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Biomedical subjects

V M Miller

Publications and source records attributed to V M Miller.

At least 109 records · Page 6Linked to original sources
PubMed1993

Endothelium-derived factors modulate contraction of bronchial smooth muscle.

Experiments were designed to determine how changes in the ratio of specific vascular endothelium-derived factors might affect reactivity of bronchial smooth muscle. The epithelium was mechanically removed from rings of third-order canine bronchi, and the rings were suspended in organ chambers for measurement of isometric force. Rings of pulmonary artery were cut; in some the endothelium was mechanically removed. The arterial rings were everted and pairs, with and without endothelium, were incubated with control solution, NG-monomethyl-L-arginine (L-NMMA), indomethacin, or both L-NMMA and indomethacin for 90 min. They were then inserted into the lumen of the bronchial rings. Cumulative concentration-response curves to acetylcholine and 5-hydroxytryptamine were obtained. There was no significant difference in response between bronchi containing arteries with or without endothelium incubated with control solution. Contractions of bronchi containing arteries without endothelium, incubated in either L-NMMA or indomethacin, increased from control. However, in rings containing arteries with endothelium, incubation with either inhibitor decreased bronchial contractions. Incubation with both inhibitors eliminated the difference. These results suggest that the vascular endothelium produces factors that can both contract and relax bronchial smooth muscle. With inhibition of production of either nitric oxide with L-NMMA or prostanoids with indomethacin, release of other endothelium-derived factors occurs that attenuates contractions of bronchial smooth muscle. Therefore, an imbalance in the ratio of production of endothelium-derived factors may contribute to bronchospastic disorders.

Animals↗
PubMed1993

Vasonatrin peptide: a unique synthetic natriuretic and vasorelaxing peptide.

This study reports the cardiovascular and renal actions of a novel and newly synthesized 27-amino acid peptide termed vasonatrin peptide (VNP). VNP is a chimera of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP). This synthetic peptide possesses the 22-amino acid structure of CNP, which is a cardiovascular selective peptide of endothelial origin and is structurally related to ANP. VNP also possesses the five-amino acid COOH terminus of ANP. The current study demonstrates both in vitro and in vivo that VNP possesses the venodilating actions of CNP, the natriuretic actions of ANP, and unique arterial vasodilating actions not associated with either ANP or CNP.

Amino Acid Sequence↗
PubMed1993

Bronchial contractions in transplanted lungs. Influence of denervation, acute rejection, and the bronchial epithelium.

The effects of pulmonary denervation and rejection on contractions of bronchial smooth muscle and epithelial modulation of these contractions were studied in dogs after denervation in right lung autotransplantation (n = 6) and acute rejection after right lung allotransplantation (n = 8). Immunosuppression was withdrawn from the latter group after 5 days; rejection developed after 3 additional days. A significant (p < 0.05) increase in mean peak airway pressure occurred with rejection of allotransplanted lungs. Rings cut from third-order bronchi of transplanted and contralateral unoperated (native) lungs in each animal were suspended in organ chambers for the measurement of isometric force. In some rings, the epithelium was removed mechanically. Acetylcholine (cholinergic neurotransmitter), serotonin (platelet-product), histamine (mast cell product), and endothelin-1 (endothelium-derived contracting factor) caused concentration-dependent contractions in all rings. In bronchi from native lungs, rings with epithelium contracted less than those without epithelium. This difference was lost after autotransplantation. The smooth muscle and epithelium were affected differently by autotransplantation. Contractions of rings without epithelium decreased in response to acetylcholine and endothelin-1, whereas contractions of rings with epithelium increased in response to histamine and 5-hydroxytryptamine (p < 0.05). During acute rejection, contractions were the same as those after autotransplantation. Bronchial content of endothelin increased fourfold with rejection. Relaxations to isoproterenol and prostaglandin E2 were similar in both groups. In conclusion, denervation reduced the ability of the smooth muscle to contract. The degree of acute pulmonary rejection seen in this study did not further affect bronchial contractions. Modulation of contractions by the bronchial epithelium was lost with both denervation and rejection.

Acetylcholine↗
PubMed1993

Cryopreserved venous allografts: effects of immunosuppression and antiplatelet therapy on patency and function.

