Rat aortic endothelium antagonizes nitroprusside-induced relaxation by release of the peptide endothelin.

1. The effects of porcine endothelin were examined in rat thoracic aortic rings. 2. Endothelin was a potent contractile agonist (EC50 4.0 +/- 0.6 nmol/L). 3. Endothelin (1 nmol/L) did not affect contractile responses to cumulative concentrations of the thromboxane analogue, U46619. 4. In the presence of U46619, but not phenylephrine, endothelin (1 nmol/L) and endothelium abrogated the vasodilator response to cumulative concentrations of sodium nitroprusside. 5. The inhibitory effect of endothelin on vasodilator responses to nitroprusside in the presence of U46619 was abolished by nifedipine (0.1 mumol/L) but unaffected by indomethacin (3 mumol/L) or haemoglobin (10 mumol/L). 6. These data suggest that endothelin generated by native endothelium exerts a physiological antagonism of sodium nitroprusside in the presence of thromboxane.

Propranolol antagonizes hypotension induced by alpha-blockers but not by sodium nitroprusside or methacholine.

A pressor response has been observed with propranolol, a nonselective beta-adrenoceptor antagonist, in animals given a nonselective alpha-adrenoceptor antagonist. This study investigates whether a pressor response to propranolol occurs in conscious unrestrained rats following a hypotensive response induced by phentolamine (nonselective alpha-antagonist), prazosin (selective alpha 1-antagonist) and (or) rauwolscine (selective alpha 2-antagonist), sodium nitroprusside (smooth muscle relaxant), or methacholine (muscarinic agonist). The rats were subjected to a continuous infusion of a hypotensive agent or normal saline followed by i.v. injection of propranolol. The infusion of phentolamine significantly decreased mean arterial pressure (MAP). Subsequent injection of propranolol restored MAP to the control level. Prazosin and rauwolscine each caused a small but not significant decrease in MAP which was reversed by propranolol. Concurrent infusions of prazosin and rauwolscine caused a significant decrease in MAP. Subsequent injection of propranolol caused a large pressor response which increased MAP to 20% above control MAP prior to the administration of drugs. Nitroprusside or methacholine each caused a significant decrease in MAP, but the hypotension was not antagonized by propranolol. The concurrent infusions of a low dose of nitroprusside and prazosin caused a significant decrease in MAP which was reversed by propranolol. The infusion of saline did not alter MAP, and propranolol did not cause a pressor response. It is concluded that propranolol antagonizes the hypotensive effect of an alpha-blocker but not that of sodium nitroprusside or methacholine. Our results suggest the presence of a specific interaction between alpha- and beta-antagonists.

Angiotensin decreases cyclic GMP accumulation produced by atrial natriuretic factor.

Atrial natriuretic factor (ANF) produced rapid increases in cyclic GMP (cGMP) in cultured aortic smooth muscle cells. Angiotensin II (ANG II) markedly decreased the accumulation of cGMP that was evoked by ANF. Arginine vasopressin and ATP, which evoke transient increases in free Ca2+ similarly to ANG II, also inhibited cGMP accumulation. The effect of the calcium mobilizing neurohormones was mimicked by the divalent cation ionophore, A23187. The cyclic nucleotide phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, prevented ANG II from inhibiting ANF-evoked cGMP accumulation. ANG II also inhibited cGMP accumulation induced by nitroprusside, a compound that activates cytosolic guanylate cyclase. These findings support the hypothesis that ANG II decreases cGMP accumulation by stimulating cGMP hydrolysis, apparently via a Ca2+-activated cGMP phosphodiesterase.

Sodium thiosulphate decreases blood cyanide concentrations after the infusion of sodium nitroprusside.

Plasma and red cell cyanide, and plasma thiocyanate, concentrations were measured in 30 patients undergoing elective nitroprusside-induced hypotension. One randomly selected group (n = 15), who received 0.21-0.70 mg kg-1 over periods of 50-160 min, were given a bolus of sodium thiosulphate 10.6-38.5 mg kg-1 immediately on cessation of the nitroprusside administration. The other group, who received infusions of 0.11-0.85 mg kg-1 for periods of 59-197 min, received no antidote. Cyanide concentrations, expressed as a percentage of the immediate post-infusion values, were significantly lower in the treated group in all subsequent blood samples (at 10, 30 and 60 min; plasma cyanide P less than 0.05; red cell cyanide P less than 0.001). Improved cyanide metabolism was further demonstrated by a sharp increase in mean plasma thiocyanate concentration (P less than 0.05) in the group receiving the antidote.

