dihydropyridines and Intestinal-Diseases

Autonomic neuropathy, including gastrointestinal dysfunction, is a common complication of type 1 diabetes; however, its cause is uncertain. This study aimed to test whether functional autoantibodies cause the gastrointestinal dysfunction.. We used isolated mouse colon undergoing colonic migrating motor complex (MMC) activity to test for autoantibodies that disrupt colonic motility. Purified immunoglobulin G (IgG) from patients with type 1 diabetes or from controls was tested either in vitro or after passive transfer. Pharmacological studies of the interaction between the IgG and L-type calcium channel activator (Bay K8644) and inhibitors (nicardipine and verapamil) were performed. The effect of IgG on nerve-evoked contraction of the vas deferens longitudinal smooth muscle was also assessed.. MMC activity was disrupted by IgG (0.2 mg/mL) from 8 of 16 patients with type 1 diabetes but not by control IgG. Passive transfer of diabetic IgG to mice also disrupted MMCs, showing access to the antigen in vivo. The acute effect of the autoantibody was mimicked by the dihydropyridine agonist, Bay K8644 (2-10 nmol/L), and both Bay K8644 and the autoantibody competitively inhibited the effect on MMC contraction of the dihydropyridine antagonist, nicardipine. Diabetic IgG, but not control IgG, altered the nerve-evoked contractile activity of vas deferens smooth muscle effects mimicked by Bay K8644.. A novel functional autoantibody that activates smooth muscle L-type calcium channels at the dihydropyridine binding site is produced specifically by patients with type 1 diabetes and may mediate gastrointestinal and autonomic dysfunction in these patients.

Topics: Adult; Aged; Animals; Autoantibodies; Binding Sites; Calcium Channel Agonists; Calcium Channel Blockers; Calcium Channels, L-Type; Colon; Diabetes Mellitus, Type 1; Dihydropyridines; Female; Gastrointestinal Motility; Humans; Intestinal Diseases; Male; Mice; Middle Aged; Myoelectric Complex, Migrating; Vas Deferens

1 The reperfusion of ischemic tissues may be associated with local and systemic inflammation that prevents the full benefit of blood flow restoration. The present study aimed to confirm a role for platelet-activating factor receptor(s) (PAFR) during ischemia and reperfusion injury by using genetically modified mice deficient in the PAFR (PAFR(-/-) mice) and to evaluate comparatively the effectiveness of pharmacological treatment using the PAFR antagonist UK-74,505 (modipafant). 2 The reperfusion of the ischemic superior mesenteric artery (SMA) induced marked local (intestine) and remote (lungs) tissue injury, as assessed by the increase in vascular permeability, neutrophil influx and intestinal hemorrhage and in the production of TNF-alpha. There was also a systemic inflammatory response, as shown by the increase in serum TNF-alpha concentrations and marked reperfusion-associated lethality. 3 After reperfusion of the ischemic SMA, PAFR(-/-) mice had little tissue or systemic inflammation and lethality was delayed, but not prevented, in these mice. Interestingly, the reperfusion-associated increases in tissue concentrations of IL-10 were significantly greater in PAFR(-/-) than wild-type mice. 4 Pretreatment with PAFR antagonist UK-74,505 (1 mg kg(-1)) markedly prevented tissue injury, as assessed by the increase in vascular permeability, neutrophil accumulation, hemorrhage and TNF-alpha concentrations in the intestine and lungs. In contrast, UK-74,505 failed to affect reperfusion-associated lethality and increases in serum TNF-alpha when used at 1 mg kg(-1). 5 Reperfusion-associated lethality and increase in serum TNF-alpha were only affected when a supra-maximal dose of the antagonist was used (10 mg kg(-1)). At this dose, UK-74,505 also induced a marked enhancement of reperfusion-associated increases in tissue concentrations of IL-10. However, at the same dose, UK-74,505 failed to prevent reperfusion-associated lethality in PAFR(-/-) mice any further. 6 The present studies using genetically modified animals and a receptor antagonist firmly establish a role of PAFR activation for the local, remote and systemic inflammatory injury and lethality which follows reperfusion of the ischemic SMA in mice. Moreover, it is suggested that high doses of PAFR antagonists need to be used if the real efficacy of these compounds is to be tested clinically.

Topics: Animals; Dihydropyridines; Disease Models, Animal; Imidazoles; Intestinal Diseases; Intestines; Lung Diseases; Male; Mesenteric Artery, Superior; Mice; Mice, Inbred C57BL; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, G-Protein-Coupled; Reperfusion Injury

The effects of two dihydropyridine (DHP) calcium channel antagonists, nifedipine and nimodipine, on migrating myoelectric complexes (MMCs) of the small intestine were studied in naive and morphine-dependent rats. In addition, the effects of two other calcium channel antagonists, verapamil and diltiazem, on the MMCs were investigated. Nifedipine (1.0-4.0 mg kg-1 intravenously) or nimodipine (1.0-4.0 mg kg-1 intravenously) had an inhibitory effect on the spontaneously occurring MMCs, whereas verapamil (2.5-5.0 mg kg-1 intravenously) or diltiazem (2.5-5.0 mg kg-1 intravenously) had no effect. Bay K 8644 (0.25 mg kg-1 intravenously), a DHP calcium channel agonist, instantly reversed the inhibition induced by nifedipine or nimodipine. When given alone, Bay K 8644 induced irregular spiking activity. In morphine-dependent rats with regular MMCs naloxone (1.0 mg kg-1 intravenously) induced intense spiking activity and profuse diarrhea. Nifedipine (2.0 and 4.0 mg kg-1 intravenously) and nimodipine (2.0 and 4.0 mg kg-1 intravenously) given before naloxone prevented the intense, abstinence-evoked spiking and associated diarrhea. In healthy volunteers nimodipine at an infusion rate of 2 mg h-1 for 4 h did not inhibit the fasting motility pattern. Our findings indicate that DHP-binding sites are involved in the regulation of MMC in the rat and that drugs acting as antagonists at these sites can be used to suppress morphine withdrawal diarrhea and, tentatively, other functional disorders of the intestine.

Topics: Adult; Animals; Calcium Channel Blockers; Diarrhea; Dihydropyridines; Fasting; Gastrointestinal Motility; Humans; Intestinal Diseases; Intestine, Small; Male; Morphine; Myoelectric Complex, Migrating; Nimodipine; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome