Abstract
Inhibition of vasocontraction accounts for side effects in treating voiding symptoms in benign prostatic hyperplasia (BPH). We examined the vasoactivity of compounds previously showing inhibition of prostate smooth muscle contraction. Contractions of porcine renal interlobar and coronary arteries were induced by agonists or electric field stimulation (EFS). Examined compounds included inhibitors for Rac GTPases (EHT1864, NSC23766), cytohesin GEFs (SecinH3), LIMK (SR7826, LIMKi3), βARKs (CMPD101), PAK (FRAX486), and ILK (Cpd22). Agonist- and EFS-induced contractions in renal and coronary arteries were completely inhibited by 100 μM EHT1864, and nearly completely at 10 μM. In renal arteries, 100 μM NSC23766 right-shifted concentration response curves (increased EC(50)) for α(1)-adrenergic agonists, halved U46619-induced and fully inhibited EFS-induced contractions. Right shifts (increased EC(50)) for phenylephrine still occurred at 10 and 1 μM. In coronary arteries, 100 μM NSC23766 produced right shifts (increased EC(50)) for cholinergic agonists. SecinH3 (30 μM) reduced cholinergic contractions in coronary but not renal arteries. In renal arteries, SR7826, but not LIMKi3 (both 1 μM), partly inhibited (< 50%) agonist- and EFS-induced contractions. CMPD101 (50 μM) inhibited (≥ 50%) α(1)-adrenergic and U46619-induced contractions, but no endothelin-1- or EFS-induced contractions. Neither FRAX486 (30 μM), nor Cpd22 (3 μM) affected contractions. Vasorelaxation by EHT1864 and NSC23766 may exclude application in BPH but may allow simultaneous treatment of cardiovascular disease and BPH. NSC23766 shows previously unrecognized α(1)-adrenoceptor antagonism. Findings with SecinH3 suggest an organ-selective involvement of cytohesin-2/Arf6 signaling in smooth muscle contractions. SR7826 may cause cardiovascular effects, while side-effect risks limit kinase inhibitors in non-malignant disease.