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A S Nies

Publications and source records attributed to A S Nies.

At least 19 recordsLinked to original sources
PubMed1992

Platelet alpha 2-adrenergic receptor responsiveness is increased in elderly men but not in elderly women.

We ascertained platelet alpha 2-adrenergic receptor responsiveness in healthy young and elderly men and women by determining the minimum concentration of methylnorepinephrine, a selective alpha 2-adrenergic receptor agonist, required to initiate the primary and secondary aggregation response in platelet-rich plasma. We observed that platelets from elderly men required a smaller concentration of methylnorepinephrine to stimulate primary aggregation than did platelets obtained from young men. However, the concentration of alpha 2-adrenergic receptor agonist to trigger the secondary aggregation response did not vary with age. There was no difference in the responsiveness of platelets from young and elderly women for either the primary or secondary aggregation response. We conclude that platelet alpha 2-adrenergic receptor responsiveness is increased with age rather than decreased, as predicted from some studies of the density of platelet alpha 2-adrenergic receptors and their coupling to adenylyl cyclase. Furthermore, the increase in alpha 2-adrenergic receptor responsiveness is gender specific.

Adult↗
PubMed1992

Terbutaline-induced desensitization of polymorphonuclear leukocyte beta 2-adrenergic receptors in young and elderly subjects.

Potential age-related differences in cardiovascular responsiveness and receptor regulation induced by short-term administration of a selective beta 2-adrenergic receptor agonist were investigated. Young (age range, 23 to 31 years) and elderly (age range, 64 to 73 years) healthy subjects were treated with terbutaline (5 mg, three times daily) for 5 days. Similar plasma terbutaline concentrations were achieved in the two age groups. The elderly group had higher baseline plasma norepinephrine concentrations and mean arterial pressures, neither of which were altered by terbutaline administration. During terbutaline treatment, heart rate increased in both age groups while subjects were supine but consistently increased only in the young group while subjects were standing. In both age groups, the density of beta 2-adrenergic receptors on polymorphonuclear leukocyte membranes was reduced by 50% during terbutaline administration and returned to baseline values at similar rates after drug administration was stopped. Isoproterenol-stimulated cyclic adenosine monophosphate accumulation in polymorphonuclear leukocytes from elderly subjects was regulated similarly. These findings suggest that the ability of terbutaline to increase standing heart rate is selectively impaired in the elderly, whereas the ability of polymorphonuclear leukocyte beta 2-adrenergic receptors to down-regulate and to return to baseline values is not.

Administration, Oral↗
PubMed1992

Age and gender influence the stereoselective pharmacokinetics of propranolol.

The effect of age and gender on the stereoselective pharmacokinetics of propranolol was studied in 12 young (25 to 33 years old) and 12 elderly (62 to 79 years old) healthy nonsmoking volunteers, half of whom were female. Racemic propranolol was administered (80 mg p.o.) each 8 hr for seven doses. Serum was obtained just before (0 time) and at 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hr after the final dose and analyzed for propranolol enantiomers. The serum concentration of alpha-1 acid glycoprotein was determined before propranolol administration. The binding of each enantiomer to serum proteins was determined in samples obtained before propranolol administration and two hr after the final dose of propranolol. We found that the intrinsic hepatic clearance of S-propranolol was about 30% smaller in the elderly than in the young, whether it was calculated for total or unbound drug. Additionally, the elimination half-lives of both enantiomers were 2- to 3-fold prolonged in the elderly compared with the young. In all subjects regardless of age or sex the intrinsic hepatic clearance of the total (bound plus free) S-isomer was smaller than that of the R-isomer. There was no age-related difference in alpha-1 acid glycoprotein concentration or protein binding of either enantiomer of propranolol. However, there was a gender-related difference with the females having significantly greater binding of the S-enantiomer than the males.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

Contrasting effects of changes in salt balance on the renovascular response to A1-adenosine receptor stimulation in vivo and in vitro in the rat.

