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Alpha2-adrenoceptors and endothelium dependent relaxation in canine large arteries
j Mol Cell Cardiol 18 (Supplement 1) (1986)
291
PROSTAGLANDIN BIOSYNTHESIS AND CAP~IAC BETA-ADRENOCE~TORS. S. VaJpoyee, U. H. Shah, M. P. Patel t G. M. Panchal and S. M, Mansu~i. Department of Pharmacology, B. J. Medical College, Ahmedabad 380 016 Gujarat, India. P~ostaglandims
(PGs) axe known t o influence ~he ~egulation of cardiovascular
function. Es~rlier we have reported modification of hypotensive action of some commonly used antihypertensive drugs by a PG synthesis inhibitor. Now we have investigated the effect of indomethacin pretrea~ment on the response of heart rate %0 propranolol in urethane (1.5 g/kg i.p.) anaesthetized rats. Electrocardiogram lead II was recorded on a Polyrite recorder and heart rate was counted. The heart rate in control group (n=7) was reduced by propranolol (5 mg/kg i.v.) from 292.85 + 8.66/sin to 225.71 + 12.71/sin after 15 sin of its administration. Recovery was slow but complete at 210 min. The reduction in heart rate in second group (n=6), which was pretreated with indomethacin (20 mg/kg i.p.), was much less i.e. from 511.66 + 13.57/sin to 286.66 + 16.93/min at 15 sin. The rocovery was also quicker as it was complete at 120 min~ These findings show that indomethacin also attenuates the bradycardiogenic action of propranolol like its blood pressure lowering response and it seems possible that the endogenous PGs probably modulate the interaction between propranolol and the oardiac beta-adrenoceptors.
292
REACTIVITY OF CANINE CAROTID AETERY IN VITRO 4 WEEKS AZ~ER DE-ENDOTHELIALIZAT!0N. K. Satoh, J.A. Angus, G.R. Campbell, T.M. Cocks. Baker Medical Research Institute, Prahran Victoria 3181, Australia. Acute removal of endothelium from large arteries such as the coronary in vitro abolishes relaxation responses to acetylcholine but enhances the constrictor response to serotonin and noradrenaline (Cocks & Angus, 1983). Here we tested whether the responses to a range of dilator and constrictor stimuli would be altered after endothelium had returned to the luminal surface of the dog carotid artery studied in vitro 4 weeks after unilateral carotid balloon catheterization. Morphological studies showed that prior intimal damage had caused concentric or eccentric intimal smooth muscle thickening (2-20 cells thick) but most (95%) rings were covered by regenerated endothelial cells. The sensitivity (from EDso values) was increased 3-5 fold in the test arteries compared with control vessels to noradrenaline, serotonin, thromboxane mimetic, U46619 and K +. Relaxation responses to endothelium dependent (EDRF release) vasodilators acetylcholine and EDRF independent agents adenosine an d nitroglycerin were unaffected in magnitude or sensitivity by the intimal thickening. We conclude that sensitivity in arteries to a range of vasoconstrictors is enhanced to a small degree with intim~l thickening but the EDRF dependent relaxation responses are normal despite this altered intimal layer. Cocks T.M., Angus J.A. : Nature 305:627-630, 1983.
2 9 3 A L P H A 2 - ADRENOCEPTORS AND ENDOTHELIUM DEPENDENT R E ~ T I O N IN CANINE LARGE ARTERIES. K. Satoh, J.A. Angus, T.M. Cocks. Baker Medical Research Institute, Prahran Victoria 3181, Australia. Alpha2-adrenoceptor agonists cause the release of endothelium derived relaxing factor (EDRF) in canine and pig coronary (Co) arteries. Here we investigated whether this also occurs in the carotid (Ca), renal (R), mesenteric (M) and femoral (F) arteries of the dog. Artery rings were precontracted with the thromboxane mimetic U46619 after ensuring that the resting conditions were comparable from the Laplace relationship. In the presence of prazosin (1 ~mol/1) and propranolol (3 ~mol/1), noradrenaline (NA) relaxed the arteries in the order Co > Ca > F >> R = M. When maximum relaxation to nitroglycerin (10 wmol/1) was taken to be 100% the maximum relaxation to noradrenaline was Co 70%; Ca 34%; F 19%; R 7% and M 2%. Substance P relaxed the arteries in the same order as for NA but showed higher efficacy i.e. : Co 100%; C a 80%; F 71%; R 49%; and M 41%. Endothelium removal abolished the relaxation to NA. In endothelium intact arteries UK14304 mimicked the relaxation responses to NA and idazoxan right shifted the curves to both agonists consisteut with an Gz-adrenoceptor classification. We conclude that endothelium dependent relaxation to NA and SP varies greatly across 5 large arteries of the dog.
