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Objectives: Vascular dysfunction is common in obesity. Insulin can directly modulate arterial function, but its role is unclear in obesity. We examined the influence of adiposity on direct effects of insulin on human artery responses., Methods: 22 healthy women were stratified by median BMI into lower (LA) (n=11) and higher adiposity (HA) (n=11). Small arteries from gluteal biopsies were tested for contractile responses to Noradrenaline (NA), the endothelium-dependent dilator Carbachol and the endothelium-independent dilator sodium nitroprusside were examined before and after incubation with 100 mU/ml human insulin., Results: Contractile responses were similar in the two groups. Insulin reduced NA-induced contraction in HA [3.5 (2.4-4.6) vs. 2.4 (1.4-3.4) mN/mm: p=0.004] but not those from LA [4.1 (2.8-5.3) vs. 3.7 (2.5-5.0) mN/mm: p=0.33]. Endothelium-dependent dilation (EDD) was significantly reduced in arteries from women in the HA (34.7 (18.8-50.6%)) compared to those from women in the LA (62.3 (46.2- 78.4); p=0.013). Insulin improved EDD (change in maximal dilation before/after insulin (%)) in arteries from the HA (37.7 (18.0 to 57.3) but not the LA (6.3 (-6.5 to 19.1), p=0.007., Conclusion: Reduced EDD evident in arteries from HA subjects improve by incubating in insulin. Hyperinsulinaemia may be necessary in maintaining endothelial function in obesity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In aquatic environments, chemical cues are believed to be associated with prey response to predation risk, yet few basic cue compositions are known despite the pronounced ecological and evolutionary significance of such cues. Previous work indicated that negatively-charged ions of m/z 501 are possibly a kairomone that induces anti-predator responses in amphibian tadpoles. However, work described here confirms that this specific ion species m/z 501.2886 is produced by injured tadpoles, exhibits increased spectral intensity with higher tadpole biomass, and is not produced by starved predators. These results indicate the anion is an alarm cue released from tadpoles. High resolution mass spectrometry (HR-MS) revealed a unique elemental composition for [M-H] - , m/z 501.2886, of C 26 H 45 O 7 S - which could not be determined in previous studies using low resolution instruments. Collision induced dissociation of m/z 501 ions formed product ions of m/z 97 and m/z 80, HSO 4 - and SO 3 - , respectively, showing the presence of sulfate. Green frog tadpoles, Lithobates clamitans, exposed to the m/z 501 anion or sodium dodecyl sulfate exhibited similar anti-predator responses, suggesting organic sulfate is a tadpole behavior modifier.

GDM (gestational diabetes mellitus) is associated with later adverse cardiovascular risk. The present study examined the relationship between glycaemia during pregnancy and small artery function and structures approx. 2 years postpartum. Women were originally enrolled in the HAPO (Hyperglycaemia and Adverse Pregnancy Outcome) study from which they were classified by their glycaemic distribution during pregnancy as controls (in the lower half of the distribution), UQ (upper quartile; in the UQ of the glycaemic distribution) or having had overt GDM. Subcutaneous arteries from a gluteal fat biopsy taken at follow-up 2 years later were examined using wire myography. Small artery structure, stiffness and vasoconstrictor responses were similar across groups. Maximal endothelium-dependent dilation in response to carbachol was impaired in arteries from both GDM (43.3%, n=8 and P=0.01) and UQ (51.7%, n=13 and P=0.04) women despite generally 'normal' current glycaemia (controls, 72.7% and n=8). Inhibition of NOS (nitric oxide synthase) significantly reduced maximum endothelium-dependent dilation in controls but had no effect on arteries from UQ and GDM women, suggesting impaired NOS activity in these groups. Endothelium-independent dilation was unaffected in arteries from previous GDM and UQ women when compared with the control group. Multiple regression analysis suggested that BMI (body mass index) at biopsy was the most potent factor independently associated with small artery function, with no effect of current glycaemia. Overweight women with either GDM or marginally raised glycaemia during pregnancy (our UQ group) had normal vascular structure and stiffness, but clearly detectable progressively impaired endothelium-dependent function at 2 years follow-up. These results suggest that vascular pathology, which may still be reversible, is detectable very early in women at risk of decline into Type 2 diabetes mellitus.