PURPOSE: Experiments were designed to determine the function of the endothelium and smooth muscle in cryopreserved and fresh canine saphenous vein allografts. METHODS: Reversed interposition saphenous vein grafts were implanted into the femoral arteries of two groups of dogs: group 1 received one freshly harvested saphenous vein allograft and group 2 received one cryopreserved saphenous vein allograft. The contralateral femoral artery in each group was replaced with a freshly harvested autogenous saphenous vein. Animals received oral cyclosporine alone (n = 3) or in combination with aspirin (325 mg/day; n = 20). RESULTS: Four weeks after surgery, none of the cryopreserved grafts was patent in the group treated with cyclosporine alone. All grafts were patent in animals treated with cyclosporine and aspirin. At 4 weeks, blood flow through cryopreserved allografts was significantly greater than in freshly harvested allografts. Platelet deposition was comparable in cryopreserved and freshly harvested allografts immediately after implantation and at 4 weeks. Rings cut from the grafts were suspended for the measurement of isometric force in organ chambers. alpha-Adrenergic agonists and endothelin caused concentration-dependent contractions in fresh autografts and allografts. After submaximal contraction with prostaglandin F2 alpha in these same grafts, calcium ionophore and thrombin caused relaxations in rings with endothelium, and nitric oxide caused relaxations in rings without endothelium. Cryopreserved allografts did not respond to any of the agonists tested. Histologic examination of the tissue indicated smooth muscle cells in cryopreserved grafts; evidence of rejection was observed in all allografts. CONCLUSION: These results indicate that cryopreserved allografts remain patent with antiplatelet and immunosuppressive therapy in spite of loss of functional smooth muscle.

Animals↗
PubMed1992

Modulation of arterial endothelin-1 receptors following chronic increases in blood flow.

Experiments were designed to determine whether or not increased contractions to endothelin-1 (ET-1) in arteries chronically exposed to increased blood flow were due to a change in the subtype, number, or affinity of ET receptors on the smooth muscle. A fistula was created between one femoral artery and vein in dogs; contralateral blood vessels were operated as shams. After 6 weeks, the femoral arteries were removed. In both fistula- and sham-operated arteries suspended for the measurement of isometric force in organ chambers, the contractile potency was ET-1 > ET-2 > ET-3. Specific binding of [125I]ET-1 as a function of membrane protein was significantly greater in fistula compared to sham-operated arteries (Bmax = 184.8 +/- 35.9 and 117.4 +/- 25.6 fmol/mg, n = 6, respectively). Affinity of binding was the same in each group of arteries. These results suggest that ETA receptors mediate contraction on canine femoral arterial smooth muscle. These receptors may be upregulated when the artery is exposed chronically to increased blood flow.

Animals↗
PubMed1992

Role of lipoxygenase and cytochrome P-450 in production of endothelium-derived relaxing factors in canine femoral veins.

We wished to determine whether the metabolism of arachidonic acid, through lipoxygenase and cytochrome P-450 pathways, is involved in production of endothelium-derived relaxing factor(s) (EDRFs) in canine femoral veins. Veins were removed from anesthetized dogs and cut into rings. Endothelium was deliberately removed from some rings. In separate sets of experiments, rings were incubated with either AA861 (10(-5) M) or TMK777 (10(-6) M), inhibitors of 5-lipoxygenase, nordihydroguaiaretic acid (NDGA 3 x 10(-6) M), an inhibitor of lipoxygenase or proadifen (SKF 525A, 10(-6) M), an inhibitor of cytochrome P-450. In addition, some rings were incubated with a combination of indomethacin (10(-5) M) and NG-monomethyl-L-arginine (L-NMMA 10(-4) M) or, where appropriate, a solvent control. Concentration-response curves were obtained for acetylcholine, adenosine diphosphate, thrombin, A23187, and nitric oxide in rings contracted with a submaximal concentration of prostaglandin F2 alpha. AA861 and TMK777 did not alter endothelium-dependent relaxations to the agonists, whether with or without indomethacin and L-NMMA. However, indomethacin plus L-NMMA reduced endothelium-dependent relaxations to thrombin. These results suggest that metabolism of arachidonic acid, through lipoxygenase and cytochrome P-450 pathways, does not produce an EDRF in veins. However, thrombin receptor-activated relaxations are mediated in part by products of the cyclooxygenase pathway and nitric oxide.