I~,I
291
PROSTAGLANDIN BIOSYNTHESIS AND CAP~IAC BETA-ADRENOCE~TORS. S. VaJpoyee, U. H. Shah, M. P. Patel t G. M. Panchal and S. M, Mansu~i. Department of Pharmacology, B. J. Medical College, Ahmedabad 380 016 Gujarat, India. P~ostaglandims
(PGs) axe known t o influence ~he ~egulation of cardiovascular
function. Es~rlier we have reported modification of hypotensive action of some commonly used antihypertensive drugs by a PG synthesis inhibitor. Now we have investigated the effect of indomethacin pretrea~ment on the response of heart rate %0 propranolol in urethane (1.5 g/kg i.p.) anaesthetized rats. Electrocardiogram lead II was recorded on a Polyrite recorder and heart rate was counted. The heart rate in control group (n=7) was reduced by propranolol (5 mg/kg i.v.) from 292.85 + 8.66/sin to 225.71 + 12.71/sin after 15 sin of its administration. Recovery was slow but complete at 210 min. The reduction in heart rate in second group (n=6), which was pretreated with indomethacin (20 mg/kg i.p.), was much less i.e. from 511.66 + 13.57/sin to 286.66 + 16.93/min at 15 sin. The rocovery was also quicker as it was complete at 120 min~ These findings show that indomethacin also attenuates the bradycardiogenic action of propranolol like its blood pressure lowering response and it seems possible that the endogenous PGs probably modulate the interaction between propranolol and the oardiac beta-adrenoceptors.
292
REACTIVITY OF CANINE CAROTID AETERY IN VITRO 4 WEEKS AZ~ER DE-ENDOTHELIALIZAT!0N. K. Satoh, J.A. Angus, G.R. Campbell, T.M. Cocks. Baker Medical Research Institute, Prahran Victoria 3181, Australia. Acute removal of endothelium from large arteries such as the coronary in vitro abolishes relaxation responses to acetylcholine but enhances the constrictor response to serotonin and noradrenaline (Cocks & Angus, 1983). Here we tested whether the responses to a range of dilator and constrictor stimuli would be altered after endothelium had returned to the luminal surface of the dog carotid artery studied in vitro 4 weeks after unilateral carotid balloon catheterization. Morphological studies showed that prior intimal damage had caused concentric or eccentric intimal smooth muscle thickening (2-20 cells thick) but most (95%) rings were covered by regenerated endothelial cells. The sensitivity (from EDso values) was increased 3-5 fold in the test arteries compared with control vessels to noradrenaline, serotonin, thromboxane mimetic, U46619 and K +. Relaxation responses to endothelium dependent (EDRF release) vasodilators acetylcholine and EDRF independent agents adenosine an d nitroglycerin were unaffected in magnitude or sensitivity by the intimal thickening. We conclude that sensitivity in arteries to a range of vasoconstrictors is enhanced to a small degree with intim~l thickening but the EDRF dependent relaxation responses are normal despite this altered intimal layer. Cocks T.M., Angus J.A. : Nature 305:627-630, 1983.
2 9 3 A L P H A 2 - ADRENOCEPTORS AND ENDOTHELIUM DEPENDENT R E ~ T I O N IN CANINE LARGE ARTERIES. K. Satoh, J.A. Angus, T.M. Cocks. Baker Medical Research Institute, Prahran Victoria 3181, Australia. Alpha2-adrenoceptor agonists cause the release of endothelium derived relaxing factor (EDRF) in canine and pig coronary (Co) arteries. Here we investigated whether this also occurs in the carotid (Ca), renal (R), mesenteric (M) and femoral (F) arteries of the dog. Artery rings were precontracted with the thromboxane mimetic U46619 after ensuring that the resting conditions were comparable from the Laplace relationship. In the presence of prazosin (1 ~mol/1) and propranolol (3 ~mol/1), noradrenaline (NA) relaxed the arteries in the order Co > Ca > F >> R = M. When maximum relaxation to nitroglycerin (10 wmol/1) was taken to be 100% the maximum relaxation to noradrenaline was Co 70%; Ca 34%; F 19%; R 7% and M 2%. Substance P relaxed the arteries in the same order as for NA but showed higher efficacy i.e. : Co 100%; C a 80%; F 71%; R 49%; and M 41%. Endothelium removal abolished the relaxation to NA. In endothelium intact arteries UK14304 mimicked the relaxation responses to NA and idazoxan right shifted the curves to both agonists consisteut with an Gz-adrenoceptor classification. We conclude that endothelium dependent relaxation to NA and SP varies greatly across 5 large arteries of the dog.
I~,I