Hypotensive Effects Of Sodium Nitroprusside Research Articles

Circadian Rhythm in Hypotensive Effect of Sodium Nitroprusside in Rats and its Relevance to Sympathetic Nervous Activity

Orcadian rhythmicity in the hypotensive effects of sodium nitroprus-side (SNP) was determined to characterize the rhythmicity in hypotension mediated by nitric oxide (NO) donor in rats. When SNP was infused for 90 seconds every hour for 48 hours and the mean blood pressure was determined automatically by telemetry under light-dark conditions (LD), the degree of SNP-induced hypotension was shown to be minimal at the onset of the dark phase and to have marked circadian rhythmicity. The possible relationship between the circadian rhythm of the sympathetic nervous system (SNS) activity and SNP-induced hypotension was examined under LD conditions. The SNS activity assessed by blood pressure beat-to-beat variability analysis using the maximum entropy method (MEM) was higher at the preinfusion time at the onset of the dark phase than during the middle of the light phase. In addition, pretreatment with an α-blocker, phentolamine, followed by SNP infusion at the onset of the dark phase restored the SNP-induced hypotension and consequently dampened the daily variation in the degree of SNP-induced hypotension. The circadian rhythmicity determined by MEM was weakened, but persisted, in constant dark conditions (DD), suggesting partial involvement of endogenously driven circadian rhythms. In conclusion, the hypotensive effect of hourly infused SNP in rats was decreased in the dark phase in LD, especially at the onset of the dark phase, and clearly showed circadian rhythmicity in both LD and DD. The SNP-induced hypotension may be affected by rapid activation of the SNS at the onset of the dark phase in LD, and regulation of the circadian rhythm in SNP-induced hypotension in rats may be affected by both exogenous light stimuli and the endogenous biological clock.

Involvement of GABA and glutamate receptors in the blood pressure responses to intrathecally injected sodium nitroprusside in anesthetized rats

In pentobarbital-anesthetized rats the intrathecal (i.t.) injection of the nitric oxide (NO) donor, sodium nitroprusside (125, 250 and 500 nmol), induced a dose-dependent hypotensive response followed by a dose-dependent pressor effect. The pressor response to sodium nitroprusside (250 nmol) was reduced to 30% of the control value by the selective antagonist for AMPA/kainate receptors, 6,7-dinitroquinoxaline-2,3-dione (50 nmol, i.t.), whereas it was not modified by the selective NMDA receptor antagonist, 2-amino-5-phosphono-valeric acid (30 nmol, i.t.). The hypotensive effect of sodium nitroprusside was antagonized by the GABA A receptor antagonists, bicuculline (4.4 nmol, i.t.) and picrotoxin (4.4 nmol, i.t.), and also by the GABA B receptor antagonist, 2-hydroxy saclofen (113 nmol, i.t.). The blood pressure responses to sodium nitroprusside were not modified by blockade of muscarinic receptors with methyl atropine (164 nmol, i.t.), or of nicotinic receptors with hexamethonium (211 nmol, i.t.), of α 1-adrenoceptors with prazosin (3.1 nmol, i.t.), of α 2-adrenoceptors with yohimbine (2.8 μmol/kg, i.v.), of 5-HT receptors with methysergide (5.1 μmol/kg, i.v.), or of glycine receptors with strychnine (65 nmol, i.t.). It is concluded that NO generated from sodium nitroprusside in the spinal cord exerts inhibitory and excitatory effects on blood pressure probably through the release of GABA and glutamate, respectively. The inhibitory action on blood pressure involves the stimulation of spinal GABA A and GABA B receptors whereas the excitatory response to glutamate appears to be mediated through the activation of spinal AMPA/kainate receptors.

Cardiovascular effects of a novel, potent and selective phosphodiesterase 5 inhibitor, DMPPO: in vitro and in vivo characterization.