Animals↗
PubMed1992

Modulation of NO and endothelin by chronic increases in blood flow in canine femoral arteries.

Experiments were designed to determine whether chronic increases in arterial blood flow alter production of or response to nitric oxide and endothelin. Canine femoral arteries proximal to an arteriovenous fistula- and from the contralateral sham-operated blood vessels were removed, cut into rings, and suspended for measurement of isometric force in organ chambers. The remainder of the artery was homogenized for measurement of endothelin content by radioimmunoassay. NG-monomethyl-L-arginine (10(-4) M) caused concentration-dependent increases in tension only in fistula-operated arteries. Endothelium-dependent relaxations to acetylcholine and BHT-920 were greater in fistula- compared with sham-operated arteries. These differences were reduced by the arginine analogue. Pertussis toxin (100 ng/ml) inhibited relaxations to acetylcholine only in fistula-operated arteries and to BHT-920 only in sham-operated arteries. Contractions to endothelin-1 were greater in fistula- compared with sham-operated arteries. These results suggest that chronic increases in blood flow enhance the tonic and receptor-stimulated production of nitric oxide and its release by receptors coupled to pertussis toxin-sensitive guanine nucleotide regulatory proteins. Furthermore, chronic increases in blood flow may either inhibit the production of endothelin or promote its depletion from endothelial cells while simultaneously increasing the sensitivity of the smooth muscle to its contractile effects.

Animals↗
PubMed1992

[Left coronary vessel anomaly and myocardial infarction].

Anomalous origin of the left main coronary artery from the right anterior aortic sinus is a rare condition (0.02 to 0.07%) and its clinical significance is sometimes controversial. The authors present the case of a 44-year-old female with this anomaly and septal course with clinical, electrocardiographic, scintigraphic and cineangiographic evidences of myocardial infarction without coronary lesions. Literature is reviewed regarding diagnosis, clinical significance, pathophysiology and management. It is probably the first evidence of the potential danger of this anomaly with septal course.

Adult↗
PubMed1992

In vitro evaluation of endothelial and smooth muscle function of primary varicose veins.

Experiments were designed to study functional changes in superficial leg veins of patients with primary varicosity. Excess segments were taken from 19 patients undergoing elective vein resection. Excess segments of greater saphenous veins taken from 13 patients undergoing coronary or lower extremity arterial bypass were used as controls. These rings, some with endothelium deliberately removed, were suspended for the measurement of isometric force in organ chambers. Segments of veins were also evaluated with respect to their total protein content, endothelin content, and histologic structure. In varicose veins, maximal contractions in response to potassium chloride (n = 9), norepinephrine (n = 9), and endothelin (n = 4) were reduced 71.1%, 78.2%, and 75.6%, respectively, compared with contractions in control veins (p < 0.01). In addition, no differences were detected in the maximal tension or tissue sensitivity (EC50) between segments of nonvaricose greater saphenous vein and adjacent varicose tributaries from the same patient. Rings with and without endothelium contracted similarly. In varicose veins, endothelium-dependent relaxations produced by the calcium ionophore A23187 were attenuated 89.7% compared with relaxations in controls (n = 6, p < 0.01). In veins from patients with primary varicosity, endothelium-independent relaxations produced by nitric oxide (n = 6) and forskolin (n = 3) were diminished 86.8% (p < 0.01) and 65.6% (p < 0.05), respectively, compared with relaxations in control veins. In primary varicose veins, protein content was decreased (n = 17, p < 0.01) and endothelin content increased (n = 17, p = 0.1) compared with those values in control veins (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelins↗
PubMed1992

Pulmonary arterial reactivity after transplantation. Differential effects of denervation and rejection.

