Rabbit Release Research Articles

Fabrication of alginate based microgels for drug-sustained release: In-vitro and in-vivo evaluation

The current study was conducted to evaluate and analyze the effect of alginate, itaconic acid, and N,N′-methylene bisacrylamide in formulation of a novel alginate based microgels for sustained release of theophylline. The fabricated microgels were characterized by PXRD, SEM, FTIR, TGA and DSC respectively. FTIR revealed that alginate reacted with itaconic acid during polymerization reaction and confirmed the overlapping of itaconic acid on the backbone of alginate. TGA and DSC depicted high thermal stability of the fabricated microgels as compared to pure unreacted polymer and monomer. Likewise, dynamic swelling and percent drug release studies were carried out at different pH media i.e., pH 1.2, 4.6 and 7.4 respectively. Greater dynamic swelling and percent drug release was observed at higher pH 7.4 as compared to lower pH 4.6 and 1.2 due to the deprotonation of COOH groups of both alginate and itaconic acid respectively. The drug release mechanism from the fabricated microgels could be described by first order model. In-vivo pharmacokinetic study was performed on rabbits and exhibited sustained release in rabbits. Hence, the developed microgels indicated higher potential as the delivery system for the sustained delivery of theophylline.

Development of injectable long‐acting controlled release intravitreal depot of BAY224 using biodegradable silica microparticle‐silica hydrogel composite

PurposeIntravitreal (IVT) therapies are a standard of care for many ocular diseases. Frequent administration and injection‐based adverse events pose a hurdle for effective upkeep of ocular health. Developing improved effective treatment durations has gained significant traction. This study investigated if a near water‐insoluble drug, BAY224, could be encapsulated in biodegradable silica microparticles (SMP) and exhibit sustained controlled in vitro and in vivo release through a surface eroding SMP‐silica hydrogel composite (silica‐silica composite).MethodsBAY224 was encapsulated in a silica matrix by sol‐gel chemistry and spray drying. In vitro silica dissolution and BAY224 release from silica‐silica composite was analyzed followed by studying in vivo IVT release in rabbits. In vitro silica dissolution was studied in sink conditions colorimetrically. Cumulative release and total BAY224 content were analyzed by HPLC. In vivo release was studied by LC‐MS/MS of sample vitreous humor up to 55 days post 30 µl IVT injections.ResultsBAY224 was encapsulated, and silica‐silica composite was made at a load of 1 mg/50 µL (5.7 wt‐%). BAY224‐SMPs were sterilized using γ‐irradiation (26.8–47.5 kGy) not affecting in vitro dissolution. Burst release of BAY224 was >9 wt‐% in SMP and silica‐silica composite. Release of API was controlled by silica matrix surface erosion. In accelerated in vitro dissolution, the release time of BAY224 from SMP was 8–9 days. The silica‐silica composite prolonged release to 9–10 days. With the relevant in vitro‐in vivo correlation factor, in vivo release of 3 months was hypothesized. In vivo PK data showed sustained release of BAY224 in vitreous for at least 55 days. Daily API release (calculated from the API remnant in depot) was ca. 5–8 µg/day.ConclusionsEfficient encapsulation of a near insoluble drug was achieved with a silica‐silica composite with no burst release and a long‐acting release in‐vivo of >55 days in line with the in‐vitro dissolution results.

Tranexamic acid loaded gellan gum-based polymeric microbeads for controlled release: In vitro and in vivo assessment

Gellan gum (GG) microbeads containing tranexamic acid (TA), an anti-fibrinolytic drug were prepared by a classic sol–gel transition induced by ionic crosslinking technique using aluminum chloride (AlCl3) as cross-linking agent. The influence of different formulation variables on in vitro physico-chemical parameters and drug release studies were performed systematically. The microbeads were evaluated by scanning electron microscopy (SEM), Fourier transform infra-red (FTIR) spectroscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC) and high performance liquid chromatographic (HPLC) analysis. Particle size and swelling behavior of microbeads were also investigated. Microbeads showed improved drug encapsulation efficiency along with enhanced drug release. The in vivo studies exhibited sustained drug release in rabbits over a prolonged period after oral administration of these newly developed TA loaded GG microbeads. Based on the results of in vitro and in vivo studies in experimental animal model it was concluded that these microbeads provided intestinal specific controlled release of TA.