1. The aim of this study was to investigate the cardiovascular effects of a novel, potent and specific phosphodiesterase 5 (PDE 5) inhibitor, 1,3 dimethyl-6-(2-propoxy-5-methane sulphonylamidophenyl)-pyrazolo[3,4-d]pyrimidin-4-(5H)-one (DMPPO) in phenylephrine-precontracted rat aortic rings and different in vivo rat preparations. 2. DMPPO elicited a concentration-dependent relaxation of rat aortic rings with functional endothelium. DMPPO-induced relaxation was abolished by endothelium removal or pretreatment with the soluble guanylate cyclase inhibitor, methylene blue (10 microM). 3. In aortic rings without endothelium, the potency (pD2= -log10 EC50) of atrial natriuretic peptide (ANP) to induce relaxation increased from 8.13 +/- 0.05 in the absence of DMPPO, to 8.32 +/- 0.05 and 8.52 +/- 0.08 in the presence of 30 nM and 100 nM DMPPO, respectively. Similarly, the potency of sodium nitroprusside (SNP) in inducing relaxation increased from 7.38 +/- 0.07 in the absence of the PDE 5 inhibitor to 8.07 +/- 0.11 and 8.15 +/- 0.08 in the presence of 30 nM and 100 nM DMPPO, respectively. In contrast, relaxation to the adenylate cyclase activator, forskolin, was unchanged by DMPPO (100 nM). 4. In rings without endothelium, DMPPO (100 nM) increased by 2.5 fold intracellular levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP). Moreover, DMPPO (100 nM) potentiated the increases in cyclic GMP levels induced by ANP (30 nM) by 3 fold and SNP (30 nM) by 2.7 fold. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were not modified by DMPPO. 5. In anaesthetized normotensive or spontaneously hypertensive rats (SHR), DMPPO (2 and 5 mg kg-1, i.v.) lowered blood pressure without affecting heart rate. Similarly, in conscious SHR, orally administered DMPPO (5 mg kg-1) induced a 25 mmHg decrease in blood pressure for at least 7 h without modifying heart rate. Meanwhile, urinary cyclic GMP was increased by 50% whereas cyclic AMP remained unchanged. 6. In normotensive anaesthetized rats, sodium nitroprusside (SNP) (i.v. bolus) induced a decrease in blood pressure which rapidly returned to baseline. In DMPPO (1 mg kg-1, i.v.)-treated rats, the hypotensive effects of SNP (10 to 100 micrograms kg-1) were prolonged over time whereas the peak effect was unchanged. 7. In pithed rats, phenylephrine (i.v. bolus) induced dose-dependent increases in blood pressure. Pretreatment with DMPPO (5 mg kg-1, i.v.) partially inhibited the pressor response to phenylephrine (0.3 to 100 micrograms kg-1). 8. In conclusion, the potent and selective PDE 5 inhibitor, DMPPO, produces relaxation in isolated vessels in the presence of a cyclic GMP drive and reduces blood pressure of intact animals. Its high oral bioavailability and long duration of action should make it a useful tool to study the role of cyclic GMP in various biological systems.

Baroreflex failure in a patient with central nervous system lesions involving the nucleus tractus solitarii.

Animal studies have shown the importance of the nucleus tractus solitarii, a collection of neurons in the brain stem, in the acute regulation of blood pressure. Impulses arising from the carotid and aortic baroreceptors converge in this center, where the first synapse of the baroreflex is located. Stimulation of the nucleus tractus solitarii provides an inhibitory signal to other brain stem structures, particularly the rostral ventrolateral medulla, resulting in a reduction in sympathetic outflow and a decrease in blood pressure. Conversely, experimental lesions of the nucleus tractus solitarii lead to loss of baroreflex control of blood pressure, sympathetic activation, and severe hypertension in animals. In humans, baroreflex failure due to deafferentation of baroreceptors has been previously reported and is characterized by episodes of severe hypertension and tachycardia. We present a patient with an undetermined process of the central nervous system characterized pathologically by ubiquitous infarctions that were particularly prominent in the nucleus tractus solitarii bilaterally but spared the rostral ventrolateral medulla. Absence of a functioning baroreflex was evidenced by the lack of reflex tachycardia to the hypotensive effects of sodium nitroprusside, exaggerated pressor responses to handgrip and cold pressor test, and exaggerated depressor responses to meals and centrally acting alpha 2-agonists. This clinicopathological correlate suggests that the patient's baroreflex failure can be explained by the unique combination of the destruction of sympathetic inhibitory centers (ie, the nucleus tractus solitarii) and preservation of centers that exert a positive modulation on sympathetic tone (ie, the rostral ventrolateral medulla).

