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PubMed1998

Prophylactic effect of papaverine prolonged-release pellets on cerebral vasospasm in dogs.

OBJECTIVE: A drug delivery system using copoly(lactic/glycolic acid) was developed for the intracranial administration of papaverine. A rod-shaped implant prepared by a heat compression method was tested to determine its efficacy in preventing cerebral vasospasm in dogs. METHODS: Sixteen dogs were randomly assigned to one of two groups, i.e., placebo or papaverine. Control angiography was performed, followed by right craniectomy and the induction of subarachnoid hemorrhage by the placement of a clot in the Sylvian fissure. Two pellets, containing either 25 mg of papaverine or no papaverine, were placed in the cistern. In in vitro studies, 56% of the actual papaverine loading was released in the first 4 days and 78% within 8 days. On Day 7, angiography was repeated and the animals were killed. A similar experiment using low-dose pellets containing 5 mg of papaverine, half of which was released within 7 days, was performed with 16 mongrel dogs. RESULTS: There were significant differences between the papaverine- and placebo-treated groups in the reductions of vessel diameters of the internal carotid, middle cerebral, and anterior cerebral arteries on the clot side. The mean concentration of papaverine in the clot was 4.5 x 10(-4) mol/L. The low-dose pellet failed to prevent cerebral vasospasm, although the mean concentration of papaverine in the clot was 2.3 x 10(-5) mol/L. CONCLUSION: A prolonged-release preparation of papaverine that could be implanted intracranially at the time of surgery prevented vasospasm significantly while maintaining an appropriate concentration of papaverine in the cistern.

Animals↗
PubMed1992

Papaverine reduces the sodium permeability of the apical membrane and the potassium permeability of the basolateral membrane in isolated frog skin.

The effect of papaverine, an inhibitor of the phosphodiesterase responsible for breakdown of cAMP, on the transepithelial sodium transport across the isolated frog skin was investigated. Serosal addition of papaverine caused initially an increase in the short-circuit current (SCC), a doubling of the cellular cAMP content and a depolarization of the intracellular potential under SCC conditions (Vscc). The initial increase in the SCC was followed by a pronounced decrease both in the SCC and in the natriferic action of antidiuretic hormone (ADH), but papaverine had no inhibitory effect on the ability of ADH to increase the cellular cAMP content. As SCC declines, no hyperpolarization was observed. The I/V relationship across the apical membrane during the inhibitory phase, revealed that papaverine reduces the sodium permeability of the apical membrane (PNaa) as well as intracellular sodium concentration. These observations and the previously noted effect of papaverine on Vscc indicates that papaverine must have an effect on the cellular Cl or K permeability. The basolateral Na,K,2Cl cotransporter was blocked with bumetanide, which should bring the cellular chloride in equilibrium. Bumetanide had no effect on basal SCC and Vscc. When papaverine was added to skins preincubated with bumetanide, the effect of papaverine on SCC and Vscc was unchanged. Therefore, the depolarization of Vscc, observed during the papaverine-induced inhibition of the SCC, must be due to a reduction in the cellular K permeability. In conclusion, it is suggested that papaverine reduces the sodium permeability of the apical membrane and the potassium permeability of the basolateral membrane of the frog skin epithelium.

Animals↗
PubMed1990

Effects of papaverine on human isolated bladder muscle.

Papaverine is a non-specific smooth muscle relaxant and is thought to act at a site beyond the receptor sites on the cell membrane. In this study the relaxing properties of papaverine were tested in isolated muscle strips from the human bladder dome. In carbachol-induced contractions papaverine, even in high concentrations of 10(-4) mol/l had virtually no effects on peak tension generation, whereas the fading was accelerated and the steady state tension at 30 min. was reduced by about 54%. In contrast, high potassium-induced contractions were relaxed by papaverine in a concentration-dependent way; a concentration of papaverine of 10(-4) mol/l produced full relaxation. These findings might possibly be explained if it is assumed that papaverine blocks calcium ion channels in the cell membrane. However, the observation that rather high concentrations of papaverine were necessary to fully relax high potassium contractions and the fact, that papaverine affects cellular cAMP levels separate this drug from more selective calcium channel blockers. The calcium movements responsible for the peak tension generation in carbachol-induced contractions are obviously not affected by papaverine. Although papaverine had little effect on carbachol-induced contractions in vitro it cannot be excluded that the drug is effective in diseases were non-cholinergic mechanisms are involved.

