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PubMed1985

Pharmacokinetics and bioavailability of pinacidil capsules in human volunteers.

Pinacidil is a new and potent vasodilator, which has recently been used in the treatment of various forms of hypertension. In this study pharmacokinetic parameters were determined following administration of intravenous (0.2 mg/kg) and capsule (12.5 mg) formulations of pinacidil to twelve healthy volunteers. The serum half-life (t1/2) and volume of distribution (Vd) of pinacidil were 2.04 +/- 0.40 h and 1.4 +/- 0.4 l/kg respectively, while the elimination rate constant (k el) was 0.34 +/- 0.07 h-1. The mean bioavailability of pinacidil (capsule formulation) was 57% +/- 16 S.D. Mild side-effects such as dizziness, headache and fatigue were noted in two volunteers following intravenous administration of pinacidil, while no side-effects were reported with the oral formulation.

Administration, Oral↗

PubMed1992

[The vasospasmolytic effects of nicorandil, cromakalim and pinacidil on 3,4-diaminopyridine-induced phasic contractions in canine coronary arteries as an experimental vasospasm model].

The spasmolytic mechanisms of nicorandil, a novel antianginal drug, were investigated using 3,4-diaminopyridine (3,4-DAP)-induced phasic contractions of isolated canine coronary arteries in comparison with those of cromakalim and pinacidil. Nicorandil (10(-4) M), cromakalim (10(-6) M) and pinacidil (10(-5) M) suppressed the phasic contractions. Pretreatment with glibenclamide (10(-6) M), a specific blocking agent of ATP-sensitive K+ channel, eliminated the suppression of phasic contractions by these drugs; glibenclamide completely eliminated the suppression by cromakalim, while the eliminations against nicorandil and pinacidil were incomplete. The recoveries of peak tensions were only 56.8% and 76.1% for nicorandil and pinacidil, respectively. Nicorandil and pinacidil may suppress the phasic contractions via K+ channel opening and additional mechanisms. Methylene blue (10(-7)-10(-5) M) alone, a guanylate cyclase inhibitor, had no effect on the suppression of phasic contractions by nicorandil. In the presence of glibenclamide (10(-6) M), however, the pretreatment with methylene blue significantly augmented the recovery of peak tension for nicorandil. These results indicate that K+ channel openers may suppress the phasic contractions induced by 3,4-DAP via ATP-sensitive K+ channels, and that additionally, nicorandil may suppress the phasic contractility through guanylate cyclase stimulation, as a nitrate.

4-Aminopyridine↗

PubMed1988

Effects of long term treatment with pinacidil and nifedipine on left ventricular anatomy and function in patients with mild to moderate systemic hypertension.

Hypertrophy of the left ventricle in hypertension is associated with an increased risk of morbidity and mortality. Thus, the prevention of and regression of left ventricular hypertrophy should be essential goals of antihypertensive treatment. Some commonly used antihypertensive drugs do not have this ability, despite achieving adequate blood pressure control. In a double-blind randomised parallel group study, we evaluated the effects of adjunctive long term therapy with either pinacidil or nifedipine on blood pressure and left ventricular function and anatomy (echocardiography) in 22 patients with a diastolic blood pressure above 95mm Hg who were already receiving bendrofluazide 5mg daily. Pinacidil reduced left ventricular mass from 326.3 +/- 126.2g to 251.2 +/- 114.6g (p less than 0.001) compared with nifedipine, which reduced ventricular mass from 293.6 +/- 35.7g to 267.3 +/- 34.7 (p = 0.04). In this respect, pinacidil was more effective than nifedipine (p = 0.013). Pinacidil improved left ventricular diastolic function, measured by the isovolumetric relaxation time, whereas nifedipine did not affect this parameter. Global systolic function was little affected by either drug. However, the end systolic wall stress was significantly reduced by both therapeutic regimens. Pinacidil may, therefore, be a potentially valuable antihypertensive drug.

Aged↗

PubMed1982

Pharmacokinetics and distribution of the new antihypertensive agent pinacidil in rat, dog and man.

