Beta-adrenoceptor alterations coupled with secretory response and experimental periodontitis in rat submandibular glands.

In this paper we have studied the influence of a well-established rat model of periodontitis on resting and adrenergic-stimulated mucin secretion from rat submandibular glands. The selective beta(1)-receptor subtype agonist, dobutamine, induced mucin secretion while the selective beta(2)-, alpha(1)- and alpha(2)-agonists, soterenol, phenylephrine and clonidine, respectively, did not. In rats subjected to ligature-induced periodontitis mucin release, under unstimulated conditions (basal values), was significantly increased. This increment was abolished in the presence of propranolol and atenolol. Isoproterenol, concentration-dependent, increased mucin release in control and in ligature-induced periodontitis rats. Maximal effect of isoproterenol was decreased in rats with ligature while EC(50) was increased. Neither, the inhibition of NOS by l-NMMA nor the inhibition of COX by indomethacin could revert the effect of ligature on mucin release under unstimulated and isoproterenol-stimulated conditions. The inhibition of adenylyl cyclase by SQ 22536 resulted in a right shift of isoproterenol concentration-response curves in both groups, control and with ligature and returned basal values of rats with ligature to control ones. beta-Receptor population was decreased in submandibular gland membranes from rats with ligature without changes in affinity. Potencies of the beta-receptor antagonists in the competition studies were similar in both groups under study, control and with ligature. We conclude that in rats subjected to ligature-induced periodontitis unstimulated mucin secretion is increased. The increment seems to be due to an activation of the sympathetic system since it is inhibited by the beta-adrenoceptors antagonists and by the inhibition of the adenylyl cyclase. We can speculate that inflammatory mediators from the experimental periodontitis could be involved in the mechanism underlying the activation of the sympathetic system.

Adenovirus-mediated expression of beta-adrenergic receptor kinase C-terminus reduces intimal hyperplasia and luminal stenosis of arteriovenous polytetrafluoroethylene grafts in pigs.

BACKGROUND: Hemodialysis vascular access dysfunction is the single most important cause of morbidity in kidney hemodialysis patients. Failure of an arteriovenous polytetrafluoroethylene (PTFE) graft, the most common form of hemodialysis access, is primarily due to intimal hyperplasia and thrombosis at the venous anastomosis. METHODS AND RESULTS: This study was aimed at evaluating the efficacy and safety of an adenoviral vector (Ad2/betaARKct) encoding the carboxyl terminus of beta-adrenergic receptor kinase (betaARKct) in a pig model of arteriovenous PTFE graft failure. Transduction of the external jugular vein with Ad2/betaARKct (5E9, 5E10, or 5E11 particles per vein) did not result in systemic toxicity, as measured by clinical and pathological assessments. Ad2/betaARKct significantly reduced neointimal hyperplasia in the graft/vein anastomosis. It also improved the graft patency rate and angiographic score, as measured histologically and angiographically, compared with vehicle or empty viral vector controls. CONCLUSIONS: Our results suggest that local administration of adenoviral vectors encoding betaARKct into the jugular vein represents a viable strategy to treat AV graft hemodialysis vascular access failure.

Inhibition of anti-IgE induced skin response in normals by formoterol, a new beta 2-adrenoceptor agonist, and terbutaline. 2. Effect on the late phase reaction.

