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Biomedical subjects

W A Murphy

Publications and source records attributed to W A Murphy.

At least 19 recordsLinked to original sources
PubMed1997

Adrenomedullin induces penile erection in the cat.

The present study was undertaken to investigate the effects of intracavernosal injections of adrenomedullin, a novel hypotensive peptide, on penile erection in anesthetized cats. Responses to adrenomedullin were compared to those elicited by intracavernosal injection of the control triple-drug combination (1.65 mg papaverine, 25 micrograms phentolamine, and 0.5 microgram prostaglandin E1). Intracavernosal injections of adrenomedullin in doses of 0.1-1.0 nmol elicited dose-related increases in cavernosal pressure and penile length. The maximal effect of adrenomedullin injection on cavernosal pressure was an 8-fold increase in pressure, which was 74% of that induced by the triple-drug combination. The maximal effect on penile length was a 43% increase when compared to baseline value, which was comparable to that induced by the triple-drug combination. The duration of the peak pressure and total duration of the peptide effect were significantly shorter in response to the 1 nmol dose of adrenomedullin than was observed with the control triple-drug combination. Intracavernous injection of the control triple-drug combination resulted in a significantly greater decrease in systemic arterial blood pressure than did adrenomedullin. Erectile responses to adrenomedullin were not altered following administration of the nitric oxide synthase inhibitor. N omega-nitro-L-arginine, at a time when erectile responses to acetylcholine were significantly reduced. These data demonstrate that intracavernous injection of adrenomedullin induces a short-lived erection in cats that is not due to the release of nitric oxide.

Adrenomedullin↗
PubMed1997

Proadrenomedullin NH2-terminal peptide (PAMP)(12-20) has vasodepressor activity in the rat and cat.

Decreases in systemic arterial pressure in response to human proadrenomedullin NH2-terminal 20 peptide (hPAMP), a truncated analog, hPAMP(12-20), and human adrenomedullin (hADM) were compared in the rat and cat. The order of potency was hADM > hPAMP > hPAMP(12-20). hPAMP(12-20) was approximately 3-fold less potent than the full sequence peptide, hPAMP, and 10-fold less potent than the related peptide, hADM. The duration of the vasodepressor responses to hPAMP(12-20) and hPAMP were similar, and responses to both peptides were significantly shorter in duration than hADM. Vasodepressor responses to hPAMP(12-20), hPAMP, and hADM were greater in the rat when compared to responses to the peptides in the cat.

Adrenomedullin↗
PubMed1997

Adrenomedullin-(22-52) antagonizes vasodilator responses to CGRP but not adrenomedullin in the cat.

The effects of adrenomedullin (ADM)-(22-52), a putative ADM receptor antagonist, on vasodilator responses to ADM and the structurally related peptide, calcitonin gene-related peptide (CGRP), were investigated in the hindlimb vascular bed of the cat under constant-flow conditions. ADM-(22-52) had no significant effect on hindlimb perfusion pressure when injected in doses up to 120 nmol; after administration of ADM-(22-52), vasodilator responses to ADM were unchanged, whereas vasodilator responses to CGRP were inhibited. The inhibitory effects of ADM-(22-52) on responses to CGRP were selective and reversible and were similar to the inhibitory effects of the CGRP antagonist CGRP-(8-37). Hindlimb vasodilator responses to CGRP and to ADM were increased in duration by the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor rolipram but were not altered by inhibitors of guanosine 3',5'-cyclic monophosphate phosphodiesterase, nitric oxide synthetase, K(+)-ATP channels, the cyclooxygenase pathway, or the adrenergic nervous system. These results demonstrate that ADM-(22-52) is a selective CGRP receptor antagonist in the hindlimb vascular bed of the cat. The present data suggest that vasodilator responses to CGRP and ADM are mediated by different receptors but that these peptides dilate the hindlimb vascular bed of the cat by a similar cAMP-dependent mechanism.

Adrenomedullin↗
PubMed1996

Analysis of cardiovascular responses to PACAP-27, PACAP-38, and vasoactive intestinal polypeptide.