1. The antihypertensive agent pinacidil was rapidly, and almost completely, absorbed following oral administration of 0.5 mg/kg of the [14C]pinacidil monohydrate to rats and dogs. The half-life was about 1 and 2 h in the two species, respectively. A bioavailability of 80% of unchanged pinacidil in the rat suggests a first-pass effect in this species. 2. After oral and intravenous administration of [14C]pinacidil about 85% of the radioactivity was recovered in the urine and 15% in the faeces in rats and dogs; 80-90% was excreted during the first 24 h. Autoradiographic studies in the rat showed similar distributions after oral and intravenous administration. 3. An oral dose of 5 or 10 mg pinacidil monohydrate was rapidly absorbed in healthy volunteers and had a pharmacokinetic profile very similar to that found in rats and dogs. Concomitant food ingestion did not change the bioavailability of the drug.

Adult↗

PubMed1986

Relaxant effects of pinacidil, nicorandil, hydralazine and nifedipine as studied in the porcine coronary artery and guinea-pig taenia coli.

Effects of pinacidil, a newly synthesized vasodilator, on contractures induced in the porcine coronary artery and the guinea-pig taenia coli were investigated in comparison with those of nicorandil, hydralazine and nifedipine. These four substances produced a dose-dependent relaxation of K+-induced contracture in the coronary artery, and the order of relaxant activity was nifedipine greater than pinacidil greater than hydralazine divided by nicorandil (IC50: 1.62 X 10(-8), 1.98 X 10(-4), 1.70 X 10(-3), 2.35 X 10(-3) M, respectively). Hydralazine inhibited the contraction induced by caffeine in a Ca2+-free (EGTA) high potassium medium in a concentration-dependent manner (IC50: 8.43 X 10(-3) M). Pinacidil and nicorandil produced a partial inhibition of this contraction (45.2, 22.3% inhibition at 10(-2) M, respectively), while nifedipine was ineffective. In the isolated guinea-pig taenia coli, these compounds caused a concentration-dependent relaxation. The relaxant action by pinacidil and nicorandil was more potent in spontaneously contracting preparation or in preparations contracted by 30 mM [K+]0 than in preparations contracted by 100 mM [K+]0, while the reverse was true with nifedipine. Hydralazine was effective at similar concentrations on these three types of contraction. From these findings it was inferred that the smooth muscle relaxing-action of pinacidil and nicorandil was ascribable to the inhibitory action on the spontaneous spike activities of the surface membrane. Inhibition of the mobilization of calcium from intracellular store sites may play some role.

Animals↗

PubMedDate not supplied

Effects of pinacidil on the heart: serial electrocardiographic and echocardiographic observations.

In a prospective, double-blind study comparing pinacidil to hydralazine in mild systemic hypertension, 33 patients were followed with serial echocardiograms and electrocardiograms. There were four study groups: pinacidil and hydralazine (long-term therapy), and pinacidil and placebo (short-term therapy). There were no significant changes in mean echo LV mass or in LV systolic function in any of the groups. One patient in each group developed LVH de novo despite decreases in blood pressure. Four patients receiving pinacidil therapy (23%) developed new T-wave abnormalities and in 1, the initially abnormal T waves returned to normal at follow-up. Seven of 9 T-wave abnormalities were minor (Minnesota Code) and were not associated with any echocardiographic abnormality. One patient in the placebo group also developed new minor T-wave abnormalities. One patient receiving pinacidil therapy who had new major T-wave abnormalities developed cardiac ischemia. There were no other cardiac events.

Clinical Trials as Topic↗

PubMed1997

Myocardial oxygen consumption in the rabbit heart after ischemia: hyperpolarized arrest with pinacidil versus depolarized hyperkalemic arrest.

