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Involvement of L-arginine-nitric oxide pathways in cardiovascular effect of cholecystokinin (CCK) in rats
CHRONIC INHIBITION OF NITRIC OXIDE SYNTHESIS IN SPONTANEOUSLY HYPERTENSIVE RATS
N I T R O E S T E R S OF P O L Y S A C C H A R I D E S AS NORELEASING AGENTS G.I. Sidor_renko~ A.V. Gourine, T.L. Yurkshtovich, V.I,. Nedorezov,'M.G. Kolyadko Research Institute of Cardiology, 110, R.Luxemburg Str:, 220036, Minsk, Belarus, CIS.
l.Varagid, M.Jerkid, .J.Markovid-Lipkovski, V.Koko, D.Jovovid, V.Veljkovid, S.Vukobratovid Institute for Medical Research and Institute of Pathology, Dr Subotida 4, PO Box 721, 11001 Belgrade, Yugoslavia
The aim of this study was to search for new NO-releasing agents. Nitroesters of sodium salt of oxidate starch (NOS) with the number of nitrogroups 1-5% and of COOH - 12-20% were studied. Oxidate starch (OS) with 12-20% of COOH-groups was used as controls. Inhibition of platelet aggregation was determined in vitro using laser aggregometer at induction with ADP, thrombin, arachidonic acid, and adrenaline. In another series of experiments the content of cGMP and cAMP 5 and 20 min after addition of NOS to the myocardiac homogenate of rats was measured. Relaxation of smooth muscles was studied by a response of ring segments of the isolated rat's aorta after addition of phenylephrine (10"SM) during peffusion with Kreb's so[ution containing NOS in concentrations 1.10~; 1.10-6; 1.104 M. NOS showed antiplatelet (AP) activity by inhibiting aggregation induced by ADP, thrombin, arachidonic acid, and adrenaline. The AP el'feet of OS was not found. The. inhibition increased with a rise in the number of nitroester groups and concentration of NOS itself. There was a significant increase in cGMP in the myocardiae homogenate (142%, P<0,05) and a decrease in cAMP (98%, P<0,05) 5 min after application of NOS as compared to OS. 20 rain after CGMP increased 1,97-fold (P
There are no data about long term blockade of nitric oxide (NO) synthesis in spontaneously hypertensive rats (SHR) except that of Chander et al. who showed that chronic inhibition of NO synthesis for 10 days did not significantly worsen the hypertension in stroke-prone STIR. Our experiment was performed in adult, male St-IR, which were divided into two groups. Rats from L-NAME group treated with L-arginine analogue N -nLtro-L-argmme-methyl ester L-NAME (lOmg/kg body weight) in the drinking water for 4 weeks, and control rats received tap water for the same period. Tail-cuff pressure increased progressively in L-NAME treated rats. This elevation of arterial pressure in rats drinking LNAME was accompanied by significantly higher total peripheral resistance, substantial reduction in cardiac output, decreased femoral and renal blood flow, while glomemlar filtration rate remained unchanged. No significant differences in kidney weight and left ventricular weight/body weight ratio were seen among the groups. Morphologic evaluation revealed a grater incidence of vascular lesions and glomemlar injury in chronically NO-blocked rats compared with control SHR.
EFFECT OF NG-NITRO L-ARGININE METHYLESTHER (L-NAME) ON GI.ADRENERGIC RESPONSES IN TAIL ARTERY (TA) RINGS. A.Tabernero, Ij.Giraldo, E.Vila I Dept de Farmacologia i Psiquiatria, Lab Medicina Computacional, Universitat Aut~noma de Barcelona, Bellaterra, Spain
INVOLVMENT OF L-ARGININE- NITRIC OXIDE PATHWAYS IN CARDIOVASCULAR EFFECT OF CHOLECYSTOKININ (CCK) IN RATS R.J.Wigniewska, K. Wi~niewski Department of Pharmacology, Medical Academy, Mickiewicza 2c 15-222 Bialystok, Poland.