Responses to pituitary adenylate cyclase polypeptide (PACAP)-27, PACAP-38, and vasoactive intestinal peptide (VIP) were compared in the peripheral and pulmonary vascular beds of the cat and in the isolated perfused neonatal pig heart. Intravenous injections of PACAP-27 and PACAP-38 produced biphasic changes in systemic arterial pressure whereas iv injections of VIP caused only decreases in arterial pressure. When blood flow to the hind limb and mesenteric vascular beds was maintained constant, PACAP-27 and PACAP-38 caused dose-related biphasic changes in perfusion pressure, whereas VIP only decreased perfusion pressure. PACAP-27 was approximately threefold more potent than PACAP-38, and the pressor component of the biphasic response was blocked by alpha-adrenergic antagonists and adrenalectomy. PACAP-27, PACAP-38, and VIP produced decreases in pulmonary vascular resistance, and all three peptides had significant vasodilator activity in the isolated perfused neonatal pig heart. Although all three peptides decreased coronary vascular resistance, only PACAP-27 and PACAP-38 increased left ventricular contractility, with PACAP-27 approaching isoproterenol in potency. The results of these experiments show that PACAP-27, PACAP-38, and VIP have significant effects on vasomotor tone that depend on the vascular bed studied and the contribution of adrenal catecholamines.

Amino Acid Sequence↗
PubMed1996

[MPR14]-rADM(14-50), a novel analog of adrenomedullin, possesses potent vasodilator activity in the hindlimb vascular bed of the cat.

Responses to [Mpr14]-ADM(14-50), a novel analog of adrenomedullin, were investigated in the hindlimb vascular bed of the cat under conditions of controlled blood flow. Intraarterial injections of [Mpr14]-rADM(14-50) in doses of 0.003-1 nmol caused dose-related decreases in hindlimb perfusion pressure. In terms of relative vasodilator activity, [Mpr14]-rADM(14-50) was more potent than human synthetic adrenomedullin (hADM) in doses of 0.003-0.1 nmol. The recovery half-times (T 1/2) for the vasodilator response to [Mpr14]-rADM(14-50) were significantly greater than the recovery half-times for hADM in all doses studied. Decreases in hindlimb perfusion pressure in response to [Mpr14]-rADM(14-50) were not altered by the calcitonin gene-related peptide receptor antagonist rCGRP(8-37) at the same time vasodilator responses to calcitonin gene-related peptide were significantly reduced. The present data demonstrate that [Mpr14]-(14-50) has potent and long-lasting vasodilator activity when compared to hADM, and that vasodilator responses to [Mpr14]-rADM(14-50) are not dependent on the activation of CGRP receptors in the hindlimb vascular bed of the cat.

Adrenomedullin↗
PubMed1996

Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial.

PURPOSE: The potent bisphosphonates offer great promise in the management of Paget's disease of bone, but are currently available only as parenteral preparations in most countries. There is a need for a well-tolerated, oral therapy. Furthermore, none of the currently available therapies have been rigorously demonstrated to heal the lytic bone lesions characteristic of this condition. Alendronate is a potent new oral aminobisphosphonate that has shown promising effects on Paget's disease in preliminary studies. METHODS: We report a double-blind, randomized comparison of oral alendronate 40 mg/day and placebo over 6 months in 55 patients with Paget's disease. Efficacy was determined from measurements of biochemical indices of bone turnover (serum alkaline phosphatase and urine N-telopeptide) and blinded radiologic assessment of lytic bone lesions. RESULTS: N-telopeptide excretion declined by 86% and serum alkaline phosphatase by 73% in patients receiving alendronate, but remained stable in patients receiving placebo (P < 0.001 between groups for both indices). Responses were similar whether or not patients had previously received bisphosphonate treatment. Alendronate treatment normalized alkaline phosphatase in 48% of patients. Forty-eight percent of alendronate-treated patients showed radiologic improvement in osteolysis whereas in the placebo group only 4% improved (P = 0.02 for between-groups comparison). No patient in either group showed worsening of osteolysis. Bone histomorphometry indicated that alendronate tended to normalize turnover indices. There was no evidence of abnormal mineralization in bone biopsies taken from 12 alendronate-treated subjects. The treatment was well tolerated. CONCLUSION: Oral alendronate appears to be a safe and effective therapy for Paget's disease and results in healing of lytic bone lesions.

Administration, Oral↗
PubMed1996

Proadrenomedullin NH2-terminal 20 peptide has cAMP-mediated vasodilator activity in the mesenteric vascular bed of the cat.

Responses to proadrenomedullin NH2-terminal 20 peptide (hPAMP), a truncated analogue [hPAMP(12-20)], and adrenomedullin (hADM) were investigated in the mesenteric vascular bed of the cat. Under constant-flow conditions, injections of hPAMP, hPAMP(12-20), and hADM caused dose-related decreases in mesenteric perfusion pressure. hADM was 100-fold more potent than hPAMP, and 1000-fold more potent than hPAMP(12-20). Vasodilator responses to hPAMP and hADM were not altered by adrenergic-blocking agents, were similar in innervated and denervated preparations, and were similar when tone was increased by sympathetic nerve stimulation or phenylephrine infusion. Vasodilator responses to hPAMP and hADM were increased in duration by rolipram, a cAMP phosphodiesterase inhibitor. The present data suggest that vasodilator responses to the hPAMP and hADM are mediated by an increase in cAMP and that an interaction with the adrenergic nervous system is not involved.