BACKGROUND: This study was designed to test the hypothesis that adenosine triphosphate-sensitive potassium channel opener (PCO)-induced hyperpolarized arrest with pinacidil minimizes cellular energy requirements during global ischemia compared with traditional, hyperkalemic depolarized arrest, which is known to be associated with ongoing energy-consuming ion transport. METHODS AND RESULTS: Using a blood-perfused parabiotic rabbit heart Langendorff model, myocardial oxygen consumption (MVO2) was compared in hearts protected with either Krebs-Henseleit solution (K-H), pinacidil (50 micromol/L in K-H), or hyperkalemic St. Thomas' solution during a 30-minute period of global, normothermic (37 degrees C) ischemia followed by 30 minutes of reperfusion. MVO2 (mL/100 g of myocardium per beat) was calculated at baseline and continuously during reperfusion with the use of an in-line flow probe and an in-line coronary sinus oximetric catheterizationeter. Systolic function (percentage recovery of developed pressure) was measured over a range of volumes using a balloon in the left ventricle. Percentage recovery of developed pressure with pinacidil (60.3%+/-3.1%) was not statistically different from that with St Thomas' solution (53.3%+/-2.8%). Pinacidil provided superior protection versus K-H (44.4%+/-4.8%, P<.05). The MVO2 was significantly (P<.05) elevated in the pinacidil group (0.77+/-0.12) compared with the St Thomas group (0.29+/-0.04) during the first 6 minutes of reperfusion. CONCLUSIONS: The cardioprotective properties of PCOs are associated with an increased myocardial oxygen demand on reperfusion. This may be related to reparative processes of viable myocytes or to a higher oxygen debt generated during ischemia that presents a significant limitation to PCO cardioplegia.

Animals↗

PubMed1995

Potassium channel modulation: effect of pinacidil on insulin release in healthy volunteers.

The effect of a potassium (K+) channel opener (pinacidil) on serum insulin levels and blood glucose levels was investigated in normal volunteers during glucose loading. An intravenous glucose load was used with and without oral pretreatment: pinacidil (25 mg) 11 hours and 1 hour before the 25-g glucose loading. Serum insulin, C-peptide, blood glucose, and plasma catecholamines were measured between t = 0 and t = 180 minutes. Pinacidil led to significantly lower insulin levels, especially in the first phase. Serum C-peptide levels were not significantly lowered, and glucose levels were not changed. Pinacidil inhibits the first phase of insulin release after glucose administration in healthy volunteers. These findings suggest that the safety of the drug regarding glucose tolerance, should be tested separately in patients with diabetes mellitus and essential hypertension.

Adult↗

PubMed2001

Delivery of genes encoding cardiac K(ATP) channel subunits in conjunction with pinacidil prevents membrane depolarization in cells exposed to chemical hypoxia-reoxygenation.

Metabolic injury is a complex process affecting various: tissues with membrane depolarisation recognised as a common trigger event leading to cell death. To examine whether, under metabolic challenge, membrane potential homeostasis can be maintained by an activator of channel proteins, we here delivered Kir6.2 and SUR2A genes, which encode cardiac K(ATP) channel subunits, into a somatic cell line lacking native K(ATP) channels (COS-7 cells). Chemical hypoxia-reoxygenation was simulated in COS-7 cells by addition and removal of the mitochondrial poison 2,4 dinitrophenol (DNP). The membrane potential of COS-7 cells at rest was -31 +/- 3 mV. This value did not change following 3 min-long exposure to DNP (-32 +/- 4 mV). In contrast, washout of DNP induced significant membrane depolarisation (-17 +/- 2 mV). Delivery of Kir6.2/SUR2A genes did not change cellular response to hypoxia-reoxygenation. Similarly, pinacidil, potassium channel opener, did not have effect on hypoxia-reoxygenation-induced membrane depolarisation in cells lacking recombinant K(ATP) channel subunits. However, gene delivery combined with pinacidil prevented membrane depolarisation induced by hypoxia-reoxygenation. This effect of pinacidil, in cells expressing Kir6.2/SUR2A, was observed regardless of whether pinacidil was added only during hypoxia or reoxygenation. The present study demonstrates that combined use of K(ATP) channel subunits gene delivery and pharmacological targeting of recombinant proteins can be used to efficiently control membrane potential under hypoxia-reoxygenation.

2,4-Dinitrophenol↗

PubMed1994

Inhibition by cromakalim, pinacidil, terbutaline, theophylline and verapamil of non-cholinergic nerve-mediated contractions of guinea-pig isolated bronchi.