Effects of nitric oxide synthesis inhibition on the goat coronary circulation under basal conditions and after vasodilator stimulation.

1. The role of nitric oxide in the coronary circulation under basal conditions and when exposed to various vasodilator stimuli was studied in instrumented, anaesthetized goats, by examining the action of inhibiting endogenous nitric oxide production with NG-nitro-L-arginine methyl ester (L-NAME). 2. In 12 goats, left circumflex coronary blood flow (electromagnetically measured), systemic arterial blood pressure and heart rate were continuously recorded. L-NAME (3-4, or 8-10 mg kg-1 injected i.v.) decreased resting coronary blood flow by 20 and 28%, increased mean arterial pressure by 23 and 30% and increased coronary vascular resistance by 47 and 65%, respectively, without affecting heart rate, or blood gases or pH. These haemodynamic effects were reversed by L-arginine (200-300 mg kg-1 by i.v. injection, 5 goats). 3. Acetylcholine (0.001-0.1 micrograms), sodium nitroprusside (0.01-0.3 mg), and diazoxide (0.1-3 mg), injected intracoronarily in 6 goats, produced dose-dependent increases in coronary blood flow; sodium nitroprusside (0.1-0.3 mg) also caused hypotension and tachycardia. 4. During the effects of L-NAME, the coronary vasodilatation to acetylcholine was attenuated, to sodium nitroprusside was increased, and to diazoxide was unaffected, in comparison with control conditions. The hypotensive effects of sodium nitroprusside were also increased during treatment with L-NAME. 5. Graded coronary hyperaemic responses occurred after 5, 10 or 20 s of coronary occlusion. The magnitude of hyerpaemia for each occlusion duration was increased during treatment with L-NAME, in comparison to control.6. The results suggest: (a) endogenous nitric oxide is involved in regulation of coronary circulation by producing a basal vasodilator tone, (b) acetylcholine-induced coronary vasodilatation is mediated, in part, by nitric oxide, and (c) inhibition of basal endogenous nitric oxide production induces supersensitivity of coronary vessels to nitrovasodilators and enhances hyperaemic responses after short periods of ischaemia of the myocardium.

Kinins, nitric oxide, and the hypotensive effect of captopril and ramiprilat in hypertension.

We investigated the role of kinins in the acute depressor effect of captopril and ramiprilat in spontaneously hypertensive rats. Since the vasodepressor action of kinins may be linked to the generation of prostaglandins and endothelium-derived relaxing factors, we also investigated the role of prostaglandins and nitric oxide in the blood pressure reduction caused by angiotensin converting enzyme inhibitors. To this end, we contrasted the hypotensive effects of captopril (10 mg/kg i.v.), ramiprilat (2 mg/kg i.v.), and the angiotensin II antagonist DuP 753 (30 mg/kg i.v.) in spontaneously hypertensive rats with and without pretreatment with a kinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg-trifluoroacetic acid) (200 micrograms/kg/min i.v.), an inhibitor of nitric oxide synthesis (NG-monomethyl-L-arginine) (15 mg/kg + 10 mg/kg/hr i.v.), or an inhibitor of prostaglandin synthesis (indomethacin) (10 mg/kg i.v.). The kinin antagonist did not affect blood pressure in spontaneously hypertensive rats but did attenuate the hypotensive effect of captopril and ramiprilat; the kinin antagonist did not minimize the depressor action of DuP 753. The nitric oxide synthesis inhibitor increased blood pressure in spontaneously hypertensive rats and attenuated the hypotensive effect of captopril, ramiprilat, and DuP 753, but it did not impede the hypotensive effect of sodium nitroprusside. Pretreatment of hypertensive rats with indomethacin did not modify the acute hypotensive effect of ramiprilat or captopril. These data suggest a contribution of endogenous kinins and nitric oxide to the acute antihypertensive effect of captopril and ramiprilat in spontaneously hypertensive rats and of nitric oxide to the hypotensive effect of DuP 753.

