Cyclic Amp and Smooth Muscle Function*

The vascular relaxant effects of histamine, adenosine, isoprenaline nitroglycerine, papaverine and 3‐isobutyl‐1‐methylxanthine (IBMX) were assessed individually, in strips of rabbit renal artery moderately contracted with noradrenaline (NA) in the absence or presence of phosphodiesterase inhibitors (papaverine and IBMX) or verapamil, a Ca2+ antagonist. The vasodilator effect of histamine was potentiated by papaverine (6.1 × 10−7 m) and IBMX (4.4 × 10−5 m) but inhibited dose‐dependently by verapamil (5.1 and 51.0 × 10−7 m). Adenosine‐induced vascular relaxations were greatly increased in the presence of papaverine (6.1 × 10−7 m) but significantly reduced in the presence of IBMX (4.4 × 10−5 m) or verapamil (5.1 and 51.0 × 10−7 m). The vasodilatation produced by isoprenaline was increased in the presence of IBMX (4.4 × 10−5 m) or papaverine (6.1 × 10−7 m), but inhibited by verapamil (5.1 and 51.0 × 10−7 m). The vascular relaxant effects of nitroglycerine and papaverine were inhibited in the presence of IBMX (4.4 × −5 m) or verapamil (5.1 and 51.0 × 10−7 m). Papaverine (6.1 × 10−7 m) also antagonized nitroglycerine‐induced vascular relaxation. The vasodilator effect of IBMX was greatly reduced in the presence of papaverine (6.1 × 10−7 m) or verapamil (5.1 and 51.0 × 10−7 m). The vascular relaxant effect of verapamil was reduced proportionally by raising the extracellular Ca2+ concentration from 1.25 to 5.0 mm while those elicited by histamine, adenosine, isoprenaline, nitroglycerine, papaverine and IBMX were not modified by this procedure. These results were taken as an indication that several vasodilators (e.g. histamine, adenosine, isoprenaline, nitroglycerine, papaverine and IBMX), but not a Ca2+ antagonist such as verapamil, produce a fraction of their vasodilator effects by promoting Ca2+ extrusion from and/or Ca2+ sequestration into the vascular smooth muscle cells, via a cyclic adenosine 3′,5′‐monophosphate‐dependent mechanism.

Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Studies on the Mechanism of Action of Various Vasodilators

Gagnon

Regoli

Rioux

1980

“…The potentiation of glucagon by Indo, a well known inhibitor of prostaglandin synthesis (Vane, 1971) may also be explained by the ability of this drug to inhibit phosphodiesterases (Flores & Sharp, 1972;Newcombe, Thanassi & Ciosek Jr., 1974). Since phosphodiesterase inhibitors are known to favour the intracellular accumulation of cyclic AMP in various organs including vascular tissues (Triner et al, 1971;Andersson, 1972) by blocking the enzymatic conversion of cyclic AMP to 5'-AMP, they may also potentiate the vascular relaxant effect of glucagon by such a mechanism. If this interpretation is correct, we would expect the vasodilator effect of exogenous cyclic AMP to be affected in a similar way to glucagon by these drugs.…”

Section: Discussionmentioning

confidence: 99%

Studies on the Mechanism of Action of Glucagon in Strips of Rabbit Renal Artery

Gagnon

Regoli

Rioux

1980

The vasodilator effects of glucagon and adenosine cyclic 3′,5′‐monophosphate (cyclic AMP) were evaluated in strips of rabbit renal artery contracted with noradrenaline (NA) in the absence and presence of phosphodiesterase inhibitors or calcium (Ca2+) antagonists. The vascular relaxant effect of glucagon was markedly potentiated by various concentrations of four different phosphodiesterase inhibitors (papaverine, theophylline, 3‐isobutyl‐1‐methylxanthine (IBMX) and indomethacin), while that of cyclic AMP was potentiated by only two of them (papaverine and indomethacin) and inhibited by the others (theophylline and IBMX). Amongst the four phosphodiesterase inhibitors, IBMX (10 μg/ml) was found to produce the largest potentiation (e.g. the sensitivity increased by a factor of 10) of glucagon‐induced vascular relaxations (ED50 of glucagon in the presence of IBMX = 9.2 ± 1.0 ng/ml). Ca2+ antagonists such as verapamil and SKF 525A produced a dose‐dependent inhibition of the vasodilator action of glucagon. Verapamil (2.5 μg/ml) also antagonized cyclic AMP‐induced vascular relaxations. The vasodilator effect of verapamil was inhibited dose‐dependently by raising the concentration of extracellular Ca2+ from 0.05 to 0.2 g/l (or 1.25 to 5.0 mm) while those elicited by glucagon or cyclic AMP were not influenced, thus suggesting that the latter two drugs do not interfere with Ca2+ influx. Disodium edetate (Na2EDTA, 210 to 840 μg/l) produced a dose‐dependent vasodilator effect which was attributed to the facilitation of Ca2+ extrusion from the smooth muscle cells and/or Ca2+ binding to the cell membrane. The relaxation produced by Na2EDTA was significantly blocked by verapamil (10 μg/ml) or SKF 525A (10 μg/ml). The results were taken as an indication that glucagon produces at least a fraction of its vasodilator effect by promoting Ca2+ extrusion from the vascular smooth muscle cells and/or Ca2+ binding to or sequestration into intracellular sites, presumably via a cyclic AMP‐dependent mechanism.

“…An age-related decrease in adenosine-induced relaxations has also been observed in isolated aortae from 30 to 360 days old rabbits . Adenosine 3', 5'-cyclic monophosphate (cyclic AMP) has been proposed as a mediator for the relexation ofvascular smooth muscle elicited by isoprenaline (Triner et al, 1971;Volicer & Hynie, 1971;Andersson, 1973), adenosine (Kukovetz et al, 1978) and PGI2 (Kukovetz et al, 1979). …”

Section: Discussionmentioning

confidence: 99%

Alterations with age of the response to vasodilator agents in isolated mesenteric arteries of the beagle

Shimizu

Toda

1986

1 Responses to vasodilator agents were compared in helical strips ofmesenteric arteries from beagles of different ages (30 days, 3 months, 2 years and 12 years old), precontracted with prostaglandin F2% (PGFu). Relaxations induced by isoprenaline and adenosine were related inversely to age, whereas those induced by PGI2 and K+ (5 mM) did not alter with age. 2 Acetylcholine-induced relaxations were less in the arteries from the aged (12 year old) beagles than in those from the younger beagles. Histamine-induced relaxations related directly to age between 30 days and 2 years. Acetylcholine-induced relaxation was reversed to a contraction in infant (30 day old) beagle arteries by removal of the endothelium, and significantly attenuted in the older beagle arteries. In adult (2 year old) and aged beagle arteries, removal of the endothelium attenuated the histamineinduced relaxation. Treatment with indomethacin reversed the histamine-induced relaxation to a marked contraction in aged beagle arteries.3 It may be concluded that responses mediated by B-adrenoceptors and PI-purinoceptors are less in aged mesenteric arteries than in those from the younger beagles, whereas responses mediated by PGI2 receptors and the electrogenic Na+ pump do not alter with age. The release of endothelium-derived relaxing factor(s) by acetylcholine appears to be inversely related to age. However, the release of PGI2 possibly caused by histamine may be less in infant beagle mesenteric arteries than in those from the older beagles.