Laparoscopic ventral hernia repair requires an intraperitoneal prosthetic; however, these materials are not without consequences. We evaluated host reaction to intraperitoneal placement of various prosthetics and the functional outcomes in an animal model. Mesh (n = 15 per mesh type) was implanted on intact peritoneum in New Zealand white rabbits. The mesh types included ePTFE (DualMesh), ePTFE and polypropylene (Composix), polypropylene and oxidized regenerated cellulose (Proceed), and polypropylene (Marlex). Adhesion formation was evaluated at 1, 4, 8, and 16 weeks using 2-mm mini-laparoscopy. Adhesion area, adhesion tenacity, prosthetic shrinkage, and compliance were evaluated after mesh explantation at 16 weeks. DualMesh had significantly less adhesions than Proceed, Composix, or Marlex at 1, 4, 8, and 16 weeks (P < 0.0001). Marlex had significantly more adhesions than other meshes at each time point (P < 0.0001). There were no statistically significant differences in adhesions between Proceed and Composix meshes. After mesh explantation, the mean area of adhesions for Proceed (4.6%) was less than for Marlex (21.7%; P = 0.001). The adhesions to Marlex were statistically more tenacious than the DualMesh and Composix groups. Overall prosthetic shrinkage was statistically greater for DualMesh (34.7%) than for the remaining mesh types (P < 0.01). Mesh compliance was similar between the groups. Prosthetic materials demonstrate a wide variety of characteristics when placed inside the abdomen. Marlex formed more adhesions with greater tenacity than the other mesh types. DualMesh resulted in minimal adhesions, but it shrank more than the other mesh types. Each prosthetic generates a varied host reaction. Better understanding of these reactions can allow a suitable prosthetic to be chosen for a given patient in clinical practice.

Background: Despite the use of a sterile technique and the administration of prophylactic antibiotics during surgical procedures, mesh infection continues to complicate the use of biomaterials. The purpose of this study was to compare the susceptibility to infection of prosthetic biomaterials in a live-animal model., Methods: The following seven prosthetic mesh biomaterials were used in this study. Expanded polytetrafluoroethylene (ePTFE) with silver/chlorhexidine (DM+), ePTFE (DM), porcine intestinal submucosa (S), polypropylene (M), ePTFE/polypropylene (X), hyaluronate/carboxymethylcellulose/polypropylene (SM), and human acellular dermal matrix (A). Lewis rats (n = 108) underwent creation of a single ventral hernia; 105 of them were repaired with a different mesh (2-cm2 piece). Twelve pieces of each mesh were inoculated at the time of hernia repair with 10(8) Staphylococcus aureus (n = 84). Three pieces of each mesh were placed without bacterial inoculation (n = 21). In three animals, no mesh was placed; instead, the peritoneum of the hernia defect was inoculated (n = 3). After 5 days, the animals were killed and the mesh was explanted (peritoneum for the nonmesh control). The mesh was vortex-washed and incubated in tryptic soy broth. Bacterial counts were determined using serial dilutions and spot plates and quantified in colony-forming units (CFU) per square centimeter of mesh present in the vortex wash fluid (wash count) and the soy broth (broth count). Data are presented as the mean log(10), with analysis of variance (ANOVA) and Tukey's test used to determine significance (p < 0.05)., Results: The DM+ material had no detectable live bacteria in the wash or broth counts in 10 of 12 tested samples (p = 0.05). Of the samples that showed bacterial growth, the peritoneum control group had a lower wash count than A (p = 0.05) and the lowest broth count of all the materials except for DM+ (p = 0.05). In addition, SM had a significantly lower wash count than A (p = 0.05), with no broth count difference. In regard to wash and broth counts, DM, M, X, SM, S, and A were no different (p = NS)., Conclusions: The DM+ material was the least susceptible to infection. Impregnation with silver/chlorhexidine killed the inoculated bacteria, preventing their proliferation on the mesh surface. Other than DM+, native peritoneal tissue appears to be the least susceptible to infection. Silver/chlorhexidine appears to be an effective bactericidal agent for use with mesh biomaterials.