In Vivo and In Vitro Studies of a Putative Inhibitor of Cyclic Guanosine 3',5'-Monophosphate Production

Our main objective was to test the efficacy of 6-anilino-5,8-quinolinedione (LY83583) in vivo, a putative inhibitor of cyclic guanosine 3',5'-monophosphate (cGMP) production. If the drug proved capable of lowering plasma, vascular, and kidney levels of cGMP and of inhibiting the hypotensive effect of sodium nitroprusside and methacholine, then LY83583 could be of potential use in exploring the contribution of cGMP to cardiovascular and renal physiology. We found that when administered to trained conscious rats, LY83583 (1-mg/kg bolus, followed by a 2-hr infusion of 3 mg/kg.hr) decreased plasma cGMP concentration by 36% (P less than 0.01). Doubling the dosage of drug (2-mg/kg bolus, 6 mg/kg.hr) decreased plasma cGMP by 46% (P less than 0.05). We next measured tissue levels of cGMP ex vivo from rats that had received LY83583 or vehicle for 2 hr. The cGMP content of aortic segments when LY83583 was infused at the low dose, or renal cortical tissue when LY83583 was infused at both doses, was not significantly different from the cGMP content of tissue from rats that had received vehicle. LY83583 in doses up to 10-mg/kg bolus, followed by 6 mg/kg.hr infusion also failed to attenuate the hypotensive response to sodium nitroprusside or methacholine in conscious rats. Last, we tested whether, in our hands, LY83583 could reduce cGMP of aortic segments and kidney cortical slices in vitro. We found that after 10 min of incubation, 10(-5) M LY83583 decreased intracellular cGMP by approximately 65% and 50% in aortic and kidney tissues, respectively. In order to ascertain whether LY83583 lowered cGMP by stimulating phosphodiesterase, we incubated tissues with 10(-4) M 3-isobutyl-1-methylxanthine to inhibit the enzyme. In the presence of 3-isobutyl-1-methylxanthine LY83583 still exerted an inhibitory effect on cGMP production by aortic and kidney tissues. In conclusion, although LY83583 is a useful agent to lower renal and vascular tissues levels of cGMP in vitro, its efficacy in vivo seems doubtful.

The Hypotensive Effect of Trimazosin Is Not Caused Solely by ??1-Adrenoceptor Blockade

Trimazosin is a quinazoline antihypertensive agent structurally related to the selective alpha 1-adrenoceptor blocker prazosin. Trimazosin has been shown previously to have less affinity for alpha 1-adrenoceptors than prazosin. In the present study we compared the hypotensive potency and efficacy of the two agents, and their effects on pressor responses to phenylephrine in anesthetized dogs. We also determined the effect of trimazosin administered during a maximum hypotensive response to prazosin, and of sodium nitroprusside administered after trimazosin or prazosin. Compared with prazosin, trimazosin was a less potent but more efficacious hypotensive agent. At doses which caused equal or even greater hypotensive effects than those caused by prazosin, trimazosin caused less inhibition of pressor responses to phenylephrine. When administered during a maximum hypotensive response to prazosin, trimazosin caused an additional fall in pressure. These results clearly demonstrate an additional action of trimazosin beyond blockade of alpha 1-adrenoceptors. Both trimazosin and prazosin augmented the hypotensive effect of sodium nitroprusside, but only trimazosin enhanced its relaxant effect on isolated rat aorta. Thus we conclude that in addition to alpha 1-adrenoceptor blockade, another mechanism contributes to the hypotensive effect of trimazosin, and we speculate that elevation of cyclic GMP levels in vascular smooth muscle may be related to this additional mechanism.

