Thrombin receptor activation peptide induces pulmonary vasoconstriction

1994 ◽  
Vol 266 (2) ◽  
pp. C448-C454 ◽  
Author(s):  
H. Lum ◽  
T. T. Andersen ◽  
J. W. Fenton ◽  
A. B. Malik
Keyword(s):  
Smooth Muscle ◽  
Arterial Pressure ◽  
Guinea Pig ◽  
Smooth Muscle Cells ◽  
Pulmonary Arterial Pressure ◽  
Muscle Cells ◽  
Receptor Activation ◽  
Thrombin Receptor ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

We investigated the involvement of the 14-residue thrombin receptor activating peptide SFLLRNPNDKYEPF (TRAP-14) in mediating the pulmonary vasoconstriction in response to alpha-thrombin. Isolated guinea pig lungs were uniformly perfused with Ringer-albumin solution at a constant flow of 28 ml/min. Addition of TRAP-14 or human alpha-thrombin to the perfusate caused dose-dependent increases of pulmonary arterial pressure within 1 min. TRAP-14 at 1 microM increased pulmonary arterial pressure to a similar extent as 10 nM alpha-thrombin (i.e., increase of 7.7 +/- 0.8 and 7.4 +/- 0.9 cmH2(0) from baseline, respectively). The increases in pulmonary venous resistance induced by TRAP-14 and alpha-thrombin were two- to fivefold greater than the increases in pulmonary arterial resistance, indicating that both agonists mediated pulmonary hypertension secondary to pulmonary venoconstriction. Stimulation of cultured guinea pig pulmonary artery smooth muscle cells with 100 microM TRAP-14 or 10 nM alpha-thrombin increased cytosolic Ca2+ concentration about five- to sevenfold over baseline. The increase in cytosolic Ca2+ concentration in smooth muscle cells was not observed with a subsequent challenge with either agonist, indicating desensitization. In the perfused lungs, an initial stimulation with alpha-thrombin or TRAP-14 desensitized the lungs to either agonist. The alpha-thrombin-desensitized lungs remained refractile to alpha-thrombin after 1 h of perfusion with fresh Ringer solution, whereas the TRAP-14-desensitized lungs recovered 79% of the vasoconstrictor response by 10 min and 93% of the response by 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of the pulmonary vasoconstriction reaction to alveolar hypoxia in systemic high blood pressure

1989 ◽  
Vol 76 (6) ◽  
pp. 589-594 ◽  
Author(s):  
Maurizio D. Guazzi ◽  
Marco Berti ◽  
Elisabetta Doria ◽  
Cesare Fiorentini ◽  
Claudia Galli ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Arterial Pressure ◽  
High Blood Pressure ◽  
Pulmonary Arterial Pressure ◽  
Systemic Hypertension ◽  
Pulmonary Vasoconstriction ◽  
Arteriolar Resistance ◽  
Alveolar Hypoxia ◽  
Pulmonary Arterial

1. In systemic hypertension the pulmonary vessels show an excessive tone at rest and hyper-react to adrenoceptor stimulation. Alterations in Ca2+ handling by the vascular smooth muscle cells seem to underlie these disorders. Alveolar hypoxia also constricts pulmonary arteries, increasing the intracellular Ca2+ availability for smooth muscle contraction. This suggests the hypothesis that hypoxic pulmonary vasoconstriction depends on similar biochemical disorders, and that the response to the hypoxic stimulus may be emphasized in high blood pressure. 2. In 21 hypertensive and 10 normotensive men, pulmonary arterial pressure and arteriolar resistance have been evaluated during air respiration and after 15 min of breathing 17, 15 and 12% oxygen in nitrogen. Curves relating changes in pulmonary arterial pressure and arteriolar resistance to the oxygen content of inspired gas had a similar configuration in the two populations, but in hypertension were steeper and significantly shifted to the left of those in normotension, reflecting a lower threshold and an enhanced vasoconstrictor reactivity. 3. This pattern was not related to differences in severity of the hypoxic stimulus, degree of hypocapnia and respiratory alkalosis induced by hypoxia, and plasma catecholamines. 4. The association of high blood pressure with enhanced pulmonary vasoreactivity to alveolar hypoxia could have clinical implications in patients who are chronically hypoxic and have systemic hypertension.

