npc-17731 and Ischemia

Ischemically sensitive visceral sympathetic nerve fibers, which are thought to represent the afferent limb of a strong cardiovascular pressor reflex, can be stimulated by exogenously applied bradykinin (BK). During ischemia, BK also is known to be produced locally and to serve as an endogenous stimulus for activation of ischemically sensitive nerve endings. It is unclear, however, whether ischemically induced BK production is sufficient to elicit a reflex cardiovascular response. Accordingly, femoral arterial and venous catheters were positioned in anesthetized cats, and the superior mesenteric and celiac arteries were isolated for placement of snare occluders. After dual occlusion of these arteries (20 min), one of two chemically dissimilar specific kinin B2 (BK2) receptor antagonists, HOE-140 (30-40 micrograms/kg iv, n = 8) or NPC-17731 (30-40 micrograms/kg iv, n = 11), was administered and dual occlusion was repeated. The reflex rise of mean arterial blood pressure (BP) of 16 +/- 3.7% was significantly (P < 0.05) reduced by HOE-140 to 8.4 +/- 2.0%. NPC-17731 similarly attenuated the reflex BP increment from 13 +/- 1.2 to 6.2 +/- 1.6% (P < 0.05). In a separate set of control animals the first and second periods of ischemia induced reflex BP increments that did not differ significantly (16 +/- 2.7 and 16 +/- 5.7%, respectively). Qualitatively similar decrements of the BP response were produced by the BK2 receptor antagonists in two additional groups in which blood flow to the superior mesenteric and celiac arteries was diverted to a venous reservoir to eliminate the initial transient (mechanically induced) rise in BP associated with artery ligation that is known not to be associated with the reflex response. These results indicate that the stimulation of BK2 receptors on visceral afferent nerves by BK is responsible, at least in part, for the reflex cardiovascular response during visceral ischemia.

Topics: Abdomen; Animals; Baroreflex; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cats; Celiac Artery; Female; Ganglia, Sympathetic; Ischemia; Male; Mesenteric Arteries; Oligopeptides; Receptors, Bradykinin

Abdominal ischemia and reperfusion reflexly activate the cardiovascular system. In the present study, we evaluated the role of endogenously produced bradykinin (BK) in the stimulation of ischemically sensitive visceral afferents. Single-unit activity of abdominal visceral C fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats during 5 min of abdominal ischemia. Abdominal ischemia increased the portal venous plasma BK level from 49 +/- 10 to 188 +/- 66 pg/ml (P < 0.05). Injection of BK (1 microgram/kg ia) into the descending aorta significantly increased impulse activity (0.88 +/- 0.16 impulses/s) of 10 C fibers, whereas a kinin B1-receptor agonist, des-Arg9-BK (1 microgram/kg), did not alter the discharge rate. Inhibition of kininase II activity with captopril (4 mg/kg i.v.) potentiated impulse activity of 14 ischemically sensitive C fibers (0.44 +/- 0.09 vs. precaptopril, 0.33 +/- 0.08 impulses/s; P < 0.05). In addition, a kinin B2-receptor antagonist (NPC-17731; 40 micrograms/kg i.v.) attenuated activity of afferents during ischemia (0.39 +/- 0.08 vs. pre-NPC-17731, 0.72 +/- 0.13 impulses/s; P < 0.05) and eliminated the response of 10 C fibers to BK. Another kinin B2-receptor antagonist, Hoe-140 (30 micrograms/kg iv), had similar inhibitory effects on six other ischemically sensitive C fibers. In 15 separate cats treated with aspirin (50 mg/kg i.v.), Hoe-140 (30 micrograms/kg i.v.) attenuated impulse activity of only 3 of 16 ischemically sensitive C fibers. These data suggest that BK produced during abdominal ischemia contributes to the stimulation of ischemically sensitive visceral C fiber afferents through kinin B2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Afferent Pathways; Animals; Aspirin; Bradykinin; Bradykinin Receptor Antagonists; Captopril; Cats; Ischemia; Nerve Fibers; Oligopeptides; Portal Vein; Receptors, Bradykinin; Viscera