Calcium Channel Blockers↗
PubMed1977

Effect of papaverine on the frequency-force relationship in guinea-pig left atria.

Contractile responses of guinea-pig atria to papaverine were analyzed under different stimulation frequencies. Atria, driven at 2 Hz, showed positive inotropic responses to papaverine which were maximal within 10-15 min. These responses were maintained for 60 min in the presence of low concentrations of papaverine (up to 10(-5) M), but reversed into marked negative inotropic effects under the influence of higher concentrations. The well-known frequency-force relationship was reversed by papaverine. At low stimulation rates papaverine elicited positive inotropic responses, which gradually decreased with increasing frequencies until strong cardiodepression occurred. A frequency-force curve obtained in the presence of both the Ca2+-antagonistic drug D 600 and the inhibitor of the phosphodiesterase theophylline was similar to that obtained under the influence of papaverine. Theophylline alone evoked positive inotropic effects at all frequencies studied and left the character of the ascending staircase unchanged. In contrast, D 600 was ineffective at low, but cardiodepressive at high stimulation frequencies. In the presence of D 600 or papaverine high external Ca2+ could not restore a normal frequency-force relationship. The reversal of the frequency-force relationship as produced by D 600 and papaverine could not be obtained by lowering of the external Ca2+. The present results show that papaverine is able to evoke marked positive inotropic effects at low stimulation frequencies by inhibition of phosphodiesterase. At high frequencies, however, these effects are masked by negative inotropic responses due to the inhibitory action of papaverine on Ca2+-exchange of the cardiac muscle cell.

Animals↗
PubMed2004

Arterial endothelial denudation by intraluminal use of papaverine-NaCl solution in coronary bypass surgery.

OBJECTIVES: Preservation of endothelial integrity during coronary artery bypass grafting is considered important for short- and long-term patency of the graft. In current literature there are controversial data about the safety of papaverine, a vasorelaxant widely used in coronary artery bypass grafting. Accordingly, we examined the immediate effects of papaverine on the endothelial morphology of arterial grafts and on viability of cultured human coronary artery endothelial cells. METHODS: Totally 22 segments of the radial artery were collected from 11 patients undergoing coronary artery bypass grafting. The segments were cut from the distal redundant parts of the arteries, which were not required for bypass grafting. A small distal segment of the artery was excised and placed into autologous heparinized whole blood (control segment). The rest of the graft, still remaining proximally attached to the circulation, was treated intraluminally with papaverine-NaCl solution (pH 4.2) for 5 min, after which another small distal segment was excised for the study (papaverine-treated segment). Segments were then perfusion-fixed and the endothelial surface was examined by scanning electron microscopy. Endothelial denudation was assessed and its severity graded. Additionally, viability of cultured human coronary artery endothelial cells after treatment with papaverine was assessed with trypan blue staining. RESULTS: Treatment with papaverine solution markedly increased the endothelial denudation (grades from 6.2+/-1.7 to 10.0+/-3.5; mean+/-SD; P=0.004). Papaverine-treatment increased trypan blue staining of cultured human coronary artery endothelial cells regardless of papaverine diluent (normal saline of pH 4.5 or 7.4 or blood). CONCLUSIONS: Treatment of arterial grafts with papaverine solutions apparently damages endothelial cells. Thus, the clinical practice of dilating arterial bypass grafts with papaverine should be reassessed, and alternative methods of vasodilatation should be considered.

Aged↗
PubMed1997

Effect of papaverine on synaptic transmission in the guinea-pig ileum.

