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PubMed1984

Transport of papaverine in rat kidney cortical slices.

Previous results (J. Pharm. Dyn., 7, 342, 1984) from this laboratory indicated that papaverine, a classical phosphodiesterase inhibitor, inhibited the transport of organic anions such as p-aminohippurate (PAH) and urate in rat kidney cortical slices. The transport of papaverine itself, an organic cationic drug, in the kidney is not yet understood. The purpose of this study was to examine the interaction of papaverine with incubated slices and basolateral membrane vesicles prepared from rat kidney cortex, in terms of the possibility of the intracellular action of papaverine in kidney cells. Papaverine was taken up against a concentration gradient by kidney cortical slices and by liver slices. The uptake of papaverine by the former slices was depressed by hypothermia and anoxia with metabolic inhibitors, but that of the drug by the latter slices was not affected by hypothermic condition. Tetraethylammonium (TEA) as a prototype for organic cationic drugs did not depress papaverine transport. TEA also had no effect on the inhibitory effect of papaverine on PAH accumulation in kidney cortical slices. Papaverine, however, inhibited TEA accumulation prominently. Kinetic studies using the slices indicated that papaverine increased the Km for TEA accumulation and decreased Vmax. Then, papaverine inhibition was a "mixed type". TEA uptake by basolateral membrane vesicles was markedly inhibited by papaverine, but PAH uptake by the vesicles was not affected by the drug. The present results indicate that papaverine may be at least partly transported by the same system which handles TEA, but some aspect of the transport system for papaverine may be qualitatively different from that for TEA. Additional studies are required, however, to unequivocally establish the relationships between papaverine and TEA renal transport mechanisms.

Animals↗
PubMed2002

[Determination of papaverine hydrochloride in skin and blood and the drug contents in pig skin].

OBJECTIVE: To explore the application of ultraviolet spectrophotometer in determining papaverine hydrochloride content in blood and skin and to determine the intradermal content after local external application of papaverine hydrochloride. METHODS: Phosphate buffer solution (pH = 10, ionic strength = 0.4) was added into the blood or ground skin tissue containing papaverine hydrochloride, and papaverine hydrochloride was extracted with chloroform-hexane mixture (ratio:2:3). After oscillation and centrifugation, partial organic phase was retrieved and dried in 60 degrees C water bath. The dried product was dissolved in 1 mol/L HCl and then underwent filtration through 0.2 micron membrane. The ultraviolet apectrophotometry was applied to determine the content of papaverine hydrochloride in the filtrate. 2% papaverine hydrochloride cream was applied on pig's skin and skin specimen was retrieved at given time to determine the papaverine hydrochloride content in skin tissue with ultraviolet spectrophotometry. RESULTS: The absorbance spectrum of the extract was typical of that of papaverine hydrochloride, with no miscellaneous peak. The extractive rate of papaverine hydrochloride in blood of was more than 92% and that in skin tissue more than 87%. Eight hours after external application of 2% papaverine hydrochloride cream on pig skin, the content of papaverine hydrochloride in skin tissue was more than 90 micrograms/g, significantly higher than the effective concentration of papaverine hydrochloride. CONCLUSIONS: Ultraviolet spectrophotometry is a simple, economical and reliable method for the determination of papaverine hydrochloride content in blood and skin tissue, with good reproducibility and sensibility. External application of papaverine hydrocholine cream can provide efficient permeation and drug concentration in the skin.

Animals↗
PubMed1995

Hemodynamic Responses to Papaverine: Do Nitric Oxide, Cyclic GMP, or Calcium Mediate the Vasodilation?

