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.
1. Cimetidine produced dose-dependent contractions in isolated guinea pig ileum and these responses were not blocked by mepyramine the H1-receptor antagonist. 2. Atropine competitively inhibited the cimetidine-induced contractions in the guinea pig ileum. 3. Cimetidine-induced responses were potentiated in the presence of eserine. Magnesium ions non-competitively inhibited the contractions due to cimetidine. Our findings suggest that cimetidine excites the guinea pig ileum through muscarinic receptors by releasing acetylcholine.
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