1. The effect of papaverine, a well known smooth muscle relaxant, was investigated on neural transmission within the enteric nervous system. Segments of guinea-pig ileum were placed in a partitioned bath to enable drugs, including papaverine, to be applied to enteric nerve pathways without interfering with the recording of the smooth muscle contraction. Ascending excitatory enteric nerve pathways were activated by electrical field stimulation in the anal compartment (10 Hz for 2 s, 45 mA, 0.5 ms pulse duration) and the resulting contraction of the intestinal circular muscle in the oral compartment was recorded isotonically. 2. Tetrodotoxin (0.6 microM) and hexamethonium (100 microM) both abolished, or greatly reduced, the contractions when applied to either compartment indicating that nicotinic synapses are involved in this pathway. 3. Papaverine (0.3-30 microM) applied independently to each compartment depressed in a concentration-dependent manner, the nerve-mediated contractions. The IC50 of this inhibitory effect was 3.53 microM for the oral and 4.76 microM for the anal compartments, respectively. Two other phosphodiesterase (PDE) inhibitors, 3-isobutyl-1-methylxanthine (IBMX 10-300 microM) and theophylline (30-1000 microM) added to the anal compartment also inhibited the nerve mediated contractions. Papaverine applied to the anal bath, after IBMX 100 microM (or theophylline 300 microM) further inhibited the nerve-mediated contractions, but was less effective than when applied alone. 4. Phentolamine (1 microM), an alpha-adrenoceptor antagonist, reduced the inhibitory effect of papaverine, but not that of IBMX (100 microM) or theophylline (300 microM). A combination of phentolamine and IBMX (or theophylline) prevented the inhibitory effect of papaverine. 5. Tetrodotoxin, but not papaverine or hexamethonium, inhibited the contraction elicited by electrical stimulation just anal to the partition indicating that papaverine did not affect the generation or conduction of nerve action potentials. 6. Verapamil (1 microM) and nifedipine (1 microM), two smooth muscle relaxants which act by blocking L-type calcium channels, only inhibited the contractions when applied directly to the recording (oral) compartment. This indicates that L-type Ca2+ channels are probably not involved in synaptic transmission in these ascending pathways and thus that the PDE inhibitors do not inhibit synaptic transmission by acting on these channels. omega-Conotoxin GVIA (10 nM), a potent inhibitor of the N-type Ca2+ channels, blocked the nerve-mediated contractions applied to either compartment. Whether the PDE inhibitors exert their inhibitory actions via these channels remains to be established. 7. The results indicate that the PDE inhibitors, papaverine, IBMX and theophylline inhibit excitatory enteric neural pathways by depressing synaptic transmission. The inhibitory effect of papaverine (but not IMBX or theophylline) involves, at least in part, the release of noradrenaline from sympathetic nerves acting on alpha-adrenoceptors on enteric neurones.

1-Methyl-3-isobutylxanthine↗
PubMed1970

The effects of papaverine on the electrical and mechanical activity of the guinea-pig taenia coli.

1. Effects of papaverine (5 x 10(-6)-5 x 10(-5)M) were studied on the spontaneous and evoked electrical and mechanical activity of the guinea-pig taenia coli. In normal Locke solution, papaverine slowed and finally stopped the spontaneous spike discharge, usually with a small hyperpolarization of a few mV.2. Papaverine did not change the membrane resistance in normal Locke solution. It abolished the repetitive firing of spikes during the depolarization in response to a current pulse, but a single spike of normal amplitude could always be evoked.3. The mechanical response elicited by a single spike was reduced by papaverine in normal Locke solution. During the maintained depolarization produced by a long current pulse the tonic component of the contraction was more reduced than the phasic component related to the initial spike activity.4. The effects of papaverine were essentially the same as in normal Locke solution when NaCl was replaced with LiCl, or in excess K (24 mM), except that the membrane resistance was increased by papaverine in the presence of excess K.5. Excess Ca (6 mM) antagonized the effect of papaverine on the mechanical response, but not on the electrical response. When the muscle was depolarized in Ca-free solution, papaverine caused repolarization of the membrane and electrical activity reappeared. This effect was similar to that of Mg (4 mM).6. The mechanism by which papaverine suppresses the spontaneous spike activity is discussed and is compared with that of isoprenaline, from which it appears to differ. The observations indicate that papaverine, like Mg, may bind with a site at the membrane with which Ca normally binds, thereby modifying the electrical and mechanical activity controlled by Ca.

Action Potentials↗
PubMed1994

Relationship between cytosolic calcium concentration and force in the papaverine-induced relaxation of medial strips of pig coronary artery.

