Biomedical subjects

R M Graham

Publications and source records attributed to R M Graham.

At least 163 records · Page 9Linked to original sources

PubMed1983

Abnormal cardiovascular regulation in the mitral valve prolapse syndrome.

Studies of patients with mitral valve prolapse syndrome have suggested autonomic nervous system dysfunction, but a precise definition of mechanisms is lacking. We measured supine and standing heart rate, blood pressure, cardiac output, oxygen consumption, plasma catecholamines, and blood volume in 23 symptomatic women with both echocardiographic and phonographic signs of MVP and in 17 normal control subjects. An analysis of the results revealed 2 distinct subgroups of patients: those with normal heart rates but increased vasoconstriction (Group I, n = 10) and those with orthostatic tachycardia (Group II, n = 13). Group II patients had heart rates at rest supine of 97 +/- 3 compared with 79 +/- 2 in Group I patients and 78 +/- 8 in control subjects. Estimated total blood volumes were lowest in Group I patients, intermediate in Group II patients, and highest in control subjects (p less than 0.05). Other measurements at rest supine were similar in patients and controls. After standing for 5 minutes, patients had a higher mean plasma epinephrine value, diastolic blood pressure (81 +/- 2 versus 74 +/- 3 mm Hg, p less than 0.05), and peripheral resistance (1,878 +/- 114 versus 1,414 +/- 92, dynes s cm-5, p less than 0.01), wider arteriovenous oxygen difference (6.7 +/- 0.4 versus 5.3 +/- 0.5 vol%), and lower stroke volume index (26 +/- 2 versus 33 +/- 2 ml/m2, p less than 0.01) than did the control subjects. Cardiac output was normal in Group II patients but reduced in Group I patients, who demonstrated marked vasoconstriction. No patient had evidence of a "hyperkinetic" circulatory state. A cycle of decreased forward stroke volume, vasoconstriction, and blood volume contraction appears to be present in at least some symptomatic patients with MVP.

Adult↗

PubMed1983

Haemodynamic responses to static and dynamic handgrip before and after autonomic blockade.

1. Six healthy men performed static and dynamic handgrip to local muscular fatigue in approximately 6 min under control conditions, i.e. without drugs and after combined parasympathetic and beta-adrenergic blockade with atropine and metoprolol. 2. From rest to exercise at fatigue, systolic, diastolic and mean arterial pressures increased by 32 +/- 4 and 39 +/- 3 mmHg, 24 +/- 3 and 26 +/- 4 mmHg, and 26 +/- 3 and 30 +/- 3 mmHg respectively for static and dynamic handgrip. There were no significant differences between the pressor responses for the two modes of contraction. Cardiac output increased significantly only during dynamic exercise. Total peripheral resistance increased by 2.3 +/- 1.0 units for static handgrip (P less than 0.05) and by 0.7 +/- 0.8 unit (P greater than 0.05) for dynamic handgrip. Autonomic blockade abolished the heart rate response to both static and dynamic handgrip. For both modes of contraction the systolic arterial pressure responses were 9-12 mmHg lower (P less than 0.05) after autonomic blockade, but the diastolic and mean pressure responses were not significantly affected. A significant increase in cardiac output persisted during dynamic exercise. The increase in peripheral resistance during static exercise tended to be greater after blockade. Plasma noradrenaline and adrenaline levels showed only minor elevations in response to static and dynamic handgrip and were not changed by autonomic blockade. 3. These data indicate that when performed to a common end-point with identical small muscle groups static and dynamic exercise produce an equally large pressor response, which is only slightly attenuated by autonomic blockade.

Adult↗

PubMed1983

Photoaffinity label for the alpha 1-adrenergic receptor: synthesis and effects on membrane and affinity-purified receptors.