A Preliminary Study to Treat Severe Endophthalmitis via a Foldable Capsular Vitreous Body with Sustained Levofloxacin Release in Rabbits

We investigated whether the foldable capsular vitreous body (FCVB) could release levofloxacin sustainably in vitro and inhibit endophthalmitis in rabbit models. Approximately 1.0 mL levofloxacin (625 μg/mL) was injected into the capsule of nine FCVBS. The levofloxacin release value was determined in the modified franz diffusion cells over time. In the in vivo study, all right eyes of 45 rabbits were infected with Staphylococcus epidermidis AND were divided randomly into three groups at 24 hours after infection: FCVB plus levofloxacin (n = 15), silicone oil plus subconjunctival levofloxacin (n = 15), and an untreated group (n = 15) during a 30-day observation time. Levofloxacin concentrations in the aqueous humor were detected, and therapeutic efficacy was evaluated with clinical evaluation, bacterial counts, cytokine profiles, and histopathology. The FCVB released levofloxacin ranging from 9 to 13.5 ng/mL in vitro and from 42 to 1.6 ng/mL in the aqueous humor during 30 days. In the FCVB and silicone-treated groups, clinical inflammation almost was abolished; no bacteria were detected in the aqueous humor; TNF-α, IL-1β, and IFN-γ expression decreased; and relatively normal corneal and retinal architecture were kept after the 30-day treatment. The FCVB could provide us with dual functions, combining a levofloxacin drug delivery system and a vitreous substitute, to treat endophthalmitis in rabbit eyes.

Vectors and Vector-Borne Diseases in Turkey

In Turkey, arthropod-borne diseases such as human babesiosis, dirofilariasis, leishmaniasis, malaria, lymphatic filariasis, onchocerciasis, anthrax, bartonellosis, louse-borne relapsing fever, lyme disease, plague, trench fever, tularemia, epidemic typhus, tick-borne typhus, Crimean-Congo hemorrhagic fever, phlebovirus infections, tick-borne encephalitis and west nile virus in humans; animal trypanosomiasis, avian haemosporidiasis, babesiosis, canine hepatozoonosis, canine lesihmaniosis, dipetalonemiasis, dirofilariosis, habronemiasis, onchocerciasis, parafilariasis, setariasis, theileriosis, thelaziasis, anaplasmosis, ehrlichiosis, feline infectious anemia, akabane, bluetongue, bovine ephemeral fever, equine infectious anemia, louping ill, west nile virus, colony collapse disorders (CCD) were reported in domestic animals and Wolbachia endobacteria infection was also reported in mosquitos so far. On the other hand, aphids (Aphididae), leafhoppers (Cicadellidae), white flies (Aleyrodidae), beetles (Coleoptera), trips (Thysanoptera), gal mites (Eriophyidae), and nematodes are also very important vectors of plant diseases in Turkey. Some of the most harmful plant viruses in the world such as tristeza, plum pox virus, and tomato ringspot viruses are also transmitted by arthropod vectors. In recent years, in spite of changes in ecological balance caused by abandoning agricultural land, use of natural areas to farm, release of rabbits, preventing water flooding, leaving the fields uncultivated, migration from urban to rural areas, hunting of wild animals, the dramatic drop in the number of farm animals, global warming and the strengthening of wild life was probably responsible for the increase of tick populations. The construction of ponds and dams, changes in riverbeds, drying out of swamps and marshes, dense ad-hoc and haphazard construction, changes in picnicking habits, wild irrigation in agriculture, and the use of unsuitable control measures by local authorities, resulted in an increase of flies. This led to an increase in infected vector populations and vector-borne diseases and a decrease in the potential for economic development. In conclusion, it is very important to initiate and develop integrated control programs targeting arthropod vectors, disease agents of human, animal and plants and natural reservoirs. These diseases have been caused high economic losses in Turkey, and therefore they should be further investigated

The role of quoll (Dasyurus) predation in the outcome of pre-1900 introductions of rabbits (Oryctolagus cuniculus) to the mainland and islands of Australia

