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Biomedical subjects

M Bresnahan

Publications and source records attributed to M Bresnahan.

31 records · Page 2Linked to original sources
PubMed1991

Effects of bradykinin and prostaglandin inhibition on systemic and regional hemodynamics in conscious normotensive rats.

These experiments were designed to study the effects of inhibition of endogenous bradykinin and/or prostaglandins on systemic and regional hemodynamics in conscious normotensive rats, using the radioactive microsphere technique. Administration of either a bradykinin antagonist (50 micrograms/min for 5 min) or indomethacin (10 mg/kg) alone, decreased the cardiac output by an average of 17.58 and 25.94%, respectively (P less than 0.05), without significant change in total peripheral resistance. Regional blood flow decreased and local vascular resistance increased in most organs. Coronary and renal blood flow decreased by an average of 16.45 and 17.26% with bradykinin antagonist and 23.85 and 19.80% with indomethacin, respectively (P less than 0.05). Indomethacin but not bradykinin antagonist also decreased cerebral blood flow by an average of 47.57% (P less than 0.01). Infusion of the bradykinin antagonist following prior prostaglandin inhibition with indomethacin did not induce further changes in either systemic or regional hemodynamics, except in the liver where a significant additional increment in vascular resistance was observed. Our data suggest that most organs have similar patterns of regional vascular sensitivity to bradykinin and prostaglandins (including the heart, kidney, testis, stomach, skin and adrenal). The major differences were in the cerebral vasculature, which was much more sensitive to prostaglandins, and in the liver, spleen and small intestine, which were more sensitive to bradykinin. We conclude that both hormonal systems participate to a varying extent in the maintenance of resting vascular tone in most organs; however, in some cases, their effects may be additive and in others they may work in opposite directions.

Animals↗
PubMed1990

Effect of aging on vasopressin, catecholamines, and alpha 2-adrenergic receptors.

To characterize normal changes with aging, we measured plasma levels of epinephrine, norepinephrine, and vasopressin, as well as alpha 2-adrenergic receptor numbers (Bmax) and the antagonist dissociation constant (Kd) from platelet-derived membranes of white, younger (aged 28 +/- 6 years, n = 30) and older (aged 70 +/- 4 years, n = 41) normotensive, healthy volunteers. There were no differences in resting vasopressin or epinephrine levels at 0.83 +/- 0.83 and 360 +/- 120 pmol/L in the younger versus 1.0 +/- 0.2 and 450 +/- 420 in the older subjects, respectively. However, plasma norepinephrine was significantly higher in the older (2.87 +/- 1.34 nmol/L) versus the younger subjects (1.50 +/- 0.53 nmol/L, P less than .01). Platelet alpha 2-receptor numbers were significantly lower in the older subjects at 289 +/- 79 fmol/mg protein versus 388 +/- 81 fmol/mg protein in the younger subjects (P less than .01), compatible with but not proof of down-regulation by norepinephrine. However, Kd, representing receptor affinity, was similar in both groups. Therefore, studies of hormone and receptor status in various pathologic conditions should always take into account the normal changes attributable to the age of the subject population.

Adult↗
PubMed1990

Pressor hormones in elderly hypertensive persons. Racial differences.

The purpose of this study was to examine pressor hormones and platelet alpha 2-adrenergic receptors in elderly unmedicated free-living subjects. Eighty-seven subjects, 70 +/- 5 years old (mean +/- SD), hypertensive or normotensive (blood pressure less than 160/90 mm Hg) were recruited for measurement of blood levels of norepinephrine, epinephrine, and vasopressin, as well as density and affinity of alpha 2-adrenergic receptors from platelet membranes, assessed by maximal binding (Bmax) and dissociation constant (Kd) of rauwolscine. They were separated into white hypertensive (n = 22) or normotensive (n = 41), and black hypertensive (n = 11) or normotensive (n = 13) groups, with similar age distribution throughout and similar blood pressure levels in the hypertensive and normotensive groups. Vasopressin was higher in the black hypertensive than white hypertensive group (1.5 +/- 1.0 vs. 0.7 +/- 0.5 pg/ml, respectively, p less than 0.005), whereas epinephrine correlated inversely with diastolic blood pressure (r = -0.7, p less than 0.02, in the black hypertensive group). Kd was higher in the black normotensive group than in the other groups (1.6 +/- 0.6 vs. 1.0 +/- 0.2, 1.1 +/- 0.3, or 1.0 +/- 0.3 nM in the white normotensive, black hypertensive, or white hypertensive group, respectively, p less than 0.002). Bmax was no different among groups but was significantly correlated with vasopressin levels for the whole group (r = 0.4, p less than 0.0004) although no such correlation existed within the black hypertensive group. The data suggest that various vasoconstrictor systems participate to different extents in the mechanisms generating and sustaining hypertension in elderly white and black subjects.

Aged↗
PubMed1989

A new cluster of genes within the human major histocompatibility complex.

