Pressor and intra-renal effects of angiotensins I and II, and noradrenaline, in anaesthetized and conscious sheep. The effects of halothane anaesthesia on pressor sensitivity and electrolyte shifts: the proposed use of angiotensin I in treating septicaemia and septic shock.

The pressor and intra-renal actions and effects of octa - and deca-peptides angiotensins II and I and of the catecholamine noradrenaline, in anaesthetized and conscious sheep, are considered. The halothane anaesthetic substantially lowers pressor sensitivity to both peptides but does not influence their ability to liberate K(+) ions into the circulating plasma. In comparison with angiotensin II, both angiotensin I and noradrenaline -- with direct presentation to the kidney -- are ineffective in decreasing intra-renal blood flow. However, with left ventricular injection, both pressor compounds immediately increase the blood pressure, as does angiotensin II. Combined doses of the decapeptide and catecholamine are thus highly effective in raising the blood pressure while having a minimal effect on blood flow through the kidney. This overall situation could provide a basis for treating clinical shock, especially regarding septicaemia and septic shock. The lowered hind-limb blood flow, with administration of the pressor compounds into the femoral artery, contrasts strongly with the raised flow resulting from intravenous injection. Experimental procedures to establish, or otherwise, relevant hypothetical situations are detailed.

Hind-limb/hind-quarter vascular resistance and blood flow changes: possible intrinsic renin--angiotensin system involvement.

For many years there was a general belief that the enzyme renin, having been secreted into the circulation by the kidney in response to appropriate stimuli, initially generates the inactive decapeptide angiotensin I in the bloodstream. This is then converted to the biologically active octapeptide angiotensin II by angiotensin converting enzyme on or near, vascular surface receptors both in the lungs and in the organs supplied by the systemic circulation. The results of various investigations have, however, latterly led to the conclusion that the overall system is widely distributed throughout the vasculature with the local intracellular formation of angiotensin II. In this review the reckoned intrinsic renin-angiotensin activity in hind-limb/hind-quarter is discussed with particular regard to the widespread use of radioimmunoassay, together with a consideration of other factors, more especially ACE inhibition, affecting the relevant regional vascular resistance and blood flow.

Aryl sulfonamides as selective PDE4 inhibitors.

A series of novel selective phosphodiesterase 4 (PDE4) inhibitors has been developed which displays activity both in vitro and in vivo. These compounds possess good selectivity for the catalytic site of PDE4 over the high affinity Rolipram binding site. In vivo studies demonstrate a reduced propensity to display the emetic side effects which are commonly observed with PDE4 inhibitors.

7-Methoxybenzofuran-4-carboxamides as PDE 4 inhibitors: a potential treatment for asthma.

The synthesis and pharmacological profile of a novel series of 7-methoxybenzofuran-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).