We investigated two questions: Why did most historical releases of rabbits on the Australian mainland fail? And why did many releases of rabbits on islands around Australia persist? We reviewed historical sources and present here nearly 300 records of the importation, sale, transportation and release of rabbits in the period 1788–1900, with >90 records before the popularly cited 1859 Barwon Park (near Geelong, Victoria) release by Thomas Austin. Similarly, we present records of localised impact of quolls (especially Dasyurus viverrinus) on rabbits and poultry, indicative of the great abundance of quolls. Rabbits were often imported and traded and releases were frequent and widespread. This evidence implicates native predators, particularly quolls (Dasyurus spp.) as responsible for the widespread and early failure of rabbits to establish on mainland Australia. In contrast, rabbits thrived on many islands, nearly all of which lacked cursorial natural enemies. We suggest that these accounts support the establishment of rabbits from several locations, with Barwon Park being a primary location and rabbit source.

Ethyl Pyruvate Attenuates Spinal Cord Ischemic Injury with a Wide Therapeutic Window through Inhibiting High-mobility Group Box 1 Release in Rabbits

Ethyl pyruvate (EP) has been reported to offer a protective effect against ischemic injury through its antiinflammatory action. The nuclear protein high-mobility group box 1 (HMGB1) can activate inflammatory pathways when released from ischemic cells. This study was designed to investigate the neuroprotective effect of EP against spinal cord ischemic injury and the potential role of HMGB1 in this process. EP was administered at various time points before or after 20 min of spinal cord ischemia in male New Zealand rabbits. All animals were sacrificed at 72 h after reperfusion with modified Tarlov criteria, and the spinal cord segment (L4) was harvested for histopathological examination and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining. The HMGB1 levels in serum and spinal cord tissue were analyzed by enzyme-linked immunosorbent assay. The treatment of EP at 30 min before ischemia or at 6 h after reperfusion significantly improved the hind-limb motor function scores and increased the numbers of normal motor neurons, which was accompanied with reduction of the number of apoptotic neurons and levels of HMGB1 in serum and spinal cord tissue. The HMGB1 contents of spinal cord tissue correlated well with the numbers of apoptotic motor neurons in the anterior spinal cord at 72 h after reperfusion. These results suggest that EP affords a strong protection against the transient spinal cord ischemic injury with a wide therapeutic window through inhibition of HMGB1 release.

The effect of exclusion of terrestrial predators on short-term survival of translocated European wild rabbits

Many translocation methods have been tested in southern Europe in recent decades to increase the translocation success of the European wild rabbit (Oryctolagus cuniculus L.) for both conservation and game purposes. The main problem experienced during such translocations is the high short-term (7 days) mortality attributed to predation during the days immediately following rabbit release. In this study, we test the effect of the exclusion of terrestrial predators on the survival of translocated rabbits for recovery purposes. Four translocation plots (4 ha with 18 artificial warrens each) were constructed, two of them with a fence to exclude terrestrial predators. In all, 724 rabbits were released to the translocation plots in five batches and forced to remain inside warrens for 7 days. Following liberation, exclusion of predators did not increase rabbit survival in the short term. Contrary to expectations, three months after release, survival of rabbits in the unfenced plot was slightly, but not significantly, higher than in the fenced plot (0.57 and 0.40 respectively). Although predator control is a frequent management practice associated with rabbit translocations, our results suggest that it may not favour rabbit survival rate as much as the adaptation of rabbits to the release site.

Effect of desflurane-induced preconditioning following ischemia-reperfusion on nitric oxide release in rabbits

