostaglandin E2. 4. We conclude that, in rats, renal prostaglandins released in response to vasoconstrictor agents could augment the effect of such agents and in genetic hypertensive rats release of renal prostaglandins could contribute to the disease.

Animals↗
PubMed1976

Possible influence of intrarenal generation of kinins on prostaglandin release from the rabbit perfused kidney.

The effects of bradykinin and kininogen on renal prostaglandin release were studied in rabbit isolated kidneys perfused with oxygenated Krebs solution. The concentration of prostaglandin-like material in kidney effluent was determined by bioassay after extraction of the samples with organic solvents. In 7 experiments the samples were assayed after separation of prostaglandins E and F by thin layer chromatography. Addition of bradykinin to the perfusing fluid increased the venous and urinary effluxes of prostaglandin E-like substance by sixfold and fivefold, respectively, but efflux of prostaglandin F-like material was unaffected. Addition of kininogen to the perfusing fluid augmented the venous and urinary release of prostaglandin E-like substances by fifteenfold and ninefold respectively and caused a twofold increase in the efflux of prostaglandin F-like material into the venous effluent. Aprotinin, a kallikrein inhibitor, reduced the prostaglandin releasing action of kininogen but not of bradykinin. In contrast, inhibition of prostaglandin synthesis by indomethacin suppressed the release of prostaglandin evoked by either bradykinin or kininogen. This study suggests that augmented release of prostaglandins in response to kininogen is a consequence of renal generation of kinins. Thus, changes in the intrarenal activity of the kallikreinkinin system may modulate renal prostaglandin release.

Animals↗
PubMed1976

Modification by prostaglandins E1 and E2, indomethacin, and arachidonic acid of the vasoconstrictor responses of the isolated perfused rabbit and rat mesenteric arteries to adrenergic stimuli.

In isolated perfused rabbit mesenteric arteries, prostaglandin (PG) E1 and E2, 1-5NG/ML, did not alter the basal perfusion pressure, but reduced the vasoconstrictor responses to sympathetic nerve stimulation; the responses to injected norepinephrine were reduced by PGE1 and variably affected by PGE2. In contrast, in rat mesenteric arteries PGE1 and PGE2, 1-5 ng/ml, potentiated the vasoconstrictor responses to nerve stimulation and to injected norepinephrine. In rabbit mesenteric arteries, the inhibitor of PG synthesis, indomethacin, augmented the responses to sympathetic nerve stimulation and to injected norepinephrine, whereas in rat mesenteric arteries indomethacin inhibited the responses to both adrenergic stimuli. Arachidonic acid, a PG precursor, reduced the vasoconstrictor responses to sympathetic nerve stimulation and to injected norepinephrine in rabbit, whereas in rat, potentiation of the responses to adrenergic stimuli occurred. Since these effects of arachidonic acid were abolished by the simultaneous infusion of indomethacin, they appear to be mediated through conversion of arachidonic acid to PG. We conclude that prostaglandins modulate adrenergic transmission in mesenteric arteries and this effect is species dependent.

Animals↗
PubMed1976

Modulation and mediation of the action of the renal kallikrein-kinin system by prostaglandins.

The coupling of the kallikrein-kinin and prostaglandin systems within the kidney may be unique: Prostaglandins mediate some of the actions of kinins and modulate others, while depending on the intrarenal generation of kinin to set their level and type of activity. Thus, not only production of prostaglandins but the functional consequences within the kidney of their enhanced production, as determined by the ratio of PGE2 to PGF2alpha, may be subject to regulation by kinins originating intrarenally.

Animals↗
PubMed1976

Prostaglandins as determinants of vascular reactivity.

Prostaglandins are primarily local or tissue hormones that have their effects at, or near to, the site of synthesis. Some blood vessels synthesize prostaglandins intramurally, where their local release influences vascular tone and reactivity. Endogenous prostaglandins (primarily prostaglandin E2 (PGE2) participate in the regulation of vascular reactivity by opposing the vasoconstrictor and antinatriuretic actions of circulating pressor hormones; and by braking the release of norepinephrine from vasoconstrictor nerves. The proposal that one or more prostaglandins affect vascular reactivity is supported by the following observations: enhanced vascular reactivity to pressor stimuli occurs in organs with low basal rates of prostaglandin synthesis and after inhibition of prostaglandin synthetase in organs with high biosynthetic capacity; and exogenous PGE2 reversibly inhibits the vasoconstrictor activity of pressor stimuli.

