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Defining the roles of arrestin2 and arrestin3 in vasoconstrictor receptor desensitization in hypertension.

Willets JM, Nash CA, Rainbow RD, Nelson CP, Challiss RA - Am. J. Physiol., Cell Physiol. (2015)

Bottom Line: Desensitization of UTP-stimulated vessel contractions was increased in 12-wk-old (but not 6-wk-old) SHR animals.In conclusion, arrestin2 and 3 expression is elevated in resistance arteries during the emergence of the early hypertensive phenotype, which underlies an enhanced ability to desensitize vasoconstrictor signaling and vessel contraction.Such regulatory changes may act to compensate for increased vasoconstrictor-induced vessel contraction.

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Affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom; and jmw23@leicester.ac.uk.

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Profiling desensitization of UTP-mediated contractile responses in mesenteric arteries from pre- and posthypertensive SHR and normotensive WKY rats. Mesenteric arteries were subjected to the following desensitization protocol: 100 or 200 μM UTP (R1, for 5 min) challenge, followed by 5 min washout, prior to maximal UTP (300 or 500 μM, Rmax, 5 min) challenge, followed by a wash period of 5 min before further 100 or 200 μM UTP (R2, 5 min) exposure, for SHR or WKY vessels, respectively. Representative myograph traces are shown for arteries isolated from 6-wk-old WKY (A) and SHR (B) animals, or 12-wk-old WKY (C) or SHR (D) animals contracted with UTP. Desensitization of vessel contraction was determined as the relative change in R2 response compared with R1. Cumulative data (E) are expressed as means ± SE for the % change in R2 relative to R1; n = 7–9 vessels from ≥6 separate animals. Statistical significance is indicated as *P < 0.05 vs. WKY (unpaired t-test).
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Figure 4: Profiling desensitization of UTP-mediated contractile responses in mesenteric arteries from pre- and posthypertensive SHR and normotensive WKY rats. Mesenteric arteries were subjected to the following desensitization protocol: 100 or 200 μM UTP (R1, for 5 min) challenge, followed by 5 min washout, prior to maximal UTP (300 or 500 μM, Rmax, 5 min) challenge, followed by a wash period of 5 min before further 100 or 200 μM UTP (R2, 5 min) exposure, for SHR or WKY vessels, respectively. Representative myograph traces are shown for arteries isolated from 6-wk-old WKY (A) and SHR (B) animals, or 12-wk-old WKY (C) or SHR (D) animals contracted with UTP. Desensitization of vessel contraction was determined as the relative change in R2 response compared with R1. Cumulative data (E) are expressed as means ± SE for the % change in R2 relative to R1; n = 7–9 vessels from ≥6 separate animals. Statistical significance is indicated as *P < 0.05 vs. WKY (unpaired t-test).

Mentions: The ability of repeated UTP additions to diminish subsequent vessel contractions was compared in SHR- versus WKY-derived mesenteric arteries as an index of intact vessel “desensitization.” Artery rings were challenged with an approximate EC50 concentration of UTP, for 5 min before (R1) and after (R2) addition of a maximal UTP concentration for 5 min (Rmax). Arteries were washed for 5 min between R1 and Rmax, and Rmax and R2 agonist challenges. The R2/R1 ratio is interpreted as an index of receptor desensitization (21, 22). Since the relative potency of UTP was different between rat strains, we applied an EC50 (R1 and R2) concentration of either 100 μM or 200 μM, and Rmax concentration of 300 μM or 500 μM UTP for SHR and WKY vessels, respectively. In all cases, R2 responses were reduced compared with R1 after stimulation with a maximal agonist concentration (Fig. 4, A–D) and the reductions in R2/R1 ratio seen with WKY vessels (at both ages) were similar to that previously observed in vessels obtained from male adult Wistar animals (21). R2/R1 ratios were similar in vessels from 6-wk-old SHR and WKY rats (Fig. 4, A, B, and E); however, in vessels from 12-wk-old SHR the R2 response was further suppressed compared with age-matched WKY (decrease in R2 relative to R1: 64.3 ± 5.9% for SHR compared with 32.3 ± 11.3% for WKY; P < 0.05), indicating a significantly greater desensitization of UTP-stimulated SHR vessel contractions (Fig. 4E).