Nitric oxide (NO) is the mediator of ischemic preconditioning against myocardial infarction. Desflurane produces anesthetic preconditioning to protect the myocardium against infarction. In the model of myocardial ischemia-reperfusion injury in rabbits, we evaluated desflurane-induced ischemic preconditioning and studied its mechanism of NO synthesis. Thirty-two male adult New Zealand white rabbits were anesthetized with intravenous (IV) 30 mg/kg pentobarbital followed by 5 mg/kg/hr infusion. All rabbits were subjected to 30 minutes (min) long lasting left anterior descending coronary artery (LAD) occlusion and three hours (hr) of subsequent reperfusion. Before LAD occlusion, the rabbits were randomly allocated into four groups for preconditioning treatment (eight for each group). The control group did not receive any preconditioning treatment. The desflurane group received inhaled desflurane 1.0 MAC (minimal end-tidal alveolar concentration) for 30 min that was followed by a 15 min washout period. The L-NAME-desflurane group received L-NAME (N G-nitro-L-arginine methyl ester; non-selective Nitric Oxide Synthetase (NOS) inhibitor) 1 mg/kg IV 15 min before 1.0 MAC inhaled desflurane for 30 min. The L-NAME group received L-NAME 1 mg/kg IV. Infarct volume, ventricular arrhythmia, plasma lactate dehydrogenase (LDH), creatine kinase (CK) activity and myocardial perfusion were recorded simultaneously. We have found that hemodynamic values of the coronary blood flow before, during, and after LAD occlusion were not significantly different among these four groups. For the myocardial ischemia-reperfusion injury animals, the infarction size (mean ± SEM) in the desflurane group was significantly reduced to 18 ± 3% in the area at risk as compared with 42 ± 7% in the control group, 35 ± 6 in the L-NAME group, and 34 ± 4% in the L-NAME-desflurane group. The plasma LDH, CK levels, and duration of ventricular arrhythmia were also significantly decreased in the desflurane group during ischemia-reperfusion injury. Our results indicate that desflurane is an anesthetic preconditioning agent, which could protect the myocardium against the ischemia-reperfusion injury. This beneficial effect of desflurane on the ischemic preconditioning is probably through NO release since L-NAME abrogates the desflurane preconditioning effect.

Controlled Delivery System for Norethindrone Based on Biodegradable Poly- α, β -(Hydroxyalkyl)-DL-Aspartamide

The article describes the preparation of poly-(hydroxyalkyl)-DL-aspartamide (PHAA) by a (ring) opening reaction by hydroxyalkylamino; norethindrone (NET), as a model drug, was coupled to the polymers via hydroxyalkylamino spacers. PHAA and NETPHAA conjugates were characterized by FTIR, DSC, x-ray, 13 C NMR, and scanning electron microscopy and their structure were confirmed. The biocompatibility of PHAA was tested. The study showed that PHAA was a hydrophilic, nontoxic in vivo, nonantigenic material and had good biocompatibility as a drug carrier. The effect on drug release from the polymer of length of side chain, initial drug loading, and particle size of the polymer drug were investigated in tris-HCl buffer solution (pH 7.4, t = 37°C). In vivo release in rabbits also was performed for 120 days. The experiment indicated that the concentration of NET in rabbits can be 1-2 μg/ml serum after 1 month; 10% of NET had been released from the polymer.

Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits.

Lyophilized polyacrylic acid powder formulations loaded with apomorphine HCl were prepared and the influence of drug loading on in vitro release and in vivo absorption studied after intranasal administration in rabbits. These formulations prepared with Carbopol 971P, Carbopol 974P and polycarbophil sustained apomorphine release both in vitro and in vivo. The in vitro release rate and mechanism were both influenced by the drug loading. There was no large influence of drug loading on the time to achieve the peak (Tmax) for a particular polymer, but Tmax differed between different polymers. For a particular drug loading, the Tmax from Carbopol 971P was the slowest compared with that for Carbopol 974P and polycarbophil; however, only the Tmax from Carbopol 971P loaded with 15% w/w of apomorphine was significantly longer than polycarbophil of similar drug loading (P=0.0386). The trend further observed was that increasing drug loading led to increased peak plasma concentration and area under the curve (AUC). In the second part of this study, a mixture containing an immediate release component and sustained release formulation was administered in an attempt to increase the initial plasma level, as this could be therapeutically beneficial. Only one peak plasma concentration was observed and the initial plasma concentrations were no higher than those obtained with solely sustained release formulation. The Tmax, the peak plasma drug concentration (Cmax) and AUC from the lactose-containing formulation were lower than the formulation without lactose but the differences were only marginally statistically significant for Cmax (P=0.0911) and AUC (P=0.0668), but not Tmax (P=0.2788).

Reduced sarcoplasmic reticulum Ca2+ release in rabbits with left ventricular dysfunction.