Background: The purpose of this study was to evaluate the effects of carbon dioxide (CO2) pneumoperitoneum and wound closure technique on port site tumor implantation., Methods: A standard quantity of rat mammary adenocarcinoma (SMT2A)was allowed to grow in a flank incision in Wistar-Furth rats (n = 90) for 14 days. Thereafter, 1-cm incisions were made in each animal in three quadrants. There were six control animals. The experimental animals were divided into a 60-min CO2 pneumoperitoneum group (n = 42) and a no pneumoperitoneum (n = 42) group. The flank tumor was lacerated transabdominally in the experimental groups. The three wound sites were randomized to closure of (a) skin; (b) skin and fascia; and (c) skin, fascia, and peritoneum. The abdominal wounds were harvested en bloc on postoperative day 7., Results: Histologic comparison of the port sites in the pneumoperitoneum and no-pneumoperitoneum groups did not demonstrate a statistically significant difference in tumor implantation for any of the closure methods. Evaluation of the closure techniques showed no statistical difference between the pneumoperitoneum group and the no-pneumoperitoneum group in the incidence of port site tumor implantation. Within the no-pneumoperitoneum group, there was a significant increase (p = 0.03) in tumor implantation with skin closure alone vs all three layers. Additionally, when we compared all groups by closure technique, the rate of tumor implantation was found to be significantly higher (p = 0.01) for skin closure alone vs closure of all three layers., Conclusions: This study suggests that closure technique may influence the rate of port site tumor implantation. The use of a CO2 pneumoperitoneum did not alter the incidence of port site tumor implantation at 7 days postoperatively.

The type of incisional instrument used to create a surgical wound can influence the rate of wound healing and overall wound strength. The purpose of this study was to evaluate several facets of wound healing within incisions created in the small intestine, uterus, and skin in a porcine model by using feedback circuit electrosurgical generators and a standard steel scalpel blade in a porcine model. Eighteen pigs were evaluated by creating surgical incisions in the skin, uterus, and small intestine utilizing 2 computerized electrosurgical generators (FX, ValleyLab, Boulder, CO, and PEGASYS, Ethicon Endo-Surgery, Inc., Cincinnati, OH) and a scalpel blade. All incisions were reapproximated with absorbable suture. Incision sites were evaluated histologically at 3, 7, or 14 days postincision according to randomization. The skin and small intestine samples were tested for wound tensile strength at 7 and 14 days. There were no statistically significant differences demonstrated with tensile strength testing comparing the electrosurgical devices to the scalpel-blade incisions for skin or small intestine at all time points. The only significant difference detected with respect to wound tensile strength was when different organ types were compared, regardless of device used (i.e., skin, 19.5 N/cm2 vs. small intestine, 5.78 N/cm2). Histologic evaluation demonstrated that the wounds created by the electrosurgical generators displayed decreased overall wound healing at 3, 7, and 14 days compared to the scalpel group. These findings indicate that the electrosurgical devices tested delay wound healing at the surgical site, but fail to demonstrate any significant difference in overall wound tensile strength. Wound healing may occur at a more rapid rate when a traditional scalpel blade is used to create the surgical incision, but no difference in global wound dynamics could be detected.

Interferons (IFN) have been shown to be effective in protecting animals against lethal viral infections when administered systemically in relatively high doses. Intraperitoneal (i.p.) injection of mice with encephalomyocarditis virus (EMCV) gives rise to a rapidly progressive fatal disease characterized by central nervous system involvement and encephalitis. IFN-alpha has been shown to be effective in protecting mice against lethal EMCV infection when given via parenteral and oral/sublingual routes. The current study was designed to explore the ability of orally/sublingually and intranasally (i.n.) administered IFN-alpha to treat mice infected with EMCV in support of a planned clinical trial to evaluate efficacy of oral IFN-alpha in human viral infections. The primary objective of the study was to determine the efficacy of recombinant murine IFN-alpha (rMuIFN-alpha) in the treatment of mice infected with 100 LD(50) EMCV following oral, i.n., and i.p. administration at doses of 20,000 and 100,000 IU. The results of the current experiment did not indicate protection from infection with EMCV in mice that received IFN by the i.n. or oral/sublingual routes. The negative controls, infection of mice with 100 LD(50) of EMCV followed by treatment with excipient via all three routes, resulted in death of nearly all mice, as expected. The positive control, treatment of EMCV-infected (100 LD(50)) mice with rMuIFN-alpha via the i.p. route, was successful in protecting a significant number of mice from death compared with matched controls. This study points out the need to determine the optimum conditions for administration of oral/sublingual or i.n. IFN to insure maximum efficacy against viral infections.

