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H A Singer

Publications and source records attributed to H A Singer.

43 records · Page 3Linked to original sources
PubMed1983

Endothelium-dependent relaxation of rabbit aorta. II. Inhibition of relaxation stimulated by methacholine and A23187 with antagonists of arachidonic acid metabolism.

Methacholine, A23187 and arachidonic acid (AA) relax segments of rabbit thoracic aorta via mechanisms which are dependent on an intact endothelium. Relaxation stimulated by AA was previously found by us to be antagonized by eicosatetraynoic acid and nordihydroguaiaretic acid, but not indomethacin. The purpose of the present investigation was to determine the effects of several inhibitors of AA metabolism on endothelium-dependent relaxation stimulated by methacholine and A23187 in rings of rabbit thoracic aorta. Relaxation in response to methacholine and A23187 was: 1) not affected by indomethacin pretreatment (20 microM, 30 min); 2) inhibited by 50 microM eicosatetraynoic acid pretreatment, 53 and 33%, respectively; and 3) inhibited in a dose-dependent manner by nordihydroguaiaretic acid (10-50 microM) with complete inhibition occurring after 25 and 50 microM pretreatment, respectively. Methacholine-induced relaxation was completely blocked by 10 microM quinacrine (QUIN), whereas A23187-stimulated responses were not significantly affected. QUIN (10 microM) antagonized methacholine-stimulated contractile responses in a noncompetitive manner in rings devoid of endothelium. QUIN may interfere with activation via muscarinic receptors, complicating interpretation of its inhibitory effects. Eicosatetraynoic acid (50 microM), nordihydroguairetic acid (50 microM) and QUIN (10 microM) do not exert significant inhibitory effects at the level of smooth muscle relaxation mechanisms as isoproterenol-induced relaxation was resistant to inhibition by these agents. We conclude that methacholine and A23187 relax rabbit aorta by mechanisms which require intact endothelium and involve noncyclooxygenase metabolites of AA.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1978

Spina bifida and anencephaly in the Cape.

In the first phase of a programme for the prevention of neural tube defects at a population level, information has been obtained concerning 285 infants born with open neural tube defects. As in other parts of the world, the months of conception of affected infants clustered in the second quarter of the year and the majority of the parents were members of lower income groups. In the years 1975-1977, the incidence of anencephaly and spina bifida in White South African patients was similar to that generally encountered in Western Europe. However, in the non-White populations the separate and combined incidence were significantly lower. It is emphasized that these are preliminary figures and that they might be subject to ascertainment biases.

Anencephaly↗
PubMedDate not supplied

Phorbol ester-induced contractions of swine carotid artery are supported by slowly cycling crossbridges which are not dependent on calcium or myosin light chain phosphorylation.

This study determined if phorbol ester-induced contraction of vascular smooth muscle requires calcium-dependent myosin light chain (MLC) phosphorylation and, if not, whether the mechanical characteristics of the contraction in terms of stiffness and crossbridge cycling are similar to those during a calcium- and MLC phosphorylation-dependent contraction. Carotid arterial strips were exposed to 1.0 microM phorbol 12,13-dibutyrate (PDBu) in the presence of normal physiological salt solution (PSS) or after calcium depletion in calcium-free PSS and compared with contraction elicited by calcium-containing 110 mM KCl-PSS. PDBu induced maximal stress in both the presence and absence of calcium. While there was a temporal correlation between MLC phosphorylation and shortening velocity during KCl depolarization, shortening velocity was dissociated from MLC phosphorylation during PDBu stimulation. The stress-stiffness relationship was not different during KCl and PDBu stimulation, suggesting similar crossbridge interactions even though MLC phosphorylation levels were significantly different. These results demonstrate that PDBu-induced contraction of the swine carotid artery is not dependent on calcium or MLC phosphorylation. We suggest the possibility that activation of a calcium-independent PKC isoform may result in the expression of an inherent level of actin-activated myosin ATPase activity resulting in the slow development of stress.

Animals↗
PubMedDate not supplied

Endothelium-derived vascular relaxing factor.