Reduced sarcoplasmic reticulum Ca2+ release in rabbits with left ventricular dysfunction.

Evaluation of free and liposome-encapsulated gentamycin for intramuscular sustained release in rabbits

Gentamycin sulphate ( GS) and gentamycin oleate ( GO) were encapsulated in liposomes composed of phosphatidylcholine ( HPC) and cholesterol ( CHOL) (molar ratio 7:7:2 and 5:5:l, respectively), and were administered via intramuscular injection to rabbits, to evaluate their potential use as sustained release formulations. Five groups of five animals each were used for the pharmacokinetic study, and treatments were established as follows: 3 mg kg −1 of GS i.v., 3 mg kg −1 of GS i.m., 3 mg kg −1 of liposome-containing gentamycin sulphate ( LGS) i.m., 3 mg kg −1 of GO i.m., and 3 mg kg −1 of liposome-containing gentamycin oleate ( LGO) i.m. Gentamycin plasma concentrations after i.m. administration of LGS were extremely low compared with those obtained after the i.m. administration of GS; the peak plasma concentration ( C max) showed an eight-fold decrease with LGS, and the area under the concentration-time curve ( AUC) was four-fold lower for the liposomal form. The apparent elimination half-life estimated after administration of LGS showed a three-fold increase compared with values calculated for free GS. After the administration of the same dose of LGO, C max obtained showed a 2·5-fold decrease in relation to peak concentrations of free GO, and the apparent β-half life of encapsulated GO showed a three-fold increase compared with i.m. GO. Large-size liposomes containing gentamycin administered i.m. to rabbits gave sustained drug release from the injection site, providing prolonged plasma concentrations of the drug in the body.

Long-acting soluble bioadhesive ophthalmic drug insert (BODI) containing gentamicin for veterinary use: optimization and clinical investigation

In animal health care, current therapeutic regimens for severe external infections require repeated instillations of antibiotic eye drop solutions. The aim of this work is to drastically decrease the frequency of instillations by developing a long-acting ophthalmic insert. Ophthalmic inserts based on mixtures of hydroxypropyl cellulose, ethyl cellulose, poly(acrylic) acid and 25.0% (w/w) of gentamicin sulfate either combined with cellulose acetate phthalate or not were prepared using a specially designed ram extruder. The content of each component was optimized by evaluating tolerance and drug release in rabbits. Preliminary in vivo assays in rabbits led to a formulation with the favourable characteristics needed. These inserts were tested in dogs for drug release and compared with a commercially sold collyrium. The results show that the inserts ensure effective gentamicin levels over 72 h with variation coefficients between 2 and 10%. These results are compared with those obtained with the eye drop solution (0.3%), which provides effective concentrations lasting less than 15 min with variation coefficients ranging from 63–96%. These soluble Bioadhesive Ophthalmic Drug Inserts (BODI) can be considered as a promising new ophthalmic delivery concept specifically designed for animal health care.

Effect of moderately increased intrapelvic pressure on renal tissue pressure and vasopressin release in rabbits.

Electrical stimulation of afferent renal nerves and activation of intrarenal receptors increases plasma vasopressin concentration, but the role of afferent renal nerves in the control of vasopressin secretion is not clear. Recently, we reported that activation of renal mechanoreceptors stimulates the release of vasopressin. However, intrapelvic pressure was increased to 50 mmHg, and this increase is above the normal physiological range. Therefore, in the present study, we investigated the effect of moderately increased intrapelvic pressure on plasma vasopressin concentration in anesthetized rabbits. First, we measured renal tissue pressure while intrapelvic pressure was increased stepwise in 10-mmHg increments. Basal renal tissue pressure was 17 +/- 2 mmHg. Renal tissue pressure increased only when intrapelvic pressure was higher than the basal tissue pressure of each animal. Usually, increases in intrapelvic pressure less than 20 mmHg did not increase renal tissue pressure. This finding suggests that only increases in intrapelvic pressure more than 20 mmHg can activate renal mechanoreceptors. Based on this finding, the effects of moderate increases in intrapelvic pressure (15 and 30 mmHg) were studied. With a 15-mmHg increase in intrapelvic pressure, plasma vasopressin concentration did not change significantly. However, when intrapelvic pressure was increased to 30 mmHg, plasma vasopressin concentration increased from 5.6 +/- 1.4 to 9.5 +/- 2.8 pg/ml at 5 min (p < 0.05) and to 8.8 +/- 2.0 pg/ml at 10 min (p < 0.05). Plasma renin activity and mean arterial pressure also increased when intrapelvic pressure was increased to 30 mmHg. We conclude that moderate increases in intrapelvic pressure stimulate vasopressin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol-induced jejunal microvascular and morphological injury in relation to histamine release in rabbits