Adamantane↗
PubMed1996

Prevalence of red marrow around the knee joint in adults as demonstrated on magnetic resonance imaging.

RATIONALE AND OBJECTIVES: We determined the prevalence of red marrow around the knee joint in adults and evaluated variations with age, gender, and other variables. METHODS: One hundred ninety-nine adult patients presenting for routine knee magnetic resonance (MR) imaging completed a questionnaire that covered age, gender, menstrual history, past pregnancies, smoking history, and medications. The presence or absence of visible red marrow in the distal femur and proximal tibia on both coronal and sagittal MR images was recorded for each patient. Associations between the presence of red marrow and the other recorded variables then were evaluated. RESULTS: Red marrow was present in more than half of the women and less than one sixth of the men, a statistically significant difference. The age distribution of red marrow in men and women also was different. Red marrow was the most common in women aged 30-60 years. In men, there was no clear-cut age trend. Red marrow also was more likely to be present in obese individuals and smokers. No association was found between the presence of red marrow and any of the other recorded variables. CONCLUSION: There are clear gender, age, obesity, and smoking-related differences in the prevalence of red marrow around the knee joint in adults. Red marrow is relatively common in this site in all age groups, and its presence should not be a cause for clinical concern.

Adolescent↗
PubMed1996

Pulmonary vasodilator responses to adrenomedullin are reduced by NOS inhibitors in rats but not in cats.

Responses to and the mechanism of action of adrenomedullin (ADM), the carboxy-terminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmonary vascular bed of the rat. Under conditions of elevated tone and controlled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM15-52), and CGRP caused dose-related decreases in pulmonary arterial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. After administration of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine benzyl ester or N omega-nitro-L-arginine methyl ester (L-NAME), pulmonary vasodilator responses to ADM, to ADM15-52, to CGRP, to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglycerin were not changed. However, in the pulmonary vascular bed of the cat, L-NAME had no significant effect on vasodilator responses to ADM in doses that attenuated vasodilator responses to acetylcholine and bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM15-52 was approximately three-fold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resistance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary vascular vascular resistance in the cat than in the rat, and vasodilator responses to ADM were independent of the intervention used to raise tone in the rat. The present data demonstrate that ADM and ADM15-52 have significant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM15-52, and CGRP are dependent on the release of nitric oxide in the rat. The present results indicate that pulmonary vasodilator responses to ADM are not dependent on the release of nitric oxide in the cat and suggest that responses to the peptide are mediated by different mechanisms in the pulmonary vascular bed of the rat and cat.

Adrenomedullin↗
PubMed1996

Catecholamine release mediates pressor effects of adrenomedullin-(15-22) in the rat.

Human adrenomedullin, a novel hypotensive peptide, contains a six-member ring structure similar to that found in calcitonin gene-related peptide and pancreatic amylin. Unlike the full-sequence peptide, human adrenomedullin-(15-22) [hADM-(15-22)], which contains the ring structure, increases systemic arterial pressure in the rat but not the cat. We undertook the present study to investigate the mechanism by which hADM-(15-22) increases systemic arterial pressure in the rat. Injection of hADM-(15-22) in doses of 10 to 300 nmol/kg i.v. increased systemic arterial pressure in a dose-dependent manner and was threefold less potent than norepinephrine when doses were compared on a nanomole basis. However, the ring structures of human calcitonin gene-related peptide and human amylin, human calcitonin gene-related peptide-(1-8) and human amylin-(1-8), respectively, had no significant effect on systemic arterial pressure in the rat. Pressor responses to hADM-(15-22) were reduced significantly after administration of phentolamine or reserpine. Responses to hADM-(15-22) were not altered by the angiotensin type 1 blocking agent DuP 753 or the endothelin-A/endothelin-B receptor blocking agent bosentan, and responses to hADM-(15-22) and the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) were reduced after bilateral adrenalectomy. Pressor responses to DMPP were reduced by hexamethonium, whereas the nicotinic blocking agent had no effect on the pressor response to hADM-(15-22). These data suggest that increases in systemic arterial pressure in response to hADM-(15-22) in the rat are mediated by the activation of alpha-adrenergic receptors by catecholamines released from the adrenal medulla. The present data suggest that hADM-(15-22) releases catecholamines from the adrenal medulla by a noncholinergic mechanism.

