Pharmacological characterization of angiotensin‐induced depolarizations of rat superior cervical ganglion in vitro

Abstract

The.AT,-selective non-peptide antagonist losartan (DuP 753; 0.03 and 0.1 uM) produced a parallel rightward displacement of the angiotensin II concentration-response curve, with an apparent pKB of 8.3 + 0.1. A higher concentration of losartan (0.3 pM) depressed the maximum agonist response by 32 + 6.5%, possibly reflecting non-competitive behaviour of the antagonist. The potency of losartan was not influenced by bacitracin. 6 The AT2-selective non-peptide antagonist, PD123177 (3pM) failed to antagonize the angiotensin IIinduced depolarizations. 7 DTT (1 mM) produced a 22% reduction of the maximum response to angiotensin II. 8 We conclude that the angiotensin II-induced depolarizations of the rat superior cervical ganglion are mediated by angiotensin II receptors of the AT1 subclass. The ability of peptidase inhibitors to modify the potency of peptide agonists and antagonists highlights the difficulties associated with the use of peptide agents to characterize angiotensin II receptors in this preparation.

Pharmacological characterization of the contractile responses to angiotensin analogues in guinea‐pig isolated longitudinal muscle of small intestine

“…The AT1 receptor antagonist losartan produced concentration-related parallel displacements of angiotensin II curves, yielding a pKB estimate of 8.56. The potency of losartan is close to that previously measured against responses to angiotensin II in other tissues (Barnes et al, 1991;Hawcock et al, 1992;Robertson et al, 1992). Furthermore, these findings agree with previous studies showing AT, receptor-mediated contractile responses to angiotensin II in guinea-pig (Wong et al, 1990) and rat ileum (Schinke et al, 1991).…”

“…In some tissues, angiotensin II and angiotensin III have been shown to be equipotent (Peach & Chiu, 1974;Jackson et al, 1988). While differences in agonist orders of potency led to early speculation about the possible heterogeneity of angiotensin receptors (Peach 1977), it is now well established that potencies of some angiotensin peptide agonists can be markedly increased by inhibitors of peptidase enzymes (Robertson et al, 1992;Hawcock et al, 1992). Thus, from these observations as well as differences in the tachyphylactic properties of different peptides in different tissues, the use of agonist orders of potency to characterize angiotensin II receptors is limited.…”

Possible Involvement of Calcium-Calmodulin Pathways in the Positive Chronotropic Response to Angiotensin II on the Canine Cardiac Sympathetic Ganglia

“…This finding is also consistent with the findings of an in vitro functional study showing that the Ang II-induced depolarization of the rat superior cervical ganglion was blocked by losartan, but not by PD-123177 (24). In the present in vivo experiment, the ganglionic stimulatory response to Ang II in the dog cardiac sympathetic ganglia was also inhibited by forasartan, which is described as a non-peptide competitive AT1-receptor antagonist (25), but not by PD-123319, an AT2-receptor antagonist.…”

Acute sympathoexcitatory action of angiotensin II in conscious baroreceptor-denervated rats

“…Because the ANG II-induced increase in HR was accompanied by an increase in LSNA and the magnitude of these two responses was highly correlated in animals subjected to sinoaortic denervation surgery, it seems likely that these two responses reflect a single mechanism. Because LSNA was recorded from postganglionic fibers and it is known that ANG II can depolarize postganglionic neurons (16,39), ANG II might act at the level of sympathetic ganglia. However, the concentration of ANG II needed to depolarize sympathetic postganglionic neurons likely exceeds the concentrations that existed in the present experiment.…”