An azide analog, 2-[4-(4-azidobenzoyl)piperazin-1-yl]-4-amino-6, 7-dimethoxyquinazoline (CP59,430), of the highly selective alpha 1-adrenergic receptor antagonist prazosin was synthesized and its effects on rat hepatic membrane and affinity-purified alpha 1-adrenergic receptor preparations were examined. CP59,430 behaved as a competitive antagonist before photolysis. When the membrane or purified preparations pretreated with CP59,430 were irradiated with UV light, CP59,430 behaved as a noncompetitive antagonist. Labeling of membrane alpha 1-adrenergic receptors was irreversible; repeated dialysis or washing could not reverse the photolysis-induced inactivation by CP59,430, whereas dialysis completely reversed the antagonism by the same concentration of the label prior to photolysis. Additionally, photolabeling of purified receptors was resistant to Sephadex G-50 chromatography, whereas in the absence of photolysis the same concentration of CP59,430 or prazosin (10 microM) could be readily removed by this procedure. CP59,430 appears to label specifically only alpha 1-adrenergic receptors because prazosin protected the membrane and purified receptors from photolysis-induced inactivation by CP59,430. Furthermore, specific [3H]dihydroalprenolol and [3H]yohimbine binding to membrane beta- and alpha 2-adrenergic receptors, respectively, was unchanged by CP59,430 at 1 microM, a concentration that decreased specific [3H]prazosin binding to alpha 1-adrenergic receptors by 72%. In additional studies, the photolysis-induced receptor inactivation by CP59,430 remained unchanged in the presence of the scavenger p-aminobenzoic acid. It is likely, therefore, that receptor labeling by CP59,430 occurs via a true photoaffinity mechanism. CP59,430, which specifically and irreversibly labels the alpha 1-adrenergic receptor after photolysis, should thus be uniquely valuable for the molecular characterization of this receptor.

Affinity Labels↗

PubMed1983

Cardiovascular responses to exercise as functions of absolute and relative work load.

The roles of absolute and relative oxygen uptake (VO2 and percent of muscle group specific VO2 max) as determinants of the cardiovascular and ventilatory responses to exercise over a wide range of active muscle mass have not previously been defined. Six healthy men performed four types of dynamic exercise--one-arm curl, one-arm cranking, and one- and two-leg cycling at four different relative work loads--25, 50, 75, and 100% of VO2 max for the corresponding muscle group. VO2 during maximal one-arm curl, one-arm cranking, and one-leg cycling averaged 20, 50, and 75%, respectively, of that for maximal two-leg cycling. Cardiac output was linearly related to VO2 with a similar slope and intercept for each type of exercise. Heart rate at a given %VO2 max was higher with larger active muscle mass. In relation to %VO2 max, systemic resistance was lower and plasma catecholamine levels were higher with larger active muscle mass. The cardiovascular responses to exercise are determined to a large extent by the active muscle mass and the absolute oxygen uptake, with the principal feature appearing to be the tight linkage between systemic oxygen transport and utilization.

Adult↗

PubMed1983

Hemodynamic and neuroendocrine responses to acute and chronic alpha-adrenergic blockade with prazosin and phenoxybenzamine.

We investigated the relevance of the selective alpha 1-adrenergic receptor blockade produced by prazosin to its blood pressure-lowering efficacy in man. The hemodynamic and neuroendocrine responses to the acute and chronic oral administration of prazosin and phenoxybenzamine were compared in a randomized, double-blind, placebo-controlled, crossover study of 11 patients with essential hypertension. These responses were also evaluated during lower body negative pressure and dynamic bicycle exercise, which produce potent but diversified activation of the sympathetic nervous system. In the acute studies, arterial blood pressure decreased to similar levels with prazosin or phenoxybenzamine; however, hemodynamic and neuroendocrine responses differed both before and during sympathetic nervous system activation. Prazosin lowered arterial blood pressure by reducing total peripheral resistance (p less than 0.05). In contrast, phenoxybenzamine produced a modest reduction in cardiac output (8%, p less than 0.05) with little change in total peripheral resistance, forearm vascular resistance or forearm blood flow. Additionally, plasma norepinephrine concentration and heart rate rose to significantly higher levels with prazosin (p less than 0.02) than with phenoxybenzamine, a difference that was most evident with lower body negative pressure or dynamic exercise. Baroreceptor control of arterial pressure homeostasis was preserved with both agents, except during marked degrees of cardiovascular stress. With chronic therapy, the circulatory responses adapted to the alpha-adrenergic antagonists, and both drugs produced similar hemodynamic and neuroendocrine profiles. The differences with acute administration may be the result of a more rapid onset of action and a more marked degree of alpha-adrenergic blockage with prazosin than with phenoxybenzamine therapy, rather than to any difference in their alpha 1- and alpha 2-adrenergic receptor blocking properties. Moreover, the findings of the present study suggest that the prejunctional alpha 2-receptor, autoinhibitory to sympathetic neuronal norepinephrine release, is of no functional significance in patients with essential hypertension.