Stimulation of renal A1-adenosine receptors produces vasoconstriction that is maximal when the animal is salt-depleted and is inhibited during salt loading. We postulated that the effect of salt balance on the vasoconstrictor response to A1-adenosine receptor stimulation was due to a change intrinsic to the kidney, perhaps related to a change in responsiveness of the renal A1-adenosine receptor population. We tested this hypothesis by determining the renovascular response to the metabolically stable, selective, A1-adenosine receptor agonist N6-cyclohexyladenosine (CHA) in salt-loaded and salt-depleted rats in vivo and in isolated, perfused kidneys harvested from these rats. CHA was a renal vasoconstrictor in the salt-depleted animals and a renal vasodilator in the salt-loaded rats. In the isolated, perfused kidneys, CHA produced a biphasic response with submicromolar concentrations being vasoconstrictor and higher concentrations being vasodilator. In contrast to the response in vivo CHA was a more potent vasoconstrictor in the isolated, perfused kidneys that had been removed from salt-loaded animals. Indomethacin enhanced the vasoconstrictor response to CHA in the kidneys removed from salt-loaded animals but had no effect on the kidneys from salt-depleted animals. These findings indicate that the inhibition of the renal vasoconstrictor response to CHA in salt-loaded animals is not related to a change within the kidney but that a factor extrinsic to the kidney must be responsible for the change in adenosine responsiveness in vivo.

Adenosine↗
PubMed1991

Release of platelet activating factor by the isolated kidney is not linked to the production of prostaglandins.

In many isolated tissues, including glomerular mesangial cells and endothelial cells, the synthesis of platelet activating factor (PAF) occurs by remodeling the phospholipids so that the production of PAF results in the release of arachidonic acid with subsequent production of cyclooxygenase or lipoxygenase products. In some tissues, including the renal medulla, another pathway for PAF biosynthesis (the de novo pathway) has been found in which the production of PAF is not linked to the production of arachidonic acid products. We tested the hypothesis that the remodeling pathway was active in the release of PAF into renal venous effluent of the isolated kidney. Isolated rat kidneys perfused at constant flow with albumin-containing buffer were stimulated to produce prostaglandin by an infusion of angiotensin II or bradykinin. Some kidneys were also challenged with the calcium ionophore A23187. Perfusate was collected for bioassay of PAF and radioimmunoassay of prostaglandin (PG) E2; urine was collected for PAF bioassay. Angiotensin II (10(-9) to 10(-8) M) increased renal vascular resistance, and bradykinin (10(-8) to 10(-7) M) and A23187 (3 x 10(-6) M) reduced renal vascular resistance. PGE2 production was increased significantly by bradykinin and angiotensin II but not by A23187. Only A23187 increased the release of PAF into the perfusate. Urine PAF was not changed by any of the stimuli. These data indicate that the release of PGE2 by the isolated, perfused rat kidney can be dissociated from the release of PAF. The findings support the suggestion that PAF released by the kidney into the renal venous effluent is not produced by remodeling the lipids that are the source of renally released prostaglandins.

Angiotensin II↗
PubMed1990

The antihypertensive efficacy of hydrochlorothiazide is not prostacyclin dependent.

