Synergistic effect of nisoldipine and nitroglycerin on human internal mammary artery.
Perioperative spasm of the internal mammary artery (IMA) can be a problem in coronary artery bypass surgery, which may be prevented by vasodilator drugs. The relaxing effect of a new calcium antagonist nisoldipine used alone or in combination with nitroglycerin (NTG) was studied in human isolated IMA in organ chambers. The results showed that nisoldipine exhibited a potent relaxing effect on IMA precontracted by membrane depolarization (K+ induced) with an EC50 of 7.58 +/- 0.08 (-log M). Nisoldipine was about 10 times more potent than was nifedipine (EC50, 6.72 +/- 0.10). However, both calcium antagonists showed much less relaxing effect on IMA precontracted with the thromboxane mimetic U46619. When IMA was pretreated with nisoldipine, this drug (range, 10-300 nM) inhibited contraction induced by either K+ or U46619 in a concentration-dependent manner. The relaxing effect of nisoldipine was long lasting and extremely hard to wash out (more than 3 hr). NTG showed a rapid and short-lasting relaxing effect on IMA precontracted with either K+ or U46619. Pretreatment of IMA with NTG had little effect for prevention of contraction to K+ or U46619. Combining nisoldipine with NTG at low concentrations (1-30 nM) produced a synergistic effect in the prevention of IMA contraction to K+ or U46619 and in relaxation of IMA precontracted with these agents. These studies reveal that combining nisoldipine with NTG combines the advantages of both and provide a scientific basis for a future clinical trial using combined nisoldipine and NTG at low concentrations for the preparation of IMA (pretreatment) to prevent IMA spasm during coronary artery bypass grafting.
Liu
J J
JJ
Department of Cardiac Surgery, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.
Johnston
C I
CI
Buxton
B F
BF
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D008323:Mammary Arteries / Q000187:drug effects* / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects; D015737:Nisoldipine / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D011450:Prostaglandin Endoperoxides, Synthetic; D014662:Vasoconstrictor Agents; D015737:Nisoldipine; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D005996:Nitroglycerin; D011188:Potassium