Functional responses to St-587, a partial ~1adrenoceptor agonist, were modified by L-NAME in aorta but not in TA rings (Vila & Tabernero, Can J P h y s i o l P h a r m a c o l 72 (sl), 161, 1994). The great difference b e t w e e n vessels was adscribed to a difference in the stimulus-response relationship. The present study was performed to further elucidate the mechanism responsible for the lack of modulation by L-NAME on ~1-adrenergic responses in TA from SpragueDawley rats. The alkylating agent phenoxybenzamine (POB,0.1 ~M,10 ~in) shifted to the right (1.66 log units) and reduced 70% the maximal effect (Ema×) of the concentration-effect curve to phenylephrine (PHE)- L-NAME (30~M) in presence of POB enhanced the Ema× (2.35 times) with no modification of sensitivity for contraction to PHE. Nevertheless, the decrease by POB of inositol phosphate (IP) formation induced by PHE was not modified by L-NAME. The study of the stimulus-response relationship for contraction and IP formation showed that 2% of receptors for contraction and 1 7 % for IP formation need to be occupied to elicite half Of the E~x response indicating a smaller receptor reserve for IP formation than for contraction. Our results do not seem to support the link between cyclic-GMP and ~I induced IP formation suggested for rat aorta (Hirata et al., J Biol C h e m 265, 268-73 1990; Rapoport, C i r c R e s 58, 497-10 1986).
The aim of the present study was determinate the role of endogenous nitric oxide (NO) in mediating or modulating the effects of CCK on blood pressure and function of isolated rat hearts. Intravenous administration of NO synthesis inhibitor N Gnitro-L-argininemethyl ester (L-NAME) at a dose 100gg/kg iv evoked increase in systolic (SBP) and diastolic (DBP) blood pressure, significantly abolished the hypertensive effect of CCK (5, 10, 20 UCHR/kg iv). L-NAME (10"2~M) decrease coronary outflow and did not change the cardiac contraction amplitude, heart rate. CCK (1, 2, 5 UCHR/0. lml) increased the cardiac contraction amplitude, heart rate and decreased coronary outflow. We did not notice changes in the function of isolated heart after administration of CCK with L-NAME. L-arginine (100 mg/kg iv) decreased systolic and diastolic blood pressure. In animals where L-arginine was given with CCK hypotension was observed (opposite effect to CCK alone) and the action was greater than after administration of L-arginine alone. The" in vitro" experiments on isolated heart of rat revealed that CCK administered with L-arginine (10 -4 M) evoked decrease the cardiac contraction amplitude and did not change coronary outflow and heart rate. Cone|usion: these results indicated that endogenous NO mediates in part the modulate effect of CCK on blood pressure and mainly the function of isolated heart.
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N I T R O E S T E R S OF P O L Y S A C C H A R I D E S AS NORELEASING AGENTS G.I. Sidor_renko~ A.V. Gourine, T.L. Yurkshtovich, V.I,. Nedorezov,'M.G. Kolyadko Research Institute of Cardiology, 110, R.Luxemburg Str:, 220036, Minsk, Belarus, CIS.
l.Varagid, M.Jerkid, .J.Markovid-Lipkovski, V.Koko, D.Jovovid, V.Veljkovid, S.Vukobratovid Institute for Medical Research and Institute of Pathology, Dr Subotida 4, PO Box 721, 11001 Belgrade, Yugoslavia
The aim of this study was to search for new NO-releasing agents. Nitroesters of sodium salt of oxidate starch (NOS) with the number of nitrogroups 1-5% and of COOH - 12-20% were studied. Oxidate starch (OS) with 12-20% of COOH-groups was used as controls. Inhibition of platelet aggregation was determined in vitro using laser aggregometer at induction with ADP, thrombin, arachidonic acid, and adrenaline. In another series of experiments the content of cGMP and cAMP 5 and 20 min after addition of NOS to the myocardiac homogenate of rats was measured. Relaxation of smooth muscles was studied by a response of ring segments of the isolated rat's aorta after addition of phenylephrine (10"SM) during peffusion with Kreb's so[ution containing NOS in concentrations 1.10~; 1.10-6; 1.104 M. NOS showed antiplatelet (AP) activity by inhibiting aggregation induced by ADP, thrombin, arachidonic acid, and adrenaline. The AP el'feet of OS was not found. The. inhibition increased with a rise in the number of nitroester groups and concentration of NOS itself. There was a significant increase in cGMP in the myocardiae homogenate (142%, P<0,05) and a decrease in cAMP (98%, P<0,05) 5 min after application of NOS as compared to OS. 20 rain after CGMP increased 1,97-fold (P
There are no data about long term blockade of nitric oxide (NO) synthesis in spontaneously hypertensive rats (SHR) except that of Chander et al. who showed that chronic inhibition of NO synthesis for 10 days did not significantly worsen the hypertension in stroke-prone STIR. Our experiment was performed in adult, male St-IR, which were divided into two groups. Rats from L-NAME group treated with L-arginine analogue N -nLtro-L-argmme-methyl ester L-NAME (lOmg/kg body weight) in the drinking water for 4 weeks, and control rats received tap water for the same period. Tail-cuff pressure increased progressively in L-NAME treated rats. This elevation of arterial pressure in rats drinking LNAME was accompanied by significantly higher total peripheral resistance, substantial reduction in cardiac output, decreased femoral and renal blood flow, while glomemlar filtration rate remained unchanged. No significant differences in kidney weight and left ventricular weight/body weight ratio were seen among the groups. Morphologic evaluation revealed a grater incidence of vascular lesions and glomemlar injury in chronically NO-blocked rats compared with control SHR.