We tested the hypothesis that vascular prostacyclin synthesis is stimulated by hydrochlorothiazide and could account for some of the drug's antihypertensive effect. We studied 13 patients with mild essential hypertension in a randomized, double-blind design to assess the effects of indomethacin on hydrochlorothiazide's ability to lower blood pressure, alter body weight, stimulate plasma renin activity, and modulate vascular prostacyclin biosynthesis as assessed by the urinary excretion of the major enzymatically produced metabolite of prostacyclin, 2,3-dinor-6-keto-prostaglandin F1 alpha (PGF1 alpha), measured by GC/MS. Administration of hydrochlorothiazide, 50 mg daily for 2 weeks, was associated with a significant decrease in both systolic and diastolic blood pressure in both supine (systolic, 148 +/- 3 to 136 +/- 3 mm Hg; diastolic, 97 +/- 2 to 94 +/- 3 mm Hg) and upright (systolic, 151 +/- 4 to 131 +/- 2 mm Hg; diastolic, 103 +/- 2 to 97 +/- 3 mm Hg) positions. Hydrochlorothiazide administration resulted in a 1 kg weight loss and stimulation of plasma renin activity from 1.7 +/- 0.4 to 5.3 +/- 1.1 ng angiotensin I/ml/hr. However, the urinary excretion of 2,3-dinor-6-keto-PGF1 alpha was unchanged after administration of hydrochlorothiazide (86 +/- 13/ng/gm creatinine during placebo, 74 +/- 13 ng/gm during week 1 of hydrochlorothiazide, and 70 +/- 9 ng/gm during week 2 of the drug). Administration of indomethacin, 50 mg twice a day, resulted in greater than 60% inhibition of 2,3-dinor-6-keto-PGF1 alpha excretion but did not affect the antihypertensive response to hydrochlorothiazide. Indomethacin did not oppose the diuretic effect of hydrochlorothiazide as assessed by weight loss but did attenuate the rise in plasma renin activity. Our data demonstrate that the blood pressure-lowering effect of a thiazide diuretic does not require enhanced prostacyclin synthesis and the cyclooxygenase inhibitor indomethacin does not antagonize the antihypertensive efficacy of hydrochlorothiazide.

Adult↗
PubMed1990

The effect of age on the sensitivity of the alpha 1-adrenoceptor to phenylephrine and prazosin.

Certain beta-adrenoceptor-mediated functions seem to diminish with age; however, information on alpha-adrenoceptor-mediated function is sparse and often conflicting but overall suggests little age-related change. To assess an age-related alteration in the responsiveness to an alpha 1-adrenergic agonist and to estimate changes in the apparent affinity of the alpha 1-adrenoceptor for the antagonist prazosin, we infused phenylephrine into 12 healthy elderly subjects and 12 healthy young subjects before and after an oral dose of prazosin, and we compared the shift in the dose-response curves for the two groups. With this protocol we were unable to detect any age-related decline in sensitivity of the alpha-adrenoceptor to either agonist or antagonist. However, oral prazosin resulted in higher plasma concentrations and a consistently greater hypotensive effect in the elderly subjects than in the young subjects. We concluded that there was no difference in alpha 1-adrenoceptor sensitivity in the elderly persons, but that the kinetics of prazosin may be altered and that the response of the blood pressure to prazosin was increased because of the kinetic changes and possibly the physiologic changes associated with aging.

Adult↗
PubMed1990

Lack of an effect of age on the response to clonidine.

The plasma concentration and appearance rate of norepinephrine are increased in the elderly. A hypothesis to explain this observation is that the elderly have a diminished response of the alpha 2-adrenoreceptor in the brainstem that modulates peripheral sympathetic tone. To evaluate the effect of age on alpha 2-adrenoreceptor function, we studied 12 healthy elderly subjects and 12 healthy young volunteers and compared the decrease in plasma norepinephrine and blood pressure in response to increasing doses of orally administered clonidine. We found that, for the same plasma clonidine concentration, the blood pressure and plasma norepinephrine concentration fell equivalently in both groups. These data imply that the increased plasma norepinephrine and the elevated blood pressure in the healthy elderly population do not appear to be secondary to a decrease in alpha 2-adrenergic response to an agonist in the central nervous system.

Adult↗
PubMed1990

Hydralazine does not stimulate prostacyclin biosynthesis in hypertensive patients.

