title: Low-dose combination of Rho kinase and L-type Ca(2+) channel antagonists for selective inhibition of depolarization-induced sustained arterial contraction.
abstract: L-type Ca(2+) channels (LTCCs) are involved in the maintenance of tonic arterial contractions and regulate the RhoA/Rho-associated kinase (ROCK) sensitization cascade. We have tested effects of individual and combined low concentrations of LTCCs and ROCK inhibitors to produce arterial relaxation without the adverse side effects of LTCCs antagonists. We have also studied whether this pharmacological strategy alters Ca(2+)-dependent electrical properties of isolated arterial and cardiac myocytes as well as cardiac contractility. Rat basilar, human carotid and coronary arterial rings were mounted on a small-vessel myograph to measure isometric tension and cardiac contractility was measured in Langendorff-perfused rat heart. Simultaneous cytosolic Ca(2+) concentration and arterial diameter were measured in intact pressurized arteries loaded with Fura-2. Patch-clamp techniques were used to measure electrical properties in isolated cardiac and arterial myocytes. Low concentrations of LTCCs and ROCK inhibitors reduced the tonic component of moderate depolarization-evoked contraction, leaving the phasic component practically unaltered. This selective vasorelaxant effect was more marked when the LTCCs and ROCK inhibitors were applied together. In the concentration range used (nM), Ca(2+) currents in arterial myocytes, cardiac action potentials and heart contractility were unaffected by this pharmacological approach. In conclusion, low doses of LTCCs and ROCK inhibitors could be used to selectively relax precontracted arteries in pathologic conditions such as hypertension, and cerebral or coronary spasms with minor side effects on physiological contractile properties of vascular and cardiac myocytes.
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Dpto. de Fisiología Médica y Biofísica. Avenida Manuel Siurot s/n, E-41013, Seville, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Porras-González
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Dpto. de Fisiología Médica y Biofísica. Avenida Manuel Siurot s/n, E-41013, Seville, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: González-Rodríguez
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Calderón-Sánchez
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Dpto. de Fisiología Médica y Biofísica. Avenida Manuel Siurot s/n, E-41013, Seville, Spain. Electronic address: lbarneo@us.es.
authors.forename: José
authors.initials: J
authors.lastname: López-Barneo
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Dpto. de Fisiología Médica y Biofísica. Avenida Manuel Siurot s/n, E-41013, Seville, Spain. Electronic address: jurena@us.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Ureña
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000166:cytology / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D014665:Vasodilator Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D009543:Nifedipine; C049347:fasudil; D002118:Calcium
keywords: Arterial vasospasm; Depolarization; Fasudil (PubChem CID: 3547); L-type Ca(2+) channels; Nifedipine (PubChem CID: 4485); Rho-associated kinase; Verapamil (PubChem CID: 62969)