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Y H Feng

Publications and source records attributed to Y H Feng.

8 recordsLinked to original sources
PubMed1996

The active state of the AT1 angiotensin receptor is generated by angiotensin II induction.

In the current model of receptor activation, the given hormone is not involved in the conversion of the inactive receptor (R) to the fully active state (R*). Rather, it preferentially selects the activated receptor conformation, thereby shifting the equilibrium toward R*. The hormone angiotensin II (Ang II) contains two residues, Tyr4 and Phe8, that are essential for agonism. We show that the conserved Asn111 in transmembrane helix III of the AT1 angiotensin receptor directly interacts with the Tyr4 side chain. A decrease in the size of the Asn111 side chain induces an intermediate activated receptor conformation (R'). The Ang II analogue [Sar1,Ile4,Ile8]Ang II fully activates the N111G mutant, indicating that either the transition from R' to R* or the stabilization of the R* state requires binding by Ang II but not its Tyr4 and Phe8 side chains. In contrast, [Sar1,Ile4,Ile8]Ang II binds to but does not activate the wild-type AT1 receptor (R), suggesting that in the wild-type receptor spontaneous occurrence of R' and R* states is rare. Thus, Ang II through interactions involving Tyr4 and Phe8 induces a transition from R to R' and through unspecified interactions induces transition from R' to R* states rather than stabilizing the spontaneously generated R* state by "conformational, selection".

Amino Acid Sequence↗
PubMed1996

Suppression of oxidant production by diltiazem, nifedipine and verapamil in human neutrophils.

1. Polymorphonuclear leucocytes are a major source of toxic oxidants in vivo, causing tissue injury in certain circumstances such as ischaemia and reperfusion. Calcium ions are a key mediator in the production of oxidants by these cells. The aim of this study was to examine the effects of the widely used calcium antagonists diltiazem, nifedipine and verapamil on the production of oxidants in neutrophils. 2. Human neutrophils were freshly prepared, suspended in different luminol media and mixed with varying amounts of each calcium antagonist. They were then stimulated with either serum-opsonized zymosan or phorbol 12-myristate 13-acetate. Oxidant production was determined by three methods, namely luminol-enhanced chemiluminescence, oxygen consumption and cytochemical staining. 3. Calcium antagonists inhibited oxidant production by neutrophils. IC50 values for diltiazem, nifedipine and verapamil in calcium-free medium were 0.32 mmol/l (SEM 0.02), 0.27 mmol/l (SEM 0.02) and 0.24 mmol/l (SEM 0.02) respectively under zymosan stimulation, and 0.33 mmol/l (SEM 0.02), 0.26 mmol/l (SEM 0.02) and 0.13 mmol/l (SEM 0.07) respectively under phorbol 12-myristate 13-acetate stimulation. These effects were independent of the presence of Ca2+ in the extracellular solution. Some inhibition was also observed when the calcium antagonists were added during the course of a respiratory burst. Oxygen uptake by the cells was reduced in the presence of each calcium antagonist. Phagocytosis by the stimulated neutrophils was not affected despite inhibition of oxidant production. 4. We conclude that calcium antagonists can suppress the capacity of neutrophils to produce oxidants. This result may provide a novel explanation for the observation that delayed treatment with calcium antagonists may attenuate post-ischaemic myocardial dysfunction.

Calcium Channel Blockers↗
PubMed1995

The docking of Arg2 of angiotensin II with Asp281 of AT1 receptor is essential for full agonism.

The structural model of AT1 angiotensin receptor contains seven-transmembrane alpha-helices with three interhelical loops on either side of the membrane. The angiotensin II binding pocket within the receptor is not clearly defined. We showed earlier that Lys199 in transmembrane-helix-5 of the AT1 receptor binds the COOH-terminal alpha-carboxyl group of angiotensin II (Noda, K., Saad, Y., Kinoshita, A., Boyle, T. P., Graham, R. M., Husain, A., and Karnik, S. S. (1995) J. Biol. Chem. 270, 2284-2289). We now show that His183 and Asp281, both located in the extracellular domain of the AT1 receptor, are involved in binding the NH2-terminal Asp1 and Arg2 residues of angiotensin II, respectively. The Asp1/His183 interaction appears to be weak and is unlikely to be important for agonism. But the loss of Arg2/Asp281 interaction leads to partial agonism of the receptor. The action of non-peptide agonists is not affected by Asp281 mutations. These results suggest that several independent interactions between angiotensin II and AT1 receptor are necessary for full agonism. Since L-162,313 the non-peptide agonist of the AT1 receptor is a partial agonist that does not make contact with Asp281, we speculate that the degree of agonism may be increased if it is redesigned to make contacts with Asp281.

Angiotensin II↗
PubMed1995

In vitro oxidative damage to tissue-type plasminogen activator: a selective modification of the biological functions.

OBJECTIVE: Tissue-type plasminogen activator (t-PA) is an important component of the blood fibrinolytic system responsible for thrombus dissolution. It is often required to function under oxidative stress, and exogenous t-PA is used clinically in the treatment of acute myocardial infarction (AMI). The aim of this study was to examine alterations in the residual activity of t-PA pre-treated with certain oxidants. METHODS: Recombinant t-PA (rt-PA) and native t-PA (nt-PA) were pre-treated with freshly generated hypochlorous acid (HOCl) and chloramine T at varying concentrations. The amidolytic activity, the plasminogenolytic activity and the fibrin-binding affinity were then examined using chromogenic assays based on S-2288 and S-2251. RESULTS: The amidolytic activity of t-PA was surprisingly found to be rather sensitive (IC50 1 and 12 mumol/1, respectively), and the plasminogenolytic activity rather resistant to pre-treatment with HOCl and chloramine T. The fibrin binding study of treated t-PA revealed substantial loss of binding to CNBr-digested fibrinogen (FDP-CNBr). The velocity of t-PA in reaction with plasminogen remained the same as non-treated t-PA. The possible mechanisms of this asymmetrical oxidative modification of the biological functions are also discussed. CONCLUSIONS: (1) The catalytic activity of t-PA and the binding affinity for its large-molecule substrate plasminogen, rather than the small-molecule substrate S-2288, are highly resistant to oxidative damage; (2) the fibrin-binding affinity of t-PA can be selectively and asymmetrically damaged by exposure to these oxidants. Thus it is possible that the characteristic advantage of thrombus selectivity of t-PA in both spontaneous thrombolysis and thrombolytic therapy may be diluted in circumstances where toxic and reactive oxidants exist.

Amino Acid Sequence↗
PubMed1993

Persistent peripheral vasodilation and sympathetic activity in hypotension after maximal exercise.

Hemodynamics (by aortic Doppler), autonomic factors (power spectrum analysis of heart rate and blood pressure variabilities and baroreceptor sensitivity), and plasma renin activity during the hypotension after maximal exercise were studied in 10 normal subjects on two separate days: a nonexercise (control) day (30 min of upright rest followed by 60 min of supine rest) and an exercise day (maximal upright bicycle exercise followed by 60 min supine) in random order. After exercise, diastolic pressure was reduced for the entire hour, cardiac output increased (+33.8%, P < 0.05), stroke volume was unchanged, and systemic vascular resistance fell (-28.6%, P < 0.01). Indexes of vagal activity were reduced for 60 min, whereas the sympathetic indexes were elevated. Baroreflex sensitivity was also reduced for the first 10 min after exercise. Renin activity increased threefold after exercise. The postexercise hypotension results from a persisting peripheral vasodilation despite an increase in renin activity: the persistent sympathetic activity and reduced vagal tone are probably reflex responses to this vasodilatation.

Adult↗