Korean J Physiol Pharmacol.  2023 Jul;27(4):325-331. 10.4196/kjpp.2023.27.4.325.

Involvement of α1B -adrenoceptors and Rho kinase in contractions of rat aorta and mouse spleen

• Alsufyani HA
• Docherty JR

• KMID: 2544134
• DOI: http://doi.org/10.4196/kjpp.2023.27.4.325

Abstract

α 1 -adrenoceptors link via the G-protein Gq/G₁₁ to both Ca²⁺ entry and release from stores, but may also activate Rho kinase, which causes calcium sensitization. This study aimed to identify the subtype(s) of α₁ -adrenoceptor involved in Rho kinase-mediated responses in both rat aorta and mouse spleen, tissues in which contractions involve multiple subtypes of α₁ -adrenoceptor. Tissues were contracted with cumulative concentrations of noradrenaline (NA) in 0.5 log unit increments, before and in the presence of an antagonist or vehicle. Contractions produced by NA in rat aorta are entirely α₁ -adrenoceptor mediated as they are competitively blocked by prazosin. The α_1A -adrenoceptor antagonist RS100329 had low potency in rat aorta. The α_1D -adrenoceptor antagonist BMY7378 antagonized contractions in rat aorta in a biphasic manner: low concentrations blocking α_1D -adrenoceptors and high concentrations blocking α_1B -adrenoceptors. The Rho kinase inhibitor fasudil (10 µM) significantly reduced aortic contractions in terms of maximum response, suggesting inhibition of α_1B -adrenoceptor mediated responses. In the mouse spleen, a tissue in which all 3 subtypes of α₁ -adrenoceptor are involved in contractions to NA, fasudil (3 µM) significantly reduced both early and late components to the NA contraction, the early component involving α_1B - and α_1D -adrenoceptors, and the late component involving α_1B - and α_1A -adrenoceptors. This suggests that fasudil inhibits α_1B -adrenoceptor mediated responses. It is concluded that α_1D - and α_1B -adrenoceptors interact in rat aorta and α_1D -, α_1A - and α_1B -adrenoceptors interact in the mouse spleen to produce contractions and these interactions suggest that one of the receptors preferentially activates Rho kinase, most likely the α_1B -adrenoceptor.

Keyword

α_1B-adrenoceptors; α_1D-adrenoceptors; BMY7378; Fasudil; Rho kinase

Figure

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  Fig. 1 Concentration-response curves to noradrenaline (NA) obtained in rat aorta in the presence of vehicle, the relatively non-selective antagonist prazosin (3 × 10–9 M), the α1D-adrenoceptor antagonist BMY7378 (10–8 M) and the α1A-adrenoceptor antagonist RS100329 (10–7 M). Values are mean ± SEM from 4–7 experiments. For NA potency (pEC50) and antagonist potency (pKB) see Tables 1 and 2.

• 

  Fig. 2 Concentration-response curves to noradrenaline (NA) obtained in rat aorta in the presence of vehicle and a range of concentrations of the α1D-adrenoceptor antagonist BMY7378: 10–8 M, 3 × 10–8 M, 10–7 M, 3 × 10–7 M, 10–6 M, 10–5 M. Values are mean ± SEM from 4–7 experiments. For NA potency (pEC50) and antagonist potency (pKB) see Tables 1 and 2.

• 

  Fig. 3 Schild plots obtained for the α1D-adrenoceptor antagonist BMY7378 against contractions to noradrenaline (NA) in rat aorta. The pA2 value is the concentration of antagonist at y = 0 (utilising all data points, both black and red; text in black). A second apparent pA2 value is shown for the concentration of BMY7378 at y = 0.75 (utilising only red data points; text in red).

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  Fig. 4 Concentration-response curves to noradrenaline (NA) obtained in rat aorta in the presence of vehicle and the Rho kinase inhibitor fasudil (3 × 10–6 M and 10–5 M). Values are mean ± SEM from 5 experiments. For NA potency calculations, see Table 1.

• 

  Fig. 5 Concentration-response curves to noradrenaline (NA) obtained in mouse spleen in the presence of vehicle and the Rho kinase inhibitor fasudil (3 × 10–6 M). Values are mean ± SEM from 4–6 experiments. For NA potency calculations, see Results.

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