8-Bromo cyclic guanosine monophosphate mimics the actions of nitroglycerin on alpha-adrenergic mechanisms in canine saphenous vein

The purpose of the present study was to determine if 8-bromo cyclic guanosine monophosphate (cGMP) mimics the actions of nitroglycerin in inhibiting alpha 1- versus alpha 2-mediated constrictor responses in vitro using rings prepared from isolated canine saphenous vein. Contractions were produced by phenylephrine, a selective alpha 1-adrenoceptor agonist and B-HT 920, a selective alpha 2-adrenoceptor agonist. The inhibitory effects of nitroglycerin and 8-bromo cGMP on contractions produced by submaximal concentrations (EC75) of phenylephrine and B-HT 920 were determined. 8-Bromo cGMP like nitroglycerin produced a selective antagonism of alpha 2-adrenoceptor-mediated responses and had minimal effects on alpha 1-adrenoceptor-induced constriction. However, after removal of spare postsynaptic vascular alpha 1-adrenoceptors by treatment with the irreversible alpha-adrenoceptor antagonist phenoxybenzamine (5 X 10(-8) M, 1 X 10(-7) M), the alpha 1-adrenoceptor-mediated vasoconstrictor responses of phenylephrine became highly sensitive to antagonism by 8-bromo cGMP and nitroglycerin. These data suggest that the action of 8-bromo cGMP like nitroglycerin is 'buffered' by the presence of a large alpha 1-adrenoceptor reserve in canine saphenous vein. The similarity in the efficacy and potency of these two agents suggests that the effects of nitroglycerin in canine saphenous vein may be the result of an increase in intracellular cGMP.     

Halothane and Isoflurane Decrease the Open State Probability of Potassium sup + Channels in Dog Cerebral Arterial Muscle Cells

Background: Both halothane and isoflurane evoke cerebral vasodilation. One of the potential mechanisms for arterial vasodilation is enhanced Potassium sup + efflux resulting from an increased opening frequency of membrane Potassium sup + channels. The current study was designed to determine the effects of volatile anesthetics on Potassium sup + channel current in single vascular smooth muscle cells isolated from dog cerebral arteries.

Methods: Patch clamp recording techniques were used to investigate the effects of volatile anesthetics on macroscopic and microscopic Potassium sup + channel currents.

Results: In the whole-cell patch-clamp mode, in cells dialyzed with pipette solution containing 2.5 mM EGTA and 1.8 mM CaCl2, depolarizing pulses from 60 to +60 mV elicited an outward Potassium sup + current that was blocked 65 plus/minus 5% by 3 mM tetraethylammonium (TEA). Halothane (0.4 and 0.9 mM) depressed the amplitude of this current by 18 plus/minus 4% and 34 plus/minus 6%, respectively. When 10 mM EGTA was used in the pipette solution to strongly buffer intracellular free Calcium2+, an outward Potassium sup + current insensitive to 3 mM TEA was elicited. This Potassium sup + current, which was reduced 51 plus/minus 4% by 1 mM 4-aminopyridine, was also depressed by 17 plus/minus 5 and 29 plus/minus 7% with application of 0.4 and 0.9 mM halothane, respectively. In cell-attached patches using 145 mM KCl in the pipette solution and 5.2 mM KCl in the bath, the unitary conductance of the predominant channel type detected was 99 pS. External application of TEA (0.1 to 3 mM) reduced the unitary current amplitude of the 99 pS Potassium sup + channel in a concentration-dependent manner. The open state probability of this 99 pS Potassium sup + channel was increased by 1 micro Meter Calcium2+ ionophore (A23187). These findings indicate that the 99 pS channel measured in cell-attached patches was a TEA-sensitive, Calcium2+ -activated Potassium sup + channel. Halothane and isoflurane reversibly decreased the open state probability (NPo), mean open time, and frequency of opening of this 99 pS Potassium sup + channel without affecting single channel amplitude or the slope of the current-voltage relationship.     

Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study

OBJECTIVE

To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily.

RESULTS

Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA_1c 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA_1c reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were −1.53 vs. −1.48 (P = 0.620), −1.63 (P = 0.328), and −1.15 (P < 0.001), respectively. Weight changes (kg) were −2.0 vs. −2.0 (P = 0.892), +1.5 (P < 0.001), and −0.8 (P < 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred.

CONCLUSIONS

EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA_1c reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.The 2009 consensus algorithm from the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) recommends lifestyle changes and metformin (MET) as the initial (tier one, well-validated) treatment at diagnosis of type 2 diabetes (1). Common adjunctive treatments not associated with an increased risk of hypoglycemia when used as monotherapy include the thiazolidinedione, pioglitazone (PIO), the dipeptidyl peptidase-4 inhibitor, sitagliptin (SITA), and the glucagon-like peptide-1 receptor agonist exenatide twice daily (BID) (2–5). PIO and exenatide BID are included in the second tier (less well-validated) of preferred agents in the ADA/EASD algorithm. SITA is not indentified, but may be an appropriate choice for selected patients (1). These agents, commonly used only in MET-intolerant patients as monotherapy, have unique risks, benefits, and mechanisms.Effective and safe monotherapy treatment options for patients unable to tolerate MET are limited. In the United States, exenatide BID is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. A new formulation of exenatide (exenatide once weekly [EQW]) has been shown to result in greater improvements in glycemic control, with no increased risk of hypoglycemia and similar weight reduction compared with exenatide BID (6,7). This randomized trial (Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once-Weekly [DURATION-4]) directly compared the safety and efficacy of EQW monotherapy versus MET, PIO, and SITA monotherapy in patients with type 2 diabetes who were suboptimally treated with diet and exercise but naive to antihyperglycemic drugs.