The hypothesis that vascular prostacyclin synthesis is stimulated by the oral administration of hydralazine and may account for part of its vascular effect was tested. Eight white patients with mild essential hypertension were studied in a randomized, double-blind design to assess the effects of indomethacin on hydralazine's ability to lower blood pressure, elevate pulse, and alter the vascular prostacyclin biosynthesis as assessed by the urinary excretion of the major enzymatically produced metabolite of prostacyclin, 2,3-dinor-6-keto-prostaglandin F1 alpha (PGF1 alpha) measured by gas chromatography-mass spectrometry. Administration of hydralazine at either 50 mg bid or 100 mg bid for a week, doses commonly administered in clinical settings, was not associated with a statistically significant fall in mean blood pressure, although there was a tendency towards a decrease but did result in an increase in heart rate. Administration of indomethacin had no effect on the hemodynamic parameters secondary to hydralazine. Administration of indomethacin resulted in a slight but significant weight gain compared to placebo, but the addition of hydralazine did not result in a further increase in weight. Neither dose of hydralazine resulted in an increase in the urinary excretion of 2,3-dinor-6-keto-PGF1 alpha. The excretion rate was 85 +/- 16 ng/g of creatinine during placebo, 88 +/- 16 ng/g of creatinine during hydralazine, 50 mg bid, and 65 +/- 8 ng/g of creatinine during hydralazine, 100 mg bid. Administration of indomethacin, 50 mg bid, resulted in a significant decrease in 2,3-dinor-6-keto-PGF1 alpha from 65 +/- 6 ng/g to 37 +/- 8 ng/g of creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Characterization of epoxides of polyunsaturated fatty acids by mass spectrometry via 3-pyridinylmethyl esters.

The isomeric epoxides of linoleic, arachidonic and docosahexaenoic acids were prepared by reaction with m-chloroperoxybenzoic acid and, after separation by normal-phase high-performance liquid chromatography, were esterified with 3-pyridylcarbinol via the unstable imidazolide generated by the reaction with 1,1'-carbonyldiimidazole. The electron impact mass spectra of these derivatives showed a molecular ion and a sequence of peaks with two characteristic abundant ions that resulted from formal cleavage of the carbon-carbon bonds at the oxirane ring. Both these ions retained the ester group. This fragmentation pattern allowed the unequivocal identification of the separate epoxide isomers.

Arachidonic Acids↗
PubMed1989

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International System of Units↗
PubMed1989

Timolol-induced up-regulation of polymorphonuclear leukocyte beta 2-adrenergic receptors in the elderly.

Drug-induced up-regulation of beta-adrenergic receptors is impaired in the brains of aged rats but not in myocardia. To investigate age-related changes in receptor regulation in human beings, young (24 to 35 years of age) and elderly (62 to 78 years of age) healthy volunteers were treated with the beta-adrenergic receptor blocking agent timolol maleate (10 mg b.i.d.) for 8 days. Baseline densities of beta 2-adrenergic receptors on polymorphonuclear leukocyte (PMNL) membranes and heart rates were the same in the two age groups. However, systolic blood pressures were higher in the elderly subjects. Administration of timolol produced similar plasma levels in the two groups. In response to timolol, the density of PMNL beta-adrenergic receptors increased at a similar rate and to the same extent (threefold) in both age groups. Likewise, hemodynamic changes were not related to age. These results suggest that up-regulation of peripheral beta 2-adrenergic receptors in human beings is not impaired with aging.

Adult↗
PubMed1989

Atrial natriuretic peptide blocks the renal vasoconstrictor response to hypertonic saline in the dog.

