Accentuated antagonism by angiotensin II on guinea-pig cardiac L-type Ca-currents enhanced by beta-adrenergic...

To examine mechanism(s) underlying the accentuated antagonism by angiotensin II (A-II) on twitch tension, we recorded L-type Ca2+ currents (ICa,L) using conventional patch-clamp techniques in single, guinea-pig, ventricular myocytes. ICa,L was recorded by a step-pulse protocol after eliminating K+ conductances (internal Cs+ plus tetraethylammonium chloride and K+-free extracellular solution). A-II (100 nM) did not affect basal ICa,L, but inhibited ICa,L that had been enhanced (approximately 200% of control) by (ISO, isoproterenol 100 nM). The inhibitory action of A-II was concentration dependent (concentration eliciting 50% inhibition 88+/-9 pM, n=41) and the ISO-enhanced component of ICa,L was completely blocked by A-II at concentrations above 10 nM. CV-11974 (500 nM), an A-II type-1 receptor (AT1) antagonist, prevented the inhibitory action of A-II. Pre-incubation with pertussis toxin (PTX) abolished the inhibitory effect of A-II. A-II also inhibited the ICa, L enhanced by histamine (500 nM) and forskolin (1 microM), but failed to affect ICa,L enhanced by intracellular cyclic adenosine monophosphate (1 mM). The inhibitory action of A-II may therefore involve AT1 receptors/PTX-sensitive, guanine nucleotide-binding (G) proteins (Gi)/adenylate cyclase and partially explains the A-II-dependent accentuated antagonism of inotropy.