1. The mechanisms of vasorelaxation induced by papaverine were investigated using front-surface fluorometry and fura-2-loaded medial strips of the pig coronary artery. 2. In the presence of extracellular Ca2+ (1.25 x 10(-3) M), histamine (10(-4) M) induced abrupt elevations of cytosolic calcium concentration, [Ca2+]i reaching a peak within 12 s (the first phase); after making a slight shoulder, [Ca2+]i declined gradually to reach sustained levels (the second phase). Force rapidly rose to reach maximum levels in 3 min, then gradually declined. Papaverine (10(-7)-10(-5) M) inhibited both the first and the second phases of [Ca2+]i elevation and the development of force induced by histamine, in a concentration-dependent manner. 3. In the absence of extracellular Ca2+, histamine (10(-4) M) induced a transient increase in [Ca2+]i and force, both of which were inhibited in a concentration-dependent manner by papaverine (10(-7)-10(-5) M). When papaverine was washed out, a second application of 10(-4) M histamine also induced transient increases in [Ca2+]i and force. The smaller the first response, the greater was the second response. The total amount of [Ca2+]i released from intracellular stores by the first and second application of histamine in the presence of papaverine was smaller than in its absence, thereby indicating a reduction of Ca2+ in the histamine-sensitive store. However, while papaverine (10(-5) M) did not affect the transient increase in [Ca2+]i induced by 2 x 10(-2) M caffeine, contractions were inhibited. 4. For a given level of [Ca2+]i, the force developed with the cumulative application of histamine(10-7 M-10-1 M) was greater than that observed with the cumulative application of extracellular Ca2+(0-7.5 x 10-3 M) during high K+ depolarization. Papaverine (10-7 M-10-5M) suppressed, in a concentration-dependent manner, the increase in [Ca2+]i and the force induced by cumulative applications of both histamine and extracellular Ca2+ during high K+ depolarization. The [Ca2+]i-force curve obtained by depolarization with K+, but not that obtained during histamine application, was shifted to the right by papaverine. Diltiazem, 10-7 M, a concentration causing a similar degree of relaxation to 10-5 M papaverine, did not shift the [Ca2+]i-force curve obtained with high K+. Nitroglycerin (10-6 M)and isoprenaline (10-6 M) shifted the [Ca2+]i-force curve to the right to a greater extent than did 10-5 M papaverine.5. These findings suggest that papaverine relaxes medial strips of the porcine coronary artery by two mechanisms. The first is mainly due to a decrease in [Ca2+]i, not only through inhibiting Ca2+ influx through either voltage-dependent or receptor-operated Ca2+ channels, but also by inhibiting agonist induced intracellular Ca2+ release. This occurs presumably by interference with the signal transduction pathway for histamine and by a depletion of Ca2+ in histamine-sensitive stores. Secondly, the [Ca2+]i-sensitivity of certain contractile mechanisms may be minimally decreased.

Animals↗
PubMed1983

The effects of papaverine on the electrical and mechanical activity of the guinea-pig ureter.

1. The effects of papaverine (10(-5)-2 X 10(-4) M) were studied on the evoked electrical and mechanical activity of the guinea-pig ureter smooth muscle. In normal conditions the action potential consists of an initial spike followed by further spikes superimposed on a plateau phase. Papaverine reversibly decreased the duration of the plateau of the action potential, blocked the associated spikes, greatly reduced the amplitude of the contraction but enhanced the initial component of the action potential. 2. Papaverine did not change the membrane potential and had little effect on the membrane resistance. 3. Tetraethylammonium (5 mM), which blocks the delayed outward K current, did not prevent the decrease in the duration of the plateau nor the decrease of the contractile response caused by papaverine. 4. In Na-free solution the duration of the action potential was decreased until only a single spike was seen, due to suppression of the plateau. An effect of papaverine could not be observed under these conditions. 5. Mn2+ ions (1 mM) completely suppressed the spike component and tension while the plateau component was substantially increased. Papaverine in the presence of Mn2+ reversibly blocked the generation of the action potential. When Mn2+ ions were added to Na-free solution the duration as well as the amplitude of the spike was increased. Again, papaverine reversibly blocked the generation of the action potential. 6. Noradrenaline (10(-4) M) and histamine (10(-5) M) in normal conditions prolonged the duration of the action potential plateau and increased both the duration and amplitude of the concentration. Papaverine again blocked the plateau and greatly reduced the contractile response. 7. Papaverine caused the relaxation of KCl-induced contractures, preferentially blocking the tonic component. 8. It is suggested that the inhibitory action of papaverine on ureter smooth muscle results from its specific blockade of the 'slow' Na/Ca channels responsible for the generation of the plateau component of the action potential.