Catecholamines (norepinephrine, epinephrine, dopamine) enhance the growth of several species of gram-negative bacteria. Since catechol rings are known siderophores in bacteria, the administration of catecholamines may enhance growth by improving iron uptake in growth-limiting media, serving as auxiliary siderophores. We have tested the iron content in bacterial growth media which are known to support rapid growth and "slow growth" media. Additionally, we have examined the uptake of 3H-norepinephrine, to determine whether the catecholamine is actually taken into the bacteria or is merely adsorbed to the outside of the bacteria. Finally, we have been examining the supernatants produced by culturing bacteria with norepinephrine. These supernatants have been shown to have the capacity to enhance growth of naive cultures of bacteria, and are suggested to contain an "autoinducer of growth". We have found that both fast-growth and slow-growth media contain similar concentrations of iron, and that these levels do not change in most supernatants from NE-supplemented bacterial cultures. Examination of culture supernatants from NE-supplemented bacteria under different temperature conditions reveals some interesting differences. First, culture supernatant from NE-treated Escherichia coli, cultured at 37 degrees C, when examined by HPLC, exhibits a change in the norepinephrine content over time which is not seen in supernatant from 21 degrees C cultures or other media treatments. Second, the 37 degrees C culture NE-supplemented E. coli supernatant was significantly more effective in enhancing growth of three bacterial species than any other culture method other than NE-supplementation itself (this includes supernatant from NE-supplemented cultures of the other two species as well as supernatants from unsupplemented cultures of all three species).

In addition to their role as sex hormones, it has been known for many years that oestrogens have protective effects on the vasculature. These have been implicated in the reduced incidence of cardiovascular disorders in premenopausal women and in post-menopausal women receiving oestrogen replacement therapy. This protection has been found to be due, in part at least, to direct effects of oestrogens on blood vessels. This review will summarize the available literature regarding oestrogenic effects on vascular contractility. Two major influences of oestrogens will be discussed; first the genomic effects induced by chronic administration of steroid hormones, and second, the rapid effects on vascular smooth muscle by non-genomic, and as yet not fully identified, mechanisms. In so doing, the diversity of oestrogenic actions on vascular contractility will be highlighted and the protective role of these agents against adverse cardiovascular events discussed.

Several species of bacteria have been shown to respond to the administration of norepinephrine and other catecholamines with increased growth (in culture) and virulence. In this study, we examined the effects of catecholamines on the growth of cultures of Aeromonas hydrophila, a Gram-negative bacillus found in brackish water. Bacterial cultures were maintained in tryptic soy both, then washed free of medium and transferred to a bovine serum-supplemented minimal salts medium. Treatment of A. hydrophila cultures with 10(-3)to 10(-5)M norepinephrine resulted in dramatic increases in growth at 24 h and longer, as assessed by spot plate analysis on tryptic soy agar plates. Norepinephrine-treated cultures had 4.5 log greater bacterial numbers than control cultures. Epinephrine, dopamine and isoproterenol were shown to be similarly effective in enhancing growth of A. hydrophila, over narrower concentration ranges. Acetylcholine supplementation of cultures did not alter the growth of A. hydrophila. Serotonin slightly enhanced Aeromonas growth when administered at very high concentrations (10(-3)M). The increased growth observed after catecholamine administration may alter the capacity to infect an animal under stressful conditions, and is another potential mechanism by which a stress response can affect susceptibility to disease., (Copyright 1999 Academic Press.)