Defining the roles of arrestin2 and arrestin3 in vasoconstrictor receptor desensitization in hypertension.

Willets JM, Nash CA, Rainbow RD, Nelson CP, Challiss RA - Am. J. Physiol., Cell Physiol. (2015)

Profiling desensitization of UTP-mediated contractile responses in mesenteric arteries from pre- and posthypertensive SHR and normotensive WKY rats. Mesenteric arteries were subjected to the following desensitization protocol: 100 or 200 μM UTP (R1, for 5 min) challenge, followed by 5 min washout, prior to maximal UTP (300 or 500 μM, Rmax, 5 min) challenge, followed by a wash period of 5 min before further 100 or 200 μM UTP (R2, 5 min) exposure, for SHR or WKY vessels, respectively. Representative myograph traces are shown for arteries isolated from 6-wk-old WKY (A) and SHR (B) animals, or 12-wk-old WKY (C) or SHR (D) animals contracted with UTP. Desensitization of vessel contraction was determined as the relative change in R2 response compared with R1. Cumulative data (E) are expressed as means ± SE for the % change in R2 relative to R1; n = 7–9 vessels from ≥6 separate animals. Statistical significance is indicated as *P < 0.05 vs. WKY (unpaired t-test).
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Figure 4: Profiling desensitization of UTP-mediated contractile responses in mesenteric arteries from pre- and posthypertensive SHR and normotensive WKY rats. Mesenteric arteries were subjected to the following desensitization protocol: 100 or 200 μM UTP (R1, for 5 min) challenge, followed by 5 min washout, prior to maximal UTP (300 or 500 μM, Rmax, 5 min) challenge, followed by a wash period of 5 min before further 100 or 200 μM UTP (R2, 5 min) exposure, for SHR or WKY vessels, respectively. Representative myograph traces are shown for arteries isolated from 6-wk-old WKY (A) and SHR (B) animals, or 12-wk-old WKY (C) or SHR (D) animals contracted with UTP. Desensitization of vessel contraction was determined as the relative change in R2 response compared with R1. Cumulative data (E) are expressed as means ± SE for the % change in R2 relative to R1; n = 7–9 vessels from ≥6 separate animals. Statistical significance is indicated as *P < 0.05 vs. WKY (unpaired t-test).
Mentions: The ability of repeated UTP additions to diminish subsequent vessel contractions was compared in SHR- versus WKY-derived mesenteric arteries as an index of intact vessel “desensitization.” Artery rings were challenged with an approximate EC50 concentration of UTP, for 5 min before (R1) and after (R2) addition of a maximal UTP concentration for 5 min (Rmax). Arteries were washed for 5 min between R1 and Rmax, and Rmax and R2 agonist challenges. The R2/R1 ratio is interpreted as an index of receptor desensitization (21, 22). Since the relative potency of UTP was different between rat strains, we applied an EC50 (R1 and R2) concentration of either 100 μM or 200 μM, and Rmax concentration of 300 μM or 500 μM UTP for SHR and WKY vessels, respectively. In all cases, R2 responses were reduced compared with R1 after stimulation with a maximal agonist concentration (Fig. 4, A–D) and the reductions in R2/R1 ratio seen with WKY vessels (at both ages) were similar to that previously observed in vessels obtained from male adult Wistar animals (21). R2/R1 ratios were similar in vessels from 6-wk-old SHR and WKY rats (Fig. 4, A, B, and E); however, in vessels from 12-wk-old SHR the R2 response was further suppressed compared with age-matched WKY (decrease in R2 relative to R1: 64.3 ± 5.9% for SHR compared with 32.3 ± 11.3% for WKY; P < 0.05), indicating a significantly greater desensitization of UTP-stimulated SHR vessel contractions (Fig. 4E).

Bottom Line: Desensitization of UTP-stimulated vessel contractions was increased in 12-wk-old (but not 6-wk-old) SHR animals.In conclusion, arrestin2 and 3 expression is elevated in resistance arteries during the emergence of the early hypertensive phenotype, which underlies an enhanced ability to desensitize vasoconstrictor signaling and vessel contraction.Such regulatory changes may act to compensate for increased vasoconstrictor-induced vessel contraction.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom; and jmw23@leicester.ac.uk.

Show MeSH
Related in: MedlinePlus