Angiotensin II↗
PubMed1976

Renal prostaglandins.

1. Renal prostaglandins act primarily as local hormones, having their effects at, or near to, sites of synthesis. PGE2 is a major determinant of renal vascular reactivity; it opposes the vasoconstrictor and natriuretic actions of pressor hormones and brakes the release of noradrenaline from adrenergic nerves. In the unanaesthetized rabbit prolonged inhibition of prostaglandin synthesis results in hypertension. In the rat, however, renal prostaglandins augment pressor stimuli. 2. Basal efflux of renal prostaglandins is positively correlated with blood flow to the inner cortex and medulla. Those stimuli which increase renal medullary blood flow do so primarily by activating prostaglandin synthetase. 3. Kinins increase prostaglandin synthesis which action modifies the renal effects of kinins. Thus, one or more renal prostaglandins contribute to the renal vasodilator action of bradykinin and mediate its effect on excretion of water as well as possibly attenuating the natriuretic action of the polypeptide. Kinins in addition to stimulating prostaglandin synthesis may determine the principal product of synthetase by regulating the enzyme PGE 9-ketoreductase, which converts PGE to PGF. The coupling of these systems within the kidney appears unique--prostaglandins mediate some of the actions of kinins and modulate others, whereas they depend on the intrarenal generation of kinins to set their level and type of activity.

Animals↗
PubMed1975

The actions of bradykinin and eledoisin in the canine isolated kidney: relationships to prostaglandins.

1. The effects of two vasodilator polypeptides, bradykinin and eledoisin, were studied in isolated blood-perfused canine kidneys before and after administration of indomethacin, an inhibitor of prostaglandin synthesis, Bradykinin, but not eledoisin, releases renal prostaglandins. 2. Before administration of indomethacin, bradykinin decreased urinary osmolality and increased free qater clearance, whereas eledoisin did not affect the excretion of solute-free water. After administration of indomethacin, the renal vasodilator action of bradykinin was reduced but the vasodilator action of eledoisin was unaffected. 3. Fractional excretion of sodium was not affected by bradykinin before but was increased after administration of indomethacin. Reduction in glomerular filtration rate contributed to changes in sodium excretion produced by bradykinin and eledoisin. 4. The release of prostaglandins from the kidney by bradykinin amplifies the renal vasodilator action of the kinin and possibly mediates its effect on excretion of solute-free water.

Animals↗
PubMed1975

Modulation by prostaglandins of adrenergic transmission in the isolated perfused rabbit and rat kidney.

In the isolated perfused rabbit kidney prostaglandins (PGS) E1 (0.02-0-1 ng/ml), E2 (0.02-0.1 ng/ml), and A2 (1-5 ng/ml) inhibited the vasoconstrictor responses to sympathetic nerve stimulation by 21-44%, 31-39%, and 20-23%, respectively, without alerting those to injected norepinephrine. In contrast, in the rat kidney PGE1 (0.5 ng/ml), PGE2 (0.5 ng/ml), and PGA2 (5 ng/ml) enhanced the vasoconstrictor responses to sympathetic nerve stimulation by 41%, 27%, and 11%, respectively; the equiconstrictor responses to injected norepinephrine remained unaltered. Higher concentrations of these agents produced vasodilation in the rabbit kidney and vasoconstriction in the rat kidney. In both species PGF2alpha produced vasoconstriction and enhanced the response to both adrenergic stumuli. In the rabbit kidney inhibitors of PG synthesis augmented the responses to sympathetic nerve stimulation without altering those to injected norepinephrine, whereas in the rat kidney inhibition of the responses to both adrenergic stimuli occurred. Arachidonic acid inhibited the vasoconstrictor responses to sympathetic nerve stimulation in the rabbit kidney, but in the rat kidney it caused augmentation of these responses. Since these effects of arachidonic acid were reduced by indomethacin, they appear to be mediated through the acid's conversion to PGS. We conclude that PGS of the E series modulate adrenergic transmission in the kidney and that their modulatory actions are species dependent.

Animals↗
PubMed1975

Possible contributions of endogenous prostaglandins to the control of blood pressure.

