Mechanisms of hydralazine induced vasodilation in rabbit aorta and pulmonary artery.
1. The directly acting vasodilator hydralazine has been proposed to act at an intracellular site in vascular smooth muscle to inhibit Ca(2+) release. 2. This study investigated the mechanism of action of hydralazine on rabbit aorta and pulmonary artery by comparing its effects on the tension generated by intact and beta-escin permeabilized vessels and on the cytoplasmic Ca(2+) concentration, membrane potential and K(+) currents of isolated vascular smooth muscle cells. 3. Hydralazine relaxed pulmonary artery and aorta with similar potency. It was equally effective at inhibiting phasic and tonic contractions evoked by phenylephrine in intact vessels and contractions evoked by inositol 1,4,5 trisphosphate (IP(3)) in permeabilized vessels. 4. Hydralazine inhibited the contraction of permeabilized vessels and the increase in smooth muscle cell Ca(2+) concentration evoked by caffeine with similar concentration dependence, but with lower potency than its effect on IP(3) contractions. 5. Hydralazine had no effect on the relationship between Ca(2+) concentration and force generation in permeabilized vessels, but it slowed the rate at which maximal force was developed before, but not after, destroying sarcoplasmic reticulum function with the calcium ionophore, ionomycin. 6. Hydralazine had no effect on membrane potential or the amplitudes of K(+) currents recorded from isolated smooth muscle cells over the concentration range causing relaxation of intact vessels. 7. The results suggest that the main action of hydralazine is to inhibit the IP(3)-induced release of Ca(2+) from the sarcoplasmic reticulum in vascular smooth muscle cells.
Ellershaw
D C
DC
Department of Pharmacology, UMDS, St Thomas's Hospital, Lambeth Palace Road, London, SE1 7EH.
Gurney
A M
AM
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006830:Hydralazine / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D006830:Hydralazine; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium