The effects of selective phosphodiesterase III and V inhibitors on adrenergic and non-adrenergic, non-cholinergic relaxation responses of guinea-pig pulmonary arteries.

1. The aim of the present study was to investigate the role of several possible neurotransmitters in mediating non-adrenergic, non-cholinergic (NANC) relaxation, and the effects of phosphodiesterase (PDE) III and V inhibitors on adrenergic and NANC relaxation in branch pulmonary artery (PA) of guinea-pig. 2. Under the NANC conditions, electrical field stimulation (EFS, 60 V, 0.2 ms, 20 Hz) induced a tetrodotoxin-sensitive relaxation of the histamine-precontracted PA rings. The nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 10(-4) m) and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10(-5) m) partially inhibited the EFS-induced relaxation. The inhibitory effect of l-NAME was reversed completely by l-arginine (10(-3) m), but not d-arginine (10(-3) m). 3. This NANC relaxation was attenuated by 8-phenyltheophylline (10(-5) m), a P1-purinoceptor antagonist. 4. The NANC response was potentiated by 10-6 m zaprinast, a type V PDE inhibitor, but was unaffected by 3 x 10-6 m milrinone, a type III PDE inhibitor. 5. Sodium nitroprusside (SNP) caused a concentration-dependent vasodilator effect which was potentiated by zaprinast, but unaffected by milrinone. Moreover, the effect of combination of zaprinast with milrinone was not significantly different from that observed with zaprinast alone. 6. Isoprenaline produced a concentration-dependent vasodilatation in branch PA of guinea-pig which was potentiated by both zaprinast and milrinone, the efficacy of milrinone being greater than zaprinast. 7. These results suggest that both nitrergic and purinergic pathways are involved in mediating the NANC relaxation in branch PA of guinea-pig. The combination of PDE III or V inhibitors with vasorelaxant drugs may be a hopeful approach for the treatment of pulmonary hypertension.

Erythrocyte, plasma, and serum antioxidant activities in untreated toxic multinodular goiter patients.

Erythrocyte, plasma, and serum antioxidant activities were studied in patients with newly diagnosed and untreated toxic multinodular hyperthyroid goiter and compared to healthy control subjects. Erythrocyte antioxidant enzyme activities, glutathione, malondialdehyde, and ceruloplasmin levels were significantly increased, whereas serum vitamin E, plasma vitamin C, and selenium levels were decreased in hyperthyroid patients compared to control subjects. The findings show that untreated toxic multinodular goiter causes profound alterations in components of the antioxidant system in erythrocytes indicative of increased oxidative stress. Taken together, these data suggest that hyperthyroid patients may benefit from dietary supplements of antioxidants.

The effects of adenosine on isolated right atrial preparations from streptozotocin-diabetic rats.

1. The aim of the present study was to investigate the inhibitory effects of adenosine on the contractile force and chronotropic action of isolated right atrial preparations from streptozotocin (STZ)-diabetic rats. 2. The rats were anaesthetized with diethyl ether and STZ (65 mg kg(-1)) was injected intravenously via the tail vein. 3. Adenosine produced concentration-dependent decreases in the force of contraction and a negative chronotropic action of atria both in control and diabetic groups. The inhibition responses to adenosine were significantly higher in diabetic rat atria than control. 4. Dypiridamole incubation caused a significant potentiation of the inhibitory effect of adenosine on contractile force and chronotropic action of atria in the control group, but not in the diabetic group. In the presence of dipyridamole, the inhibitory effects of adenosine on measured parameters in diabetic rats were not significantly different from those in control rats. 5. These results suggested that atria from 6 weeks STZ-diabetic rats exhibited a supersensitivity to the negative inotropic and chronotropic effects of adenosine compared with atria from control rats because of an impairment in adenosine uptake mechanism. Altered sensitivity to effects of adenosine might reflect relatively early changes in the course of diabetes.

The effects of short-term nifedipine treatment on responsiveness of aortic rings of cadmium-hypertensive rats.

The effects of short-term antihypertensive treatment with nifedipine on blood pressure and vascular responsiveness were studied in cadmium-hypertensive and normotensive control rats. Cadmium administration caused a significant increase in mean arterial blood pressure. Endothelin-1, noradrenaline and angiotensin II produced concentration dependent contractions of aortic rings that attained a lower maximal contraction in cadmium-hypertensive rats. Responses of aortic rings to KCl did not show a significant difference between the groups. Nifedipine administered simultaneously with cadmium inhibited the induction of hypertension. Nifedipine treatment for 5 days significantly reduced the blood pressure in cadmium-hypertensive and normotensive rats. Neither inhibition of hypertension nor normalization of blood pressure in cadmium-hypertensive rats caused an alteration in contractile responses of aortic rings to vasoconstrictors which suggested that development of decreased vascular reactivity and of hypertension occurs simultaneously in cadmium-hypertensive rats but the role of decreased vascular reactivity in maintenance of hypertension is questionable in cadmium-hypertension.

Responsiveness of aortic rings of cadmium-hypertensive rats to endothelin-1.

Cadmium administered intraperitoneally at a dose of 1 mg/kg/day for 15 days caused a significant increase in mean arterial blood pressure. Endothelin-1 and noradrenaline produced concentration-dependent contractions of aortic rings that attained a lower maximal contraction in cadmium-injected rats as compared with control rats (p < 0.05). On the other hand, responses of aortic rings to different concentrations of potassium chloride did not show a significant difference between the groups. The decreased responsiveness of the aortae of cadmium-hypertensive rats to endothelin-1 and noradrenaline could either be due to an interaction of cadmium with receptors or intracellular signal transduction pathways of these agents, or it may simply reflect the adaptive changes in vascular tissues following hypertension development.