Vasodilator Effects Of Sodium Nitroprusside Research Articles

Twenty-four-hour variations in the effect of nitrodilators in rat aorta: lack of influence of the endothelium.

Time-dependent variations of the vasodilator effects of sodium nitroprusside and glyceryl trinitrate on isolated smooth muscle have been studied on rings of rat thoracic aorta, both endothelium-intact and endothelium-denuded. For most of the concentrations of sodium nitroprusside used the induced relaxations were significantly dependent on the time the tissues were obtained. However, significant temporal differences were obtained for glyceryl trinitrate-induced relaxations at lower concentrations only for both endothelium-intact and endothelium-denuded preparations. EC50 values of sodium nitroprusside and glyceryl trinitrate (i.e. the concentrations inducing half the maximum response) were also significantly different and they had quite similar rhythmic features both in endothelium-intact and in endothelium-denuded preparations. These results clearly show that the in-vitro sensitivity of rat thoracic aorta to nitrodilator agents varies over a 24-h period and thus depends on when the animals were killed; the presence of endothelium does not change the rhythm of nitrodilator activity. These variations might be a result of circadian rhythm in the guanylate cyclase-cGMP system which mediates responses to nitrodilator agents.

Down‐regulation of BK channels contributes to pregnancy‐induced nitrate tolerance in rat maternal uteroplacental circulation

Normal pregnancy is associated with enhanced uterine vasodilation secondary to up-regulation of endothelial NO signaling. Continuous exposure of uteroplacental vessels to high levels of NO might result in induction of nitrate tolerance. The objectives of this study were to: (1) characterize vasodilator effects of sodium nitroprusside, (SNP) in uterine arteries of non-pregnant (NP) and late pregnant (LP) rats; (2) define the role of smooth muscle cell (SMC) Ca2+ signaling in mediating the effects of SNP; (3) explore the role of SMC calcium-activated potassium (BK) channels in development of nitrate tolerance. Uterine radial arteries were pressurized to 50 mmHg and pre-constricted with phenylephrine. Changes in arterial diameter and SMC [Ca2+]i in response to SNP (0.001–10 μM) were studied using arteries loaded with fura 2. BK currents and single channel activity were characterized in myocytes using the whole-cell patch clamp technique. Maximal vasodilation and sensitivity to SNP were both significantly decreased in LP vs. NP arteries. SNP-induced vasodilation was associated with a reduction in SMC [Ca2+]i that was significantly attenuated during gestation. BK currents and single channel activity were both significantly reduced in late pregnancy. In summary: (1) Late pregnancy is associated with a marked reduction in uterine vasodilation to SNP linked to SMC Ca2+ signaling, (2) Inhibition of BK channel function and/or expression in part contributes to the development of nitrate tolerance in the maternal uteroplacental circulation. Supported by NIH HL067250 and HL073895

Vasodilator effects of sodium nitroprusside, levcromakalim and their combination in isolated rat aorta.

1. The endothelial modulation of the relaxant responses to the nitric oxide (NO) donor sodium nitroprusside (SNP) and the KATP channel opener levcromakalim (LEM) and the interactions between these agents were analysed in isolated rat aorta. 2. LEM-induced relaxation was unchanged by endothelium removal or by the presence of L-NAME (10-4 M) or ODQ (10-6 M). In contrast, in KCl- (25 mM), but not in noradrenaline- (NA, 10-6 M) contracted arteries, SNP-induced relaxation was augmented by endothelium removal but not by L-NAME, indomethacin, glibenclamide nor charybdotoxin plus apamin. 3. The isobolographic analysis of the interactions between exogenously activated KATP channels and cyclic GMP using mixtures of SNP and LEM revealed that there were no interactions between both drugs at the proportions at which both drugs were active. However, the points for the SNP : LEM mixtures in proportions 10:1 and 1:10,000 (i.e. at concentrations at which LEM and SNP were inactive, respectively) fell significantly above the line of additivity indicating that there were negative interactions between both drugs at these selected proportions (about 5- and 2 fold inhibition, respectively). The former interaction was sensitive to glibenclamide, whereas the latter was insensitive ODQ. The magnitude of the 10:1 SNP:LEM interaction was smaller in endothelium-intact arteries and was absent in arteries stimulated by NA. 4. In conclusion, the relaxations induced by LEM and SNP were additive. However, the presence of endothelium and low concentrations of LEM inhibited SNP-induced relaxation. Both inhibitory effects were not additive and were only observed in KCl- and not in NA-contracted aortae.

