The ischemia induced vasospasm of the renal arterial blood vessels mediated by alpha1-adrenoceptors is of importance for the loss of kidney function. This is based on reduced perfusion of the kidney cortex occurring in kidney transplant and organ preserving surgery. The present study considered the intracellular mechanism of the norepinephrine (NE) induced renal artery vasospasm by using swine renal artery smooth muscle ring. Norepinephrine and phenylephrine (PE) induced dose-dependent and fully reversible isometric contractions with a threshold concentration of 10 nM (n = 7) and 10 nM (n = 4), and an EC50 of 0.3 microM and 1 microM, respectively. The receptor was identified as alpha1A-subtype. The contraction was completely inhibited by verapamil (IC50 = 1.51 microM; n = 11) and diltiazem (IC50 = 9.49 microM; n = 8) and 85% by nifedipine (IC50 = 0.13 microM; n = 21). Blockade of the intracellular inositol- 1,4,5-trisphosphate (IP3)-sensitive Ca2+ store by thapsigargin (1 microM, n = 7) or suppression of Ca2+ release from the intracellular Ca2+-sensitive Ca2+ store by ryanodine (100 microM, n = 4) inhibited the PE induced contraction by 39.5% and 47.6%, respectively. The results suggest a key role of voltage-dependent Ca2+ channels and intracellular Ca2+ stores in the alpha1A-adrenoceptor induced contraction of the renal artery.
rings were assessed in a standard organ bath, the rings pre-tensioned at 2 g. Contractions were evoked by applying the a 1 -adrenoceptor selective agonist phenylephrine (1 nmol/L to 0.3 mmol/L). Isometric contractions of the tissue were registered and stored digitally. Dose-response curves were obtained sequentially with a wash-out of 20 min between each concentration; the maximum contractility of an individual muscle ring was set at 100%. Dose-response curves of inhibitory agents (e.g. WB4101, cholera and pertussis toxins) were determined by comparing the remaining contractility after incubating with the respective drug with a control contraction that was evoked three times (10 m mol/L phenylephrine) and the mean set at 100%.
RESULTSPhenylephrine induced dose-dependent and fully reversible isometric contractions with a threshold concentration of 100 nmol/L and an EC 50 of 0.8 m mol/L. The receptor was identified as the a 1A -subtype by the selective antagonist WB4101. Pre-treatment of tissue rings with 5 m g/mL pertussis toxin (120 min, 37 ∞ C) inhibited the control contraction by a mean ( SEM ) of 52.0 (4.6)%, whereas pre-treatment with 1 m g/mL cholera toxin (60 min, 37 ∞ C), leading to a permanent activation of the G Sprotein via blockade of the GTPase activity, decreased the response by 39.0 (8.2)%.
CONCLUSIONThese results suggest a coupling of a 1A -adrenoceptors in renal vascular tissue to the heterotrimeric G S -protein and to heterotrimeric G-proteins of the G I -and/or G O -family in the phenylephrine-induced contraction.
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