# Vasoactivity of Rac GTPase, Cytohesin and Kinase Inhibitors in Renal Interlobar and Coronary Arteries Reveals Shared and Distinct Patterns of Inhibitory Effects in Vascular and Prostate Smooth Muscle Contraction

## TL;DR

This study explores how certain inhibitors affect blood vessel and prostate muscle contractions, revealing insights into their potential use in treating benign prostatic hyperplasia and cardiovascular disease.

## Contribution

The study identifies shared and distinct inhibitory effects of Rac GTPase, cytohesin, and kinase inhibitors on vascular and prostate smooth muscle contraction.

## Key findings

- EHT1864 and NSC23766 inhibit contractions in renal and coronary arteries, suggesting potential for treating BPH and cardiovascular disease.
- NSC23766 shows previously unrecognized α1-adrenoceptor antagonism and organ-selective effects in smooth muscle contractions.
- Some kinase inhibitors like SR7826 may cause cardiovascular effects, while others like FRAX486 and Cpd22 have no significant impact on contractions.

## 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 EC50) for α1‐adrenergic agonists, halved U46619‐induced and fully inhibited EFS‐induced contractions. Right shifts (increased EC50) for phenylephrine still occurred at 10 and 1 μM. In coronary arteries, 100 μM NSC23766 produced right shifts (increased EC50) 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%) α1‐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 α1‐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.