Inhibition of Endogenous Nitric Oxide Synthesis Potentiates the Effects of Sodium Nitroprusside but Not of Adenosine in Experimental Pulmonary Hypertension

This study examined the systemic and pulmonary vasodilator effects of sodium nitroprusside (SNP) and adenosine during experimental pulmonary hypertension with and without inhibition of endogenous NO synthesis. Male New Zealand White rabbits were anesthetized and mechanically ventilated. The NO synthesis inhibitor N^G-nitro-L-arginine methyl ester (L-NAME) was administered to 15 of the 28 rabbits. Pulmonary hypertension was then produced in all rabbits by U46619, a thromboxane A₂ mimetic. SNP was infused in 14 rabbits (7 L-NAME, 7 control) at doses of 0.5–20 µg/kg/min; adenosine was infused in the other 14 rabbits (8 L- NAME, 6 control) at doses of 12.5–300 µg/kg/min. The U46619 dose required to produce pulmonary hypertension was significantly lower in the L-NAME group. SNP dose-dependently decreased pulmonary (Ppa) and systemic (Psa) artery pressures and systemic vascular resistance (SVR). Both Ppa and Psa were decreased more with SNP in the L-NAME than in the no L-NAME group. The SNP ED₅₀ for the decrease in PVR was almost threefold lower in the L-NAME group. Adenosine dose-dependently decreased Ppa, Psa, PVR and SVR. The adenosine ED₅₀ for the decreases in PVR and SVR were similar in the L-NAME group and the control group. We conclude that inhibition of endogenous NO synthesis shifts the dose-response curves for both the pulmonary and systemic vasodilator effects to the left for the nitrovasodilator SNP but not for the non-nitrovasodilator adenosine.

Morphologic and functional consequences of intimal hyperplasia in the rat carotid artery.

The influence of neointima formation on functional characteristics was investigated in rat carotid artery preparations. The process of intimal hyperplasia development in the injured carotid arteries was followed in time both morphologically and morphometrically. Simultaneously with the loss of endothelial cells due to the balloon injury procedure, the vasodilator responses to methacholine were abolished. The sensitivity for the alpha1-adrenoceptor agonist phenylephrine appeared to be increased only immediately after injury. The balloon injury method led to significant neointima formation in the rat left common carotid artery 14 days after the intervention. Eight weeks after balloon injury, the neointimal mass reached its maximum. Parallel to the development of intimal hyperplasia, the alpha1-mediated vasoconstrictor responses to phenylephrine were significantly impaired. After 12 weeks of observation, reoccurrence of mature endothelial cells on the luminal surface of the neointima could be observed. Simultaneously, the vascular responses to phenylephrine and methacholine recovered. The vasoconstrictor responses to high potassium concentrations (100 mM) as well as the vasodilator effects of sodium nitroprusside appeared to be uninfluenced by balloon injury throughout the period of observation. From this study we conclude that both the receptor-mediated contractile responses to alpha1-adrenoceptor stimulation and the endothelium-dependent vasodilator responses to methacholine become severely impaired as a consequence of balloon catheter injury followed by intimal hyperplasia. However, these pharmacological responses may fully recover upon a prolonged period of endothelial regeneration.

Effects of glibenclamide on the regional haemodynamic actions of alpha-trinositol and its influence on responses to vasodilators in conscious rats.

1. In conscious rats, alpha-trinositol (D-myo-inositol-1, 2, 6 triphosphate; 5-80 mg kg-1 h-1 infusion) caused dose-dependent hypotension, tachycardia and hyperaemic dilatation in renal, mesenteric and hindquarters vascular beds. These effects were accompanied by inhibition of the renal vasodilator effects of acetylcholine (ACh), and of the mesenteric vasodilator effects of sodium nitroprusside (SNP) and, particularly, of levcromakalim (LCK). 2. In the light of the latter finding, in a second experiment, we assessed the influence of the KATP channel inhibitor, glibenclamide (20 mg kg-1), on resting haemodynamics, on responses to ACh, bradykinin (BK), SNP and LCK, on the haemodynamic action of alpha-trinositol, and on the effects of the latter on responses to the vasodilators, over a period of 3 days. 3. In the presence of saline, glibenclamide caused a reproducible pressor effect, accompanied by renal, mesenteric, and hindquarters vasoconstrictions on all 3 experimental days; these effects were unrelated to changes in blood glucose. In the presence of glibenclamide, only the hindquarters vasodilator response to BK, and all the cardiovascular actions of LCK were inhibited. 4. On the first experimental day, the hindquarters vasodilator effect of alpha-trinositol was substantially inhibited by glibenclamide, the renal vasodilatation less so, and the mesenteric vasodilatation not at all. However, over the subsequent two days, the mesenteric vasodilator effect of alpha-trinositol became increasingly sensitive to glibenclamide. 5. In the presence of alpha-trinositol and glibenclamide, on the first experimental day, the inhibition of the renal vasodilator effect of ACh was no greater than with alpha-trinositol alone in the first experiment. Moreover, on the third experimental day, both before and after glibenclamide, the inhibition by alpha-trinositol of the renal vasodilator response to ACh was less than on the first experimental day. Similarly, the alpha-trinositol-induced inhibition of the mesenteric vasodilator effect of SNP, and of the hindquarters vasodilator action of BK, waned over the 3 experimental days. The inhibition of the cardiovascular effects of LCK were similar on all 3 experimental days, but no greater in the presence of alpha-trinositol and glibenclamide than with glibenclamide alone. 6. These results indicate that KATP channels are involved in the maintenance of resting vasodilator tone in renal, mesenteric and hindquarters vascular beds. However, although additional activation of KATP channels is responsible for all the haemodynamic effects of LCK, it contributes only to the hindquarters vasodilator action of BK and is not involved in any of the responses to ACh or SNP. The hindquarters, renal and mesenteric vasodilator effects of alpha-trinositol may involve (in the same rank order) activation of KATP channels, probably through an indirect mechanism. However, it is unlikely that direct or indirect interaction of alpha-trinositol with KATP channels explains the ability of the drug to inhibit the renal vasodilator action of ACh, or the mesenteric vasodilator effects of SNP or LCK.