Action Potentials↗
PubMed1986

Influence of papaverine on cyclic nucleotide level and cellular metabolism in rat kidney cortex in terms of its inhibitory effect on p-aminohippurate transport.

We attempted to determine whether there is a possible link between the effect of papaverine on p-aminohippurate (PAH) accumulation, on cyclic nucleotide content and on certain other cellular functional parameters in rat kidney cortical slices in vitro. Papaverine at a concentration of 0.1 mM almost completely inhibited PAH accumulation in the slices. However, cyclic guanosine 3', 5'-monophosphate (cyclic GMP) and cyclic adenosine 3', 5'-monophosphate (cyclic AMP) levels in the slices were not significantly affected by papaverine at 0.1 mM, though papaverine at a concentration of 1 mM increased the cyclic GMP level without affecting the cyclic AMP level. Papaverine (0.1 mM) produced a decrease in the sodium gradient and in the adenosine triphosphate (ATP) level in the slices. Calcium uptake by mitochondria, isolated from kidney cortex, was apparently decreased in the presence of 0.1 mM papaverine. These results suggest that the inhibition of phosphodiesterase probably does not explain the action of papaverine on PAH accumulation in the slices. The inhibition of PAH accumulation by papaverine is partly a reflection of the fall in the sodium gradient in the slices treated with papaverine. In addition, a depression of ATP level in the slices and an inhibition of mitochondrial calcium uptake may be related to a possible mechanism of action of papaverine on PAH accumulation.

1-Methyl-3-isobutylxanthine↗
PubMed1993

CT arterial portography of the abdomen: effect of injecting papaverine into the mesenteric artery on hepatic contrast enhancement.

OBJECTIVE: The purpose of this study was to determine the effect of precontrast injection of papaverine hydrochloride into the superior mesenteric artery on the degree of contrast enhancement of the hepatic parenchyma during CT arterial portography (CTAP, CT with injection of contrast material into the superior mesenteric artery). SUBJECTS AND METHODS: Twenty-two patients were included in this study. All patients had a baseline unenhanced CT scan and then had CTAP performed with transcatheter injection of 150 ml of nonionic iodinated contrast material (30 g iodine/100 ml) at a rate of 2 ml/sec. Eleven patients received a precontrast injection of 40 mg of papaverine hydrochloride via catheter into the superior mesenteric artery, and 11 patients had CTAP without papaverine hydrochloride. Attenuation of the liver was measured before and after contrast administration in both groups of patients. For each CTAP section, the absolute hepatic enhancement (postcontrast attenuation--precontrast attenuation) and the relative hepatic enhancement ([absolute hepatic enhancement/precontrast attenuation] x 100) were calculated. Also, the mean absolute enhancement and the mean relative enhancement for the entire liver were calculated for each patient. RESULTS: The mean relative enhancement (+/- SD) of hepatic parenchyma was 192 +/- 54% with papaverine hydrochloride and 146 +/- 26% without papaverine hydrochloride. Relative enhancement was significantly higher when papaverine hydrochloride was used (p < .02). The mean absolute enhancement (+/- SD) of hepatic parenchyma was 123 +/- 25 H with papaverine hydrochloride and 91 +/- 19 H without papaverine hydrochloride. Absolute enhancement was significantly higher in patients who had papaverine hydrochloride (p < .01). CONCLUSION: The results show that precontrast transcatheter infusion of papaverine hydrochloride increases the degree of contrast enhancement of the liver during CTAP.

Aged↗
PubMed1981

Influence of papaverine on bethanechol or OP-CCK stimulation of feline colonic muscle.