Papaverine is a commonly used vasodilator of the internal mammary artery in cardiac surgery. The effects of papaverine with and without N(omega)-L-arginine methyl ester (L -NAME) (a nitric oxide production inhibitor) and/or zaprinast (a cyclic GMP inhibitor) or verapamil (calcium channel antagonist) on systemic vascular resistance in vivo have not been well documented. This study examines the hemodynamic responses to papaverine and attempts to identify the role of nitric oxide, cyclic guanosine monophosphate (GMP), and calcium in the vasodilation. The effects of varying doses of papaverine were evaluated with and without L-NAME and/or zaprinast or verapamil on the hindlimb vascular resistance in the male rat. With institutional approval, 40 male Sprague--Dawley rats (400--450 g) were anesthetized with intraperitoneal pentobarbital (50 mg kg(minus sign1)). The carotid artery, jugular vein, and abdominal aorta were cannulated by cutdown; mean arterial pressure (MAP) and hindlimb perfusion pressure (HPP) were recorded. Rats were heparinized (1000 U kg(minus sign1)). Papaverine (1, 3, 10, 30, and 100 &mgr;g) was injected into the hindlimb, whereas MAP was maintained constant, and the HPP was recorded. Both L-NAME (25 mg kg(minus sign1)) and/or verapamil and then papaverine (1, 3, and 10 &mgr;g) were injected into the hindlimb, and changes in HPP were recorded. A Student's t-test was used for statistical analysis, with a p < 0.05 considered significant. Papaverine, in increasing doses, decreased HPP incrementally. L-NAME partially blocked the effects of papaverine (p < 0.05), as did verapamil (p < 0.05). The combination of L-NAME and verapamil further decreased papaverine's vasodilation to almost eliminate it (p < 0.05). We demonstrated the effect of papaverine on the hindlimb vasculature is similar to its effects noted in the internal mammary artery. Nitric oxide is known to be an agent causing vasodilation. It was demonstrated that papaverine vasodilation in the hindlimb vascular bed is modified by L-NAME, which suggests that nitric oxide production inhibition is partially responsible for this effect. It was demonstrated that there is an effect of calcium channel blockade on the vasodilation caused by papaverine. Both L-NAME and verapamil together appear to modify further the vasodilation caused by papaverine, suggesting both calcium channel and nitric oxide mechanisms for vasodilation. Zaprinast, a specific cyclic GMP phosphodiesterase inhibitor, did not effect the vasodilation caused by papaverine, acetylcholine, nitroglycerin, or verapamil.

Journal Article↗
PubMed1996

Intracoronary papaverine induced myocardial lactate production in patients with angiographically normal coronary arteries.

Although intracoronary papaverine has been widely used for the measurement of coronary flow reserve, little is known concerning whether papaverine may produce deleterious metabolic changes in humans. We investigated the effect of papaverine on lactate metabolism in 28 patients with normal coronary arteries. We continuously monitored phasic coronary flow velocity in the proximal left anterior descending coronary artery using Doppler guidewire. We also obtained paired samples of arterial and coronary sinus blood for the measurement of lactate at control and at 1 min after administration of 10 mg of intracoronary papaverine. There were no serious side effects during papaverine infusion. Sixteen patients showed ST-T abnormalities after papaverine. The QTc interval increased from 450 +/- 42 msec to 571 +/- 58 msec (P < 0.001). Average peak velocity increased significantly (% increase: 198.5 +/- 87.8%, range: 27.8-374.1%) after papaverine. Although intracoronary papaverine produced no significant change in arterial lactate levels (8.5 +/- 4.0-8.8 +/- 5.0 mg/ml), it induced a significant increase in coronary sinus lactate levels (5.4 +/- 3.2-15.3 +/- 8.2 mg/ml, P < 0.001). Lactate extraction ratio decreased significantly (36.4 +/- 18.4--82.2 +/- 58.4%, P < 0.001), and all patients showed net lactate production (-3.9--198.0%) after papaverine. There was weak but significant correlation between lactate extraction ratio after papaverine and coronary flow reserve (R2 = 0.15, P < 0.05). There was no correlation between lactate extraction ratio and QTc interval after papaverine. The mean value of lactate extraction ratio was not different in patients with ST-T abnormalities induced by papaverine compared to those without. These results demonstrate that intracoronary papaverine induces myocardial lactate production irrespective of the degree of coronary flow reserve and electrocardiographic changes in patients with normal coronary arteries. A safer and more reliable agent is needed for the measurement of coronary flow reserve.

Adult↗
PubMed1997

Effectiveness of intra-arterially infused papaverine solutions of various concentrations for the treatment of cerebral vasospasm.