A 435-kilobase (kb) DNA segment, which is centromeric to HLA-B in the human major histocompatibility complex, was isolated by chromosome walking with overlapping cosmids. Within the cloned region, the genes for the tumor necrosis factors (TNFs) alpha and beta and HLA-B were 210 kb apart. The human homolog of a mouse gene, B144, was located next to TNF alpha. Moreover, the presence of additional genes was suggested by a large cluster of CpG islands. With cosmid probes, several distinct transcripts were detected in RNA samples from a variety of cell lines. Altogether, five novel genes were identified by isolation of corresponding complementary DNA clones. These "HLA-B-associated transcripts" (BATs) were mapped to different locations within a 160-kb region that includes the genes for TNF alpha and TNF beta. The presence of the genes for BAT1 and BAT5 in the vicinity of HLA-B again raises the question of which gene in this region determines susceptibility to ankylosing spondylitis.

Animals↗
PubMed1989

Human major histocompatibility complex contains a minimum of 19 genes between the complement cluster and HLA-B.

A 600-kilobase (kb) DNA segment from the human major histocompatibility complex (MHC) class III region was isolated by extension of a previous 435-kb chromosome walk. The contiguous series of cloned overlapping cosmids contains the entire 555-kb interval between C2 in the complement gene cluster and HLA-B. This region is known to encode the tumor necrosis factors (TNFs) alpha and beta, B144, and the major heat shock protein HSP70. Moreover, a cluster of genes, BAT1-BAT5 (HLA-B-associated transcripts) has been localized in the vicinity of the genes for TNF alpha and TNF beta. An additional four genes were identified by isolation of corresponding cDNA clones with cosmid DNA probes. These genes for BAT6-BAT9 were mapped near the gene for C2 within a 120-kb region that includes a HSP70 gene pair. These results, together with complementary data from a similar recent study, indicated the presence of a minimum of 19 genes within the C2-HLA-B interval of the MHC class III region. Although the functional properties of most of these genes are yet unknown, they may be involved in some aspects of immunity. This idea is supported by the genetic mapping of the hemopoietic histocompatibility locus-1 (Hh-1) in recombinant mice between TNF alpha and H-2S, which is homologous to the complement gene cluster in humans.

Cell Line↗
PubMed1987

Central catecholamines and alpha-adrenoceptors in acute hypertension induced by intracerebroventricular hypertonic saline.

We measured the tissue content of catecholamines and the numbers and affinities of alpha 1- and alpha 2-adrenergic receptors in specific areas of the hypothalamus and medulla oblongata of rats treated with intracerebroventricular microinjection of hypertonic saline, in comparison to controls treated with an equal volume of iso-osmolar dextrose solution. Rats given 20 microliter of 4% NaCl into the lateral ventricle showed an average rise in blood pressure of 14 +/- 2 mmHg and a decrease in heart rate of 63 +/- 11 beats/min (P less than 0.001 for both), associated with dopamine suppression in the anteroventral area of the third ventricle (AV3V) and increased concentrations of dopamine in the C2 region of the medulla and of epinephrine in the area postrema. Affinities of medullary alpha 2-adrenoceptors were decreased in the saline-treated rats, whereas the number of receptors tended to be higher. It is suggested that sodium may produce its pressor effect by diminishing the affinity of central alpha 2-adrenoceptors for neurotransmitters, resulting in disinhibition of certain sympathoinhibitory neurons and increased sympathetic outflow.

Animals↗
PubMed1984

Acute cardiovascular effects of two central phenylethanolamine-N-methyl-transferase inhibitors in unanesthetized desoxycorticosterone-salt hypertensive rats.

SKF 64139, an inhibitor of phenylethanolamine-N-methyltransferase (PNMT), has a marked hypotensive effect in models of sodium-dependent hypertension. The mechanism of this effect is obscure, the compound having in addition alpha-adrenoceptor blocking properties. We compared the acute effects of SKF 64139 with those of LY 134046, another PNMT inhibitor with minimal alpha-blocking capacity, in desoxycorticosterone-salt hypertensive rats. The former agent produced profound hypotension whereas the latter caused only bradycardia. Both induced a similar pronounced suppression of PNMT activity in the C1 and C2 region of the medulla oblongata. These results suggest that the alpha-adrenergic effect rather than PNMT inhibition accounts for the acute lowering of blood pressure in this model.

Animals↗
PubMed1978

Studies on the activity of the sympathetic nervous system in essential hypertension.

Plasma catecholamine and norepinephrine concentrations have been measured in carefully characterized ambulatory patients with essential hypertension under basal conditions and following experimental procedures known to enhance sympathetic activity. The studies have demonstrated increased levels of plasma catecholamines in patients with mild hypertension as compared with matched controls following 70 degree upright tilt or cold pressor testing. Considerable heterogeneity was apparent in the population of patients with essential hypertension with respect to their plasma norepinephrine concentrations. Significantly greater levels of plasma norepinephrine were present in patients with high plasma renin activity and lesser levels in patients with low renin activity than in normal renin or labile hypertensives. Blood pressure correlated significantly with plasma norepinephrine in male patients with normal renin essential hypertension but not in females. Administration of the diuretic furosemide produced an increase in plasma norepinephrine in almost all hypertensive subjects studied. These studies suggest that peripheral sympathetic activity is abnormal in certain patients with essential hypertension. The results underscore the need to differentiate between subgroups of essential hypertension in studies relating to the role of the adrenergic system in the hypertension. The findings also suggest that the recently developed sensitive techniques for measuring plasma catecholamines of plasma norepinephrine are of value in assessing changes in peripheral sympathetic activity but that enzymatic assays of serum dopamine-beta-hydroxylase activity are probably not useful for this purpose.