Propranolol prevents hemodynamic and humoral events after abrupt withdrawal of nitroprusside.

Hemodynamic and humoral events after intraoperative discontinuation of nitroprusside were studied in subjects without and with pretreatment with intravenous propranolol, 0.1 mg X kg-1. Nitroprusside-induced hypotension was associated with increases in heart rate, cardiac output, plasma renin activity (PRA), and catecholamine levels; these changes were prevented by propranolol. In subjects pretreated with propranolol, dose requirements of nitroprusside for hypotension of comparable degree and duration decreased 40%. On discontinuation of nitroprusside, mean systemic pressure rose to 100.2 mm Hg--a level higher than prehypotension and awake values--because of increased systemic vascular resistance. Hemodynamic events were associated with persistent elevations of PRA and catecholamine levels. These rebound changes were maximal 15 min after nitroprusside withdrawal and returned to control levels 30 to 60 min later. Pretreatment with propranolol completely prevented rebound hemodynamic events after nitroprusside. Persistent elevations of PRA and catecholamine levels after nitroprusside action subsided were responsible for the effects of withdrawal.

Effect of cyanide on nitrovasodilator-induced relaxation, cyclic GMP accumulation and guanylate cyclase activation in rat aorta.

The effects of sodium cyanide on relaxation, increases in cyclic GMP accumulation and guanylate cyclase activation induced by sodium nitroprusside and other nitrovasodilators were examined in rat thoracic aorta. Cyanide abolished nitroprusside-induced relaxation and the associated increase in cyclic GMP levels. Basal levels of cyclic GMP and cyclic AMP were also depressed. Reversal of nitroprusside-induced relaxation by cyanide was independent of the tissue level of cyclic GMP prior to addition of cyanide. Incubation of nitroprusside with cyanide prior to addition to aortic strips did not alter the relaxant effect of nitroprusside. Sodium azide-, hydroxylamine-, N-methyl-N'-nitro-N-nitrosoguanide-, nitroglycerin- and acetylcholine-induced relaxations and increased levels of cyclic GMP were also inhibited by cyanide. Relaxations induced by nitric oxide were also inhibited by cyanide, although the relaxation with the low concentration of nitric oxide employed was not accompanied by detectable increases in cyclic GMP. Relaxation to 8-bromo-cyclic GMP was essentially unaltered by cyanide; however, isoproterenol-induced relaxation was inhibited. Guanylate cyclase in soluble and particulate fractions of aorta homogenates was activated by nitroprusside and the activation was prevented by cyanide. The present results suggest that cyanide inhibits nitrovasodilator-induced relaxation through inhibition of guanylate cyclase activation; however, cyanide may also have nonspecific effects which inhibit relaxation.

Cyanide prevents the inhibition of platelet aggregation by nitroprusside, hydroxylamine and azide.

Sodium cyanide (CN-) in concentrations of 10 uM or more prevented the inhibition of epinephrine (2.5 uM) and of ADP (4.0 uM) induced primary and secondary aggregation brought about by 10 uM sodium nitroprusside (SNP). Cyanide alone in the same concentration had no effect on platelet aggregation induced by epinephrine or ADP. Even when the addition of CN- was delayed for as long as 9 min after epinephrine and SNP, it immediately reversed the SNP block and initiated a bimodal wave of aggregation. The effect of CN- on SNP inhibition of platelet aggregation appears to be competitive and reversible. Although they are less potent inhibitors of platelet aggregation than SNP, the effects of hydroxylamine (HA) and azide were also prevented by SNP. In our hands, sodium nitrite did not inhibit platelet aggregation consistently. The inhibitory effects of glyceryl trinitrate, papaverine and nitric oxide hemoglobin on platelet aggregation were not prevented by CN-. These interactions probably have no significance in vivo, but they indicate that SNP, HA and azide act on platelets and on vascular smooth muscle by similar or identical biochemical mechanisms. They also suggest that there are at least two sub-classes of so-called nitric oxide vasodilators. The effect of CN- may be mediated through an inhibition of the formation of nitric oxide from SNP, HA and azide.