We evaluated the effect of intra-arterially infused papaverine solutions of various concentrations on cerebral vasospasm following subarachnoid haemorrhage. A total of 90 vascular territories in 46 patients with symptomatic cerebral vasospasm after subarachnoid haemorrhage were treated with intra-arterial infusions of papaverine. In all patients, papaverine was infused at the top of the internal carotid artery (ICA). Of the 90 vascular territories, 30 vascular territories in 14 patients were treated with an infusion of 0.1-0.2% (weight/volume) papaverine (Group 1), 30 vascular territories in 16 patients were treated with a 0.4% (w/v) papaverine infusion (Group 2), and 30 vascular territories in 16 patients were treated with an infusion of 0.8-2.0% (w/v) papaverine (Group 3). Among the three groups, we compared the vasodilatory effects of papaverine by assessing the angiographical and clinical improvements following the treatment. When 0.4% (w/v) papaverine was infused, 24 vascular territories (80%) were successfully dilated and 7 patients (44%) showed a marked reversal of neurological deficits due to vasospasm. Therefore, 80 mg/20 ml (0.4% (w/v)) papaverine infused over a 10-minute period proved to be a beneficial concentration. Transient focal neurological deficits due to the infusion of papaverine occurred in 1 Group 1 patient (7%), 1 Group 2 patient (6%), and 7 Group 3 patients (44%). Highly concentrated papaverine had a higher risk of temporary deterioration. In conclusion, the papaverine concentration of 0.4% (w/v) infused at the top of the ICA was a safe and adequate concentration for treating cerebral vasospasm.

Adult↗
PubMed1992

Objective double-blind evaluation of erectile function with intracorporeal papaverine in combination with phentolamine and/or prostaglandin E1.

We performed a double-blind, crossover study using objective measurements to compare maximum rigidity and duration of erections with papaverine hydrochloride in combination with phentolamine mesylate and/or prostaglandin E1. The rationale for the protocol was to combine a smooth muscle relaxant (papaverine) with either or both vasodilating agents (phentolamine and prostaglandin E1) commonly used for injection therapy. The 7 volunteer patients with organic impotence documented by abnormal nocturnal penile tumescence testing were injected with 0.5 to 1.0 ml. papaverine (30 mg./ml.) in combination with phentolamine (0.5 mg./ml.) and/or prostaglandin E1 (5 micrograms./ml.). Each patient received 2 injections on each of 2 testing dates; injection 2 was given after tumescence resulting from injection 1 had subsided completely. The medications were given in a randomized, counterbalanced order following double-blind procedures. Patients evaluated the erections subjectively. In addition, the RigiScan device was used to measure maximum rigidity and duration of erections. All patients observed increased duration of erections with both combinations containing prostaglandin E1. Analysis of RigiScan measurements showed no statistically significant differences for maximum rigidity (p greater than 0.1) but significantly greater duration of erections with papaverine plus prostaglandin E1, and papaverine plus phentolamine plus prostaglandin E1 compared to papaverine plus phentolamine (p less than 0.001). There was no statistical difference in rigidity or duration of erections between papaverine plus prostaglandin E1 and papaverine plus phentolamine plus prostaglandin E1. No patient reported significant penile pain with any of the injections. We conclude that the combination of papaverine and prostaglandin E1 produces erections of longer duration than papaverine plus phentolamine and that no additional benefit is gained by adding phentolamine to a combination of papaverine and prostaglandin E1. Further studies are in progress to define optimal dose response curves for papaverine and prostaglandin E1 as individual agents and in combination.

Alprostadil↗
PubMed1991

Modulation of noradrenaline-induced membrane currents by papaverine in rabbit vascular smooth muscle cells.