Adrenergic alpha-Antagonists↗

PubMed1983

Considerations in the long-term treatment of hypertension.

The indications for treatment of hypertension, the goals of therapy, and the effects of long-term treatment are considered. The importance of individualized therapy (eg, for systolic hypertension, for borderline hypertension, and for hypertension in the elderly) and the problems of noncompliance, tolerance, and withdrawal are discussed. Beneficial and adverse effects of long-term treatment with beta-blockers, captopril, clonidine, diuretics, guanethidine, hydralazine, methyldopa, minoxidil, prazosin, and reserpine are outlined.

Adult↗

PubMed1982

Biophysical characterization of the purified alpha 1-adrenergic receptor and identification of the hormone binding subunit.

The alpha 1-adrenergic receptor has been solubilized in active form from rat hepatic membranes with the nonionic detergent, digitonin, and purified by affinity and gel filtration chromatography to homogeneity with a specific activity of 14,400 pmol/mg of protein. The affinity chromatographic steps of the purification procedure were achieved by the use of a newly synthesized analog (2-[4(2-succinoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline, CP-57,609) of the highly selective alpha 1-adrenergic antagonist, prazosin, immobilized via an amide linkage to agarose. The resulting purified receptor bound [3H]prazosin and a variety of adrenergic agents with the specificity, stereoselectivity, and affinities equivalent to those observed with membrane-bound and solubilized receptor preparations. The purified receptor.digitonin complex had a Stokes radius of 49 A and a sedimentation coefficient (s20w) of 7.1, as determined by AcA-34 gel filtration chromatography and sucrose gradient density centrifugation, respectively. Based on these hydrodynamic parameters, the calculated molecular weight of the receptor.digitonin complex was estimated at 147,000. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis following the final purification step revealed a single band of protein at 59,000 daltons from which [3H]prazosin binding activity could be recovered after renaturation of the receptor protein. These findings indicate that the protein purified from rat hepatic membranes is the hormone binding component of the alpha 1-adrenergic receptor and that the receptor molecule most likely contains more than one Mr = 59,000 subunit.

Adrenergic alpha-Agonists↗

PubMed1982

Effects of short-term beta blockade on blood pressure, plasma thromboxane B2, and plasma and urinary prostaglandins E2 and F2 alpha in normal subjects.

The effect of short-term beta blockade with the nonselective antagonist propranolol and with the cardioselective antagonist metoprolol on arterial blood pressure, heart rate, serum renin activity, plasma thromboxane (Tx) B2 (the stable metabolite of TxA2). and plasma and urinary prostaglandin (PG) E2 and F2 alpha levels were examined in 11 normal subjects. After propranolol (160 mg by mouth), supine and standing mean arterial pressure (MAP) fell from 82 +/- 2 and 88 +/- 4 mm Hg to 71 +/- 3 (P less than 0.001) and 78 +/- 3 mm Hg (P less than 0.01) within 13 hr. MAP fell from 78 +/- 2 and 88 +/- 3 mm Hg to 72 +/- 2 (P less than 0.025) and 80 +/- 2 mm Hg (P less than 0.01) after metoprolol (200 mg by mouth). These blood pressure effects were associated with beta blockade; both drugs induced reduction in heart rate and serum renin activity and the reductions were of the same order. Propranolol and metoprolol also reduced plasma TxB2 levels by 33% (P less than 0.005) and 46% (P less than 0.05), but plasma and urinary PGE2 and PGF2 alpha levels were not changed by either drug. These findings suggest that changes in PGE2 or PGF2 alpha levels are unlikely to contribute to the short-term hypotensive effects of propranolol or metoprolol in normal subjects. Alterations in the synthesis or metabolism of the potent vasoconstrictor and proaggregatory drug TxA2, however, may be involved in the hypotensive, cardioprotective, and antiplatelet effects of beta-adrenergic antagonists.