Little is known regarding changes in reactivity of the vasculature of transplanted solid organs. Experiments were designed to differentiate the effects of denervation and rejection on the function of the endothelium and smooth muscle of pulmonary arteries in transplanted lungs of the dog. Single lungs were transplanted as autografts to study the effects of denervation or as allografts to study the additional effects of rejection. Immunosuppression was stopped in animals receiving allografts 5 days after operation, and rejection was allowed to proceed for an average of 3 days. Animals receiving autografts were studied after the same time period. There were no differences in concentrations of circulating leukocytes, platelets, or lymphocytes between the two groups. Circulating concentrations of angiotensin-converting enzyme were significantly reduced during rejection; concentrations of endothelin were unchanged. Rings of pulmonary arteries with and without endothelium were suspended for the measurement of isometric force in organ chambers. Contractions to angiotensin I and endothelin were less in rejecting than in autotransplanted arteries, whereas those to 5-hydroxytryptamine were enhanced. Contractions to norepinephrine were comparable in both autograft and rejecting allograft arteries. Relaxations to isoproterenol were greater in the autograft than in the rejecting autografted arteries; the opposite was observed for relaxations to histamine. Endothelium-dependent relaxations to adenosine diphosphate and bradykinin but not to calcium ionophore A23187 were reduced with rejection; relaxations to nitric oxide were unchanged. These results suggest that transplantation per se affects vascular reactivity. However, there are selective dysfunctions of receptor-operated mechanisms in arteries that are associated with rejection and that are distinct from denervation. Further, serum concentrations of angiotensin-converting enzyme may be an indicator of rejection of transplanted lungs.

Animals↗
PubMed1991

Cryopreservation affects endothelial and smooth muscle function of canine autogenous saphenous vein grafts.

Cryopreserved veins used as arterial grafts may be affected by both rejection and the cryopreservation process. Experiments were designed to study changes in endothelial and smooth muscle function after cryopreservation but independent of rejection. One saphenous vein from each of eight dogs was cryopreserved for subsequent use as autografts. After 3 weeks one cryopreserved and one freshly harvested autogenous saphenous vein were implanted as bilateral femoral arterial interposition grafts. Platelet deposition was studied in vivo with indium 111-labeled platelets. At 4 weeks the autografts were removed, and the functional characteristics of the grafts were studied in organ chambers; and the ability of nerve terminals to uptake transmitter was studied with 3H-norepinephrine. Neither patency rates, blood flows, nor platelet deposition were significantly different between freshly harvested and cryopreserved grafts. Uptake of 3H-norepinephrine was significantly reduced in both grafts as compared to unoperated veins. The smooth muscle of the cryopreserved and fresh grafts contracted comparably to alpha-adrenergic agonists and endothelin. In cryopreserved grafts, the maximal tensions that developed to KCl, prostaglandin F2 alpha, and endothelin were greater when the endothelium was present compared to that developed by the smooth muscle alone. Calcium ionophore A23187 caused relaxations only in rings with endothelium; these were not significantly different between graft types. However, relaxations of the smooth muscle to nitric oxide were decreased in the cryopreserved grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Dissociation between endothelium-dependent relaxations and increases in cGMP in systemic veins.

In canine systemic veins, in contrast to what is observed in mammalian systemic arteries, endothelium-dependent relaxations to the calcium ionophore A23187 are not diminished by the inhibitor of soluble guanylate cyclase, methylene blue. Therefore, experiments were designed to determine whether these relaxations in the veins are associated with the accumulation of guanosine 3',5'-cyclic monophosphate (cGMP). Rings of canine femoral arteries and veins with and without endothelium were suspended for the measurement of isometric force in organ chambers; cGMP was measured by radioimmunoassay. In arteries and veins contracted with norepinephrine, the tissue content of cGMP was greater in rings with than without endothelium. This difference was decreased by methylene blue (10(-5) M). A23187 (3 X 10(-7) M, for 1 min) increased the accumulation of cGMP, which was temporally related with the onset of relaxation in tissues with endothelium. Methylene blue inhibited the accumulation of cGMP in both blood vessels but inhibited the relaxations only in the arteries. In rings without endothelium, sodium nitroprusside (3 X 10(-7) and 10(-5) M) initiated increases in cGMP, which followed the onset of relaxation. Neither response to sodium nitroprusside was reduced by methylene blue. These results suggest that in canine femoral arteries and veins, relaxation of the smooth muscle to sodium nitroprusside are mediated by a mechanism distinct from changes in cGMP. Likewise, in canine systemic veins, endothelium-derived factor(s) released in response to A23187 also can initiate relaxation of the smooth muscle by a mechanism distinct from changes in cGMP.

