bibp-3226 and Bradycardia

Neuropeptide Y (NPY), a sympathetic neurotransmitter, is highly associated with baroreflex dysfunction and multiple cardiac diseases such as diabetic myocardiopathy. In the present study, we aimed to explore the role of peripheral NPY Y1 receptor (Y1R) and Y2 receptor (Y2R), which are dominantly present in peripheral cardiovascular control, in baroreflex sensitivity (BRS) of streptozotocin (STZ)-induced diabetic rats. Peripheral Y1R and Y2R were antagonized by specific antagonists (BIBP 3226 and BIIE 0246, respectively) from subcutaneously implanted ALZET mini-osmotic pump in STZ-induced diabetic rats for 4 weeks. Then baseline systolic blood pressure, heart rate, cardiac function, BRS, plasma NPY and lipid levels were evaluated. We found that STZ led to increased plasma NPY and lipid level. And the STZ-increased lipid levels were reduced by BIBP 3226 and BIIE 0246. BIBP 3226 ameliorated the aberrant BRS, but had little effect on the impaired cardiac function of the STZ rats. BIIE 0246 alleviated sodium nitroprusside (SNP)-induced but not phenylephrine (PE)-induced aberrant baroreflex control of heart rate in the STZ rats. In addition, BIIE 0246 alleviated the bradycardia, but further impaired cardiac contractility in the STZ rats. These results suggest that peripheral Y1R and Y2R play different roles in STZ-induced impairment of BRS.

Topics: Animals; Arginine; Baroreflex; Benzazepines; Blood Pressure; Bradycardia; Diabetes Mellitus, Experimental; Heart Rate; Myocardial Contraction; Neuropeptide Y; Rats; Receptors, Neuropeptide Y; Streptozocin

Diaspirin crosslinked hemoglobin (DCLHb) is a chemically stabilized hemoglobin (Hb) that induces an increase in blood pressure and a decrease of heart rate when injected intravenously in some animals. The mechanism by which DCLHb elicits these hemodynamic effects was studied in pentobarbital-anesthetized, vagotomized rats using a variety of drugs known for their inhibitory action towards endogenous hemodynamically active systems. The hypertensive episode elicited by DCLHb (100 or 400 mg.kg-1) was attenuated in animals pretreated with NG-nitro-L-arginine (inhibitor of nitric oxide synthases) throughout the 30-min period of observation, but it was not reduced in those pretreated with a variety of sympatholytic drugs (e.g., prazosin), atropine, BIBP-3226 (neuropeptide Y antagonist), indomethacin, [1-(beta-mercapto-beta,beta-cyclopentanemethylene propionic acid), 2-(0-methyl) tyrosine]-Arg8 vasopressin (vasopressin antagonist), losartan (angiotensin antagonist), bosentan (endothelin antagonist), or L-arginine-(nitric oxide precursor), compared with control animals. With the exception of propranolol and BIBP-3226, none of the aforenamed inhibitors reduced the amplitude of the bradycardia associated with the pressor effect of DCLHb. These results suggest that: (i) the acute (< 30 min) pressor activity of DCLHb in our animal model requires the presence of an endogenous nitric oxide generating system to be expressed; (ii) the bradycardia elicited by DCLHb might involve the participation of neuropeptide Y and (or) its NPY-1 receptors, but it is unlikely to involve a baroreceptor-mediated vagal reflex, at least in our animal model.

Topics: Animals; Arginine; Aspirin; Blood Pressure; Blood Substitutes; Bradycardia; Enzyme Inhibitors; Hemoglobins; Male; Neuropeptide Y; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Vagotomy