Background: To investigate the relation between ethanol-induced jejunal microvascular injury, morphological changes, and histamine release, the present study examined whether the attenuation of microvascular effect of ethanol by 16,16-dimethyl prostaglandin E2 (dmPGE2) (reported by us previously) was associated with an attenuation of epithelial damage and histamine release. Methods: Rabbits were used. Mucosal microvascular injury was assessed by determining jejunal plasma protein loss (JPPL), histamine release by measuring histamine concentration of the gut effluent, and epithelial damage by routine histology. Results: (1) During 90-minute jejunal ethanol perfusion, there was a direct relation between the time course of histamine release and that of JPPL. (2) dmPGE2 attenuated the ethanol-induced JPPL and histamine release, and the decrease in JPPL was directly proportional to the decrease in histamine release. (3) dmPGE2 did not alleviate ethanol-induced epithelial damage. (4) Ketotifen (a mast cell stabilizer), similar to dmPGE2, attenuated ethanol-induced JPPL and histamine release. (5) Ethanol caused histamine release by the jejunum in vitro; this was attenuated by dmPGE2 and also by phloretin (a mast cell stabilizer). Conclusions: It appears that (1) ethanol causes JPPL by inducing release of mediators from mucosal mast cells. (2) dmPGE2 attenuates JPPL by stabilizing mast cells. (3) The ethanol-induced mucosal microvascular injury is directly related to histamine release but not to epithelial damage.

Modulation of noradrenaline release via activation of presynaptic beta-adrenoceptors in rabbits with adriamycin-induced cardiomyopathy.

We investigated the role of beta-adrenoceptors at postganglionic sympathetic nerve endings in noradrenaline release in rabbits with cardiomyopathic congestive heart failure produced by adriamycin (1 mg/kg, I.V., twice a week for 8 weeks). Plasma noradrenaline levels were measured before, 30 min after, and 60 min after the start of continuous intravenous administration of adrenaline (0.06 micrograms/kg/min) in adriamycin-treated and vehicle-treated rabbits in anesthetized condition and pithed condition with electrically stimulated sympathetic outflow (3 Hz, 1 ms square wave pulse, 90 V). In both the anesthetized and pithed conditions, adrenaline increased plasma noradrenaline levels in vehicle-treated rabbits. However, in the adriamycin-treated rabbits, adrenaline had no effect on the plasma noradrenaline level. Pretreatment with propranolol (0.2 mg/kg, bolus I.V. + 0.1 mg/kg/hr, continuous infusion) almost completely abolished the rise in plasma noradrenaline associated with adrenaline infusion in vehicle-treated rabbits. These results suggest that in rabbits with adriamycin-induced cardiomyopathy, the noradrenaline release from the sympathetic nerve endings via the activation of presynaptic beta-adrenoceptors is reduced. This might be due to down-regulation of presynaptic beta-adrenoceptors caused by the elevated plasma noradrenaline due to cardiac failure. However, other possibilities such as reduced affinity or impaired signal transduction cannot be excluded.

Effect of intrarenal bradykinin infusion on vasopressin release in rabbits.

