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. 2024 Feb 21;14(3):257.
doi: 10.3390/biom14030257.

Contractions Induced in Human Pulmonary Arteries by a H2S Donor, GYY 4137, Are Inhibited by Low-Frequency (20 kHz) Ultrasound

Agilė Tunaitytė  1   2 , Silvijus Abramavičius  1   2 , Augusta Volkevičiūtė  1   2 , Mantas Venslauskas  3 , Algimantas Bubulis  3 , Vytis Bajoriūnas  1 , Ulf Simonsen  4 , Vytautas Ostaševičius  3 , Vytautas Jūrėnas  3 , Kasparas Briedis  5 , Edgaras Stankevičius  1   2
Affiliations

Contractions Induced in Human Pulmonary Arteries by a H2S Donor, GYY 4137, Are Inhibited by Low-Frequency (20 kHz) Ultrasound

Agilė Tunaitytė et al. Biomolecules. .

Abstract

The present study aimed to investigate the effect of a H2S donor, GYY 4137, on human pulmonary arteries and whether low-frequency ultrasound (20 kHz, 4 W/cm2) inhibits GYY 4137 contractions. Functional studies were conducted on human and rat pulmonary arteries mounted on microvascular myographs. We placed an ultrasonic gadget in the tissue organ bath to insonate the arteries with low-frequency ultrasound. To measure the effect of the low-frequency ultrasound on the entrance of extracellular Ca2+, the preparations were placed in a Ca2+-free solution, and the thromboxane agonist, U46619, and extracellular calcium were added in the presence of insonation. In isolated human pulmonary arteries, GYY 4137 induced contractions, which were most pronounced in the arteries contracted with the thromboxane analogue, U46619. The transient GYY4137 contractions were reversed by low-frequency ultrasound, a blocker of KV7 channels, XE-991 (10 µM), and glibenclamide (1 μM), a blocker of ATP-sensitive channels. Low-frequency ultrasound also inhibited the contractions induced by the smooth muscle entrance of increasing extracellular calcium concentrations. The present findings show that GYY 4137 can cause a transient contraction of pulmonary arteries in human arteries. GYY 4137 alone does not cause significant vascular contraction in rat lung arteries, but it contracts rat lung arteries precontracted with U46619. The transient contractions induced by GYY 4137 can be inhibited by low-frequency ultrasound, probably by counteracting the influx of external Ca2+. The effect of low-frequency ultrasound counteracts contraction in pulmonary arteries; therefore, a possibility could be to develop a larger device allowing treatment of patients with pulmonary hypertension.

Keywords: human pulmonary arteries; insonation; low-frequency (20 kHz) ultrasound; pulmonary hypertension.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure A1
Figure A1
GYY 4137 induced vascular contraction interacting with increasing concentrations of tadalafil insonation (UTGYY) vs. control (TGYY). Two-way (class factors: groups and concentration) analysis of variance (ANOVA): F (10) = [2.96, 5.37], p = [0.1161, 0.0260], n = 6 per group. The graphs represent the vascular response to increasing concentrations of tadalafil in vessels contracted with GYY 4137 (1 × 10−4 M). These concentrations are used for exploratory purposes and are above therapeutic concentrations. Data are represented as mean and S.E.M.
Figure A2
Figure A2
GYY 4137 induced vascular contraction interacting with increasing concentrations of ambrisentan insonation (UAGYY) vs. control (AGYY). Two-way (class factors: groups and concentration) analysis of variance (ANOVA): F (10) = [1.25, 11.39], p = [0.2904, 0.0026], n = 6 per group. The graphs represent the vascular response to increasing concentrations of ambrisentan in vessels contracted with GYY 4137 (1 × 10−4 M). Data are represented as mean and S.E.M.
Figure 1
Figure 1
(A)—Average contraction induced by 10−4 M GYY 4137 in human pulmonary arteries. The data are mean ± standard error of the mean (S.E.M.), n = 3. (B)—Concentration–response curve for GYY 4137 in rat lung arteries. Data points are means ± S.E.M. of 5 preparations.
Figure 2
Figure 2
Baseline contractions (A–D), n = 3 (for each graph): (A). Ultrasound (US) does not significantly change the function of normalized pulmonary arteries. (B). After GYY 4137 precontraction, additional insonation causes no discernable effect. (C). XE-991 does not cause vascular contraction in resting pulmonary arteries. (D). XE-991 and US do not cause vascular contraction in normalized pulmonary arteries. (E). Adding GYY 4137 to rat lung U46619-contracted rat arteries (n = 7) elicits a biphasic response. Mean 45.8 (SD 55.5) at t0 (which lasts for about 1 min after adding GYY 4137) and a relaxation −70.0 % (SD 23.4) from t1 to later time points.
Figure 3
Figure 3
Concentration–response curve for GYY4137 in the absence (control) or in the presence of insonation (GYY + insonation). Two-way (class factors: groups and concentration) analysis of variance (ANOVA): F (8) = [3.22, 10.86], p = [0.1106, 0.0052], n = 5 per group. The graphs represent the vascular response to increasing concentrations of GYY4137. Data are represented as mean ± S.E.M.
Figure 4
Figure 4
Average contractions induced by GYY 4137 in the absence and the presence of the potassium channel blockers, glibenclamide and XE991. (A)—Average GYY 4137 contraction in the absence (GYY) and the presence of a blocker of ATP-sensitive potassium channels, glibenclamide (GLGYY) and glibenclamide plus low-frequency ultrasound (USGLGYY) compared with each other with two-way (class factors: groups and concentration) analysis of variance (ANOVA): F (12) = [5.25, 7.77], p = [0.0231, 0.0069], n = 5 per group. (B)—GYY 4137 induced vascular contraction in the absence (GYY) and the presence of a blocker of KV7 channels, XE-991 incubation (XGYY) and XE991 plus low-frequency ultrasound (USXGYY), compared with each other with two-way (class factors: groups and concentration) analysis of variance (ANOVA): F (12) = [3.73, 21.93], p = [0.0550, <0.0001], n = 5 per group. The graphs represent the vascular response to increasing concentrations of GYY4137. Data are represented as mean ± S.E.M.
Figure 5
Figure 5
(A)—U46619 and CaCl2 induced vascular contraction in the absence (U46C) or in the presence of insonation (USU46C). Two-way (class factors: groups and concentration) analysis of variance (ANOVA): F (8) = [5.66, 21.64], p = [0.0489, 0.0006], n = 5 per group. The graphs represent the average vascular responses to increasing concentrations of extracellular CaCl2. Data are represented as mean and S.E.M. (B)—Proposed mechanism of GYY 4137 vascular contraction and insonation.
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