Animals↗
PubMed1991

Selective production of endothelium-derived nitric oxide in canine femoral veins.

In arteries, analogues of L-arginine inhibit the synthesis of nitric oxide and thereby reduce endothelium-dependent relaxations. Experiments were designed to determine whether analogues of L-arginine affect endothelium-dependent responses in a systemic vein. Rings cut from canine femoral arteries and veins were suspended for the measurement of isometric force in organ chambers. In some rings, the endothelium was deliberately removed. All experiments were conducted in the presence of indomethacin (10(-5) M). NG-monomethyl-L-arginine (L-NMMA, 10(-4) M) reduced significantly endothelium-dependent relaxations to acetylcholine, ADP, and thrombin in arteries but not in veins. In the veins, the alpha 2-adrenergic agonist BHT-920 caused contractions which were reduced in rings with endothelium. L-NMMA eliminated the difference in contraction between rings with and without endothelium in the veins. This effect was reversed by L- but not D-arginine (3 x 10(-4) M). N omega-nitro-L-arginine (10(-4) M) reduced endothelium-dependent relaxations to acetylcholine, thrombin, and the calcium ionophore A23187 in venous rings. However, it did not alter the contractions to BHT-920 in rings with or without endothelium. L-Canavanine did not alter endothelium-dependent relaxations in the veins. These results suggest that synthesis of nitric oxide is associated with stimulation of alpha 2-adrenergic, muscarinic, and thrombin receptors on venous endothelial cells. Furthermore, the analogues of L-arginine affect endothelium-dependent relaxations in canine veins differentially.

Acetylcholine↗
PubMed1991

Progesterone and modulation of endothelium-dependent responses in canine coronary arteries.

Chronic treatment with estrogens enhances some endothelium-dependent relaxations. Whether or not progesterone would exert a similar effect is unknown. Experiments were designed to determine the effect of chronic treatment with progesterone on endothelium-dependent responses. Adult female dogs were ovariectomized and pellets containing carrier substance, estrogen, progesterone, or estrogen plus progesterone were implanted subcutaneously. After 14-21 days coronary arteries were removed, cut into rings, and suspended for the measurement of isometric force in organ chambers in the presence of indomethacin. Endothelium-dependent relaxations to ADP, bradykinin, or the calcium ionophore did not differ among groups. However, relaxations to acetylcholine and to the alpha 2-adrenergic agonist BHT-920 were greater in the estrogen-treated group than in the estrogen plus progesterone-treated group. In rings without endothelium, relaxations to nitric oxide and isoproterenol did not differ among groups. However, relaxations of the smooth muscle to ADP were greater in the progesterone-treated group than in the progesterone plus estrogen group. These results suggest that progesterone alone minimally affects endothelium-dependent responses. However, progesterone seems to antagonize the stimulatory effects of estrogen on two endothelium-dependent responses that are associated with pertussis toxin-sensitive guanine nucleotide regulatory proteins and the production of nitric oxide. These studies suggest that a specific receptor/second messenger system can be modulated by female reproductive steroid hormones.

Acetylcholine↗
PubMed1991

Pertussis toxin reduces endothelium-dependent and independent responses to alpha-2- adrenergic stimulation in systemic canine arteries and veins.