P-6 - The relationship between the hypotensive effect of sodium nitroprusside and adrenal catecholamine release

P-6 - The relationship between the hypotensive effect of sodium nitroprusside and adrenal catecholamine release

Accentuated hypotensive effect of sodium nitroprusside in man after captopril.

1. The effects of graded intravenous infusions of sodium nitroprusside on resting blood pressure and heart rate and on the reflex changes in these variables evoked by a standardized Valsalva manoeuvre were studied in six normal subjects. The effects of nitroprusside on the above variables were also studied after pre-treatment with captopril, to allow assessment of the role of angiotensin II. 2. Nitroprusside given in doses ranging from 7.5 to 150 μg/min elicited dose-related decreases in resting blood pressure and rise in heart rate and in plasma renin activity (PRA). After pretreatment with captopril, nitroprusside could not be given at doses above 60 μg/min without producing an unacceptable fall in blood pressure. The rise in heart rate in response to a given dose of nitroprusside was little altered after captopril. 3. Blood pressure and heart rate were studied during the last 10 s of the Valsalva manoeuvre. Before captopril the normal response (maintenance of blood pressure with tachycardia) was not altered by any dose of nitroprusside. Captopril alone also had no effect on the response but, with captopril plus high dose nitroprusside, mean arterial pressure during the manoeuvre decreased significantly, indicating impairment of reflex constrictor response. 4. These findings support the proposition that the angiotensin II response normally limits the fall in blood pressure during vasodilator therapy. We conclude that the greater fall in blood pressure and the impaired constrictor response to the Valsalva manoeuvre during nitroprusside infusion at moderate doses, in the presence of captopril, is due to the effect of the latter on the renin—angiotensin system. 5. A practical consequence of the present findings is that combined use of captopril and arterial vasodilators requires reduction in the dose of the latter drug. Awareness of this interaction may avert hypotension and could also allow nitroprusside infusion for longer periods without toxicity.

Sodium Nitroprusside

To date there has been no description of the hemodynamic dose-response relationship between enflurane and sodium nitroprusside (SNP), although these drugs are often used together to induce deliberate hypotension. Utilizing aortic root cannulation and thermistor-tipped pulmonary artery catheters, this relationship was studied in six beagles during 1 and 2% enflurane anesthesia and compared with the hemodynamic response induced by SNP in the awake state and during anesthesia with intravenous morphine (6 mg/kg). Each animal received a standard infusion of 100 microgram/kg of SNP administered at three different flow rates (5, 10, and 20 microgram/kg/min). SNP infusion resulted in dose-related reductions in mean arterial pressure, systemic vascular resistance and left ventricular stroke work, whereas cardiac output increased. Enflurane potentiated the hypotensive effects of SNP in a dose-related fashion. During morphine anesthesia, however, the hemodynamic effects of SNP were virtually indistinguishable from those observed in the awake state.

Sodium nitroprusside: factors which attenuate its action. Studies with the isolated gracilis muscle of the dog.

In a laboratory preparation of the isolated, acutely denervated, and separately perfused canine gracilis muscle we have made the following observations: 1. At physiological pH, sodium nitroprusside significantly decreases the vascular resistance; 2. At physiological pH, cyanide significantly attenuates the effect of sodium nitroprusside; 3. In an acidaemic milieu, our data suggest that the effect of sodium nitroprusside may be attenuated. We speculate that patients who manifest resistance to the hypotensive effect of sodium nitroprusside may not normally eliminate the cyanide that is released from the biodegradation of sodium nitroprusside. They accumulate free cyanide which interferes with the action of sodium nitroprusside at the receptor level, leading to administration of more nitroprusside and setting in motion a positive feedback vicious cycle. When one is faced with the problem of an abnormal response to sodium nitroprusside in a fit patient, although many factors may be involved, we suggest that the possibility of rising blood cyanide levels and acidosis be given high priority.