Contractions induced by electrical field stimulation of sensory non-cholinergic excitatory nerves in guinea-pig isolated bronchi are due to the release of substance P (SP) and related tachykinins. Release of such neuropeptides are thought to play a pathophysiological role in asthma. Two K+ channel openers cromakalim (pD2 = 6.45; Emax = 95%) and pinacidil (pD2 = 6.06; Emax = 87%) were shown to concentration-dependently inhibit non-cholinergic nerve-mediated contractions in guinea-pig bronchi in vitro. Cromakalim (pD2 = 6.27; Emax = 25%) and pinacidil (pD2 = 6.03; Emax = 25%) each had a much lower inhibitory efficacy against contractions induced by exogenously applied SP but the same potency as found against contractile responses to non-cholinergic neurostimulation. Also the beta 2-adrenoceptor agonist terbutaline (pD2 = 8.29; Emax = 83%), the xanthine derivative theophylline (pD2 = 4.19; Emax = 100%) and the Ca2+ blocker verapamil (pD2 = 5.55; Emax = 100%) suppressed responses to non-cholinergic neurostimulation. Terbutaline (pD2 = 6.32; Emax = 74%), theophylline (pD2 = 3.25; Emax = 71%) and verapamil (pD2 = 4.01; Emax = 100%) had a 10-100-fold lower inhibitory potency against SP-induced contractions but each drug showed about the same efficacy as found against nerve-mediated contractions. Glibenclamide (1 microM) reversed the inhibitory effects of cromakalim and pinacidil on neurally-mediated contractions but did not influence the effects of terbutaline, theophylline and verapamil. The results demonstrate that cromakalim, pinacidil, terbutaline, theophylline and verapamil inhibit non-cholinergic excitatory neurotransmission in guinea-pig bronchi and suggest that they act preferentially at a pre-junctional site.

Animals↗

PubMed1994

Pinacidil-induced relaxation in pulmonary arteries isolated from pulmonary hypertensive and normotensive rats and pre-contracted with different spasmogens.

Vasorelaxant responses to the potassium channel opening drug, pinacidil, were obtained on preparations of pulmonary artery and aorta taken from rats with pulmonary hypertension (induced by chronic hypoxia or monocrotaline) and pre-contracted either submaximally with endothelin-1 (ET-1), PGF2 alpha, U46619 (thromboxane-mimetic) or noradrenaline (NA), or with 80 mM K+. In pulmonary artery, but not aorta, from pulmonary hypertensive rats the maximum relaxant response to pinacidil was increased, when compared with data in control rats, irrespective of the spasmogen used to precontract the tissues. The increase in maximum was associated with relaxation to below the tissue resting baseline and probably reflected the presence of inherent contractile tone in arteries from pulmonary hypertensive rats. In addition the potency (-log EC50) of pinacidil was increased in pulmonary arteries from pulmonary hypertensive rats but this was seen only in preparations contracted with ET-1 (30-fold increase) or NA (seven-fold increase) and not in those contracted with PGF2 alpha, U46619 or K+. As a result, in ET-1 contracted preparations from pulmonary hypertensive rats pinacidil was 29-fold more potent on pulmonary artery than on aorta. To explain the increase in potency it is speculated that during the development of pulmonary hypertension the mechanism whereby ET-1 and NA contract pulmonary arteries may change from one in which Ca2+ influx plays only a minor role to one in which Ca2+ influx predominates, although no direct evidence to support this speculation has yet been obtained.

Animals↗

PubMed1983

Pinacidil, a new vasodilator: pharmacokinetics and pharmacodynamics of a new retarded release tablet in essential hypertension.

In an open study increasing doses of a retarded tablet formulation of pinacidil were given twice daily for four weeks to 9 patients with untreated essential hypertension (WHO I-II). In all patients a decrease in diastolic blood pressure to below 100 mmHg, or a fall exceeding 15 mmHg, was obtained 2 h after tablet intake (p less than 0.02), but in only two patients was the effect maintained after 10 hours (n.s.). At a mean serum concentration of 100 ng/ml 2 h after pinacidil 30 mg, the mean blood pressure had decreased by 14 and 12.7 mmHg in the supine and erect positions, respectively (p less than 0.05). In contrast, mean blood pressure 10 h after the same dose was unchanged, when the mean serum concentration was 47.5 ng/ml. No change in heart rate was observed. Pharmacokinetic and pharmacodynamic investigations showed a tendency towards a more gradual and longer lasting antihypertensive effect and serum concentration-time curve after the retarded tablet than the previous tablet. Pinacidil 40 mg in the retarded tablet reduced mean blood pressure and increased heart rate for at least 8 h. There was a linear correlation between the serum concentration and the change in mean blood pressure, and between the changes in mean blood pressure and in heart rate. There was no indication of tachyphylaxis. A serum level of 50 ng/ml of pinacidil appeared to be the minimal effective concentration. The side effect consisted of fluid retention, and the body weight increased by 1.0 kg (p less than 0.05); four patients complained of oedema.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1984

Pinacidil, a new vasodilator, in the treatment of patients with moderate to severe hypertension.

