Zoltán Szilvássy

Direct myocardial anti‐ischaemic effect of GTN in both nitrate‐tolerant and nontolerant rats: a cyclic GMP‐independent activation of KATP

We have recently demonstrated that glyceryl trinitrate (GTN) exerts a direct myocardial anti‐ischaemic effect in both GTN‐tolerant and nontolerant rats. Here we examined if this effect is mediated by GTN‐derived nitric oxide (NO) and involves guanosine 3′5′ cyclic monophosphate (cyclic GMP) and ATP‐sensitive K+ channels (KATP). Rats were treated with 100u2003mgu2003kg−1 GTN or vehicle s.c. three times a day for 3 days to induce vascular GTN‐tolerance or nontolerance. Isolated working hearts obtained from either GTN‐tolerant or nontolerant rats were subjected to 10u2003min coronary occlusion in the presence of 10−7u2003M GTN or its solvent. GTN improved myocardial function and reduced lactate dehydrogenase (LDH) release during coronary occlusion in both GTN‐tolerant and nontolerant hearts. Cardiac NO content significantly increased after GTN administration in both GTN‐tolerant and nontolerant hearts as assessed by electron spin resonance. However, cardiac cyclic GMP content measured by radioimmunoassay was not changed by GTN administration. When hearts from both GTN‐tolerant and nontolerant rats were subjected to coronary occlusion in the presence of the KATP‐blocker glibenclamide (10−7u2003M), the drug itself did not affect myocardial function and LDH release, however, it abolished the anti‐ischaemic effect of GTN. We conclude that GTN opens KATP via a cyclic GMP‐independent mechanism, thereby leading to an anti‐ischaemic effect in the heart in both GTN‐tolerant and nontolerant rats.

Role of voltage-gated cation channels and axon reflexes in the release of sensory neuropeptides by capsaicin from isolated rat trachea.

In order to reveal the role of axon reflexes and sensory receptors in sensory neuropeptide release in response to capsaicin, liberation of substance P, calcitonin gene-related peptide and somatostatin from isolated rat tracheae was investigated in the presence of voltage-sensitive Na(+) and Ca(2+) channel blocking agents. Neuropeptide release induced by capsaicin (10 nM) remained unchanged in the presence of 25 mM lidocaine, 1 microM tetrodotoxin or the N-type Ca(2+) channel inhibitor, omega-conotoxin GVIA (100-300 nM). Peptide release by 100 pulses of 2 Hz field stimulation was prevented by lidocaine or tetrodotoxin. Omega-agatoxin TK (250 nM) significantly inhibited and Cd(2+) (200 microM) prevented capsaicin-induced neuropeptide release. These results suggest that chemical stimulation-induced neuropeptide release does not involve activation of fast Na(+) channels or N- and P-type voltage-dependent Ca(2+) channels, but contribution of Q-type Ca(2+) channels is possible. Sensory neuropeptides are released by capsaicin from sensory receptors without axon reflexes.

Interaction between capsaicin and nitrate tolerance in isolated guinea-pig heart

Capsaicin-induced increases in heart rate and coronary flow were blocked by N(G)-nitro-L-Arg-methyl ester (30 mM) in Langendorff-perfused guinea-pig hearts. Neither heart rate nor coronary flow changed by capsaicin in hearts from animals made tolerant to the hypotensive effect of 30 microg/kg nitroglycerin by the administration of 50 mg/kg nitroglycerin subcutaneously 4 times a day over 3 days. We conclude that the effector function of sensory nerves may deteriorate in nitrate tolerance.