The role of atrial natriuretic peptide to modulate the renal tubuloglomerular feedback response was examined in the dehydrated anesthetized dog using an infusion of hypertonic sodium chloride to increase renal plasma sodium concentration by 30 mEq/l as the stimulus to activate the tubuloglomerular feedback. Two sequential infusions of hypertonic sodium chloride into the renal artery for 10 min were separated by 90 min, and various interventions were introduced before the second hypertonic saline infusion. In the first group of dogs, the first infusion of hypertonic saline resulted in a significant decrease in renal blood flow from 234 +/- 36 to 199 +/- 31 ml/min, but when atriopeptin III (APIII) was infused into the renal artery at 3 x 10(-10) mol/min, the repeat infusion of hypertonic saline resulted in a significant increase in blood flow from 221 +/- 28 to 269 +/- 35 ml/min that was maintained throughout the 10 min of hypertonic saline. In the second group of dogs only the vehicle for APIII was infused during the second hypertonic saline infusion. In these dogs, renal blood flow decreased significantly the first time from 201 +/- 17 to 170 +/- 16 ml/min, and the second time from 232 +/- 22 to 177 +/- 20 ml/min. In a third group of dogs, the vasodilator sodium nitroprusside, a stimulator of smooth muscle soluble guanylate cyclase, was infused into the renal artery during the second hypertonic saline infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1988

Renal effects of nonsteroidal anti-inflammatory drugs.

All nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase, and consequently renal functions dependent upon prostaglandin synthesis can be affected. Fortunately, renal function in normal individuals is relatively independent of the PG system, and thus the NSAIDs don't usually produce any renal dysfunction. However, in some circumstances, inhibition of PG dependent renal functions can produce clinically significant effects. When the kidney is in a salt retaining state or when there is renal vascular damage, NSAIDs can reduce renal blood flow and glomerular filtration rate producing acute renal failure that is reversible upon discontinuation of the drug. NSAIDs can also: 1) reduce sodium excretion and blunt the diuretic effect of loop diuretics, thus producing or exacerbating edema, 2) inhibit PG dependent renin secretion occasionally resulting in hyperkalemia, 3) enhance the antidiuretic effects of vasopressin and 4) reduce the antihypertensive efficacy of several drugs. Evidence that any NSAID "spares" renal cyclooxygenase is controversial, and no NSAID is devoid of clinical problems. Syndromes that are less obviously related to inhibition of renal PG synthesis are acute interstitial nephritis with or without the nephrotic syndrome, renal papillary necrosis, and chronic interstitial nephritis. Recently a unique syndrome of flank pain and mild reversible renal dysfunction has been described in healthy individuals receiving suprofen, a uricosuric NSAID. This syndrome may be due to uric acid crystal deposition in the renal tubules and has resulted in the removal of suprofen from the US market.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Facile method for preparation of 2,3-dinor-6-keto PGF1 alpha, the major urinary metabolite of prostacyclin.

We report a convenient and efficient method for the preparation of prostaglandin 2,3-dinor-6-keto-F1 alpha by incubating prostaglandin 6-keto-F1 alpha (6-keto-PGF1 alpha) with dispersed rat hepatocytes. Chromatographic separation revealed a single product from the hepatocyte metabolism of 6-keto-PGF1 alpha whose structure was positively confirmed by mass spectrometry as 2,3 dinor-6-keto-PGF1 alpha. This method allowed for the preparation of high specific activity radioactive 2,3-dinor-6-keto-PGF1 alpha which can be utilized to determine the recovery of urinary dinor-6-keto-PGF1 alpha during extraction and separation of the compound for radioimmunoassay measurements, as well as deuterated 2,3-dinor-6-keto-PGF1 alpha which can be used as an internal standard in the gas chromatography-mass spectrometric assay of this compound.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Age does not alter human vascular and nonvascular beta 2-adrenergic responses to isoproterenol.

beta-Adrenoceptor-mediated functions appear to diminish with aging, but the exact scope of these changes is unknown, because most studies have been limited to beta 1-adrenergic cardiac phenomena. To evaluate both a vascular and a nonvascular beta 2-adrenergic response in the aged, we have studied 12 healthy elderly and 12 healthy young subjects infused with increasing doses of isoproterenol and compared the change in peripheral vascular resistance, measured by venous occlusion plethysmography, and insulin release. In both groups vascular resistance fell and insulin concentrations increased. These changes were equivalent in both groups, and we therefore infer no significant decline in either of these beta 2-adrenergic functions in the elderly.

Adult↗