A large number and variety of compounds (acetylcholine, adenosine diphosphate, adenosine triphosphate, arachidonic acid, bradykinin, Ca2+ ionophores, calcitonin gene-related peptide, histamine, hydralazine, substance P, thrombin, and vasoactive intestinal polypeptide) have been shown to relax arterial smooth muscle indirectly. The endothelium in muscular arteries from several species appears to have receptors for these vasodilators. Binding of one of these compounds to its endothelial receptors results in the release (and presumably synthesis) of substance(s) that act on arterial smooth muscle to cause relaxation. The name endothelium-derived relaxing factor (EDRF) has been proposed for the substance or substances responsible for inhibition of contraction. Studies to determine additivity of endothelium-dependent relaxing agents and sensitivity of EDRF-mediated responses to a variety of inhibitors suggest that a single factor or a single common mechanism induces relaxation of vascular smooth muscle. Pharmacological studies have been equivocal with regard to the postulated involvement of phospholipases or arachidonic acid and to the suggestion that EDRF is an oxidative, non-cyclooxygenase product of arachidonate. Experiments on transfer of EDRF and reversal of endothelium-dependent relaxation consistently indicate that EDRF is quite labile. There is convincing evidence that EDRF activates smooth muscle guanylate cyclase, which results in an increase in intracellular cyclic guanosine 3',5'-monophosphate levels. The stimulation of guanylate cyclase by EDRF provides a valuable and sensitive parameter for studies with arteries as well as cells in culture. At present, the identity of EDRF and its role in cardiovascular homeostasis are unknown.

Animals↗
PubMedDate not supplied

Role of endothelium in conversion of angiotensin I to angiotensin II in rabbit aorta.

Rabbit aortic rings with either an intact endothelium or a disrupted endothelium were used to generate dose response curves to angiotensin I (AI) in the presence (ED50 = 3 X 10(-7) M) and absence (ED50 = 1.7 X 10(-8) M) of 10 micrograms/ml teprotide, a converting-enzyme inhibitor. Treatment with teprotide did not alter responses to angiotensin II (AII). Comparable dose-dependent responses were obtained with AII regardless of endothelial integrity. Contraction velocities in response to angiotensin I (10(-7) M) and AII (10(-7) M) were also measured. Angiotensin II produced a significantly greater contraction velocity (p less than 0.001) than that produced by AI. The amount of conversion to AII by both intact rabbit aortic rings and rings following removal of the endothelium was determined using 125I-AI and 125I-AII. Waters C18 SEP-PAK columns were used to separate AI and AII. During the first 3 to 4 minutes after the addition of AI, contraction velocity measurements and conversion were greater in intact rings than rings without endothelium. Conversion of AI to AII in endothelial-disrupted rings was the same as in intact rings by 5 minutes after the addition of AI. Conversion of AI to AII was inhibited by 30 micrograms/ml teprotide at all times measured, and there was no evidence of an alternate route of metabolism. Angiotensin I contraction velocity measurements after 10 micrograms/ml teprotide also demonstrated impaired efficiency of conversion of AI to AII. Thus, it was established that a lack of endothelium attenuated the rate of conversion of AI to AII initially, and formation of AII with or without endothelium was blocked by teprotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗
PubMedDate not supplied

Calcium- and endothelial-mediated vascular smooth muscle relaxation in rabbit aorta.

The role of calcium in the relaxations evoked by methacholine and A23187 in intact rabbit aortic rings was investigated. Methacholine (10(-8) to 10(-6) M) and the calcium ionophore A23187 (10(-8) to 10(-6) M) produced dose-dependent relaxations of rings which had been contracted with the alpha-adrenergic agonist phenylephrine. The ability of a ring to relax in this manner was correlated with the presence of endothelium as judged by transmission and scanning electron microscopy. Purposely disrupting the endothelium led to a loss of the relaxation response. In these rings methacholine caused dose-dependent contractions at concentrations greater than 10(-7) M. Deletion of Ca++ from the incubation medium inhibited maximum methacholine-induced relaxations by 67% and A23187-induced relaxations by 92%. The Ca++-channel blockers verapamil (10 microM) and nifedipine (0.5 microM) inhibited maximum methacholine-induced relaxations by 39% and 45%, respectively. The blockers had no effect on the methacholine ED50 (2.5 x 10(-7) M) for relaxation. Verapamil and nifedipine also inhibited maximum A23187-induced relaxations by 43% and 47% with no effect on the ED50 (6 x 19(-8) M) for relaxation. A structurally dissimilar vasodilator, sodium nitroprusside (10(-7) M), had no effect on the A23187-induced relaxation. These data are consistent with a role of Ca++ in regulating either the production or release of endothelial-derived relaxing factor(s).

Animals↗