Adrenergic beta-Antagonists↗

PubMed1982

Solubilization and purification of the alpha 1-adrenergic receptor using a novel affinity resin.

The highly selective alpha 1-adrenergic receptor antagonist prazosin was used to identify binding sites having alpha-adrenergic specificity in rat hepatic plasma membranes. Solubilization of the membrane-bound receptors was achieved by incubation with the nonionic detergent digitonin, and binding activity was assayed by using [3H]prazosin and a polyethylene glycol precipitation technique. Only 20-30% of the total receptor pool was released by the solubilization procedure. However, binding of [3H]prazosin was saturable [maximal value, 206 +/- 8 fmol/mg of protein (membrane) vs. 74 +/- 4 fmol/mg of protein (soluble)] and of high affinity [Kd, 0.6 +/- 0.2 nM (membrane) vs. 0.8 +/- 0.2 nM (soluble)]. To aid in purification of the receptors, an affinity resin was developed using an analog of prazosin, 2-(4-succinoylpiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline (CP 57,609; Kd 2.7 X 10(-7) M) immobilized via an amide linkage to agarose. The resulting resin demonstrated high affinity (Kd 3.2 X 10(-7) M) for the solubilized receptors, as determined by competitive inhibition assay. The degree of substitution to the resin was determined by a direct radioimmunoassay using antibodies against albumin-complexed CP 57,609 and found to be 0.1 to 0.2 mumol/ml of agarose. Affinity chromatography using the resin resulted in 513-fold purification in a single step. Moreover, the specificity of the purified binding sites was similar to that of membrane-bound receptors. This novel affinity resin should thus provide a powerful tool for isolating the receptor protein in quantities sufficient for detailed biochemical characterization.

Cell Fractionation↗

PubMed1982

An assessment of health hazard/health risk appraisal.

A state-of-the-art review of a widely-used health promotion technique, the health hazard/health risk appraisal (HHA/HRA), was conducted. The review included preparing a 212-item annotated bibliography, compiling an inventory of 217 programs that have used HHA/HRA, holding discussions with HHA/HRA developers and users, conducting formal site visits to 15 HHA/HRA programs, and consultation with experts on epidemiology, biostatistics, and behavioral science as well as developers and users of HHA/HRA. Programs use HHA/HRA primarily as a promotional device, as a tool for structuring education about health-related behaviors, and as a motivational device for stimulating behavioral change. The scientific basis for HHA/HRA risk predictions is problematic, but their arithmetic imprecision is of less concern than insufficiency of the scientific evidence for certain behavioral recommendations, and inaccuracies in client-supplied data. Widely-held beliefs in HHA/HRA's efficacy for motivating behavioral change cannot be substantiated from available evidence, nor can the assumed absence of adverse effects. The importance of this particular health promotion technique appears to have been exaggerated.

Evaluation Studies as Topic↗

PubMed1981

New health practitioners in rural satellite health centers: the past and future.

Data from a 1975 and a follow-up 1979 survey of 44 rural, satellite health centers staffed by new health practitioners (NHPs)are compared to determine what changes have taken place in these centers during this period when the number of physicians in the United States has markedly increased. Of the surveyed clinics, 8 closed and 12 converted to having physicians on their staffs by 1979. The remaining 24 NHP-staffed centers realized growth in staff size and budget, patient utilization, and proportion of budget generated by revenues from patients. (Despite these positive changes, most of these 24 clinics expressed concern about their financial situations-a reflection of the considerable room for further improvement.) The general growth of the 24 NHP-staffed satellites, however, was not as substantial as that achieved by the 12 clinics staffed by physicians in 1979. The rapidly increasing supply of physicians in the United States and the potential effects of this trend on NHP-staffed rural satellite centers are discussed. Possible reasons why these satellites may continue to be of value in making primary care available in rural areas are enumerated.