Endothelium-derived relaxant factor inhibits effects of nitrocompounds in isolated arteries.

We investigated the influence of endothelial cells on the smooth muscle vasodilator effects to sodium nitroprusside (SNP) or Teopranitol (an organic mononitrate) in isolated segments of rabbit aorta and femoral artery. In the femoral artery, the vasodilator responses to both nitrocompounds were significantly higher in the absence of endothelial cells or after pretreatment with the endothelium-derived relaxant factor (EDRF) inhibitor nordihydroguaiaretic acid (NDGA; 10 microM). Moreover, under conditions of stimulated EDRF release (induced by acetylcholine; 30-100 nM) the vasodilator responses to SNP were further attenuated in vessels with intact endothelium. By contrast, in the rabbit aorta, the vasodilator responses to the nitrocompounds were not significantly altered by either endothelium removal or treatment with NDGA. However, in the presence of the EDRF stimulator acetylcholine, the dose-response curve to SNP was shifted to right in the aorta as well. The role of EDRF in the endothelium-mediated attenuation of the dilator potency of SNP was further investigated by using EDRF released from cultured (bovine aortic) endothelial cells. The dilator effects of SNP were compared in endothelium denuded femoral or aortic segments in the presence or absence of EDRF. The vasodilator effects of SNP in both types of arteries were significantly reduced in the presence of EDRF. We conclude that EDRF attenuates the arterial vasodilation induced by SNP and Teopranitol. The results further suggest that endothelial cells exhibit a greater basal release of EDRF in the femoral artery than in the aorta, since under unstimulated conditions an EDRF-induced attenuation was seen only in femoral and not in aortic segments.

Nitroprusside increases cyclic guanylate monophosphate concentrations during relaxation of rabbit aortic strips and both effects are antagonized by cyanide.

The authors have confirmed previous observations that sodium cyanide (CN-) partially reverses the vasodilator effects of sodium nitroprusside (SNP) on vascular smooth muscle. As tested on rabbit aortic strips contracted by norepinephrine (NE), the final tension is independent of the order of addition of reagents. In the same concentration, CN- alone had no effect on tension also as reported by others. The ED50 values for relaxation of aortic strips for a series of directly acting agonists ("nitric oxide vasodilators") were: sodium azide (N-3) 2.1 X 10(-7) M; SNP 2.7 X 10(-7) M; hydroxylamine (H2NOH) hydrochloride 2.5 X 10(-6) M; human nitric oxide hemoglobin (HbNO) 3.5 X 10(-6) M; and sodium nitrite (NO-2) 1.2 X 10(-4) M. In addition to SNP, CN- antagonized the vasodilator effects of N-3 and H2NOH, but it failed to reverse relaxation by HbNO, NO gas, NO-2 (as observed by us), glyceryl trinitrate, adenosine, or papaverine (as observed by others). The only change noted in cyclic-adenosine monophosphate (c-AMP) concentrations in aortic strips exposed to 1) NE, 2) NE + NO-2 or SNP, or 3) NE + NO-2 or SNP + CN- was an increase due to NE. The only statistically significant change noted in cyclic-guanosine monophosphate (c-GMP) concentrations exposed to 1) NE, 2) NE + NO-2 or 3) NE + NO-2 + CN- was also an increase due to NE. In contrast, SNP resulted in further increases in c-GMP after NE, and when cyanide was added, a significant decrease in c-GMP followed. These results are only partially consistent with a role for c-GMP in relaxation of vascular smooth muscle, but cyanide may become a useful tool for the study of mechanisms of action of the nitric oxide vasodilators.