Papaverine relaxes smooth muscle from various organ systems throughout the body. The purpose of this study was to determine the effects of papaverine on colonic smooth muscle from the transverse colon of the cat. Myoelectrical activity was recorded with monopolar glass pore electrodes. Papaverine was administered alone and simultaneously with bethanechol or the octapeptide of cholecystokinin. Higher concentrations of papaverine (10(-4) M, 10(-5) M) abolished both slow-wave activity and migrating spike bursts. Lower concentrations of papaverine (10(-6) M) had no effect on slow waves or the migrating spike burst. Bethanechol (10(-6) M) or OP-CCK (4 x 10(-9) M, 4 x 10(-10) M) stimulated spike activity (p < 0.001). Papaverine (10(-6) M had a minimal effect on the increase in spike activity that occurred after octapeptide of cholecystokinin in a concentration of 4 x 10(-10) M (p < 0.05). Papaverine had no effect on the stimulation of the colonic smooth muscle by 4 x 10(-10) M octapeptide of the colonic smooth muscle by 4 x 10(-9) M octapeptide of cholecystokinin. These studies show that (a) papaverine can inhibit smooth muscle myoelectrical activity, (b) papaverine is a potent inhibitor of cholinergic stimulation of colonic smooth muscle, but (c) papaverine has a minimal effect on octapeptide of cholecystokinin stimulation of the isolated colonic smooth muscle.

Animals↗
PubMed1996

[Oral papaverine prevents morphine-induced constipation without interfering with analgesia achieved with oral morphine].

Long-term administration of morphine for the treatment of chronic pain produces constipation; this requires the use of laxatives, which impair water absorption and upset the electrolyte balance. Morphine-induced constipation is mainly due to inhibition of the propulsive movement of the gastrointestinal tract combined with spastic contraction of smooth circular muscles as a result of drug binding to opioid receptors in the tract. Since papaverine lacks affinity for opioid receptors but relaxes smooth muscle, it seemed possible that oral papaverine might be capable of diminishing constipation without impairing the analgesia achieved with morphine. For this purpose, experiments were carried out on rats: constipation was checked for by measuring the intestinal transit time, and analgesia was assessed by measuring the latency of the tail-flick response to radiant heat or nociceptive activity in single neurons of the thalamus evoked by supramaximal electrical stimulation of afferent C fibres in the sural nerve. Morphine and papaverine were administered by the oral route. Control animals received saline. To measure the intestinal transit time, India ink solution was given orally. Morphine (2.5 and 5 mg/kg orally) prolonged the transit time from approx. 420 min in the controls to more than 600 min, a dose of 2.5 mg/kg producing the maximum effect. Papaverine (0.5, 1, and 2 mg/kg) administered orally together with morphine significantly reduced morphine-induced constipation (Tables 1, 2). Papaverine given alone at a dose of 2 mg/kg caused no change in transit time, while 5 mg/kg significantly increased it (Table 2). The latency of the tail-flick response was increased by oral morphine (2.5 and 5 mg/kg) at 1, 2, and 3 h after administration. Papaverine (0.5, 1 and 2 mg/kg) given in combination with morphine left the antinociceptive effect of morphine unchanged (Figs. 1-3). A study of the nociceptive activity evoked in thalamus neurons of rats under urethane anaesthesia indicated that intestinal absorption of morphine was blocked. Therefore, metoclopramide (0.15 mg/kg) was injected i. v. 10 min before oral administration of morphine or the combination of morphine plus papaverine. Subsequently, morphine produced a dose-dependent depression of evoked nociceptive activity (Fig. 4), the mean effect amounting to 60 % of the control activity and being produced by 2.5 mg/kg (Fig. 5). Since in former experiments on nociceptive activity evoked in thalamus neurones it has been found that the ED(50) of i. v. morphine is 0.05 mg/kg, it is very likely that the presystemic elimination of orally administered morphine is very high and, in addition, that the efficiency of its active metabolite, morphine-6-glucuronide, is rather poor. When morphine 2.5 mg/kg was given together with papaverine 0.5 mg/kg, and morphine 5 mg/kg was administered in combination with papaverine 2 mg/kg, there was no significant reduction in the depressant effect of morphine on nociceptive activity evoked in thalamus neurons (Figs. 6, 7). The results suggest that papaverine given by the oral route may reduce morphine-induced constipation without impairment of the analgesic action of morphine in patients suffering from pain.

