icatibant and Reflex--Abnormal

Static muscle contraction activates the exercise pressor reflex, which in turn increases sympathetic nerve activity (SNA) and blood pressure (BP). Bradykinin (BK) is considered as a muscle metabolite responsible for modulation of the sympathetic and cardiovascular responses to muscle contraction. Prior studies have suggested that kinin B2 receptor mediates the effects of BK on the reflex SNA and BP responses during stimulation of skeletal muscle afferents. In patients with peripheral artery disease and a rat model with femoral artery ligation, amplified SNA and BP responses to static exercise were observed. This dysfunction of the exercise pressor reflex has previously been shown to be mediated, in part, by muscle mechanoreflex overactivity. Thus, in this report, we determined whether kinin B2 receptor contributes to the augmented mechanoreflex activity in rats with 24 h of femoral artery occlusion. First, Western blot analysis was used to examine protein expression of B2 receptors in dorsal root ganglion tissues of control limbs and ligated limbs. Our data show that B2 receptor displays significant overexpression in ligated limbs as compared with control limbs (optical density: 0.94 ± 0.02 in control and 1.87 ± 0.08 after ligation, P < 0.05 vs. control; n = 6 in each group). Second, mechanoreflex was evoked by muscle stretch and the reflex renal SNA (RSNA) and mean arterial pressure (MAP) responses to muscle stretch were examined after HOE-140, a B2 receptors blocker, was injected into the arterial blood supply of the hindlimb muscles. The results demonstrate that the stretch-evoked reflex responses were attenuated by administration of HOE-140 in control rats and ligated rats; however, the attenuating effects of HOE-140 were significantly greater in ligated rats, i.e., after 5 μg/kg of HOE-140 RSNA and MAP responses evoked by 0.5 kg of muscle tension were attenuated by 43% and 25% in control vs. 54% and 34% in ligation (P < 0.05 vs. control group; n = 11 in each group). In contrast, there was no significant difference in B1 receptor expression in both experimental groups, and arterial injection of R-715, a B1 receptors blocker, had no significant effects on RSNA and MAP responses evoked by muscle stretch. Accordingly, results obtained from this study support our hypothesis that heightened kinin B2 receptor expression in the sensory nerves contributes to the exaggerated muscle mechanoreflex in rats with femoral artery occlusion.

Topics: Animals; Arterial Pressure; Baroreflex; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Femoral Artery; Ganglia, Spinal; Ligation; Male; Muscle Contraction; Muscle Spindles; Muscle, Skeletal; Peripheral Arterial Disease; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Reflex, Abnormal; Sympathetic Nervous System

The influence of kinin and opioid receptor blockade in the paratrigeminal nucleus (Pa5) on the somatosensory reflex (SSR) to sciatic nerve stimulation (SNS) was assessed in anaesthetized-paralyzed rats. SNS (square 1 ms pulses at 0.6 mA and 20 Hz for 10s) increased mean arterial pressure from 87+/-3 to 106+/-3 mmHg. Pressor responses to SNS were reduced 40-60% by HOE-140 and LF 16-0687 (B2 receptor antagonists; 20 and 100 pmol respectively), CTOP or nor-binaltorphimine (mu and kappa opioid receptor antagonists, respectively; 1 microg) but potentiated by naltrindole (delta opioid receptor antagonist) receptor antagonist microinjections into the contralateral (but not ipsilateral) Pa5. The SSR to sciatic nerve stimulation was not changed by B1 kinin receptor or NK1, NK2 and NK3 tachykinin receptor antagonists administered to the Pa5. Capsaicin pretreatment (40 mg/kg/day, 3 days) abolished the effects of the opioid receptor antagonists, but did not change the effect of kinin B2 receptor blockade on the SSR. Thus, the activity of B2 and opioid receptor-operated mechanisms in the Pa5 contribute to the SSR in the rat, suggesting a role for these endogenous peptides in the cardiovascular responses to SNS.

Topics: Animals; Arteries; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Electric Stimulation; Evoked Potentials, Somatosensory; Male; Models, Biological; Naltrexone; Narcotic Antagonists; Quinolines; Rats; Rats, Wistar; Receptors, Bradykinin; Receptors, Opioid; Reflex, Abnormal; Sciatic Nerve; Somatostatin; Trigeminal Nuclei

This study assessed the relative involvement of the two bradykinin (Bk) receptors (B1 and B2) in the viscero-visceral hyper-reflexia (VVH) and plasma extravasation observed in an animal model of cystitis. The effects of the competitive receptor antagonists des-Arg9[Leu8]-Bk (B1) and HOE 140 (B2) were tested both in prophylactic (pre-inflammation administration) and therapeutic (post-inflammation administration) scenarios. Compared with control animals, des-Arg9[Leu8]-Bk had no effect on the hyper-reflexic response of the bladder to inflammation unless it was administered 5 h after inflammation. However, HOE 140 was able to attenuate the inflammation-induced viscero-visceral hyper-reflexia (VVH) at doses of 1 mg/kg, 2 mg/kg and 7.5 mg/kg. This effect was apparent whether the drug was administered before, or after inflammation. In contrast, neither compound was effective in attenuating the intravesical plasma extravasation induced by turpentine. The data therefore suggest that the VVH and tissue inflammation responses are mediated via different mechanisms. In addition, the turpentine-induced VVH appears to be mediated, at least partially, by the B2 receptor in the early phase, with the B1 receptor only becoming important later.

Topics: Adrenergic beta-Antagonists; Animals; Bradykinin; Bradykinin Receptor Antagonists; Coloring Agents; Cystitis; Evans Blue; Female; Hyperalgesia; Rats; Rats, Wistar; Reflex, Abnormal; Urinary Bladder; Viscera