dinoprost and azepexole

In rat aorta, the presence of functional alpha(2)-adrenoceptors (alpha(2)-AR) was investigated in ring preparations preconstricted with alpha(1)-adrenergic and non- alpha(1)-adrenergic agonists. Particularly, the hypothetical interference of alpha(2)-AR agonists with alpha(1)-AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to alpha(2)-AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 x 10(-6) m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (-log EC(50)) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective alpha(2)-AR antagonist, rauwolscine (< or =1 x 10(-6) m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F(2alpha) (3 x 10(-7) m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration-contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the alpha(1D)-AR selective antagonist, BMY 7378, and rauwolscine. The pA(2) and pK(B) values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the alpha(1D)-AR. The other selective alpha(2)-AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional alpha(2)-AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the alpha(1)-AR), inhibitory and excitatory, interaction with alpha(1)-ARs.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Aorta, Thoracic; Azepines; Brimonidine Tartrate; Clonidine; Dinoprost; Dose-Response Relationship, Drug; Endothelium, Vascular; In Vitro Techniques; Male; Methoxamine; Nitric Oxide; Phenylephrine; Piperazines; Quinoxalines; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Serotonin; Vasoconstrictor Agents; Vasodilation; Yohimbine

1. The effect of noradrenaline (NA) on the vascular smooth muscle and endothelial cells in isolated ring segments from the proximal and distal part of the left coronary artery (LCA) in rats was examined. 2. NA had a weak concentration-dependent contractile effect on proximal but relaxed distal segments of the LCA. The maximal NA-induced contraction of the proximal segments was doubled while the relaxation of the distal LCA segments was converted to a contraction after blockade of beta-adrenoceptors with propranolol 3 x 10(-6) M, thus indicating the presence of both alpha- and beta-adrenoceptors in the arteries, with dominance of alpha-adrenoceptors and of beta-adrenoceptors in the proximal and distal segments of the LCA, respectively. 3. The contractile effect of NA (beta-adrenoceptors blocked) was doubled in the proximal LCA segments after the endothelium was removed. Endothelial denudation had, in contrast, no potentiating effect on the contractile response of the distal arteries to NA. Both proximal and distal segments became more sensitive to the contractile action of NA after removal of the endothelium. 4. The spontaneous myogenic tone increased in both proximal and distal LCAs after endothelial removal, indicating spontaneous release of a relaxing endothelial factor in the vessels. 5. Following contraction with prostaglandin F2 alpha (PGF2 alpha), and in the presence of propranolol, 3 x 10(-6) M, and prazosin, 10(-6) M, NA induced an endothelium-dependent relaxation of only proximal but not distal segments of the precontracted LCA. The NA-induced relaxation of the proximal segments of the LCA was not altered by indomethacin 10- M but was completely abolished after incubation with methylene blue, 3 x 10-6 M, or following endothelium removal. These results are compatible with NA-induced release of EDRF in these arteries. 6. The selective alpha 2-adrenoceptor agonist, B-HT 933, only induced a weak relaxation of PGF2 alpha,-precontracted proximal (endothelium intact) LCA segments at a concentration of 10-4M. The NA-induced relaxation of these vessels was unaffected by incubating the vessels with 10- IM B-HT 933. The NA relaxation response curve was shifted ca 1.1 log unit to the right by rauwolscine, 1o- 6M, giving an estimated pA2-value of 7.12. The receptor through which NA activates the endothelium appears to be of an atypical alpha 2-subtype.

Topics: Acetylcholine; Adrenergic alpha-Agonists; Animals; Arteries; Azepines; Coronary Vessels; Dinoprost; Endothelium, Vascular; In Vitro Techniques; Indomethacin; Muscle Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Nitric Oxide; Norepinephrine; Prazosin; Propranolol; Rats

The influence of nisoldipine, a calcium entry antagonist, on vascular resistance and vasoconstrictor responses was investigated in the anesthetized cat. Nisoldipine, a dihydropyridine calcium entry blocking agent, decreased total peripheral resistance and dilated the intestinal vascular bed. This calcium antagonist blocked intestinal vasoconstrictor responses to BAY K 8644, a nifedipine analogue, which promotes calcium entry. The calcium entry antagonist decreased intestinal vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine, and tyramine. Nisoldipine also reduced intestinal vasoconstrictor responses to potassium chloride and agonists that elicit vasoconstriction by specific receptor-mediated actions including stimulation of alpha 1- and alpha 2-adrenoceptors. The vasodilator and inhibitory effects of nisoldipine on vasoconstrictor responses were reversible, and responses returned to control value over a 60-min period. The present data suggest that an extracellular source of calcium is required for maintenance of tone and for vasoconstriction induced by neuronally released or exogenous norepinephrine as well as a diverse group of agents that act through specific receptor mechanisms or depolarize vascular smooth muscle. The present results suggest that similar sources of calcium are required for vasoconstriction elicited by alpha 1- and alpha 2-adrenoceptor agonists in the feline intestinal vascular bed.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Angiotensin II; Animals; Azepines; Blood Pressure; Brimonidine Tartrate; Cardiac Output; Cats; Dinoprost; Dioxanes; Electric Stimulation; Female; Idazoxan; Male; Methoxamine; Nifedipine; Nisoldipine; Norepinephrine; Phenylephrine; Prostaglandin Endoperoxides, Synthetic; Prostaglandins F; Quinoxalines; Splanchnic Circulation; Sulfonamides; Sympathetic Nervous System; Tyramine; Vascular Resistance; Vasoconstriction

Alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction was studied in the in situ, autoperfused pulmonary circulation of the open-chest anesthetized dog under conditions of normal and elevated pulmonary vascular tone. Under conditions of normal pulmonary vascular tone (10 +/- 1 mm Hg), methoxamine, a selective alpha-1 adrenoceptor agonist, and B-HT 933, a selective alpha-2 adrenoceptor agonist, elicited maximal increases in lobar perfusion pressure of 5 and 2 mm Hg above resting pulmonary tone, respectively. When pulmonary vascular tone was elevated progressively with the thromboxane mimetic, U-46619, serotonin or PGF2 alpha, alpha-1 adrenoceptor-mediated pulmonary vasoconstrictor responses to methoxamine were unaffected, whereas alpha-2 adrenoceptor-mediated pulmonary pressor responses to B-HT 933 were enhanced. Overall the response to B-HT 933 was enhanced 4-fold when pulmonary perfusion pressure was elevated to 19.8 +/- 0.8 mm Hg with U-46619 and almost 5-fold when elevated to 27.0 +/- 1.2 mm Hg. Pulmonary vasoconstrictor responses to angiotensin II were unaffected by elevated pulmonary vascular tone. Enhanced responsiveness of B-HT 933 to elevated pulmonary vascular tone was antagonized by the selective alpha-2 adrenoceptor antagonist, rauwolscine (100 micrograms/kg i.v.), and unaffected by the selective alpha-1 adrenoceptor antagonist, prazosin (100 micrograms/kg i.v.). When canine intralobar pulmonary veins were studied in vitro they contracted to B-HT 933 whereas intralobar pulmonary arteries did not respond. These data indicate that alpha-2 adrenoceptor responsiveness is enhanced markedly and selectively under conditions in which pulmonary vascular tone is elevated.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Azepines; Blood Pressure; Dinoprost; Dogs; Female; Lung; Male; Methoxamine; Prazosin; Prostaglandin Endoperoxides, Synthetic; Prostaglandins F; Receptors, Adrenergic, alpha; Serotonin; Vasoconstriction; Yohimbine