Combined effects of sodium nitroprusside and propranolol on hypoxic pulmonary vasoconstriction.

Recent clinical experience and previous experimental work indicate that propranolol may reverse sodium-nitroprusside-induced inhibition of hypoxic pulmonary vasoconstriction (HPV). Accordingly, the authors decided to test this possibility in an experimental model that allows direct examination of pharmacologic influence on HPV. Six mongrel dogs were anesthetized with pentobarbital and intubated. Following a left thoracotomy, the left lower lobe (LLL) was ventilated independently but synchronously with the rest of the lung. Selective hypoxia of the LLL (95% nitrogen and 5% CO2) caused a 59 +/- 6% (mean +/- SE) decrease in the electromagnetically measured fraction of the cardiac output perfusing the LLL and a 287 +/- 65% increase in the pulmonary vascular resistance of the LLL from their respective prehypoxic values. Propranolol, 1 mg/kg intravenously, caused a 76 +/- 5% beta-blockade, as determined by an isoproterenol infusion test, but did not cause a significant change in the LLL HPV response. Sodium nitroprusside (SNP) infusion, caused a 38 +/- 4% decrease in systemic arterial pressure, and nearly abolished LLL HPV. Most important, the addition of propranolol to sodium nitroprusside did not significantly change the SNP induced inhibition of LLL HPV. The authors conclude that in acute lung disease, propranolol does not alter lobar HPV and does not reverse sodium nitroprusside inhibition of lobar HPV.

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.

Failure of cyanide to antagonize sodium nitroprusside in vivo in dogs.

The role of cyanide (CN) in the mechanism of action of sodium nitroprusside (SNP) has not been well defined. Some authors consider accumulation of CN in muscle to be the principal factor responsible for resistance to SNP when given to induce hypotension. To test this hypothesis, SNP was infused in 12 anesthetized dogs. Mean aortic blood pressure was reduced 50% and dogs were maintained at this pressure for 5 minutes. After recovery, eight of the dogs (group 1) received a potassium cyanide (KCN) infusion at a rate of 0.0125 mg/kg/min for 180 minutes; the other four dogs (group 2) were given saline solution and served as controls. After 180 minutes, all 12 dogs received a second infusion of SNP in the same dose as their first. No significant differences in blood pressure or heart rate were observed between groups. Left ventricular end-diastolic pressure (LVEDP) and dP/dt were elevated following KCN; however, after the second SNP infusion these parameters decreased in both groups. Cardiac output (Qt) decreased to 55% of baseline during the first SNP infusion and showed no significant changes during the second SNP infusion, but total peripheal resistance decreased significantly during both SNP infusions. Although whole-blood CN levels and gracilis muscle tissue CN concentrations were significantly greater (p < 0.05) in group 1 after KCN, the cardiovascular effects of SNP were not significantly altered by these increases in KCN, the cardiovascular effects of SNP were not significantly altered by these increases in CN. The authors conclude that resistance to SNP in induced hypotension is not the result of direct effects of CN on smooth muscle.

Sodium cyanide antagonism of the vasodilator action of sodium nitroprusside in theisolated rabbit aortic strip.

Resistance to sodium nitroprusside (SNP) is uncommon, but its occurrence has led to massive overdoses of SNP and sometimes death. To examine the mechanism responsible for resistance, aortic smooth muscle strips were prepared and dose-response curves for norepinephrine (NE) obtained. SNP alone caused a shift of the dose-response curve for NE to the right. However, this shift was less when the strips were exposed to both SNP and sodium cyanide (CN-). When CN- alone was added to the aortic strips, the response to NE was unchanged. In a further group of aortic muscle strips first contracted with NE and then relaxed with SNP, the addition of CN- caused the muscles to contract again. It is concluded that CN- antagonizes the action of SNP in vitro, and that this antagonism is specific for SNP.