To delineate ligand binding and functional characteristics of the human B1 kinin receptor, a stable clone of Chinese hamster ovary cells expressing a single class of binding sites for [3H]des-Arg10-lysylbradykinin with a Kd of 0.3 nM and a Bmax of 38 fmol/mg protein ( approximately 40,000 receptors/cell) was isolated. Studies with peptide analogs showed that a lysine residue at position 1 (based on the lysylbradykinin sequence) of ligands was essential for high affinity binding to the human B1 receptor. In marked contrast to cloned Chinese hamster ovary cells expressing the human kinin B2 receptor, which internalized approximately 80% of the ligand within 5 min upon exposure to 2 nM [3H]bradykinin, exposure of cells expressing the B1 receptor to 1 nM [3H]des-Arg10-lysylbradykinin resulted in minimal ligand internalization. Stimulation of the B1 receptor led to inositol phosphate generation and transient increases in intracellular calcium, confirming coupling to phospholipase C, while immunoprecipitation of photoaffinity-labeled G-proteins from membranes indicated specific coupling of the receptor to Galphaq/11 and Galphai1,2. The B1, unlike the B2, receptor does not desensitize (as demonstrated by continuous phosphoinositide hydrolysis), enhancing the potential role of this receptor during inflammatory events.

Bradykinin, 10 to 1000 micrograms given by aerosol into the nasal cavity of normal, healthy volunteers, produced a dose-related increase of nasal airway resistance. Bradykinin also reduced the minimal nasal cross-sectional area (Amin), increased albumin release into nasal lavage fluid and increased the symptoms of nasal inflammation. Pretreatment with cetirizine (10 mg orally) reduced the fall in Amin induced by bradykinin, 300 micrograms, but not by bradykinin, 100 micrograms. Pre-treatment of the subjects with the H1 histamine receptor antgonist cetirizine (10 mg, orally) or terfenadine (60 mg, orally) 3 h before bradykinin administration caused significant reduction of the bradykinin-induced increase in nasal airway resistance in the upper range of bradykinin doses (300-1000 micrograms) but not in the lower range (10-100 micrograms). Cetirizine reduced the albumin release into the nasal airway and the symptoms induced by bradykinin, 1000 micrograms. Following nasal challenge with bradykinin 300 micrograms or 1000 micrograms, no increase could be detected in the histamine content of nasal lavage fluid. Isolated human nasal cells released histamine in response to bradykinin, 33 and 100 microM, anti-IgE and calcium ionophore, A23187. We conclude that the actions of bradykinin in the human nasal airway are, in part, accounted for by the release of histamine.

The new, low-range Ferraris pocket peak flow meter was compared with the well established low-range mini Wright peak flow meter for measuring peak flow rates in children. The peak flow meters were compared by performing three forced expirations using each meter, in 50 children. On average the pocket peak flow meter gave higher readings than the mini Wright, by a mean of 15 l/min. The peak flow rates obtained by the two meters were highly correlated (P < 0.001, r = 0.882 n = 50). In conclusion, the Ferraris pocket peak flow meter is easy and comfortable to use, giving reproducible measurements of peak flow in children.

1. Studies of cardiac and vascular responses have previously demonstrated that diabetes influences the sensitivity of these tissues to adrenoceptor stimulation. Adrenoceptors are also present on platelets where they modulate aggregatory responses. The present study investigates the influence of diabetes on these platelet adrenoceptor-mediated responses. 2. Rats were made diabetic with streptozotocin and platelet aggregatory responses to ADP were examined 2 or 12 weeks later. Aggregation to ADP of platelets from 2-week-diabetic rats was similar to that of platelets from age-matched controls, but platelets from 12-week-diabetic animals exhibited an enhanced aggregation to ADP. 3. In all groups studied, beta-adrenoceptor stimulation with isoprenaline caused a concentration-dependent inhibition of aggregation to ADP, whilst alpha-adrenoceptor stimulation with adrenaline was found to potentiate aggregation to ADP. The degree of inhibition or potentiation was found to remain unchanged by diabetes of either 2 or 12 weeks duration. 4. Previously reported increases in cardiac beta-adrenoceptor sensitivity and aortic alpha-adrenoceptor sensitivity were confirmed 2-week-diabetic animals, but these sensitivity changes were not observed in 12-week-diabetic rats. 5. The results indicate that, unlike the heart and vasculature, the influences of adrenoceptor stimulation on platelet aggregation are not altered by diabetes, even when aggregation to ADP is enhanced.