A new vasodilator drug, pinacidil, N'-cyano-N-4-pyridyl-N'-1, 2,2-trimethylpropylguanidine, was studied in an open trial in 15 patients with moderate to severe hypertension. Four patients received pinacidil monotherapy, and in 11 patients it was used with a diuretic or a beta-blocker. In all but one patient normotension was achieved with a mean daily pinacidil dose of 46.7 mg b.i.d. (range 20-100 mg). Side effects were few and were action-related. There was no evidence of early toxicity. Pinacidil is a promising new antihypertensive vasodilator, which deserves further clinical evaluation.

Adult↗

PubMed1985

Effect of pinacidil on blood pressure, plasma catecholamines and plasma renin activity in essential hypertension.

Pinacidil, a new cyanoguanidine derivative, is an antihypertensive agent with arteriolar vasodilating properties, which acts on precapillary resistance vessels. A trial was carried out in 30 patients with essential hypertension WHO I-II. The treatment period was divided into three phases. Hydrochlorothiazide (HCTZ) and amiloride were administered for 4 weeks in Phase 1 and supine and standing blood pressure decreased significantly. During Phase 2 pinacidil was added to HCTZ/amiloride for the following 3 months. A further significant reduction in blood pressure was obtained. In the next period of treatment (Phase 3) patients were divided into two groups. For 1 month Group A (15 patients) received pinacidil alone and Group B (15 patients) received HCTZ/amiloride. Conventional laboratory blood tests in all patients remained unchanged during treatment. Reported side effects during Phase 2 were headache (2 patients), dizziness (3 patients), palpitations (2 patients) and ankle oedema (2 patients). Plasma renin activity was slightly increased at the end both of Phases 1 and 2. Plasma catecholamines were increased but not significantly at the end of Phase 2 as compared to Phase 1. The results indicate that pinacidil is effective in lowering blood pressure in mild to moderate essential hypertension.

Adult↗

PubMed1986

Renal effects of pinacidil in hypertensive patients on chronic beta-blocker therapy.

The acute and chronic effects of pinacidil on blood pressure (BP) and renal function were investigated in 10 patients with moderate arterial hypertension insufficiently controlled by chronic beta-blockade. Acute i.v. administration of pinacidil caused a significant fall in BP of 29.9/18.3 mm Hg and, despite beta-blockade, a concomitant rise in heart rate (HR) of 21%. Renal vascular resistance (RVR) showed a marked reduction as a consequence of the fall in BP, and a transient rise in renal plasma flow (RPF). Diuresis and renal clearance of sodium and uric acid showed a parallel fall. The excretion rates of albumin and beta 2-microglobulin were also significantly reduced. Pharmacokinetic studies indicated that glomerular filtration was responsible for elimination of the parent drug, and that proximal tubular secretion was the pathway of excretion of the main metabolite, pinacidil pyridine-N-oxide. During therapy for 4 months there was no further significant reduction in BP, despite increases in the daily dose of pinacidil. The effects on HR were less conspicuous after 4 months; renal haemodynamic parameters and body weight were not significantly changed. The initial level of RVR and the initial acute reduction in this parameter appeared to be major determinants of the long-term BP response. The drug was well tolerated apart from one patient who developed slight fluid retention. However, concomitant administration of a diuretic will probably be necessary during routine use of this therapeutic combination.

Adrenergic beta-Antagonists↗

PubMed1996

Effects of pinacidil, verapamil, and heart rate on afterdepolarizations in the guinea-pig heart in vivo.