A pertussis toxin-sensitive guanine nucleotide regulatory protein (G-protein) is involved in the signal transduction of certain endothelium-dependent responses in mammalian arteries. To determine whether a similar mechanism mediates endothelium-dependent responses in mammalian veins, rings of canine femoral arteries and veins with and without endothelium were suspended for the measurement of isometric force in organ chambers. In femoral arteries, incubation of the rings with pertussis toxin (from Bordetella pertussis, 100 ng/ml for 2 hr) in the presence of indomethacin and propranolol did not reduce significantly endothelium-dependent relaxations to acetylcholine and adenosine diphosphate, thrombin or the calcium ionophore A23187. However, endothelium-dependent relaxations evoked by the alpha-2 adrenergic agonist UK 14,304 were blocked by the pertussis toxin. In venous rings, endothelium-dependent relaxations to acetylcholine were reduced by the toxin, whereas the endothelium-dependent relaxations evoked by adenosine diphosphate, thrombin and A23187 were not affected. UK 14,304 contracted the veins; these contractions were augmented by removal of the endothelium. Pertussis toxin inhibited contractions to UK 14,304 in venous rings without but not with endothelium. Relaxations of arterial and venous smooth muscle to nitric oxide were unaffected by the toxin. Contractions to phenylephrine were not altered by either removal of the endothelium or the toxin in the arteries or veins. These results suggest that the release of endothelium-derived relaxing factor in response to stimulation of purine and thrombin receptors probably does not involve a pertussis toxin-sensitive G-protein in canine femoral arteries or veins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Methods of cardiac preservation alter the function of the endothelium in porcine coronary arteries.

This study was undertaken to determine whether clinical methods for preservation and storage of hearts explanted for transplantation affect the responsiveness of coronary arteries to vasoactive agents. Porcine hearts were perfused with crystalloid or blood cardioplegic solution. Rings of coronary arteries were suspended in organ chambers for measurement of isometric force (1) immediately after perfusion and (2) after 5 hours' storage of the hearts at 4 degrees C in the same cardioplegic solution (n = 6 in each group). The maximal contraction of the smooth muscle to potassium chloride, 40 mmol/L, was reduced significantly after perfusion with crystalloid cardioplegic solution (10.8 +/- 1.2 gm) compared with blood cardioplegic solution (17.3 +/- 0.8 gm) and nonperfused coronary arteries (control group 16.9 +/- 1.8 gm). The sensitivity of the arteries with endothelium to the contractile effects of prostaglandin F2 alpha increased after perfusion with crystalloid cardioplegic solution (ED50, [-log mol/L] 5.8 +/- 0.04) compared with blood cardioplegic solution (5.3 +/- 0.02) and the control group (5.7 +/- 0.03). In addition, relaxations to the calcium ionophore A23187, bradykinin, and the alpha 2-agonist BHT-920, which depend on the presence of endothelial cells, were significantly reduced after perfusion with crystalloid compared with blood cardioplegic solution or the control group. The responsiveness of the endothelium and smooth muscle after 5 hours' cold storage was unaltered in the blood cardioplegia group, whereas storage resulted in functional recovery in the crystalloid cardioplegia group, with the result that all groups were comparable. These data suggest an immediate and reversible change in vascular function with crystalloid cardioplegia, which was not apparent with blood cardioplegia.

Animals↗
PubMed1990

Endothelium-dependent vasorelaxations in response to aggregating platelets are impaired in reversed vein grafts.

The endothelium releases factor(s) that are potent vasodilators and inhibitors of platelet aggregation. Experiments were performed to determine whether the endothelium-dependent responses to aggregating platelets are altered in vein grafts. Segments of jugular veins were grafted in the reverse position into the carotid arteries in 16 rabbits. After 4 weeks the patent grafts (14 of 16) were removed, and the endothelium-dependent responses were examined in vitro. In control veins aggregating platelets, adenosine diphosphate, and serotonin caused endothelium-dependent relaxations. The platelet-induced relaxations were attenuated by apyrase (adenosine diphosphatase and adenosine triphosphatase) but not by methiothepin (serotonergic blocker). In vein grafts, endothelium-dependent relaxations in response to aggregating platelets were absent, and only contractions that could be attenuated by methiothepin were observed. In vein grafts, endothelium-dependent relaxations in response to adenosine diphosphate were reduced, and only endothelium-independent contractions were observed in response to serotonin. These contractions were attenuated by methiothepin. These results suggest that (1) the endothelium exerts an inhibitory effects mediated mainly by adenosine diphosphate in response to aggregating platelets in rabbit jugular veins and (2) endothelium-dependent relaxations in response to aggregating platelets are impaired in vein grafts because of reduced endothelium-independent contractions in response to serotonin. This impairment of endothelium-dependent responses in vein grafts may contribute to failure of the grafts.

Adenosine Diphosphate↗