Prostaglandins are primarily local or tissue hormones which have their effects at or near the site of release and are metabolized before reaching the arterial circulation. A possible exception is prostaglandin A-2, which has been proposed as a circulating hormone; however, there is no evidence that prostaglandin A-2 is biosynthesized in the mammalian kidney or even in extrarenal tissues. The prostaglandin generated and released in the kidney is predominantly E-2. Some blood vessels also synthesize prostaglandins intramurally, where their local release influences vascular tone and reactivity. Endogenous prostaglandin E-2 production contributes to the regulation of blood pressure by (1) opposing the vasoconstrictor and antidiuretic actions of circulating pressor hormones; (2) braking the release of norepinephrine from vasoconstrictor nerves; and (3) participating in the control extracellular fluid volume through its renal hemodynamic actions.

Angiotensin II↗
PubMed1975

Prostaglandin synthesis by bovine mesenteric arteries and veins.

Prostaglandins (PG) were synthesized at similar rates by bovine mesenteric arteries and veins; viz., ca. 200 ng/g wet weight after one hour of incubation. After synthesis, PGE and PGF compounds were released from slices of arteries and veins into the incubating medium; PG were not detected in the walls of these blood vessels. Arachidonic acid, the precursor to PGE-2 and PGF-2-alpha, did not affect PG synthesis, whereas meclofenamate, an aspirin-like agent, decreased synthesis in arteries and veins by 90%. The PG biosynthetic capacity of these blood vessels is high, as indicated by greater than 20% conversion of (1-14C)-arachidonic acid to radiolabeled PG. Under control conditions in both arteries and veins, synthesis of PGE-2 exceeded that of PGF-2-alpha twofold. Bradykinin selectively increased the synthesis of a PGE-like substance in arteries and of a PGE-like substance in veins.

Animals↗
PubMed1975

Disappearance of bradykinin in the renal circulation of dogs. Effects of kininase inhibition.

In chloralose-anesthetized dogs, we investigated the disappearance of bradykinin on passage across the renal circulation. The peptide was infused into a renal artery at various doses (5-200 ng/kg min-1); renal blood flow and the concentration of kinins in renal venous blood were then determined and the percent survival of bradykinin on passage through the kidney calculated. Bradykinin caused a dose-related increase in renal blood flow, urine flow, sodium excretion, and kinin content of renal venous blood. Intravenous administration of BPP9alpha (300 mug/kg), a peptide kininase II inhibitor, potentiated the renal vasodilator, diuretic, and natriuretic actions of bradykinin and augmented the survival of the kinin on passage through the kidney from 12.72 +/- 1.64% in control dogs to 53.92 +/- 7.48% (P less than 0.001). Furthermore, the values of peptide survival were positively correlated with the increases in renal blood flow (r = 0.92, P less than 0.01), urine flow (r = 0.75, P less than 0.01), and sodium excretion (r = 0.68, P less than 0.01) produced by bradykinin. In addition, BPP9alpha by itself increased renal blood flow (16%, P less than 0.01), urine flow (115%, P less than 0.005), and sodium excretion (167%, P less than 0.02). Similarly, the concentration of kinin in renal venous blood and the excretion of urinary kinins rose from 0.11 +/- 0.03 ng/ml and 4.1 +/- 1.1 ng/min to 0.24 +/- 0.05 ng/ml (P less than 0.005) and 38.5 +/- 12.2 ng/min (P less than 0.02). These studies suggest that kinins generated intrarenally play a role in the regulation of renal blood flow and salt-water excretion and that variations in the capacity of the kidney to inactivate kinins may be a determinant of the intrarenal activity of the kallikrein-kinin system.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1975

Assay of kinins by their effects on canine femoral blood flow.

In pentobarbital anesthetized dogs, close arterial injections of bradykinin and kallidin elicit a dose related increase in femoral blood flow. Treatment with the kininase inhibitor BPP9alpha augments the femoral blood flow responses to bradykinin and kallidin by five and threefold respectively. The sensitivity of the preparation permits the detection of 0.5-1 ng of either bradykinin or kallidin in untreated dogs and as little as 0.1 ng of kinin peptides in animals receiving BPP9alpha. This sensitivity and the steepness of the dose response curves make this procedure suitable for the assay of kinins.

Angiotensin-Converting Enzyme Inhibitors↗