Formoterol, a new beta 2-selective long-acting bronchodilator, was compared with terbutaline in terms of ability to inhibit dual phase skin reactions to anti-human IgE in volunteers. Anti-IgE induced an early wheal and flare reaction (WFR) followed by a progressively increasing induration, the late phase reaction (LCR), lasting greater than or equal to 24 h. Intradermal injection of formoterol 20 ng or terbutaline 500 ng 5 min before challenge gave equal inhibition of the WFR. The subsequent LCR was suppressed by formoterol (30%) for the whole 24 h period, while terbutaline only attenuated the first 4 h period. Increasing the dose range of both drugs 25-fold, caused a further analogous reduction of the WFR to anti-IgE. In this higher dose range formoterol (0.5 micrograms) antagonized the following 1-24 h LCR by 50%, while terbutaline (25 micrograms) only attenuated the LCR by an average of 20%, with higher effect in the first 6 h period. The anti-LCR capacity of formoterol was highly superior to that of terbutaline (P less than 0.001). The histamine-elicited wheal response was attenuated by both drugs, but they had no effect on the flare response, favouring an anti-permeability action of both compounds. The data support the concept that terbutaline, given locally in a single dose shortly before challenge, inhibits the mast cell mediator release reaction with limited consequences for the following LCR. In contrast to terbutaline, formoterol exerted a substantial anti-LCR action, probably by interfering with inflammatory mechanisms after the initial mast cell mediator release.

Interactions of vasodilators with calcium entry- and beta-blockers in patients with coronary heart disease.

Combinations of antianginal drugs may be used for an additive effect against angina, but also to off-set unwanted effects of one drug with another, either by direct effects or by a reduction of dosage of each drug. Based on earlier studies with separate drugs we have now examined the effect of 150 mg bupranolol combined with 40 mg isosorbide dinitrate (ISDN) in one retarded tablet, given twice daily. 22 patients with CHD entered the study, 11 of those with and 11 without signs of ischemia during exercise. In an acute radionuclide ventriculographic (RNV) study 2 h after the tablet, ejection fraction (EF) during exercise increased only in patients with exercise ischemia (+6%, p less than 0.001). In the other patients EF did not change. After 21 days of treatment echocardiographically determined end-systolic and end-diastolic diameters decreased, resulting in an increase of shortening fraction by 15.6% (p less than 0.05). Heart rate, systolic and diastolic pressure and ST-segment depression decreased significantly. In another acute RNV study the effect of a venous vasodilator, molsidomine 4 mg s.l., was examined after nifedipine 10 mg s.l. in 19 patients with CHD, 9 with and 10 without exercise ischemia. Differences between drugs were most prominent during exercise. In the nonischemic group EF rose by 6.6% after nifedipine (n.s.) and by 14% after molsidomine (p less than 0.01 against control). In the group with ischemia EF rose by 12.6% after nifedipine and by 17.4% after additional molsidomine, significant against control (p less than 0.01) as well as against nifedipine (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute intravenous and sustained oral treatment with the beta1 agonist prenalterol in patients with chronic severe cardiac failure.

Prenalterol, a beta1 agonist, was given in a single blind acute intravenous study to seven patients with cardiac failure (New York Heart Association class II and III). It was then given in a double blind crossover study of sustained oral prenalterol to six of them. As a result of dose titration studies the oral dose of prenalterol given was 100 mg twice a day in all patients. Erect bicycle sprint tests were performed to exercise tolerance before and after treatment had been started. Cardiac function was assessed at rest and during graded supine bicycle exercise by determining haemodynamic indices using a Swan-Ganz catheter and radionuclide left ventricular ejection fractions. In the intravenous study cardiac function was assessed at rest and during exercise after a control infusion of dextrose and after an infusion of 5 mg prenalterol. In the oral crossover study a placebo or prenalterol were given for two periods of two weeks; at the end of each period exercise tolerance was measured and cardiac function assessed at rest and during exercise. Throughout the study period there was no change in symptoms, medication, or exercise tolerance. Intravenous prenalterol significantly improved cardiac function; left ventricular ejection fraction and cardiac index increased and left ventricular filling pressure fell both at rest and during exercise. Sustained oral treatment with prenalterol, however, did not improve resting left ventricular filling pressure or left ventricular ejection fraction at rest or during exercise but did increase heart rate at rest, and mean blood pressure and peripheral vascular resistance at rest and during exercise; in fact, during exercise left ventricular filling pressure was significantly increased while cardiac index and stroke volume index were decreased by prenalterol. Sustained oral treatment with prenalterol did not have the beneficial effects on cardiac function produced by intravenous treatment and in fact had deleterious effect on the measured indices of cardiac function during exercise.