The effect of NG-nitro-L-arginine methyl ester upon basal blood flow and endothelium-dependent vasodilatation in the dog hindlimb.

1. The role played by the endothelium-derived relaxing factor (EDRF), nitric oxide (NO) in the regulation of blood flow to the skeletal muscle vasculature of the dog skinned hindlimb has been determined by examining the effects of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) upon (i) basal iliac artery blood flow, (ii) vasodilator responses to endothelium-dependent and -independent agonists and (iii) reactive hyperaemic responses to arterial occlusion. 2. L-NAME (0.1-3 mg min-1) infused directly into the iliac artery dose-dependently reduced basal iliac artery blood flow by a maximum of 48.6 +/- 6.9% (n = 4) and also increased mean systemic arterial blood pressure by 25.6 +/- 5.0 mmHg (n = 4) (at 3 mg min-1 L-NAME). 3. Over the same dose range, L-NAME also inhibited the peak vasodilator responses to intra-arterially administered, submaximal bolus doses of the endothelium-dependent agonists, bradykinin (3-300 ng) and acetylcholine (30-300 ng) by approximately 40%. In contrast, peak vasodilator responses to the endothelium-independent agonists, sodium azide (3-30 micrograms) and adenosine (0.3-1 mg), and peak reactive hyperaemic responses to arterial occlusion (60 s) were largely unaffected by L-NAME. 4. The dose-related effects of L-NAME on basal iliac artery blood flow, mean systemic arterial blood pressure and endothelium-dependent vasodilator responses were significantly attenuated by pretreatment with L-arginine (100 mg min-1) followed by co-infusion of L-arginine (100 mg min-1) with L-NAME. 5. In conclusion, these data suggest that NO plays some role in regulating basal blood flow and in mediating the vasodilator responses to the endothelium-dependent agonists bradykinin and acetylcholine in the skeletal muscle vasculature of the dog hindlimb. The substantial component (~60%) of the peak vasodilator responses to bradykinin and acetylcholine, unaffected by L-NAME, may be independent of NO, or be mediated by an alternative EDRF-dependent but L-NAME-insensitive mechanism.

A comparison of contractile function between papillary muscles and isolated myocytes from the same human hearts.

The contractile function in response to increasing extracellular calcium and isoprenaline has been investigated using papillary muscles from seven human hearts (failing and non-failing) obtained at the time of transplant. Myocytes have been enzymatically isolated from adjacent myocardium, and their contractile characteristics measured in parallel to those of the intact papillary muscle. Similar experiments were performed on rabbit hearts, but in this case separate animals were used for the papillary muscles and cells. For human myocardium, the EC50 (concentration for half-maximal effect) for calcium, and the percentage increase in amplitude between basal (1.3mM) and maximally activating calcium, was similar between papillary muscle and cells. Variability of absolute responses was 4-5 times greater for papillary muscle than for myocytes. Isoprenaline accelerated the time to peak tension, time to 50% relaxation and time to 90% relaxation in papillary muscle; a similar effect on shortening was seen for time to peak tension and time to 50% relaxation in cells. Time to peak tension and time to 50% relaxation were not significantly different between the human preparations with isoprenaline, but the time to 50% relaxation with high calcium was faster for myocytes than for papillary muscle (p less than 0.05). Isoprenaline induced after-contractions in some cells, prolonging the time to 90% relaxation. This was not observed in papillary muscle preparations. Papillary muscles were less sensitive to the stimulatory effects of isoprenaline than cells taken from the same hearts. EC50 values were higher (p less than 0.05) and increases in contraction were lower (p less than 0.05) in whole tissue. This difference between cells and papillary muscle was not seen in rabbit hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the properties of prenalterol and corwin at beta 1- and beta 2-adrenoreceptors in vitro.

1. The affinities and efficacies (relative to isoprenaline) of prenalterol and corwin at beta 1- and beta 2-adrenoreceptors, have been determined in isolated cardiac and vascular tissues respectively. 2. Prenalterol and corwin have similar affinities for cardiac beta 1-adrenoreceptors. The affinity of prenalterol for beta 2-adrenoreceptors is approximately 10 times lower than for beta 1-adrenoreceptors; that for corwin is approximately 100 times lower than for beta 1-adrenoreceptors. 3. The efficacies of prenalterol and corwin, relative to isoprenaline, at beta 1 and beta 2-adrenoreceptors, are similar. 4. The greater selectivity of corwin compared with prenalterol, as an agonist at beta 1-adrenoreceptors, is a reflection of its lower affinity for beta 2-adrenoreceptors.