Red cell CA I and CA II activity was determined every day from blood collected before and 30 min after the administration of glycerol trinitrate. The blood samples for the determination of red cell CA I and CA II activity were collected before treatment, after 5 and 10 min of infusion, and 30 min after discontinuing treatment. CA activity was determined by the stopped-flow method. These results are summarized in Table 1 and Fig. NG predominantly inhibited CA I, the inhibition being complete after 2 days of treatment.
SNP reduced total CA activity in the red blood cells of rabbits; the decrease was progressive over the whole period of treatment. The presence of the same isozyme, CA I, both in erythrocytes and in vascular walls leads to the assumption that the modifications of its activity occur in parallel in both locations, which allows us to use the erythrocyte activity of CA I which can easily be determined as an indicator for CA I activity changes in vascular walls. The vasodilating mechanism of organic nitrates, such as NG and ISDN, described so far consists in generating NO by metabolic conversion mediated by free thiols or by an enzymatic mechanism such as is achieved by glutathione- S -transferase or the P cytochrome.
These results show that, along with the vasodilating effects of the three substances studied here, there also occurs a parallel inhibition of CA I.
This inhibition is progressive over the duration of the treatment, CA I activity being completely inhibited after 2 or 3 days of treatment, respectively, with NG and ISDN. After administration of SNP, whose effect sets in immediately, CA I activity is abolished within a 10 min infusion, but, after discontinuing treatment, the activity of the enzyme soon and gradually returns to initial values. Other studies performed here show that the rapid return of CA I activity to initial values after discontinuing treatment with SNP is parallel to the return of arterial hypertension to its initial values after the same therapy.
Our previous studies have in fact shown that NO is an inhibitor of CA I by a direct mechanism of action, 5 , 9 and that other vasodilators, substances such as PGE 2 , PGI 2 , 5 , 10 adrenergic receptor antagonists, nicotinates, calcium channel blockers, 5 thiazidic diuretics, amiloride, and triamterene, 11 also inhibit CA I along with vasodilation. Since the decrease of CA I activity accompanies the vasodilating effects of substances with various chemical structures, it leads to the hypothesis that CA I is involved in the modulation of vascular tonus.
This hypothesis is supported by the increase of CA I activity induced by vasoconstrictive substances with various chemical structures that activate the same isozyme in parallel with vasoconstriction. Our hypothesis is strengthened by other studies that show that acetazolamide, known as a specific inhibitor of CA, 1 doubtlessly possesses cerebral vasodilating properties, 12 as well as the hypotensive properties described by us.
As far as the mechanism of action of CA is concerned, its involvement in the modulation of the intra- and extracellular pH in vascular walls has been demonstrated. This hypothesis is also supported by recent studies carried out by a highly prestigeous team who reported that the blood pressure lowering effects of calcium channel blockade were inversely related to intracellular pH—ie, the lower the initial pH, the greater the antihypertensive effect.
Furthermore, nifedipine consistantly elevated intracellular pH values. The literature data prove more and more the role of intracellular pH in the regulation of vascular smooth muscle. An evaluation of steady-state intracellular pH in erythrocytes, using a nuclear magnetic resonance technique, has indicated that intracellular pH is reduced by about 0.
Other studies show that the intracellular control of pH in vascular smooth muscle cells is also modified. This might be important for the pathogenesis of hypertension by affecting either vascular smooth muscle tone or vascular smooth muscle growth. The hydrogen ion attracts interest in hypertension because plasma pH affects peripheral resistance vascular smooth muscle tone. In vascular smooth muscles, intracellular pH is rapidly modified, within the first 35 sec approximately, under the impact of extracellular pH changes.
Consequently a slight modification of plasmatic pH will affect intracellular pH and, as a consequence, vascular tonus. Studies concerning intracellular pH show that the action of primary extracellular messengers on secondary messengers cyclic nucleotide and calcium is a pH-dependent process. Thus a rise of intracellular pH is accompanied by activation of adenylate cyclase and guanylate cyclase, with production of cAMP and cGMP.