Community Health Centers↗

PubMed1981

Plasma substance P levels in normotensive and hypertensive subjects.

Since substance P is a potent natriuretic, diuretic, and vasodilatory peptide, a radioimmunoassay for substance P was developed, and its levels measured in the plasma of normal subjects and patients with essential hypertension. The plasma substance P levels were 186+/-14 pg/ml in normal subjects and 164+/-3 pg/ml in hypertensive patients. When the sodium content of their diet was reduced to 10 mEq/day, substance P levels failed to change, but plasma renin activity and urinary kallikrein increased. An acute saline infusion also failed to alter plasma substance P levels. Assuming an upright posture increased plasma renin activity, but not substance P, in both groups of subjects. Thus, it appears that substance P is not involved in the control of blood pressure, kallikrein excretion or renin release in man.

Diet↗

PubMed1981

Speculative approaches in hypertension: concepts and drugs of the future.

Despite the availability and application of more effective antihypertensive drugs over the past 3 decades, hypertension continues to be a major risk factor for the development of premature cardiovascular disease. Moreover, failure to elucidate the pathogenesis of essential hypertension, noncompliance, and difficulties in defining the appropriate level of blood pressure elevation requiring therapy, continue to mitigate against the adequate control of hypertension. Some of these problems may be overcome by the availability of depot forms of antihypertensive medication or implantable drug delivery systems, or by the use of several recently developed antihypertensive drugs. These include dopaminergic agonists, selective alpha-adrenergic agents, calcium antagonists, medullary neutral lipids, gamma-aminobutyric acid agonists, and inhibitors of renin or phenethylamine N-methyl-transferase. In addition, the potential involvement of morphinomimetic peptides, prostaglandins, tonin, and bradykinin in blood pressure control or certain hypertensive states suggests that drugs developed to block or potentiate the actions of these substances may have important therapeutic applications.

Animals↗

PubMed1981

Renal alpha-1 and alpha-2 adrenergic receptors: biochemical and pharmacological correlations.

[3H]Dihydroergocryptine, a nonselective alpha adrenergic antagonist, the alpha-1 selective antagonist, [3H]prazosin and the alpha-2 selective antagonist, [3H]yohimbine, were used to study binding sites in rat renal membranes. To establish a correlation between binding and a biological function, the ability of alpha adrenergic agents to stimulate or inhibit vasoconstriction was quantified in vitro using an isolated perfused kidney preparation. Binding with each radioligand was rapid, saturable and specific. Moreover, the order of potencies of a variety of adrenergic agents, determined by competitive inhibition studies, suggested that the binding of each radioligand was to sites with alpha adrenergic specificity. The total number of binding sites in these rat renal membranes. determined with [3H]dihydroergocryptine (Bmax, 212 fmol/mg of protein; KD, 12.8 nM) was approximately equal to the sum of binding site concentrations determined with the alpha-1 and alpha-2 selective radioligands (Bmax, 57 and 170 fmol/mg of protein; KD, 0.85 and 20 nM, respectively). However, the alpha receptor mediating renal arteriolar vasoconstriction appeared to be of the alpha-1 subtype as there was a close correlation between the in vitro results and the binding data determined with [3H]prazosin (r = 0.93). In addition, in both the functional and [3H]prazosin binding studies, unlabeled prazosin ws 5 to 40-fold more potent than the nonselective antagonist, phentolamine, and 400- to 1500-fold more potent than the alpha-2 antagonist, yohimbine. These studies suggest that rat renal plasma membranes contain binding sites with both alpha-1 and alpha-2 adrenergic receptor specificity, in a ratio of approximately 1:3. Despite the preponderance of alpha-2 receptors, the alpha receptor mediating renal vasoconstriction appears to be of the alpha-1 type.

Animals↗

PubMed1981