English Abstract↗
PubMed1988

Does intracoronary papaverine dilate epicardial coronary arteries? Implications for the assessment of coronary flow reserve.

Intracoronary papaverine is used as a means to induce a strong and short-lasting hyperemia in several recently developed methods to measure coronary flow reserve. Changes in stenosis geometry from papaverine would influence the measured coronary flow reserve. Therefore, we investigated the influence of intracoronary papaverine on stenosis geometry with quantitative analysis of the coronary angiogram and assessed the influence of papaverine on pressure-flow characteristics of the stenosis and coronary flow reserve. The cross-sectional areas (mean +/- SD) of the stenosis increased 18% +/- 7% after papaverine. The normal proximal and distal parts of the coronary artery dilated 5% +/- 2% after papaverine. This results in a decrease of the calculated pressure drop over the stenosis varying from 20% to 30%. Coronary flow reserve of a flow-limiting epicardial stenosis is overestimated by 16% when papaverine is used to induce hyperemia. These papaverine-induced changes can nevertheless be circumvented by maximal vasodilation of the major epicardial coronary artery with 3 mg intracoronary isosorbidedinitrate prior to the investigation of the coronary flow reserve with papaverine.

Angiography↗
PubMed1975

Effects of papaverine on isolated rabbit papillary muscle.

The effect of papaverine on the positive inotropic response to isopreqaline and to calcium was studied on the rabbit isolated papillary muscle; theophylline and the calcium antagonistic D600 were used for comparison. The dose-response curve for isoprenaline was shifted to the left by papaverine (3 times 10- minus 6 to 3 times 10- minus 5 M), in a dose-dependent manner, while that for calcium was not affected by the same concentration. In this respect papaverine was about 30 times more potent than theophylline. In the presence of papaverine isoprenaline induced arrhythmic contractions of the papillary muscle: the incidence of arrhythmic contractions was positively correlated to the concentration of papaverine. Papaverine 10- minus 5 to 10- minus 4 M caused only a positive inotropic response whereas 3 times 10- minus 4 to 10- minus 3 M induced a biphasic response, i.e., after a positive inotropic effect followed a negative one. In the presence of 3 times 10- minus 4 M papaverine isoprenaline failed to cause a positive inotropic response but exclusively induced arrhythmic contractions. Calcium, on the other hand, readily antagonized the negative inotropic effect of papaverine (3 times 10- minus 4 M) and caused a contracture of the papillary muscle. The results indicate that papaverine (3 times 10- minus 6 to 10- minus 5 M) like theophylline (10- minus 4 to 10- minus 3 M) produces its effect by phosphodiesterase inhibition and thereby specifically potentiates the response through beta-adrenoceptor stimulation. In higher concentrations (3 times 10- minus 4 to 10- minus 3 M) it acts as a calcium antagonistic, like D600, and furthermore may interact with calcium moving through myocardial cell membranes to cause a contracture via a mechanism which it shares with theophylline.

Animals↗
PubMed1976

Pharmacologic analysis of papaverine-induced positive chronotropic and inotropic effects.

Effects of papaverine on sinus rate and atrial contractility were investigated using the isolated atrium preparation of the dog perfused with heparinized arterial blood led from a support dog. When papaverine was injected into the cannulated sinus node artery, positive chronotropic and inotropic responses were dose-relatedly produced from about 3 mug. At a dose level above 100 mug, papaverine induced initially slightly negative chronotropic and inotropic effects followed by marked positive ones. Papaverine-induced positive chronotropic and inotropic effects (P-PCIE) were not influenced by treatment with tetrodotoxin which blocked the action of nicotine. P-PCIE were slightly suppressed by an adrenergic beta-blocking agent, alprenolol, which blocked the action of norepinephrine. They were however potentiated by treatment with desmethylimipramine which completely blocked the action of tyramine. A large amount of MnCl2 suppressed the actions of both papaverine and norepinephrine. Papaverine-induced negative chronotropic and inotropic effects were not influenced by atropine treatment. In addition, papaverine slightly potentiated the negative chronotropic and inotropic responses to adenosine. From these results, it appears that papaverine has a direct stimulating property on sinus rate and atrial contractility which may be due to inhibition of phosphodiesterase and successive accumulation of cyclic AMP. Moreover, papaverine may partially cause catecholamine release from adrenergic nerve fibers and it may inhibit the adenosine uptake mechanism.