The decrease of intracellular pH was considered responsible for the reduction of adenylate and guanylate cyclase activity, and, consequently, for the reduction of cAMP and cGMP production. A summary of the data in the medical literature thus shows that arterial hypertension can be associated with anomalies in the regulation of intracellular pH. This hypothesis maintains that vasodilating stimuli and NO, respectively, possess dual and direct mechanism of action both on soluble guanylate cyclase 3 and on CA I, the latter being followed by a rise of intracellular pH with repercussions on the ligand-receptor complex, the G proteins, and the effector system.
Consequently CA is not a mere catalyst of CO 2 hydration, but, through the pH changes induced by its inhibition by means of various endogenous and exogenous vasodilating agents, might modulate the physiologic and pathologic vascular processes in the organism. The activation of CA I by vasoconstrictors, as described by us, 5 supports the hypothesis concerning the involvement of this isozyme in the regulation of vascular tonus.
Further research work is required to confirm this hypothesis and to assess the quantitative relations between CA I inhibition, intracellular pH modifications, and the production of cGMP. Maren TH : Carbonic anhydrase: chemistry, physiology and inhibition. Physiol Rev ; 47 4 : — Google Scholar. Gastroenterology ; 88 : — Feelisch M , Noack EA : Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase.
Eur J Pharmacol ; : 19 — Eur J Pharmacol ; : 29 — Puscas I et al. Helicon Publishing House , Timisoara, Romania , , pp — Google Preview. Aalkjaer C : Regulation of intracellular pH and its role in vascular smooth muscle function. J Hypertens ; 8 : — Khalifah RG : The carbon dioxide hydration activity of carbonic anhydrase. Stop-flow kinetic studies on the native human isozymes B and C. J Biol Chem ; : — Puscas I , Coltau M : Inhibition of carbonic anhydrase by nitric oxide.
Arzneim-Forsch Drug Res ; 8 : — Puscas I , Coltau M : Prostaglandins with vasodilating effects inhibit carbonic anhydrase while vasoconstrictive prostaglandins and leukotriens B 4 and C 4 increase CA activity. Int J Clin Phramacol Ther ; 33 3 : — Vorstrup S , Brun B , Lassen NA : Evaluation of the cerebral vasodilatatory capacity by the acetazolamide test before EC-C bypass surgery in patients with occlusion of the internal carotid artery. Stroke ; 17 : — Relation to blood pressure and effects of calcium channel blockade.
J Clin Invest ; 94 3 : — Austin C , Wray S : Extracellular pH signals affect rat vascular tone by rapid transduction into intracellular pH changes. J Physiol ; : 1 — 8. Ho KA et al.
Am J Physiol ; : C — C Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Nitroprusside is a potent arterial and venous vasodilator.
It produces more balanced arterial and venous dilation compared to nitroglycerin which is more of a venodilator particularly at low doses.
In contrast to nitroglycerin, nitroprusside does not depend on intracellular metabolism for conversion to NO, and can therefore deliver abundant NO to the coronary microcirculation.
It can also be used as an alternative to adenosine for the induction of hyperemia for the physiological assessment of coronary artery lesions. Adenosine is a potent vasodilator of small coronary resistance arterioles and does not have any vasoactive effects on the large epicardial arteries. The no-reflow phenomenon is characterized by a reduction in epicardial blood flow despite patency of the vessel, and is due to compromise of the integrity of the microvascular circulation.
The pathophysiology may vary depending on the clinical circumstances, but it is primarily due to distal microembolization, vasoconstriction and dysfunction of the microcirculation. No-reflow is most commonly encountered during percutaneous intervention in the setting of acute myocardial infarction or a high thrombus burden, with revascularization of degenerated saphenous vein grafts, and during the use of rotational atherectomy.
