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In order to test the hypothesis that the contraction induced in human resistance arterioles by porcine tetradecapeptide renin substrate (TDP) is mediated by enzymes specific to the renin–angiotensin cascade, human resistance vessels from skin and subcutaneous fat were mounted in a myograph and exposed to TDP in the presence and absence of the human renin inhibitor H261, the serine protease inhibitor aprotinin, a polyclonal anti-human renin antibody and captopril. TDP induced a dose-dependent contraction that could be abolished by saralasin. The sensitivity to TDP was significantly attenuated by H261, aprotinin and combinations of captopril with aprotinin and captopril plus aprotinin and H261, as indicated by a significant reduction in pD2 (-log10ED50 [mmol/l]) for TDP. However, captopril alone was ineffective. It was concluded that at physiological pH, porcine TDP induces contraction in human resistance vessels by the action of enzymes not specific to the renin–angiotensin cascade. Whilst a clear inhibitory effect of H261 was demonstrated, a significant comparable inhibition by captopril and a polyclonal renin antibody was not observed. This may reflect the difficulty with which these inhibitors gain access to their intracellularry located substrates.