Electrical stimulation of afferent renal nerves and activation of renal mechanoreceptors increase plasma vasopressin concentrations. In the present study, the effect of renal chemoreceptor activation on plasma vasopressin concentration was investigated in anesthetized rabbits. Renal chemoreceptors were activated with intrarenal infusions of bradykinin. With intrarenal infusion of bradykinin at 136 ng/min, plasma vasopressin concentration increased from 4.5 +/- 1.5 to 26.8 +/- 14.2 pg/ml at 5 minutes (p less than 0.01), whereas with infusion at 1,360 ng/min, plasma vasopressin increased from 5.9 +/- 2.0 to 54.4 +/- 16.4 pg/ml at 5 minutes (p less than 0.01). There was no significant change in plasma vasopressin during intravenous infusion of bradykinin at 136 ng/min. Infusion at 1,360 ng/min increased plasma vasopressin from 2.7 +/- 0.5 to 14.8 +/- 6.4 pg/ml (p less than 0.01), but this increase was significantly less than that produced by intrarenal infusion of the same dose of bradykinin. Similar effects on plasma vasopressin were observed during paired intrarenal and intravenous infusions of bradykinin at 136 ng/min. Renal denervation markedly reduced the vasopressin responses to intrarenal infusion of bradykinin at 136 ng/min (2.8 +/- 0.5 to 4.0 +/- 0.7 pg/ml, p less than 0.01) and 1,360 ng/min (3.2 +/- 0.7 to 7.8 +/- 1.8 pg/ml, p less than 0.05). These results indicate that bradykinin stimulates vasopressin release by an intrarenal action and suggest that this action is mediated by afferent renal nerves.

Adrenergic Stimulation of Regional Plasminogen Activator Release in Rabbits

The purpose of this study was to determine whether different regions of the rabbit vascular system show variations in the rate of plasminogen activator (PA) secretion. To start, we evaluated the time course, dose response and adrenergic specificity of PA release. Infusion of 1 microgram/kg of epinephrine stimulated a 116 +/- 60% (SD) increase in PA activity that peaked 30 to 60 s after epinephrine administration. Infusion of 1 microgram/kg of norepinephrine, isoproterenol and phenylephrine had no effect on PA activity. Pretreatment with phentolamine, an alpha adrenergic antagonist, blocked the release of PA by epinephrine while pretreatment with the beta blocker propranolol had no effect. This suggests that PA release in the rabbit was mediated by some form of alpha receptor. Significant arterio-venous differences in basal PA activity were found across the pulmonary and splanchnic vascular beds but not the lower extremity/pelvic bed. After stimulation with epinephrine, PA activity increased 46% across the splanchnic bed while no change was seen across the lower extremity/pelvic bed. We conclude that several vascular beds contribute to circulating PA activity in the rabbit, and that these beds secrete PA at different rates under both basal and stimulated conditions.

Activation of renal mechanoreceptors increases vasopressin release in rabbits

Electrical stimulation of afferent renal nerves increases plasma vasopressin (AVP) concentration, but the role of these nerves in the control of AVP release is not known. The aim of the present study was to investigate the effect of activation of renal mechanoreceptors and chemoreceptors on plasma AVP concentration in anesthetized rabbits. Intrapelvic pressure was increased to activate renal mechanoreceptors, and the renal pelvis was perfused with 1.0 M NaCl, 0.1 M KCl, and 1.0 M mannitol solutions to activate R2 chemoreceptors. With increased pelvic pressure, plasma AVP concentration increased from 12.4 +/- 3.8 to 36.2 +/- 16.1 pg/ml at 5 min and to 37.4 +/- 16.1 pg/ml at 10 min (P less than 0.01). Plasma renin activity increased from 15.7 +/- 4.0 to 22.1 +/- 3.3 ng.ml-1.2 h-1 (P less than 0.05), but blood pressure and heart rate did not change significantly. Similar increases in plasma AVP concentration occurred during perfusion of the renal pelvis with 1.0 M NaCl (17.6 +/- 8.1 to 53.7 +/- 24.0 pg/ml), 0.1 M KCl (9.2 +/- 2.1 to 39.7 +/- 17.3 pg/ml), and 1.0 M mannitol (27.5 +/- 10.9 to 77.5 +/- 30.8 pg/ml) solutions. However, because pelvic pressure increased by 40-50 mmHg during the perfusions, the experiments were repeated with use of a different perfusion method in which pelvic pressure increased by less than 5 mmHg. Under these conditions, plasma AVP concentration did not change significantly during perfusion with any of the solutions. To determine whether the mechanoreceptor-induced increase in AVP release is mediated by the renal nerves, pelvic pressure was increased in another group of rabbits after renal denervation.(ABSTRACT TRUNCATED AT 250 WORDS)