It is clinically important because its presence is associated with increased infarct size, impaired left ventricular function, and increased in-hospital and long-term mortality. One of the most common strategies to manage no-reflow during cardiac catheterization involves the use of vasodilators of the coronary microvasculature, such as adenosine or sodium nitroprusside. Maximal coronary hyperemia is required for the physiologic assessment of intermediate epicardial coronary lesions in the catheterization laboratory.
Adenosine is the drug of choice for induction of maximal hyperemia when performing fractional flow reserve FFR or coronary flow reserve CFR measurements.
Calcium channel blockers dilate vascular smooth muscle cells, reduce cardiac contractility, and some agents even slow AV node conduction. They lower global myocardial oxygen demand through reductions in myocardial oxygen demand arterial pressure, heart rate, and contractility.
However, their negative inotropic and chronotropic properties may be harmful in patients with severe heart failure or hemodynamic instability. IC calcium channel blockers exert their effects predominantly by dilating the small resistance arterioles but may also inhibit platelet aggregation in the microvasculature. Compared to adenosine and the nitro-vasodilators, calcium channel blockers are less commonly used during cardiac catheterization and intervention. Common routes of nitroglycerin administration in the catheterization laboratory are: intracoronary IC , intraarterial IA , sublingual SL , and intravenous IV.
SL nitroglycerin is rapidly absorbed with onset of action occurring within a few minutes, maximal effects occurring within 3 to 15 minutes, and effects subsiding within 20 to 30 minutes.
The rapid decrease in plasma concentration after discontinuation of the infusion is due to its short half-life. Optimal IC dosing of nitroglycerin and many other vasodilators remains uncertain due to the lack of adequately powered clinical trials.
Spasm of the ostium of the right coronary artery or the left main artery may be more effectively treated with sublingual or IV nitrates, since ostial segments may be less exposed to nitroglycerin administered through the diagnostic or guiding catheter. Since vasodilators delivered through the guiding catheter may not reach the microcirculation due to no-reflow itself, an infusion catheter can be used to maximize delivery of the drug to the distal microvasculature.
IV infusion of nitroprusside should begin at 0. Invasive arterial pressure monitoring is generally recommended due to its potent hemodynamic effects. The infusion should be limited to 48 hours in duration because cyanide toxicity can occur over time as cumulative doses increase. It should be used cautiously in patients with liver or kidney disease.
Tapering the dose of nitroprusside prior to discontinuation is recommended to avoid the possibility of rebound hypertension. For the treatment of no-reflow, multiple boluses of high doses of IC adenosine should be administered. Since vasodilators delivered through the guiding catheter may not reach the microvessels due to no-reflow itself, an infusion catheter can be used to maximize delivery of the drug to the distal microvasculature. Either IV or IC adenosine can be used to induce maximal hyperemia for the physiologic assessment of coronary artery lesions.
IC adenosine achieves maximal hyperemia within 5 to 30 seconds. Adenosine hyperemia lasts less than 60 seconds after drug administration has ended. For the treatment of reentrant supraventricular arrhythmias, 6 to 12 mg IV boluses are usually administered and repeated if necessary. Intraarterial verapamil 3 mg may be given for the prevention of radial artery spasm during transradial catheterization.
Nitroglycerin produces its major biological effect by releasing nitric oxide NO. Its actions are, therefore, similar to the endothelium-derived NO; however, it does not require endothelium to exert its action i. It produces vasodilation by directly relaxing vascular smooth muscle cells in the walls of arteries and veins. The mechanism involves the biotransformation of nitroglycerin to NO, which subsequently activates cyclic GMP and results in smooth muscle relaxation through mechanisms involving intracellular calcium reduction.
The hemodynamic effects of nitrates are dose-dependent. Systemic veins become near maximally dilated at relatively low doses, while arterial vasodilation occurs at higher doses.
At very high doses, arterioles or resistance vessels also dilate. This differential activity occurs because biotransformation of nitroglycerin in the coronary circulation primarily occurs in the epicardial arteries, while the small coronary arterioles are not capable of converting nitroglycerin to nitric oxide. Since coronary perfusion is predominantly regulated by the coronary microcirculation, nitroglycerin produces only a small and brief effect on coronary flow.
In addition to vasodilation of epicardial coronary vessels, nitroglycerin dilates and augments coronary collateral blood flow. This is likely due to a combination of factors including nitroglycerin-induced alterations in regional flow and collateral perfusion pressure, reduction in left ventricular wall stress, and direct action on collateral vessel smooth muscle. The antianginal effects of nitroglycerin are due to a combination of enhanced oxygen delivery via coronary vasodilation and decreased myocardial oxygen consumption from reductions in left ventricular preload, afterload, and wall tension.
Nitroprusside is an endothelial-independent direct donor of NO. NO activates smooth muscle soluble guanylyl cyclase to form cGMP. Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and resulting in smooth muscle relaxation.
It is effective at dilating both the epicardial coronary arteries and the small resistance arterioles. The hyperemic response to IC nitroprusside is fast, with peak coronary blood flow occurring within 20 seconds after IC bolus administration, and is more prolonged compared with adenosine. Cyanide molecules are released as nitroprusside undergoes metabolism to NO, but cyanide toxicity is rare at clinically used doses. Cyanide is metabolized to thiocyanate in the liver and then eliminated via the kidneys.
Adenosine is an endogenous purine nucleoside with a very short half-life 5 to 10 seconds. Vasodilation of the coronary arteries occurs through activation of the A2A receptors in vascular smooth muscle cells and is endothelium-independent.
Activation of the A2A receptor leads to an increase in adenylate cyclase activity and subsequent increase in intracellular cyclic AMP. The electrophysiologic effects of adenosine result from binding to specific A1 receptors, which slow conduction in the sinoatrial node, AV node, and atrial myocytes. Methylxanthines e. In contrast, dipyridamole inhibits the breakdown of adenosine and enhances its effect.
Calcium channel blockers bind to and block the L-type voltage-gated calcium channels located on vascular smooth muscle cells. The intracellular calcium reduction promotes smooth muscle relaxation and results in vasodilation. Calcium channel blockers also bind to calcium channels on cardiac myocytes resulting in reduced cardiac contractility.
Certain nondihydropyridine calcium channel blockers bind to receptors on the sinoatrial and AV nodes and decreased nodal conduction. No reflow: Nitroprusside has been shown to be a safe and effective therapy for no-reflow during PCI. Various doses of IC nitroprusside have been used in the management of no-reflow and repeated doses may be required to achieve satisfactory coronary flow. It is important to administer the IC nitroprusside into the distal coronary bed via a microcatheter or the lumen of a balloon angioplasty catheter advanced distally.
In cases of refractory no-reflow, the combination of IC adenosine and nitroprusside is safe and may be potentially more effective than adenosine alone. There may also be a role for prophylactic IC nitroprusside in patients at high-risk of developing no-reflow with PCI e. Physiologic assessment of coronary artery lesions: Nitroprusside appears to be a suitable hyperemic stimulus for coronary physiologic measurements, but is used less frequently than adenosine.
No-reflow: Studies have shown that IC adenosine is associated with decreased incidence of no-reflow and improved LV function in patients undergoing emergent revascularization for acute myocardial infarction AMI. Intragraft administration of adenosine is also effective when employed during percutaneous intervention of saphenous vein grafts.
Multiple boluses of intragraft adenosine are associated with improvement of no-reflow complicating vein graft interventions. Adenosine may be given either IV or IC for the induction of maximal coronary hyperemia. However, in few cases, coronary hyperemia may be suboptimal with IC adenosine compared with IV.
IV adenosine produces more uniform hyperemia and is generally the recommended approach when performing FFR. IV adenosine has also the advantage of being weight-based and free of operator interference. It is also required for ostial lesions or for the assessment of diffuse disease during pullback recordings.
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