Acoustic rhinometry was used to assess nasal airway patency objectively and was compared with the more established method of anterior rhinomanometry. Ten patients with allergic rhinitis underwent 15 nasal challenges with allergen to which they showed positive skin-prick tests. Responses were assessed by measuring the minimum nasal cross-sectional area (Amin.) using acoustic rhinometry and by measuring nasal airway resistance (NAR) using anterior rhinomanometry. The measurements of Amin. and NAR showed a significant negative correlation. Acoustic rhinometry appears to be superior to anterior rhinomanometry in quantifying the response to nasal allergen challenge and may be particularly useful in patients with initial nasal blockage.

1. The aim of this study was to investigate the action of bradykinin on resistance to airflow and on vascular permeability in the human nasal airway, and to explore the receptor mediating these effects. 2. Aerosol administration of bradykinin (10-1000 micrograms) caused a dose-related increase in nasal airway resistance (NAR) and an increase in albumin content of nasal lavage. 3. The bradykinin antagonists, [1-adamantane acetyl-D-Arg0, Hyp3, Thi5,8, D-Phe7]-bradykinin, 100 micrograms, and [D-Arg0, Hyp3, Thi5, D-Tic7, Oic8]-bradykinin, 100 micrograms, given 2 min before bradykinin, inhibited the increase in NAR and the increase of albumin content of nasal lavage caused by bradykinin. 4. The bradykinin antagonist, [D-Arg0, Hyp3, D-Phe7]-bradykinin (100 micrograms) did not affect the increase in NAR produced by bradykinin, or the albumin content of nasal lavage. Increasing the dose of the antagonist to 1000 micrograms did not change the increase in NAR induced by bradykinin. 5. The selective B1 kinin receptor agonist, [Des-Arg10]-kallidin (100 micrograms) did not affect NAR or the albumin content of nasal lavage. 6. The receptor mediating increased NAR and the release of albumin induced by bradykinin in the human nasal airway appears not to be a B1 kinin receptor. The data are not entirely consistent with the effects of bradykinin in the human nasal airway being mediated by a B2 kinin receptor.

In subjects with allergic rhinitis to house-dust mite (HDM), antigen challenge produced a significant increase in nasal blockage but had no effect on nasal vascular permeability. The B2 kinin receptor antagonist, [D-Arg0,Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140), 200 micrograms administered by intranasal aerosol 2 min prior to challenge with HDM, 500 u significantly reduced nasal blockage induced by the antigen challenge. The data are compatible with a role for B2 kinin receptors in the nasal response to challenge with antigen which is responsible for nasal blockage.

1. The effects of inhaled platelet-activating factor (PAF) on responsiveness of the human nasal airway were examined in normal subjects by measuring nasal airway resistance in response to histamine and bradykinin at 2, 6, 24, 48 h and 7 d after PAF administration. Eosinophil cationic protein (ECP) in nasal secretions was also measured. 2. Intranasal aerosol administration of PAF, 30 or 60 micrograms per nostril to normal human subjects induced an increased responsiveness to inhaled histamine, 50 to 400 micrograms and bradykinin, 100 micrograms per nostril at 2, 6 and 24 h following PAF treatment. However the effect was not apparent at 48 h or 7 days after PAF administration. 3. Intranasal administration of lyso-PAF, 60 micrograms by aerosol did not increase the reactivity of the nasal airway in response to histamine, 200 micrograms. 4. There was no difference in the time course of the PAF-induced hyperresponsiveness to histamine or bradykinin. 5. PAF-induced nasal hyperresponsiveness at 2 and 6 h was associated with increases in the ECP concentration of the nasal lavage fluid. 6. Vitamin E pretreatment of subjects resulted in the attenuation of the PAF-induced hyperresponsiveness to histamine, and a decrease in ECP levels of the nasal lavage fluid. 7. The results suggest that in the human nasal airway, PAF induces a non-specific hyperresponsiveness which is accompanied by eosinophil activation in the nasal cavity. Free radical production induced by PAF may contribute to the hyperresponsiveness and the activation of eosinophils.

