Nitric oxide, a possible mediator of 1,4-dihydropyridine-induced photorelaxation of vascular smooth muscle.
1. In rat aortic tissues pre-contracted with phenylephrine, certain 1,4-dihydropyridines (DHPs) such as Bay K 8644 (0.1 microM), PN 202791 (1 microM), RK 30 (1 microM), NI 104 (1 microM) and NI 105 (1 microM) enhanced photoactivated relaxations (photorelaxation or PR) whereas NI 72, NI 85, NI 99, NI 102, amlodipine, felodipine, nifedipine and nimodipine were inactive. 2. The PR inducing effects of Bay K 8644 were mimicked by the diabetogenic agent, streptozotocin (STZ). 3. Solutions of Bay K 8644 which had been irradiated for various periods of time initiated light independent transient relaxations followed by contractile responses in aortic tissue partially contracted with phenylephrine. With exposure times to light of 30 to 120 min, the intensity of the relaxation response to irradiated Bay K 8644 increased from 26 +/- 3.3 to 71 +/- 3.7% of the maximum contractile response to phenylephrine (n = 5). Conversely the contractile responses decreased, from 84.2 +/- 4.1 to 19.8 +/- 10.4% of the maximum contractile response to phenylephrine (n = 5). 4. Superoxide ions, generated by incubation of xanthine (2mM) plus xanthine oxidase (10 mu ml-1) in physiological saline solution (PSS) NaCl 118, KCl 4.7, CaCl2 2.5, KH2PO4 1.2, MgSO4 1.2, NaHCO3 12.5 and glucose 11.1 (mM) for 1 h. reduced the PR induced by DHPs, STZ, and also NO-induced relaxations of rat aortic preparations. 5. Direct measurements of NO indicate that, following exposure to a polychromatic light source, equimolar concentrations (0.1 mM) of the DHP compounds that enhance PR, as well as STZ, photodegrade to release NO (25 +/- 2-40.3 +/- 5.9 nmol min-1, n = 6). 6. Structure-activity studies indicate that a nitro group at the -3 position of the dihydropyridine ring is essential for DHPs to support PR. 7. These data suggest that the photodegradation of DHPs and STZ leading to the release of NO provides the primary cellular process underlying the PR response.
Lovren
F
F
Smooth Muscle Research Group, Faculty of Medicine, University of Calgary, Alberta, Canada.
O'Neill
S K
SK
Bieger
D
D
Igbal
N
N
Knaus
E E
EE
Triggle
C R
CR
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology* / Q000528:radiation effects; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000528:radiation effects; D002120:Calcium Channel Agonists / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008027:Light; D009126:Muscle Relaxation / Q000187:drug effects* / Q000528:radiation effects*; D009129:Muscle Tonus / Q000187:drug effects / Q000528:radiation effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000528:radiation effects*; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D010777:Photochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D009569:Nitric Oxide; D013311:Streptozocin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester