Caffeine elicits physiological responses in a variety of cell types by triggering the mobilization of Ca2+ from intracellular organelles. Here we investigate the effects of caffeine on intracellular Ca2+ concentration ([Ca2+]i) and ionic currents in anterior pituitary cells (GH3) cells. Caffeine has a biphasic effect on Ca(2+)-activated K+ current [IK(Ca)]: it induces a transient increase superimposed upon a sustained inhibition. While the transient increase coincides with a rise in [Ca2+]i, the sustained inhibition of IK(Ca) is correlated with a sustained inhibition of the L-type Ca2+ current. The L-type Ca2+ current is also inhibited by other agents that mobilize intracellular Ca2+, including thyrotropin releasing hormone (TRH) and ryanodine, but in a matter distinct from caffeine. Unlike the caffeine effect, the TRH-induced inhibition "washes-out" under whole-cell patch-clamp conditions and is eliminated by intracellular Ca2+ chelators. Likewise, the ryanodine-induced inhibition desensitizes while the caffeine-induced inhibition does not. Simultaneous [Ca2+]i and Ca2+ current measurements show that caffeine can inhibit Ca2+ current without changing [Ca2+]i. Single-channel recordings show that caffeine reduces mean open time without affecting single-channel conductance of L-type channels. Hence the effects of caffeine on ion channels in GH3 cells are attributable both to mobilization of intracellular Ca2+ and to a direct effect on the gating of L-type Ca2+ channels.
The exaggerated sensitivity of spontaneously hypertensive rat (SHR) renal microvasculature to angiotensin II (ANG II) may be due to an imbalance between the effectiveness of Gαs-utilizing vasodilator pathways and vasoconstrictor pathways activated by ANG II (mediated by Gαi-1, Gαi-2, Gαi-3, and Gαq). Because the alteration appears to be distal to the hormone receptors and proximal to the effector adenylyl cyclase, we hypothesized that SHR have altered amounts of signal-transducing G proteins. This was examined by quantifying the steady-state mRNA levels of specific Gα subunits in renal microvessels of 12- to 14-wk-old SHR and control Wistar-Kyoto (WKY) rats, using a quantitative-competitive polymerase chain reaction technique coupled to reverse transcription. No significant differences were detected in the absolute levels of Gαs (0.96 ± 0.35 vs. 0.74 ± 0.25 amol/50 ng RNA) or in the relative levels of Gαi-1 (0.44 ± 0.05 vs. 0.48 ± 0.13), Gαi-2 (40.9 ± 7.8 vs. 45.2 ± 8.9), or Gαi-3 (0.79 ± 0.05 vs. 0.82 ± 0.15) normalized to the level of Gαs for WKY vs. SHR, respectively. The ratio of Gαqto Gαs tended to be higher in SHR, but this difference did not achieve statistical significance (0.41 ± 0.08 vs. 1.04 ± 0.32, P = 0.08). In conclusion, the steady-state levels of Gαs, Gαi-1, Gαi-2, Gαi-3, and Gαq are similar in SHR and WKY renal microvasculature, suggesting that other components of the ANG II signal transduction mechanism are responsible for the enhanced renal vascular responsiveness in SHR.
A double-blind study using Euphrasia 30c or placebo was carried out during an epidemic of viral conjunctivitis. Nine hundred and ninety-four subjects were available at follow-up, when 48 subjects in the group given Euphrasia and 43 subjects in the placebo group had signs and symptoms of conjunctivitis, a difference which was not statistically significant. The protocol by which Euphrasia was tried may be used without change to scientifically confirm the efficacy of a genus epidemicus. The concept of genus epidemicus lends itself well to experimental double-blind studies in homœopathy during epidemics.
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