Recently, ionic current simulation in the Luo-Rudy model has elucidated putative mechanisms of afterdepolarizations under various experimental conditions. The present study was aimed at gaining insight into the differential mechanism of different types of afterdepolarizations in the guinea-pig heart in vivo. The effects of pharmacological and heart rate perturbations on early (EADs) and delayed (DADs) afterdepolarizations, induced by either digoxin, CsCl, or BayK 8644 were studied, using mid-myocardial left ventricular monophasic action potential (MAP) recordings. Digoxin insignificantly shortened sinus cycle length (SCL) and CsCl and BayK 8644 differentially prolonged SCL and MAP duration. Digoxin induced phase 3-EADs and DADs and CsCl or BayK 8644 induced phase 2- and phase 3-EADs. Pinacidil shortened MAP duration, suppressed almost all the phase 2-EADs and some of the phase 3-EADs, but not the DADs. In a few cases, DADs were manifested following the abolishment of phase 2-EADs by pinacidil, but this phenomenon did not occur in the presence of hexamethonium. Verapamil prolonged SCL, did not significantly affect phase 2-EADs, but suppressed almost all of the DADs, including those which appeared after pinacidil, and all but one of the phase 3-EADs. The effects of pinacidil and verapamil were independent of the mode of afterdepolarization induction. A pacing-induced heart rate increase, which shortened MAP duration, and vagal stimulation, which prolonged MAP duration, attenuated and enhanced phase 2-EADs, respectively. The amplitude of phase 3-EADs was inversely related to the heart rate. These data, taken together, are consistent with those obtained previously by others in a computer model and recent observations on CsCl-induced EADs in the guinea-pig Purkinje fibers in vitro which have indicated that the mechanism of phase 2-EADs is different from that of DADs and that late phase 3-EADs generated under conditions of Ca2+ overload and DADs share similar properties.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1990

The protective effects of cromakalim and pinacidil on reperfusion function and infarct size in isolated perfused rat hearts and anesthetized dogs.

The direct myocardial protective effects of intracoronary infusions of cromakalim and pinacidil were determined in an anesthetized canine model of coronary occlusion and reperfusion. The left circumflex coronary artery was occluded for 90 minutes and reperfused for 5 hours, at which time the infarct size was determined. Cromakalim (0.1 micrograms/kg/min) or pinacidil (0.09 micrograms/kg/min) were infused into the left circumflex coronary artery starting 10 minutes preischemia. Cromakalim significantly reduced infarct size as a percent of the left ventricular area at risk (25 +/- 5%) compared with vehicle controls (55 +/- 7%). Pinacidil did not reduce infarct size at an equimolar dose, but at the higher dose also significantly reduced infarct size. Collateral blood flow was not significantly altered by either drug, though reperfusion flow was significantly higher in cromakalim-treated animals, particularly in the subepicardial region. When the same dose of cromakalim was given starting 2 minutes before the initiation of reperfusion, no significant beneficial effect of cromakalim was observed. In another study, isolated buffer-perfused rat hearts were subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. These hearts were treated with 7 microM cromakalim, either starting 10 minutes before ischemia or only during reperfusion, and its effect on reperfusion function and LDH release were determined. Cromakalim pretreatment (both when given throughout the experiment and when not present in the reperfusion buffer) resulted in significant improvements in the reperfusion function. Reperfusion contracture and LDH were also significantly reduced with this treatment. When given only during reperfusion, cromakalim did not reduce the severity of ischemia when compared with vehicle controls. Thus, both cromakalim and pinacidil reduce ischemic/reperfusion injury, though the timing of treatment may be important.

Animals↗

PubMed1983

Vascular effects in dogs of pinacidil (P 1134), a novel vasoactive antihypertensive agent.

In pentobarbital sodium-anaesthetized dogs, pinacidil was infused for approximately 5 min into the carotid, coronary, femoral or renal artery at a rate of 10 micrograms/kg per min. The infusion, which did not affect systemic blood pressure, rapidly and markedly increased blood flow to any of the regions studied. When given i.v., 0.2 mg/kg pinacidil caused a moderate reduction in mean arterial blood pressure (15-20 mmHg) associated with an increase in coronary and renal blood flow while femoral and carotid blood flow remained unchanged; 0.5 mg/kg led to a marked (40-60 mmHg) reduction in blood pressure associated with an increase in coronary blood flow whereas renal, carotid and femoral blood flow stabilized at control levels. Indomethacin (2.5 mg/kg i.v.) failed to reverse the hypotension induced by pinacidil. The results are in accord with the concept that the vascular effect of pinacidil is due to direct smooth muscle relaxation which does not depend on prostaglandin synthesis.

Animals↗