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

To examine mechanism(s) underlying the accentuated antagonism by angiotensin II (A-II) on twitch tension, we recorded L-type Ca2+ currents (I-Ca,I-L) using conventional patch-clamp techniques in single, guineapig, ventricular myocytes. I-Ca,I-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 I-Ca,I-L but inhibited I-Ca,I-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 I-Ca,I-L was completely blocked by A-II at concentrations above 10 nM. CV-11974 (500 nM), an A-II type-1 receptor (AT(1)) 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 I-Ca,I-L enhanced by histamine (500 nM) and forskolin (1 mu M), but failed to affect I-Ca,I-L enhanced by intracellular cyclic adenosine monophosphate (1 mM). The inhibitory action of A-II may therefore involve AT(1) receptors/PTX-sensitive, guanine nucleotide-binding (G) proteins (Gi)/adenylate cyclase and partially explains the A-II-dependent accentuated antagonism of inotropy.