Adrenalectomy↗
PubMed1996

Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone.

Alendronate, an aminobisphosphonate, is much more potent than etidronate, an older bisphosphonate, in inhibiting osteoclast-mediated bone resorption, and unlike etidronate, therapeutic doses of alendronate are not associated with abnormal mineralization. In the present study, we compared the effectiveness, safety, and tolerability of 6 months of daily oral administration of alendronate (40 mg) with those of etidronate (400 mg) in 89 patients with clinically active Paget's disease. The primary efficacy end point was the percent change in serum alkaline phosphatase. Other end points included changes in urinary deoxypyridinoline excretion, pain, functional impairment scores, and radiological osteolysis. Tetracycline-labeled bone biopsies were obtained for histomorphometric analysis from a subset of 43 patients at the 6-month visit. The alendronate-treated group had significantly greater decreases in both serum alkaline phosphatase (79% vs. 44%) and urinary deoxypyridinoline (75% vs. 51%) than the etidronate-treated group (P < 0.001 in both cases). Normalization of serum alkaline phosphatase was much more frequent in alendronate-treated patients (63.4% vs. 17.0%; P < 0.001). Alendronate was well tolerated and had a safety profile similar to that of etidronate. Histomorphometry revealed decreased bone turnover and no qualitative abnormalities, including no direct negative effects on bone mineralization, with alendronate treatment. One patient receiving etidronate developed frank osteomalacia. Alendronate appears to be a highly effective treatment for Paget's disease of bone that offers an important therapeutic advance over etidronate.

Administration, Oral↗
PubMed1995

Three-dimensional quantitative structure-activity relationships of somatostatin analogues. 1. Comparative molecular field analysis of growth hormone release-inhibiting potencies.

Somatostatin is a hypothalamic hormone that inhibits the release of growth hormone (GH). It has also been shown to inhibit the release of a broad range of hormones including insulin, glucagon, and gastrin. Presently, five different receptor subtypes of somatostatin have been characterized and cloned. Our previous work on the structure-activity relationship of somatostatin and that of many others has generated a large database of analogues with different biological activities and receptor affinities. This present work is an investigation of the growth hormone release-inhibiting potencies of somatostatin analogues by the three-dimensional quantitative structure-activity paradigm, comparative molecular field analysis (CoMFA). A total of 64 analogues were modeled in SYBYL using structural information from two NMR studies. The molecules were aligned by a root-mean-square fit of atoms and field-fit of the steric and electrostatic molecular fields and the resulting databases analyzed by partial least squares analysis with cross-validation to extract the optimum number of components. The analysis was then repeated without cross-validation to give the final QSAR models. Preliminary investigations with the CoMFA models led to the synthesis of a new somatostatin analogue. This compound together with five other newly synthesized compounds not included in the original training sets were used to test the predictive ability of the CoMFA models. Two models with good predictive powers are presented.

Amino Acid Sequence↗
PubMed1995

Comparison of responses to adrenomedullin and adrenomedullin analogs in the mesenteric vascular bed of the cat.

Responses to adrenomedullin, a newly discovered hypotensive peptide isolated from human pheochromocytoma cells, and the carboxy terminal 15-52 (adrenomedullin-(15-52)) and 22-52 (adrenomedullin-(22-52)) amino acid fragments of adrenomedullin were investigated in the mesenteric vascular bed of the cat. Under constant flow conditions, injections of adrenomedullin, adrenomedullin-(15-52), and calcitonin gene-related peptide (CGRP) in doses of 0.003-1 nmol into the perfused superior mesenteric artery caused significant dose-related decreases in mesenteric arterial perfusion pressure. Mesenteric vasodilator responses to adrenomedullin and adrenomedullin-(15-52) were similar in magnitude and duration, while vasodilator responses to CGRP were greater in magnitude and longer in duration than those produced by adrenomedullin or adrenomedullin-(15-52) when these agents were injected in doses of 0.1-1 nmol. Adrenomedullin-(22-52) caused no significant change in mesenteric arterial perfusion pressure when injected in doses up to 10 nmol. These results suggest that amino acids 15-52 and the six-membered ring structure of adrenomedullin are important for the expression of vasodilator activity in the mesenteric vascular bed of the cat.

Adrenomedullin↗
PubMed1995

Updated osteoarthritis reference standard.