EFFECT OF NG-NITRO L-ARGININE METHYLESTHER (L-NAME) ON GI.ADRENERGIC RESPONSES IN TAIL ARTERY (TA) RINGS. A.Tabernero, Ij.Giraldo, E.Vila I Dept de Farmacologia i Psiquiatria, Lab Medicina Computacional, Universitat Aut~noma de Barcelona, Bellaterra, Spain
INVOLVMENT OF L-ARGININE- NITRIC OXIDE PATHWAYS IN CARDIOVASCULAR EFFECT OF CHOLECYSTOKININ (CCK) IN RATS R.J.Wigniewska, K. Wi~niewski Department of Pharmacology, Medical Academy, Mickiewicza 2c 15-222 Bialystok, Poland.
Functional responses to St-587, a partial ~1adrenoceptor agonist, were modified by L-NAME in aorta but not in TA rings (Vila & Tabernero, Can J P h y s i o l P h a r m a c o l 72 (sl), 161, 1994). The great difference b e t w e e n vessels was adscribed to a difference in the stimulus-response relationship. The present study was performed to further elucidate the mechanism responsible for the lack of modulation by L-NAME on ~1-adrenergic responses in TA from SpragueDawley rats. The alkylating agent phenoxybenzamine (POB,0.1 ~M,10 ~in) shifted to the right (1.66 log units) and reduced 70% the maximal effect (Ema×) of the concentration-effect curve to phenylephrine (PHE)- L-NAME (30~M) in presence of POB enhanced the Ema× (2.35 times) with no modification of sensitivity for contraction to PHE. Nevertheless, the decrease by POB of inositol phosphate (IP) formation induced by PHE was not modified by L-NAME. The study of the stimulus-response relationship for contraction and IP formation showed that 2% of receptors for contraction and 1 7 % for IP formation need to be occupied to elicite half Of the E~x response indicating a smaller receptor reserve for IP formation than for contraction. Our results do not seem to support the link between cyclic-GMP and ~I induced IP formation suggested for rat aorta (Hirata et al., J Biol C h e m 265, 268-73 1990; Rapoport, C i r c R e s 58, 497-10 1986).
The aim of the present study was determinate the role of endogenous nitric oxide (NO) in mediating or modulating the effects of CCK on blood pressure and function of isolated rat hearts. Intravenous administration of NO synthesis inhibitor N Gnitro-L-argininemethyl ester (L-NAME) at a dose 100gg/kg iv evoked increase in systolic (SBP) and diastolic (DBP) blood pressure, significantly abolished the hypertensive effect of CCK (5, 10, 20 UCHR/kg iv). L-NAME (10"2~M) decrease coronary outflow and did not change the cardiac contraction amplitude, heart rate. CCK (1, 2, 5 UCHR/0. lml) increased the cardiac contraction amplitude, heart rate and decreased coronary outflow. We did not notice changes in the function of isolated heart after administration of CCK with L-NAME. L-arginine (100 mg/kg iv) decreased systolic and diastolic blood pressure. In animals where L-arginine was given with CCK hypotension was observed (opposite effect to CCK alone) and the action was greater than after administration of L-arginine alone. The" in vitro" experiments on isolated heart of rat revealed that CCK administered with L-arginine (10 -4 M) evoked decrease the cardiac contraction amplitude and did not change coronary outflow and heart rate. Cone|usion: these results indicated that endogenous NO mediates in part the modulate effect of CCK on blood pressure and mainly the function of isolated heart.
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G
64
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.
,
•