11
Pharmacological Research, Vol. 25, Supplement 1, 1992 ISCHEMIA-REPERFUSION INJURY AND HISTAMINE RELEASE IN ISOLATED PERFUSED GUINEA-PIG HEART : EFFECTS OF NITRIC OXIDE GENERATORS . F. Gambassi, A . Pistelli, M .G . Di Bello, M . Lupini, P.F. Mannaioni and E . Masini . Department of Preclinical and Clinical Pharmacology, University of Florence, Viale G .B . Morgagni 65, 50134 Florence, Italy . Key words : Ischemia-reperfusion, Histamine release, Nitric oxide . Endothelium-derived relaxing factor is a labile humoral substance which relaxes vascular smooth muscle and inhibits platelet aggregation and adhesion . Its chemical nature has now been identified as nitric oxide (NO) [1] . Isolated rat serosal mast cells release an inhibitor of platelet aggregation which possesses the characteristics of NO and has a negative modulatory action on histamine release 121. It has been demonstrated that myocardial ischemia-reperfusion inhibits endothelial dependent relaxation, probably due to reduced NO release, supporting the hypotesis that a lack of NO may play a role in the genesis of vasospasm . In the present study we have investigated the effect of L-arginine, its analogue NG-monomethyl-L-arginine (MeArg), and some nitrovasodilators which spontaneously release NO on ischemia-reperfusion injury and histamine release in isolated perfused guinea-pig heart . Ischemia-reperfusion was obtained in a Langendorff preparation of guinea-pig heart by mean of a double ligature and release of the left anterior descending coronary artery . Force of contraction and ECG were recorded and the perfusates collected for histamine and lactate dehydrogenase release ; the densitometric analysis of mast cell metachromasia was determined in left ventricular samples from control, ischemic-reperfused and drug treated hearts as previously described 131 . The result obtained show a slight but significant increase in histamine release during ischemia and reperfusion, a time dependent leakage of lactate dehydrogenase and a loss of mast cell densitometry . The perfusion of the heart with L-arginine (L-Arg), the natural substrate for NO endogenous synthesis and with some ntrovasodilators, such as sodium nitroprusside (NaNP) and 3morpholinosydnonimine (SIN 1) which spontaneously release NO, decreases histamine and lactate
dehydrogenase release
and
prevents
mast cell
degranulation . These effects were amplified when superoxide dismutase (SOD) in low concentrations (50 IU/ml) was perfused together with the drugs (Figure 1) . MeArg which inhibits endogenous NO biosynthesis, has an opposite effect .
1043-6618/92/2510011-02/S03 .00/0
© 1992 The Italian Pharmacological Society
Pharmacological Research, Vol . 25, Supplement 1, 1992
12
The results
here
reported suggest that the endogenous formation of nitric oxide
and molecules able to generate NO are effective in reducing ischemicreperfusion
histamine and lactate dehydrogenase release and might have a
beneficial role in the prevention of post ischemic tissue injury . (6) T
I
A (,O7
T
(5)
T •
u) T
(4)
T
(e) 1 ,20 F w (n Q w = J C W S J
••
()0) T
(5) T
601
(4)
60 d0
T (e)
20
Q Q C>
7, W ~
O
M
•
f E
1
•
•
'O O
W
C
•3
za
Fig . 1. Effect of L-arginine (L-Arg), NG-monomethyl-L-arginine (MeArg), sodium nitroprusside (NaNP), 3-morpholinosydnonimine (SIN-1) on histamine (panel A) and lactate dehydrogenase (LDH) (panel E) release in isolated guinea-pig heart after ischemia reperfusion . The values are the means ± S .E . of the number of experiments reported in parenthesis . *p
Pharmacological Research, Vol. 25, Supplement 1, 1992 ISCHEMIA-REPERFUSION INJURY AND HISTAMINE RELEASE IN ISOLATED PERFUSED GUINEA-PIG HEART : EFFECTS OF NITRIC OXIDE GENERATORS . F. Gambassi, A . Pistelli, M .G . Di Bello, M . Lupini, P.F. Mannaioni and E . Masini . Department of Preclinical and Clinical Pharmacology, University of Florence, Viale G .B . Morgagni 65, 50134 Florence, Italy . Key words : Ischemia-reperfusion, Histamine release, Nitric oxide . Endothelium-derived relaxing factor is a labile humoral substance which relaxes vascular smooth muscle and inhibits platelet aggregation and adhesion . Its chemical nature has now been identified as nitric oxide (NO) [1] . Isolated rat serosal mast cells release an inhibitor of platelet aggregation which possesses the characteristics of NO and has a negative modulatory action on histamine release 121. It has been demonstrated that myocardial ischemia-reperfusion inhibits endothelial dependent relaxation, probably due to reduced NO release, supporting the hypotesis that a lack of NO may play a role in the genesis of vasospasm . In the present study we have investigated the effect of L-arginine, its analogue NG-monomethyl-L-arginine (MeArg), and some nitrovasodilators which spontaneously release NO on ischemia-reperfusion injury and histamine release in isolated perfused guinea-pig heart . Ischemia-reperfusion was obtained in a Langendorff preparation of guinea-pig heart by mean of a double ligature and release of the left anterior descending coronary artery . Force of contraction and ECG were recorded and the perfusates collected for histamine and lactate dehydrogenase release ; the densitometric analysis of mast cell metachromasia was determined in left ventricular samples from control, ischemic-reperfused and drug treated hearts as previously described 131 . The result obtained show a slight but significant increase in histamine release during ischemia and reperfusion, a time dependent leakage of lactate dehydrogenase and a loss of mast cell densitometry . The perfusion of the heart with L-arginine (L-Arg), the natural substrate for NO endogenous synthesis and with some ntrovasodilators, such as sodium nitroprusside (NaNP) and 3morpholinosydnonimine (SIN 1) which spontaneously release NO, decreases histamine and lactate
dehydrogenase release
and
prevents
mast cell
degranulation . These effects were amplified when superoxide dismutase (SOD) in low concentrations (50 IU/ml) was perfused together with the drugs (Figure 1) . MeArg which inhibits endogenous NO biosynthesis, has an opposite effect .
1043-6618/92/2510011-02/S03 .00/0
© 1992 The Italian Pharmacological Society
Pharmacological Research, Vol . 25, Supplement 1, 1992
12
The results
here
reported suggest that the endogenous formation of nitric oxide
and molecules able to generate NO are effective in reducing ischemicreperfusion
histamine and lactate dehydrogenase release and might have a
beneficial role in the prevention of post ischemic tissue injury . (6) T
I
A (,O7
T
(5)
T •
u) T
(4)
T
(e) 1 ,20 F w (n Q w = J C W S J
••
()0) T
(5) T
601
(4)
60 d0
T (e)
20
Q Q C>
7, W ~
O
M
•
f E
1
•
•
'O O
W
C
•3
za
Fig . 1. Effect of L-arginine (L-Arg), NG-monomethyl-L-arginine (MeArg), sodium nitroprusside (NaNP), 3-morpholinosydnonimine (SIN-1) on histamine (panel A) and lactate dehydrogenase (LDH) (panel E) release in isolated guinea-pig heart after ischemia reperfusion . The values are the means ± S .E . of the number of experiments reported in parenthesis . *p