1. The effects on cardiac responsiveness of diabetes of up to 12 weeks duration has been examined in streptozotocin-pretreated rats. 2. Two weeks of diabetes resulted in a supersensitivity of isolated left atria and papillary muscles to isoprenaline, which was associated with an increase in the density of ventricular [3H]-dihydroalprenolol binding sites. 3. The beta-adrenoceptor supersensitivity was still evident in both tissues after 4 weeks of diabetes, but in left atria the supersensitivity was reduced compared with that observed at 2 weeks, while for papillary muscles it was greater than at 2 weeks. 4. Following 12 weeks of diabetes, responses of papillary muscles to isoprenaline were similar to controls, while beta-mediated responses of left atria were significantly depressed. 5. The alpha-adrenoceptor-mediated responses of cardiac tissues to phenylephrine were similar to controls following diabetes of 2 or 4 weeks duration. At 12 weeks, however, papillary muscle alpha-adrenoceptor-mediated responses were enhanced. The change in ventricular responsiveness to phenylephrine was not accompanied by any change in [3H]-prazosin binding to ventricular membranes. 6. The results demonstrate a transient elevation of cardiac beta-adrenoceptor sensitivity and receptor density during acute diabetes and illustrate the time- and tissue-dependence of diabetes-induced changes in cardiac adrenoceptor sensitivity.

1. The responses of isolated left atria and papillary muscles to isoprenaline, forskolin and calcium have been examined in 3 week streptozotocin-diabetic rats and the effects of oral ponalrestat administration (25 mg kg-1 daily) on diabetes-induced changes in cardiac responsiveness investigated. 2. Three weeks after animals were made diabetic, cardiac responses to isoprenaline were enhanced and this was accompanied by an increase in the density of ventricular [3H]dihydroalprenolol binding sites. Treatment of animals with ponalrestat prevented the increase in cardiac beta-adrenoceptor responsiveness and receptor number. 3. Diabetes also enhanced the sensitivity of cardiac tissues to forskolin, an effect that was not prevented by the treatment of animals with ponalrestat. 4. Ponalrestat treatment increased the resting and maximum tensions developed by cardiac tissues from diabetic animals and increased the maximum tensions developed by tissues from control animals. Diabetes alone had no effect on resting or maximum developed tensions. 5. Ponalrestat therefore prevents the changes in beta-adrenoceptor density and responsiveness induced by short-term diabetes in the rat and also increases the tension developed by cardiac muscle, an effect observed in diabetic and normal animals.

1. The chronotropic and inotropic responses of the young chick heart to noradrenaline have been investigated in isolated right atria, left atria and ventricular strips from 14-day-old chicks. 2. In the presence of desipramine and metanephrine to inhibit amine uptake, concentration-response curves to noradrenaline in all three tissues were shifted to the right by propranolol (1 microM) but were not altered by the presence of either phentolamine (5 microM) or prazosin (10 microM). 3. Similar results were obtained in the presence of cocaine (10 microM) and corticosterone (10 microM) to inhibit amine uptake. Propranolol (0.3-3.0 microM) produced rightward shifts of noradrenaline concentration-response curves which gave pA2 values of 8.1-8.4. Phentolamine (5 microM), in contrast, did not affect responses to noradrenaline in any tissue, either in the absence or presence of propranolol (1 microM). 4. Isoprenaline produced positive chronotropic responses in right atria and positive inotropic responses in left atria and ventricular strips. Methoxamine elicited positive inotropic responses in left atria but only negative chronotropic responses in right atria and negative inotropic responses in ventricular strips. 5. These results demonstrate that cardiac responses to noradrenaline in the chick heart are mediated via beta-adrenoceptors only, and that cardiac alpha-adrenoceptors are not involved in these responses.