Different Effects of Thrombin Receptor Activation on Endothelium and Smooth Muscle Cells of Human Coronary Bypass Vessels

Circulation ◽  
1997 ◽  
Vol 95 (7) ◽  
pp. 1870-1876 ◽  
Author(s):  
Zhihong Yang ◽  
Frank Ruschitzka ◽  
Ton J. Rabelink ◽  
Georg Noll ◽  
Friedgard Julmy ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Coronary Bypass ◽  
Muscle Cells ◽  
Receptor Activation ◽  
Thrombin Receptor

scholarly journals Flow shear stress enhances intracellular Ca2+ signaling in pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension

2014 ◽  
Vol 307 (4) ◽  
pp. C373-C383 ◽  
Author(s):  
Shanshan Song ◽  
Aya Yamamura ◽  
Hisao Yamamura ◽  
Ramon J. Ayon ◽  
Kimberly A. Smith ◽  
...  
Keyword(s):  
Blood Flow ◽  
Shear Stress ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Flow Shear ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Flow Shear Stress

An increase in cytosolic Ca2+ concentration ([Ca2+]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for pulmonary arterial medial hypertrophy in patients with idiopathic pulmonary arterial hypertension (IPAH). Vascular smooth muscle cells (SMC) sense the blood flow shear stress through interstitial fluid driven by pressure or direct exposure to blood flow in case of endothelial injury. Mechanical stimulus can increase [Ca2+]cyt. Here we report that flow shear stress raised [Ca2+]cyt in PASMC, while the shear stress-mediated rise in [Ca2+]cyt and the protein expression level of TRPM7 and TRPV4 channels were significantly greater in IPAH-PASMC than in normal PASMC. Blockade of TRPM7 by 2-APB or TRPV4 by Ruthenium red inhibited shear stress-induced rise in [Ca2+]cyt in normal and IPAH-PASMC, while activation of TRPM7 by bradykinin or TRPV4 by 4αPDD induced greater increase in [Ca2+]cyt in IPAH-PASMC than in normal PASMC. The bradykinin-mediated activation of TRPM7 also led to a greater increase in [Mg2+]cyt in IPAH-PASMC than in normal PASMC. Knockdown of TRPM7 and TRPV4 by siRNA significantly attenuated the shear stress-mediated [Ca2+]cyt increases in normal and IPAH-PASMC. In conclusion, upregulated mechanosensitive channels (e.g., TRPM7, TRPV4, TRPC6) contribute to the enhanced [Ca2+]cyt increase induced by shear stress in PASMC from IPAH patients. Blockade of the mechanosensitive cation channels may represent a novel therapeutic approach for relieving elevated [Ca2+]cyt in PASMC and thereby inhibiting sustained pulmonary vasoconstriction and pulmonary vascular remodeling in patients with IPAH.

Thrombin Prevents the Expression of Inducible Nitric Oxide Synthase in Vascular Smooth Muscle Cells by a Proteolytically-Activated Thrombin Receptor

1995 ◽  
Vol 74 (03) ◽  
pp. 980-986 ◽  
Author(s):  
Valérie B Schini-Kerth ◽  
Beate Fißithaler ◽  
Thomas T Andersen ◽  
John W Fenton ◽  
Paul M Vanhoutte ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Inducible Nitric Oxide Synthase ◽  
Muscle Cells ◽  
Thrombin Receptor ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

SummaryProteolytically active forms of thrombin (α- and γ-thrombin) and thrombin receptor peptides inhibited the release of nitrite, a stable endproduct of nitric oxide, evoked by interleukin-1 β(IL-1 β) in cultured vascular smooth muscle cells while proteolytically inactive forms [D-Phe-Pro-Arg chloromethyl ketone-α-thrombin (PPACK-α- thrombin) and diisopropylphosphoryl-α-thrombin (DIP-α-thrombin)] had either no or only minimal inhibitory effects. Under bioassay conditions, perfusates from columns containing IL-1 β-activated vascular smooth muscle cells or cells treated with IL-1βplus PPACK-α-thrombin relaxed detector blood vessels. These relaxations were abolished by the inhibitor of nitric oxide synthesis, NG-nitro-L arginine. No relaxations were obtained with untreated cells or IL-1 β-treated cells in the presence of α-thrombin. The expression of inducible nitric oxide synthase mRNA and protein in vascular smooth muscle cells by IL-1 β was impaired by α-thrombin. These results demonstrate that thrombin regulates the expression of the inducible nitric oxide synthase at a transcriptional level via the proteolytic activation of the thrombin receptor in vascular smooth muscle cells

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