Alprenolol↗
PubMed1992

Papaverine effects on PGI2 and TXA2 release from the canine vascular wall.

Operative manipulation of blood vessels might lead to spasm, thereby destroying the endothelial cell function: the spasm can be prevented by the vasodilator papaverine. To study if this was mediated via the prostanoid pathway the following investigation was undertaken: canine jugular veins and carotid arteries were dissected with or without papaverine. Vessel segments were then perfused with Hank's balanced salt solution for five times 15 min. Prostacyclin was measured as the stable degradation product 6-keto-PGF1 alpha and thromboxane as TXB2, by radioimmunoassay. Control arterial segments' 6-keto-PGF1 alpha release was initially 129.5 + 20.1 pg/mm2/15 min, and 29.7 + 10.4 after 60 min (p less than 0.05 vs initial value) and responded to arachidonic acid (AA) with an increase to 139.2 +/- 23.1 pg/mm2/15 min (p less than 0.05). Segments treated with papaverine had the same release as the controls. In venous segments there was a lower initial release (p less than 0.05) from segments given papaverine than from controls, but this was more likely an effect of papaverine on the assay. There was no difference in release of prostacyclin from segments given papaverine in the perfusate compared to controls when using 125I tracer. When using 3H tracer including absorption of free antigen to dextran coated charcoal, papaverine displaced the free tracer giving artificially low values. There was no effect of papaverine given intraoperatively on the TXB2 release, neither from arteries nor from veins. In another experiment the vessel wall tension was examined and the cyclooxygenase inhibitor diclofenac did not inhibit the vasodilating effect of papaverine.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Clinical significance of coronary flow reserve: effect of papaverine and exercise.

BACKGROUND: The clinical significance of coronary flow reserve (CFR) was evaluated after pharmacological (papaverine) and physiological (exercise) vasodilation in patients with coronary artery disease (CAD). METHODS: CFR was determined using parametric imaging in 10 patients with normal coronary arteries (group 1) and in 10 with CAD (group 2). Contrast density and mean appearance time were measured (region of interest = 249 pixels) in the perfusion beds of the left circumflex and the left anterior descending coronary arteries at rest, 45 s after 10 mg intracoronary papaverine, and during supine bicycle exercise. CFR was calculated from coronary perfusion after papaverine divided by perfusion at rest and coronary perfusion during exercise divided by perfusion at rest. Perfusion zones in patients with CAD were subdivided into regions supplied by a non-stenosed (group 2a) and a stenosed (group 2b) coronary artery. RESULTS: In control patients, heart rate increased from 75 beats/min at rest to 125 beats/min during exercise, and in patients with CAD from 63 to 107 beats/min, respectively. Mean aortic pressure showed a significant increase during exercise in both groups. Mean pulmonary artery pressure increased significantly during exercise from 19 to 28 mmHg in control patients and from 22 to 42 mmHg in the CAD group (P < 0.001). Coronary driving pressure (mean aortic minus diastolic pulmonary artery pressure) tended to increase during exercise in the control group (from 90 to 101 mmHg, NS) and remained nearly unchanged in patients with CAD (from 92 to 94 mmHg, NS). In the control group, CFR was significantly higher during exercise than after papaverine (4.0 versus 3.5, respectively; P < 0.01). However, coronary resistance (coronary driving pressure divided by coronary flow index) was similar after papaverine and during exercise. In patients with CAD, papaverine-dependent CFR was significantly reduced in the perfusion zone of the stenosed (2.1) but not of the non-stenosed coronary artery (3.0). In contrast, CFR during exercise was significantly decreased in both perfusion zones (2.5 in non-stenosed arteries and 1.5 in stenosed vessels). CONCLUSIONS: In control patients, CFR is slightly but significantly larger during exercise than after papaverine because of the exercise-induced increase in coronary driving pressure. In contrast, CFR is smaller during exercise than after papaverine in patients with CAD, most probably as a result of secondary mechanisms such as exercise-induced narrowing of stenosed vessels or an increase in extravascular resistance. Thus, CFR based on papaverine appears to be of limited value for assessing the functional significance of a stenotic lesion.

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