1. The modulation of noradrenaline-induced membrane currents by papaverine was studied with the nystatin whole-cell technique in freshly isolated rabbit ear artery and portal vein cells. 2. At a holding potential of -50 mV (in potassium-free conditions), papaverine inhibited the Ca(2+)-activated inward chloride current ICl(Ca) evoked by ionophoretic application of noradrenaline in rabbit portal vein cells in a concentration-dependent (10(-5)-10(-4) M) manner. 3. With potassium-containing solutions (at 0 mV) 10(-4) M-papaverine reversibly abolished the Ca(2+)-activated outward potassium current IK(Ca) induced by noradrenaline in both protal vein and ear artery cells. Occasionally, 10(-4) M-papaverine itself activated IK(Ca) before it abolished the response to noradrenaline. 4. Higher concentrations of papaverine (up to 10(-3) M) always evoked both ICl(Ca) and IK(Ca) at -50 and 0 mV respectively, before it abolished these responses to noradrenaline in both ear artery and portal vein cells. In the presence of 10(-3) M-papaverine higher doses of noradrenaline evoked the non-selective cation current in some portal vein cells. 5. In the presence of 10(-2) M-caffeine, which elicited both IK(Ca) and ICl(Ca), papaverine (10(-3) M) failed to activate either current and 10(-3) M-papaverine reduced the caffeine-induced IK(Ca) by 94%. In contrast, IK(Ca) induced by the calcium ionophore ionomycin was unaffected by papaverine. In Ca(2+)-free, 1 mM-EGTA external solutions, 10(-3) M-papaverine still induced IK(Ca) and blocked the response to noradrenaline. 6. The alpha 1-adrenoceptor antagonist prazosin (5 x 10(-8) M) completely blocked the noradrenaline-induced IK(Ca) but currents evoked by papaverine (10(-3) M) were unaffected by prazosin. 7. It was concluded that papaverine modulated noradrenaline-induced membrane currents in vascular smooth muscle cells by releasing and depleting caffeine-sensitive intracellular Ca2+ stores.

Animals↗
PubMed1998

Drug-induced vasodilation: in vitro and in vivo study on the effects of lidocaine and papaverine on rabbit carotid artery.

Flap ischemia is often encountered during pedicled and free tissue transfer. In this study, the vascular effects of varying doses of lidocaine, papaverine, and a combination of the two agents were evaluated and compared in an in vitro and in vivo model in the rabbit carotid artery. In the in vitro study, 14 rings from the rabbit carotid artery were bathed in Krebs-Ringers solution and stretched progressively to an optimal tension of 3.7-4.2 grams. Their isometric contractile activity was measured. The specimens were precontracted with norepinephrine (1 microM), and a dose response curve was established by adding cumulatively either lidocaine (to 7 arterial rings) or papaverine (to 7 arterial rings) at increasing concentrations. In the in vivo study, microvascular anastomoses were performed bilaterally in the rabbit carotid artery in 30 animals using 9-0 nylon suture and standard microsurgical techniques. In each animal, one side was treated with heparinized sodium chloride and served as the control. The other side was treated blindly, during and after the anastomoses, with a topical application of 1 ml of either lidocaine 2% (n = 5), lidocaine 20% (n = 5), papaverine (30 mg/ml, n = 5), lidocaine 2% combined with papaverine (30 mg/ml, n = 5), or lidocaine 20% combined with papaverine (30 mg/ml, n = 5). For 30-60 minutes after the procedure, blood flow changes in the vessels were continuously monitored with a transonic doppler applied to both carotid arteries. The 20% lidocaine group was flushed with saline at the end of the first hour and monitored for an additional 60 minutes. Papaverine elicited a concentration-dependent relaxation of norepinephrine precontracted carotid artery rings in vitro. Lidocaine elicited a biphasic response, with low concentrations (10(-6)-10(-4) M) increasing the norepinephrine-induced contraction and high concentrations (10(-4)-10(-2) M) relieving this contraction. Microsurgical anastomosis produced a significant decrease of blood flow through the rabbit carotid artery as measured by the transonic doppler. Drug application did not alter the systemic blood pressure of the animals. Topical application of lidocaine 2% did not significantly change the blood flow after microvascular anastomosis. Topical application of lidocaine 20%, papaverine (30 mg/ml), or lidocaine (2% or 20%) combined with papaverine significantly increased the blood flow in the rabbit carotid artery. In the lidocaine 20% group, the blood flow remained significantly increased after the drug was flushed with heparinized saline solution. These results demonstrate that topical lidocaine 20%, papaverine, and lidocaine 2% or 20% combined with papaverine significantly increase blood flow in the rabbit carotid artery after microvascular anastomosis. The data confirm the use of papaverine and lidocaine 20%, alone or in combination, as spasmolytics during clinical microsurgery. This suggests that lidocaine 2% alone is not the ideal drug to relieve vascular constriction, and further studies on the clinical use of low concentrations of topical lidocaine in microsurgery is warranted.

Animals↗