Adult↗
PubMedDate not supplied

Effect of pindolol on blood pressure, plasma renin activity, and catecholamines in hypertensive patients.

The effects of 45 mg pindolol daily on blood pressure, heart rate, plasma renin activity, and plasma catecholamines were assessed on 11 hospitalized hypertensive patients. Blood pressure decreased significantly after nine days of treatment, but heart rate remained unchanged. Plasma renin activity was in the same average range before and during treatment, with individual values variably increasing, decreasing, or remaining unchanged. Blood pressure changes were independent from the baseline level of plasma renin activity or the change in renin activity observed during treatment. Plasma epinephrine and norepinephrine levels also remained unchanged during treatment. Lack of change in heart rate and hormonal levels may be attributed to the combined effects of the beta-antagonistic and partial agonistic properties of this agent. Thus, pindolol used as monotherapy at this dose significantly lowered blood pressure, but not to normal levels, with only minimal side effects. Because of its combined adrenergic agonistic and antagonistic effects, it may be a preferable alternative to pure antagonists in selected patients.

Adult↗
PubMedDate not supplied

A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway.

Major histocompatibility complex (MHC) class I molecules export peptides to the cell surface for surveillance by cytotoxic T lymphocytes. Intracellular peptide binding is critical for the proper assembly and transport of class I molecules. This mechanism is impaired as a result of a non-functional peptide supply factor gene (PSF) in several human mutant cell lines with genomic lesions in the MHC. We have now identified PSF in the MHC class II region by deletion mapping in mutants and chromosome-walking. PSF is homologous to mammalian and bacterial ATP-dependent transport proteins, suggesting that it operates in the intracellular transport of peptides.

Amino Acid Sequence↗
PubMedDate not supplied

Interaction of the sympathetic nervous system with vasopressin and renin in the maintenance of blood pressure.

To evaluate the partial contributions and interaction of three vasopressor systems in blood pressure maintenance, nephrectomized rats and rats with intact kidneys were submitted sequentially to catecholamine depletion, elimination of vasopressin's vasoconstrictor action, and (for those with kidneys in situ) angiotensin blockade. Catecholamine depletion decreased blood pressure and stimulated vasopressin levels in all rats, but significantly more so in the anephric ones. Subsequent injection of an antagonist to the vasopressor effect of vasopressin produced a lasting fall of blood pressure in anephric rats, but only transient fall in those with intact kidneys. Infusion of teprotide--an angiotensin converting enzyme inhibitor--in the latter animals also produced transient blood pressure fall, but if this were followed by injection of the vasopressin antagonist, the pressure remained low for several hours. Blood pressure levels were closely correlated with those of plasma catecholamines throughout these maneuvers. Catecholamine levels were inversely correlated with those of plasma vasopressin, which were far greater in anephric rats through both stimulation and accumulation. Plasma renin activity was increasingly stimulated by falling blood pressure after each maneuver in rats with intact kidneys. Thus, it appears that in the resting state the sympathetic nervous system is more involved in the maintenance of blood pressure, whereas vasopressin and renin are important backup mechanisms.

Animals↗
PubMedDate not supplied

Central and peripheral indices of sympathetic activity after blood pressure lowering with enalapril (MK-421) or hydralazine in normotensive rats.

Various antihypertensive drugs have different effects on vasoactive mechanisms. In normotensive Wistar rats, we investigated the effects on plasma and tissue catecholamines of chronic treatment with two agents: MK-421, an angiotensin converting-enzyme inhibitor (CEI), and hydralazine, a vascular smooth muscle relaxant. Both agents lowered blood pressure via arteriolar dilation, to the same final level. However, hydralazine stimulated the renin-angiotensin system and elevated the plasma norepinephrine (NE) and epinephrine (E) levels, whereas MK-421 did not. In MK-421-treated animals, NE, E, and the ratio of E/NE were decreased in the brain stem, and this ratio was increased in the heart. In hydralazine-treated rats, the catecholamine levels were unchanged in the brain stem and heart. The turnover rate of NE was significantly reduced in the brain stem and heart of MK-421-treated rats, whereas, after hydralazine, the turnover rate in the heart was increased (decreasing the half-life of NE by about 50%), indicating increased sympathetic activity. Thus, elimination of angiotensin II (AII) by CEI is associated with decreased sympathetic activity in both the brain stem and heart, whereas an equipotent antihypertensive action by smooth muscle relaxation leads to stimulation of both the renin-angiotensin and the sympathetic systems. These differences are more readily apparent by measurement of catecholamine turnover rates in tissues than of catecholamine levels, and they may account for the different hemodynamic effects of the two agents, even though both drugs act through arteriolar dilation.

Animals↗