The Kellgren and Lawrence atlas has been the reference standard for radiographic classification of osteoarthritis (OA) for nearly 40 years. Limitations include employment of a global grade, over-emphasis of the osteophyte, and submergence of other features so measurement of disease progression is difficult. Observer bias, drift, and variability cause concern. To address deficiencies and optimize observer accuracy, precision, and agreement, an updated atlas was created. From a photographic set of clinical radiographs, 4 readers selected a subset by consensus. Major radiographic features of hand, hip, and knee OA are graded on a 4-point scale. Using this atlas, it should be possible to individually score each relevant feature in a given joint. It is hoped the atlas will be adopted for population studies, assessment of disease progression, and protocols that evaluate new agents capable of modifying disease.

Hand↗
PubMed1995

Comparative effects of adrenomedullin, an adrenomedullin analog, and CGRP in the pulmonary vascular bed of the cat and rat.

Responses to synthetic human adrenomedullin (ADM), a novel hypotensive peptide initially isolated from human pheochromocytoma cells, an ADM analog (ADM15-52), and a structurally related peptide, calcitonin gene-related peptide (CGRP), were compared in the pulmonary vascular bed of the cat and rat under constant flow conditions. When tone was increased with U46619, intraarterial injections of ADM (0.03-0.3 nmol), ADM15-52 (0.03-0.3 nmol), and of CGRP (0.03-0.3 nmol) caused dose-related decreases in pulmonary arterial perfusion pressure. When the relative vasodilator activity of the peptides was compared on a nmol basis, ADM was approximately 10-fold more potent in the cat than in the rat, whereas vasodilator responses to CGRP were very similar in both species. CGRP was slightly more potent than ADM in the rat, whereas ADM was slightly more potent than CGRP in the cat. ADM and ADM15-52 had similar pulmonary vasodilator activity in the cat, whereas the full sequence peptide was slightly more potent than ADM15-52 in the rat. The present data demonstrate that ADM has significant vasodilator activity in the pulmonary vascular beds of the cat and of the rat, and that the relative potency of the vasodilator effects of ADM and ADM15-52 are different in the two species.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Atlas of individual radiographic features in osteoarthritis.

Radiographs of the hand, hip and knee were screened for evidence of osteoarthritis (OA). Specific sites selected for screening on the postero-anterior radiographs of the hand included the base of the thumb with distal and proximal interphalangeal joints; these regions were examined for formation of marginal osteophytes, joint space narrowing and subchondral lucency. Sites selected from antero-posterior radiographs of the hip included the acetabular and femoral portions of the joint; these regions were examined for joint space narrowing, subchondral lucency, marginal osteophytes and subchondral sclerosis. Sites selected from antero-posterior weight-bearing radiographs of the knee included distal femora and proximal tibiae including the medial and lateral compartments; these regions were examined for joint space narrowing, marginal osteophytes and subchondral sclerosis. Sites selected from axial views of the patellofemoral joint examined the medial and lateral portions; these regions were examined for joint space narrowing, osteophytes, subluxations and subchondral sclerosis. A set of photographic prints was made from the collection of radiographs. These specific features of OA were graded on each print and a subset of prints was selected that best demonstrated the spectrum of severity for each feature of OA. This resultant atlas is offered as an updated guide to standardize interpretation of radiographs prior to and during clinical trials.

Cartilage, Articular↗
PubMed1994

Comparison of responses to adrenomedullin and calcitonin gene-related peptide in the pulmonary vascular bed of the cat.

Pulmonary vascular responses to the newly discovered hypotensive peptide, adrenomedullin, were compared with responses to the structurally related peptides, calcitonin gene-related peptide (CGRP) and amylin, in the intact-chest cat. Under conditions of controlled blood flow, when tone in the pulmonary vascular bed had been raised to a high steady level, intralobar injections of adrenomedullin (0.03-1 nmol), CGRP (0.1-3 nmol), and amylin (0.1 and 0.3 nmol) caused dose-related decreases in lobar arterial pressure without changing left atrial pressure. In terms of relative vasodilator activity in the pulmonary vascular bed, the dose of the peptide that decreased lobar arterial pressure 7.5 mm Hg (ED7.5 mm Hg) was significantly lower for adrenomedullin than for CGRP. The duration of the pulmonary vasodilator responses to CGRP was longer than for adrenomedullin, and both peptides decreased systemic arterial pressure when injected into the perfused lobar artery in the higher doses studied. The present data demonstrate that synthetic human adrenomedullin and CGRP have potent but relatively short-lasting vasodilator activity in the pulmonary vascular bed. These data show also that amylin, a structurally related pancreatic peptide, also has significant pulmonary vasodilator activity.

Adrenomedullin↗